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Repetitive Head Injury Syndrome

StatPearls-/-ä 2019; ä (ä): ä

Originally known as "punch drunk" syndrome and first documented in boxers in the 1920s, chronic traumatic encephalopathy (CTE) has grown to be a well-known topic in the sports medicine community.[1] Repetitive head injury syndrome or the newly coined "chronic traumatic encephalopathy" (CTE) is a unique variant of progressive neurodegenerative entity seen especially among people who are indulged in contact sports or working in military services wherein there is added risk of repeated head injuries.[1]

Sports-related Traumatic Brain Injury (TBI, Pugilistica Dementia)

StatPearls-/-ä 2019; ä (ä): ä

Sports-related traumatic brain injury (TBI) has become increasingly popular in the scientific literature over the past few decades.[1]However, the first mention of such a subject in the literature occurred in the 1920s with reference to the "punch drunk" syndrome of boxers. About a decade later, the term "dementia pugilistica," which literally means "boxer's dementia," was born. The now more commonly used term chronic traumatic encephalopathy (CTE) was coined later in the 1940s.[2]This term has gained favor in the modern literature because it is now understood that exposure to TBI from any sport or source increases the risk for neurodegenerative disease first described in boxers. While there has been some effort to distinguish dementia pugilistica from CTE or to classify dementia pugilistica as a subtype of CTE, the two are now widely considered to be equivalent.[3]Thus, while the term dementia pugilistica is certainly of historical significance, this article will focus on the neurodegenerative disease resulting from (mainly sports-related) TBI that is now most commonly referred to as CTE.

The Problem of Neurodegeneration in Cumulative Sports Concussions: Emphasis on Neurofibrillary Tangle Formation

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects-/-Frontiers in Neuroengineering 2015; ä (ä): ä

Traumatic brain injury (TBI) has been a common cause of morbidity and mortality throughout history, but has had interesting twists in the industrial era and in the world of aggressive sports or modern warfare. The American public is especially troubled by the problem of hundreds of thousands of injured veterans returning from the lengthy post-9/11 campaigns and is also fearful that repeat concussions experienced in contact sports played by millions of young athletes may result in progressive neurodegenerative disease and dementia. The problem of traumatic degeneration, termed chronic traumatic encephalopathy (CTE), has been long recognized in the world of boxing, but has recently come to the forefront because of several highly publicized deaths of popular NFL protagonists. Despite extensive publicity, the real risk of CTE among amateur and professional players has not been measured or adequately characterized and notions derived from autopsy studies, although useful for understanding mechanisms, cannot give an accurate picture of the range of outcomes after repeat concussions and are limited because of ascertainment bias. It is imperative that prospective studies are designed and deployed to the problem, but such approaches will take a long time to bear fruits in view of the long incubation time of key pathologies. Meanwhile, emphasis on molecular and cellular mechanisms of deposition of a key protein, the microtubule-associated protein tau, as well as the construction of relevant animal models, may help define cause-and-effect relationships, shed light into mechanisms, and generate ideas about biomarkers and therapeutic targets. Imports from extensive work in other degenerative tauopathies such as frontotemporal degeneration may greatly facilitate innovation in this area.

Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules.

ACS Chem Biol 2016; 11 (7): 2041-8

Three scaffolds with inhibitory activity against the heat shock protein 70 (Hsp70) family of chaperones have been found to enhance the degradation of the microtubule associated protein tau in cells, neurons, and brain tissue. This is important because tau accumulation is linked to neurodegenerative diseases including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Here, we expanded upon this study to investigate the anti-tau efficacy of additional scaffolds with Hsp70 inhibitory activity. Five of the nine scaffolds tested lowered tau levels, with the rhodacyanine and phenothiazine scaffolds exhibiting the highest potency as previously described. Because phenothiazines also inhibit tau aggregation in vitro, we suspected that this activity might be a more accurate predictor of tau lowering. Interestingly, the rhodacyanines did inhibit in vitro tau aggregation to a similar degree as phenothiazines, correlating well with tau-lowering efficacy in cells and ex vivo slices. Moreover, other Hsp70 inhibitor scaffolds with weaker tau-lowering activity in cells inhibited tau aggregation in vitro, albeit at lower potencies. When we tested six well-characterized tau aggregation inhibitors, we determined that this mechanism of action was not a better predictor of tau-lowering than Hsp70 inhibition. Instead, we found that compounds possessing both activities were the most effective at promoting tau clearance. Moreover, cytotoxicity and PAINS activity are critical factors that can lead to false-positive lead identification. Strategies designed around these principles will likely yield more efficacious tau-lowering compounds.

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease.

Acta Neuropathol 2019; 137 (4): 585-598 bcaughey@nih.gov.

Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD's tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploited the seeded polymerization growth mechanism of tau filaments to develop a highly selective and ultrasensitive cell-free tau seed amplification assay optimized for AD (AD real-time quaking-induced conversion or AD RT-QuIC). The reaction is based on the ability of AD tau aggregates to seed the formation of amyloid fibrils made of certain recombinant tau fragments. AD RT-QuIC detected seeding activity in AD (n = 16) brains at dilutions as extreme as 10(7)-10(10)-fold, but was 10(2)-10(6)-fold less responsive when seeded with brain from most cases of other types of tauopathy with comparable loads of predominant 3R or 4R tau aggregates. For example, AD brains had average seeding activities that were orders of magnitude higher than Pick disease brains with predominant 3R tau deposits, but the opposite was true using our previously described Pick-optimized tau RT-QuIC assay. CTE brains (n = 2) had seed concentrations comparable to the weakest of the AD specimens, and higher than 3 of 4 specimens with 3R/4R primary age-related tauopathy. AD seeds shared properties with the tau filaments found in AD brains, as AD seeds were sarkosyl-insoluble, protease resistant, and reactive with tau antibodies. Moreover, AD RT-QuIC detected as little as 16 fg of pure synthetic tau fibrils. The distinctive seeding activity exhibited by AD and CTE tau filaments compared to other types of tauopathies in these seeded polymerization reactions provides a mechanistic basis for their consistent propagation as specific conformers in patients with 3R/4R tau diseases. Importantly, AD RT-QuIC also provides rapid ultrasensitive quantitation of 3R/4R tau-seeding activity as a biomarker.

First confirmed case of chronic traumatic encephalopathy in a professional bull rider.

Acta Neuropathol 2018; 135 (2): 303-305 cmacd@uw.edu.

The aftermath of boxing revisited: identifying chronic traumatic encephalopathy pathology in the original Corsellis boxer series.

Acta Neuropathol 2018; 136 (6): 973-974 s.gentleman@imperial.ac.uk.

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players.

Acta Neuropathol 2017; 133 (3): 337-352 janice.holton@ucl.ac.uk.;

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer's disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer's disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.

Acta Neuropathol 2017; 133 (3): 353-366 daniel.perl@usuhs.edu.;

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical beta-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E epsilon4 haplotype showed scattered beta-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E epsilon3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and beta-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Acta Neuropathol 2016; 131 (1): 75-86 amckee@bu.edu.;

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.

Beta-amyloid deposition in chronic traumatic encephalopathy.

Acta Neuropathol 2015; 130 (1): 21-34 tdstein@bu.edu.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid beta peptide (Abeta) levels, the extent of Abeta deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Abeta deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Abeta deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Abeta deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Abeta plaques and those without. Abeta deposition was significantly associated with the presence of the APOE epsilon4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (beta = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both Abeta plaques and total levels of Abeta1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that Abeta deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that Abeta is associated with both pathological and clinical progression of CTE independent of age.

Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank.

Acta Neuropathol 2015; 130 (6): 877-89 dickson.dennis@mayo.edu.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.

The neuropathology of sport.

Acta Neuropathol 2014; 127 (1): 29-51 ann.mckee@va.gov.

The benefits of regular exercise, physical fitness and sports participation on cardiovascular and brain health are undeniable. Physical activity reduces the risk for cardiovascular disease, type 2 diabetes, hypertension, obesity, and stroke, and produces beneficial effects on cholesterol levels, antioxidant systems, inflammation, and vascular function. Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration. Nonetheless, the play of sports is associated with risks, including a risk for mild TBI (mTBI) and, rarely, catastrophic traumatic injury and death. There is also growing awareness that repetitive mTBIs, such as concussion and subconcussion, can occasionally produce persistent cognitive, behavioral, and psychiatric problems as well as lead to the development of a neurodegeneration, chronic traumatic encephalopathy (CTE). In this review, we summarize the beneficial aspects of sports participation on psychological, emotional, physical and cognitive health, and specifically analyze some of the less common adverse neuropathological outcomes, including concussion, second-impact syndrome, juvenile head trauma syndrome, catastrophic sudden death, and CTE. CTE is a latent neurodegeneration clinically associated with behavioral changes, executive dysfunction and cognitive impairments, and pathologically characterized by frontal and temporal lobe atrophy, neuronal and axonal loss, and abnormal deposits of paired helical filament (PHF)-tau and 43 kDa TAR deoxyribonucleic acid (DNA)-binding protein (TDP-43). CTE often occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including motor neuron disease (CTE-MND). Although the incidence and prevalence of CTE are not known, CTE has been reported most frequently in American football players and boxers. Other sports associated with CTE include ice hockey, professional wrestling, soccer, rugby, and baseball.

Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans.

Acta Neuropathol 2011; 122 (6): 715-26

The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer's disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP-43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1-47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI.

Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue.

Acta Neuropathol Commun 2019; 7 (1): 37 tgomezisla@mgh.harvard.edu.;

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick's disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing beta-amyloid, alpha-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.

Variation in TMEM106B in chronic traumatic encephalopathy.

Acta Neuropathol Commun 2018; 6 (1): 115 amckee@bu.edu.;

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22-0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29-0.98, p = 0.043), and increased synaptic protein density (beta = 0.306, 95% CI 0.065-0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16-0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.

Co-occurrence of chronic traumatic encephalopathy and prion disease.

Acta Neuropathol Commun 2018; 6 (1): 140 sxn194@case.edu.;

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid beta (Abeta), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and alpha-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrP(D)) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrP(D) type were used as controls. The histopathology phenotype and PrP(D) properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrP(D) conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.9310(- 6)). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.

Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein.

Acta Neuropathol Commun 2017; 5 (1): 30 richard.rubenstein@downstate.edu.;

Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrP(C)) and amyloid-beta oligomers (Abetao). This PrP(C)-Abetao complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrP(C) accumulate Abeta, but show normal survival and no loss of spatial learning and memory suggesting that PrP(C) functions downstream of Abetao production but upstream of intracellular toxicity within neurons. Since AD and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are tauopathies, we examined whether similar mechanistic pathways are responsible for both AD and TBI pathophysiologies. Using transgenic mice expressing different levels of PrP(C), our studies investigated the influence and necessity of PrP(C) on biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured biochemically following severe TBI in the form of severe closed head injury (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the brain were associated with the PrP(C) expression levels. A similar relationship between PrP(C) expression and P-Tau levels following sCHI were found in blood in the absence of significant T-Tau changes. This effect was not seen with GFAP which increased within 24 h following sCHI and progressively decreased by the 7 day time point regardless of the PrP(C) expression levels. Changes in the levels of all biomarkers were independent of gender. We further enhanced and expanded the quantitation of brain biomarkers with correlative studies using immunohisochemistry. We also demonstrate that a TBI-induced calpain hyperactivation is not required for the generation of P-Tau. A relationship was demonstrated between the presence/absence of PrP(C), the levels of P-Tau and cognitive dysfunction. Our studies suggest that PrP(C) is important in mediating TBI related pathology.

Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy.

Acta Neuropathol Commun 2016; 4 (1): 112 tdstein@bu.edu.;

The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran's Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

ARTAG in the basal forebrain: widening the constellation of astrocytic tau pathology.

Acta Neuropathol Commun 2016; 4 (1): 59 s.gentleman@imperial.ac.uk.

Concomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer.

Acta Neuropathol Commun 2014; 2 (ä): 24 Janice.holton@ucl.ac.uk.

We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60's followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed.

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.

Ageing Res Rev 2017; 34 (ä): 51-63 ikonomovicmd@upmc.edu.;

Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-beta (Abeta) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Abeta and cerebral vascular dysfunction in this relationship. Evidence is discussed that Abeta is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of neurovascular function.

In vivo tau imaging: obstacles and progress.

Alzheimers Dement 2014; 10 (3 Suppl): S254-64 victorlv@unimelb.edu.au.;

The military conflicts of the last decade have highlighted the growing problem of traumatic brain injury in combatants returning from the battlefield. The considerable evidence pointing at the accumulation of tau aggregates and its recognition as a risk factor in neurodegenerative conditions such as Alzheimer's disease have led to a major effort to develop selective tau ligands that would allow research into the physiopathologic underpinnings of traumatic brain injury and chronic traumatic encephalopathy in military personnel and the civilian population. These tracers will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis, and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as Alzheimer's disease and some variants of frontotemporal lobar degeneration, in which tau plays a role. The field of selective tau imaging has to overcome several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. A worldwide effort has focused on the development of imaging agents that will allow selective tau imaging in vivo. Recent progress in the development of these tracers is enabling the noninvasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics, and other biomarkers, as well as assessment of efficacy and patient recruitment for antitau therapeutic trials.

Military-related traumatic brain injury and neurodegeneration.

Alzheimers Dement 2014; 10 (3 Suppl): S242-53 amckee@bu.edu.;

Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion syndrome and posttraumatic stress disorder, suggesting that the three disorders might share some biological underpinnings.

Imaging chronic traumatic brain injury as a risk factor for neurodegeneration.

Alzheimers Dement 2014; 10 (3 Suppl): S188-95 deborahmlittle@gmail.com.;

Population-based studies have supported the hypothesis that a positive history of traumatic brain injury (TBI) is associated with an increased incidence of neurological disease and psychiatric comorbidities, including chronic traumatic encephalopathy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These epidemiologic studies, however, do not offer a clear definition of that risk, and leave unanswered the bounding criteria for greater lifetime risk of neurodegeneration. Key factors that likely mediate the degree of risk of neurodegeneration include genetic factors, significant premorbid and comorbid medical history (e.g. depression, multiple head injuries and repetitive subconcussive impact to the brain, occupational risk, age at injury, and severity of brain injury). However, given the often-described concerns in self-report accuracy as it relates to history of multiple TBIs, low frequency of patient presentation to a physician in the case of mild brain injuries, and challenges with creating clear distinctions between injury severities, disentangling the true risk for neurodegeneration based solely on population-based studies will likely remain elusive. Given this reality, multiple modalities and approaches must be combined to characterize who are at risk so that appropriate interventions to alter progression of neurodegeneration can be evaluated. This article presents data from a study that highlights uses of neuroimaging and areas of needed research in the link between TBI and neurodegenerative disease.

White matter signal abnormalities in former National Football League players.

Alzheimers Dement (Amst) 2018; 10 (ä): 56-65

Introduction: Later-life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players. Methods: Eighty-six clinically symptomatic former NFL players and 23 same-age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs. Results: In former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores (P = .043) and worse psychomotor speed and executive function (P = .015). Although former NFL players had greater WMSA volume than controls (P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure. Discussion: In former NFL players, WMSAs may reflect long-term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition.

Alzheimer's disease genetic risk variants beyond APOE epsilon4 predict mortality.

Alzheimers Dement (Amst) 2017; 8 (ä): 188-195

INTRODUCTION: We hypothesized that, like apolipoprotein E (APOE), other late-onset Alzheimer's disease (LOAD) genetic susceptibility loci predict mortality. METHODS: We used a weighted genetic risk score (GRS) from 21 non-APOE LOAD risk variants to predict survival in the Adult Changes in Thought and the Health and Retirement Studies. We meta-analyzed hazard ratios and examined models adjusted for cognitive performance or limited to participants with dementia. For replication, we assessed the GRS-longevity association in the Cohorts for Heart and Aging Research in Genomic Epidemiology, comparing cases surviving to age >/=90 years with controls who died between ages 55 and 80 years. RESULTS: Higher GRS predicted mortality (hazard ratio = 1.05; 95% confidence interval: 1.00-1.10, P = .04). After adjusting for cognitive performance or restricting to participants with dementia, the relationship was attenuated and no longer significant. In case-control analysis, the GRS was associated with reduced longevity (odds ratio = 0.64; 95% confidence interval: 0.41-1.00, P = .05). DISCUSSION: Non-APOE LOAD susceptibility loci confer risk for mortality, likely through effects on dementia incidence.

Repetitive head impact exposure and later-life plasma total tau in former National Football League players.

Alzheimers Dement (Amst) 2017; 7 (ä): 33-40

INTRODUCTION: Blood protein analysis of total tau (t-tau) may be a practical screening biomarker for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We examined plasma t-tau in symptomatic former National Football League (NFL) players compared with controls and the relationship between RHI exposure and later-life plasma t-tau. METHODS: Ninety-six former NFL players (age 40-69) and 25 same-age controls underwent blood draw to determine plasma t-tau levels. The cumulative head impact index (CHII) quantified RHI exposure. Subjects completed measures of clinical function. RESULTS: A higher CHII predicted greater plasma t-tau in the former NFL players (P = .0137). No group differences in plasma t-tau emerged, but a concentration >/=3.56 pg/mL was 100% specific to former NFL players. Plasma t-tau did not predict clinical function. DISCUSSION: Greater RHI exposure predicted higher later-life plasma t-tau concentrations, and further study on plasma t-tau as a candidate screening biomarker for CTE is warranted.

Untangling tau imaging.

Alzheimers Dement (Amst) 2016; 4 (ä): 39-42

In vivo imaging of tau deposits is providing a better understanding of the temporal and spatial tau deposition in the brain, allowing a more comprehensive insight into the causes, diagnoses, and potentially treatment of tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. The assessment of tau deposition in the brain over time will allow a deeper understanding of the relationship between tau and other variables such as cognition, genotype, and neurodegeneration, as well as assessing the role tau plays in ageing. Preliminary human studies suggest that tau imaging could also be used as a diagnostic, prognostic, and theranostic biomarker, as well as a surrogate marker for target engagement, patient recruitment, and efficacy monitoring for disease-specific therapeutic trials.

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study.

Alzheimers Res Ther 2015; 7 (1): 62 jessemez@bu.edu.;

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE. METHODS: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE. RESULTS: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology. CONCLUSIONS: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.

Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy.

Alzheimers Res Ther 2015; 7 (1): 13

INTRODUCTION: The goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY). METHODS: To achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil. RESULTS: The variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P

Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome.

Alzheimers Res Ther 2014; 6 (5): 68

The long-term consequences of repetitive head impacts have been described since the early 20th century. Terms such as punch drunk and dementia pugilistica were first used to describe the clinical syndromes experienced by boxers. A more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma. This article reviews the literature of the clinical manifestations of CTE from 202 published cases. The clinical features include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria). We present proposed research criteria for traumatic encephalopathy syndrome (TES) which consist of four variants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixed variant, and TES dementia) as well as classifications of 'probable CTE' and 'possible CTE'. These proposed criteria are expected to be modified and updated as new research findings become available. They are not meant to be used for a clinical diagnosis. Rather, they should be viewed as research criteria that can be employed in studies of the underlying causes, risk factors, differential diagnosis, prevention, and treatment of CTE and related disorders.

Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy.

Alzheimers Res Ther 2014; 6 (5): 64

The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath.

Acetylation: a new key to unlock tau's role in neurodegeneration.

Alzheimers Res Ther 2014; 6 (3): 29

The identification of tau protein as a major constituent of neurofibrillary tangles spurred considerable effort devoted to identifying and validating pathways through which therapeutics may alleviate tau burden in Alzheimer's disease and related tauopathies, including chronic traumatic encephalopathy associated with sport- and military-related injuries. Most tau-based therapeutic strategies have previously focused on modulating tau phosphorylation, given that tau species present within neurofibrillary tangles are hyperphosphorylated on a number of different residues. However, the recent discovery that tau is modified by acetylation necessitates additional research to provide greater mechanistic insight into the spectrum of physiological consequences of tau acetylation, which may hold promise as a novel therapeutic target. In this review, we discuss recent findings evaluating tau acetylation in the context of previously accepted notions regarding tau biology and pathophysiology. We also examine the evidence demonstrating the neuroprotective and beneficial consequences of inhibiting histone deacetylase (HDAC)6, a tau deacetylase, including its effect on microtubule stabilization. We also discuss the rationale for pharmacologically modulating HDAC6 in tau-based pathologies as a novel therapeutic strategy.

Neuroimaging in repetitive brain trauma.

Alzheimers Res Ther 2014; 6 (1): 10

Sports-related concussions are one of the major causes of mild traumatic brain injury. Although most patients recover completely within days to weeks, those who experience repetitive brain trauma (RBT) may be at risk for developing a condition known as chronic traumatic encephalopathy (CTE). While this condition is most commonly observed in athletes who experience repetitive concussive and/or subconcussive blows to the head, such as boxers, football players, or hockey players, CTE may also affect soldiers on active duty. Currently, the only means by which to diagnose CTE is by the presence of phosphorylated tau aggregations post-mortem. Non-invasive neuroimaging, however, may allow early diagnosis as well as improve our understanding of the underlying pathophysiology of RBT. The purpose of this article is to review advanced neuroimaging methods used to investigate RBT, including diffusion tensor imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging, susceptibility weighted imaging, and positron emission tomography. While there is a considerable literature using these methods in brain injury in general, the focus of this review is on RBT and those subject populations currently known to be susceptible to RBT, namely athletes and soldiers. Further, while direct detection of CTE in vivo has not yet been achieved, all of the methods described in this review provide insight into RBT and will likely lead to a better characterization (diagnosis), in vivo, of CTE than measures of self-report.

Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel.

Alzheimers Res Ther 2014; 6 (1): 4

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive traumatic brain injury experienced in sport and military service. In most instances, the clinical symptoms of the disease begin after a long period of latency ranging from several years to several decades. The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss and heightened suicidality. The symptoms progress slowly over decades to include cognitive deficits and dementia. The pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer's disease. The hyperphosphorylated tau abnormalities begin focally, as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci, and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon and brainstem. Most instances of CTE (>85% of cases) show abnormal accumulations of phosphorylated 43 kDa TAR DNA binding protein that are partially colocalized with phosphorylated tau protein. As CTE is characterized pathologically by frontal and temporal lobe atrophy, by abnormal deposits of phosphorylated tau and by 43 kDa TAR DNA binding protein and is associated clinically with behavioral and personality changes, as well as cognitive impairments, CTE is increasingly categorized as an acquired frontotemporal lobar degeneration. Currently, some of the greatest challenges are that CTE cannot be diagnosed during life and the incidence and prevalence of the disorder remain uncertain. Furthermore, the contribution of age, gender, genetics, stress, alcohol and substance abuse to the development of CTE remains to be determined.

Epidemiology of neurodegeneration in American-style professional football players.

Alzheimers Res Ther 2013; 5 (4): 34

The purpose of this article is to review the history of head injuries in relation to American-style football play, summarize recent research that has linked football head injuries to neurodegeneration, and provide a discussion of the next steps for refining the examination of neurodegeneration in football players. For most of the history of football, the focus of media reports and scientific studies on football-related head injuries was on the acute or short-term effects of serious, traumatic head injuries. Beginning about 10 years ago, a growing concern developed among neurologists and researchers about the long-term effects that playing professional football has on the neurologic health of the players. Autopsy-based studies identified a pathologically distinct neurodegenerative disorder, chronic traumatic encephalopathy, among athletes who were known to have experienced concussive and subconcussive blows to the head during their playing careers. Football players have been well represented in these autopsy findings. A mortality study of a large cohort of retired professional football players found a significantly increased risk of death from neurodegeneration. Further analysis found that non-line players were at higher risk than line players, possibly because of an increased risk of concussion. Although the results of the studies reviewed do not establish a cause effect relationship between football-related head injury and neurodegenerative disorders, a growing body of research supports the hypothesis that professional football players are at an increased risk of neurodegeneration. Significant progress has been made in the last few years on detecting and defining the pathology of neurodegenerative diseases. However, less progress has been made on other factors related to the progression of those diseases in football players. This review identifies three areas for further research: (a) quantification of exposure - a consensus is needed on the use of clinically practical measurements of blows to the head among football players; (b) genetic susceptibility factors - a more rigorous set of unbiased epidemiological and clinical studies is needed before any causal relationships can be drawn between suspected genetic factors, head injury, and neurodegeneration; and (c) earlier detection and prevention of neurodegenerative diseases.

What boxing tells us about repetitive head trauma and the brain.

Alzheimers Res Ther 2013; 5 (3): 23

Boxing and other combat sports may serve as a human model to study the effects of repetitive head trauma on brain structure and function. The initial description of what is now known as chronic traumatic encephalopathy (CTE) was reported in boxers in 1928. In the ensuing years, studies examining boxers have described the clinical features of CTE, its relationship to degree of exposure to fighting, and an array of radiologic findings. The field has been hampered by issues related to study design, lack of longitudinal follow-up, and absence of agreed-upon clinical criteria for CTE. A recently launched prospective cohort study of professional fighters, the Professional Fighters Brain Health Study, attempts to overcome some of the problems in studying fighters. Here, we review the cross-sectional results from the first year of the project.

Mild traumatic brain injury: a risk factor for neurodegeneration.

Alzheimers Res Ther 2010; 2 (3): 18 begavett@bu.edu.

Recently, it has become clear that head trauma can lead to a progressive neurodegeneration known as chronic traumatic encephalopathy. Although the medical literature also implicates head trauma as a risk factor for Alzheimer's disease, these findings are predominantly based on clinical diagnostic criteria that lack specificity. The dementia that follows head injuries or repetitive mild trauma may be caused by chronic traumatic encephalopathy, alone or in conjunction with other neurodegenerations (for example, Alzheimer's disease). Prospective longitudinal studies of head-injured individuals, with neuropathological verification, will not only improve understanding of head trauma as a risk factor for dementia but will also enhance treatment and prevention of a variety of neurodegenerative diseases.

Encephalopathy and hypotonia due to baclofen toxicity in a patient with end-stage renal disease.

Am J Case Rep 2015; 16 (ä): 232-5

BACKGROUND: Baclofen is a centrally acting gamma-aminobutyric acid agonist used for the symptomatic relief of skeletal muscle spasm and spasticity in traumatic spinal cord lesions, multiple sclerosis, cerebral palsy, and stroke. It is also used in the treatment of chronic hiccups and cocaine abuse. Baclofen-induced central nervous system depression is rare at the usual therapeutic doses. However, patients with impaired renal function are at a higher risk of developing baclofen toxicity, even at a lower dose. CASE REPORT: A 57-year-old woman with end-stage renal disease on hemodialysis was admitted to our emergency department with progressive confusion and a generalized decrease in muscular tone. There was no obvious metabolic or infectious etiology that could have explained her condition. A comprehensive laboratory and imaging workup was negative. A review of her medication showed that she had recently been prescribed baclofen for muscular spasm. She was diagnosed with baclofen toxicity and was treated with emergent hemodialysis, which improved her mental status and her decreased muscle tone. Repeated sessions of hemodialysis administered on her second and third days of admission ultimately produced sustained clinical improvement and a complete return to her baseline mental status. She was subsequently discharged home with instructions to stay off baclofen. CONCLUSIONS: Baclofen toxicity is an under-diagnosed condition, especially in patients with renal dysfunction. Physicians should consider baclofen toxicity in patients with suboptimal kidney function on baclofen who present with altered mental status. Emergent hemodialysis and intensive care unit monitoring is recommended.

Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy.

Am J Geriatr Psychiatry 2016; 24 (10): 784-90 cyrusraji@gmail.com.;

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

Multiple mechanisms of extracellular tau spreading in a non-transgenic tauopathy model.

Am J Neurodegener Dis 2012; 1 (3): 316-33

While the interneuronal propagation of neurofibrillary lesions in Alzheimer's disease and other tauopathies now appears to involve the spreading of tau-associated toxicity, little is known about its mechanism. We characterized the movement of human tau through the brain of a non-transgenic lower vertebrate tauopathy model in which full-length wild type and mutant human tau isoforms were expressed in identified neurons, thus permitting the identification and localization of EC tau sources. We describe two distinct patterns of tau spreading that correspond to tau species that lack (MTBR-) and contain (MTBR+) the tau microtubule-binding region. These patterns illustrate the production, migration and uptake of EC tau and resemble some of the extracellular tau deposits typically seen in human brain after repeated traumatic injury in cases of chronic traumatic encephalopathy (CTE). We propose that misprocessed human tau can spread between CNS neurons via a variety of non-synaptic mechanisms as well as synaptically mediated mechanisms.

Exposure of the Amino Terminus of Tau Is a Pathological Event in Multiple Tauopathies.

Am J Pathol 2017; 187 (6): 1222-1229 benjamin.combs@hc.msu.edu.;

Pathological changes to the tau protein, including conformational changes and aggregation, are major hallmarks of a group of neurodegenerative disorders known as tauopathies. Among the conformational changes are alterations involving the extreme amino terminus of the protein, known as the phosphatase-activating domain (PAD). Aberrant PAD exposure induces a signaling cascade that leads to disruption of axonal transport, a critical function for neuronal survival. Conformational display of PAD is an early marker of pathological tau in Alzheimer disease (AD), but its role in other tauopathies has yet to be firmly established. We used a relatively novel N-terminal, conformation-sensitive antibody, TNT2, to determine whether misfolding in the amino terminus (ie, PAD exposure) occurs in non-AD tauopathies. We found that TNT2 specifically labeled pathological tau in post-mortem human brain tissue from Pick disease, progressive supranuclear palsy, corticobasal degeneration, and chronic traumatic encephalopathy, but did not label nonpathological, parenchymal tau. Tau13, another N-terminal antibody, was not sensitive to pathological N-terminal conformations. Tau13 did not readily distinguish between normal (ie, parenchymal tau) and pathological tau species and showed a range of effectiveness at identifying tau pathologies in the non-AD tauopathies. These findings demonstrate that the conformational display of the PAD in tau represents a common pathological event in many tauopathies.

Neurofibrillary tangles in some cases of dementia pugilistica share antigens with amyloid beta-protein of Alzheimer's disease.

Am J Pathol 1990; 136 (2): 255-60

Formalin-fixed, paraffin-embedded temporal lobe sections from eight former boxers' brains were examined using an immunohistochemical method with antibodies to amyloid beta protein. In accord with recent observations in Alzheimer's disease, significant numbers of beta-protein immunoreactive neurofibrillary tangles (NFT) were observed in three cases. Most of these immunoreactive NFTs appeared to be tombstone tangles, although not all such tangles were stained. This immunoreaction was completely abolished by preincubation of antibodies with synthetic beta-protein peptides, and the identity of the immunostained NFTs was confirmed by polarization microscopy of sections counterstained with Congo red. However, it is not yet clear if the beta-protein antigens are, in fact, an integral part of paired helical filaments. These observations, together with our recent finding of beta-immunoreactive plaque-like lesions in dementia pugilistica, also emphasize the many similarities in pathology between this condition and Alzheimer's disease.

Suicide Mortality Among Retired National Football League Players Who Played 5 or More Seasons.

Am J Sports Med 2016; 44 (10): 2486-2491 DYT1@cdc.gov.;

BACKGROUND: There is current disagreement in the scientific literature about the relationship between playing football and suicide risk, particularly among professional players in the National Football League (NFL). While some research indicates players are at high risk of football-related concussions, which may lead to chronic traumatic encephalopathy and suicide, other research finds such a connection to be speculative and unsupported by methodologically sound research. PURPOSE: To compare the suicide mortality of a cohort of NFL players to what would be expected in the general population of the United States. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A cohort of 3439 NFL players with at least 5 credited playing seasons between 1959 and 1988 was assembled for statistical analysis. The vital status for this cohort was updated through 2013. Standardized mortality ratios (SMRs), the ratio of observed deaths to expected deaths, and 95% CIs were computed for the cohort; 95% CIs that excluded unity were considered statistically significant. For internal comparison purposes, standardized rate ratios were calculated to compare mortality results between players stratified into speed and nonspeed position types. RESULTS: Suicide among this cohort of professional football players was significantly less than would be expected in comparison with the United States population (SMR = 0.47; 95% CI, 0.24-0.82). There were no significant differences in suicide mortality between speed and nonspeed position players. CONCLUSION: There is no indication of elevated suicide risk in this cohort of professional football players with 5 or more credited seasons of play. Because of the unique nature of this cohort, these study results may not be applicable to professional football players who played fewer than 5 years or to college or high school players.

Clinical Practices in Collegiate Concussion Management.

Am J Sports Med 2016; 44 (6): 1391-9 cbaugh@g.harvard.edu.;

BACKGROUND: In recent years, sports leagues and sports medicine experts have developed guidelines for concussion management. The extent to which current clinical practice is consistent with guideline recommendations is unclear. At the collegiate level, there have been few examinations of concussion management practices and the extent to which meaningful differences across divisions of competition exist. PURPOSE: The purposes of this study were to (1) examine current practices in concussion diagnosis and management at National Collegiate Athletic Association (NCAA) member colleges, (2) explore the extent to which current practices reflect current recommendations for concussion diagnosis and management, and (3) determine whether there are differences in management patterns across divisions of competition. DESIGN: Descriptive epidemiology study. METHODS: An electronic questionnaire was sent to sports medicine clinicians at all NCAA member colleges during September and October 2013. Clinicians were asked about baseline assessments, diagnosis and management practices, return-to-play protocols, the perceived prevalence of underdiagnosis, and basic demographic information. RESULTS: Approximately 30% (n = 866) of contacted clinicians, representing nearly 50% (n = 527) of NCAA member colleges, responded to the questionnaire. Preparticipation baseline examinations were administered at the majority of schools (95%), but most (87.5%) administered baseline assessments only to selected high-risk athletes. Computerized neurocognitive testing and balance assessments were most commonly used as preseason baseline and postinjury assessments. Multimodal examination in line with NCAA and other guidance was used only at a minority of institutions. Athletic trainers most commonly administered and interpreted the preseason baseline examination. Most clinicians reported that their institutions' practices were in line with NCAA guidelines during the first 24 hours of an athlete's concussion diagnosis, with exact percentages varying across measures. Differences across divisions of competition included shorter return-to-play time at Division I schools than Division III schools (9.13 vs 10.31 days, respectively) and more frequently referring concussed athletes to a physician within 24 hours of diagnosis at Division I schools. CONCLUSION: Concussion management at many colleges in the United States incorporates elements recommended by current guidelines; however, there is room to improve. Increasing the use of a multimodal baseline and postinjury examination will elevate the concussion care provided to college athletes and better align with best practice guidance.

Should Potential Risk of Chronic Traumatic Encephalopathy Be Discussed with Young Athletes?

AMA J Ethics 2017; 19 (7): 686-692

As participation in youth sports has risen over the past two decades, so has the incidence of youth sports injuries. A common topic of concern is concussion, or mild traumatic brain injury, in young athletes and whether concussions sustained at a young age could lead to lifelong impairment such as chronic traumatic encephalopathy (CTE). While the pathway from a concussed young athlete to an adult with CTE remains unknown, current research is attempting to provide more clarity. This article discusses how health care professionals can help foster an informed, balanced decision-making process regarding participation in contact sports that involves the parents as well as the children.

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury.

Ann Clin Transl Neurol 2018; 5 (1): 64-80

Objective: Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival. Methods: Male C57BL/6J mice (aged 2-3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety-like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies. Results: At 24 months survival animals exposed to r-mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule-motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI. Interpretation: In this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.

Frontotemporal dementia: a bridge between dementia and neuromuscular disease.

Ann N Y Acad Sci 2015; 1338 (ä): 71-93

The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.

Chronic traumatic encephalopathy and age of first exposure to American-style football.

Ann Neurol 2018; 83 (5): 884-885

Age of first exposure to tackle football and chronic traumatic encephalopathy.

Ann Neurol 2018; 83 (5): 886-901

OBJECTIVE: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE. INTERPRETATION: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.

Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury.

Annu Rev Pathol 2016; 11 (ä): 21-45 william.stewart@glasgow.ac.uk.;

Almost a century ago, the first clinical account of the punch-drunk syndrome emerged, describing chronic neurological and neuropsychiatric sequelae occurring in former boxers. Thereafter, throughout the twentieth century, further reports added to our understanding of the neuropathological consequences of a career in boxing, leading to descriptions of a distinct neurodegenerative pathology, termed dementia pugilistica. During the past decade, growing recognition of this pathology in autopsy studies of nonboxers who were exposed to repetitive, mild traumatic brain injury, or to a single, moderate or severe traumatic brain injury, has led to an awareness that it is exposure to traumatic brain injury that carries with it a risk of this neurodegenerative disease, not the sport or the circumstance in which the injury is sustained. Furthermore, the neuropathology of the neurodegeneration that occurs after traumatic brain injury, now termed chronic traumatic encephalopathy, is acknowledged as being a complex, mixed, but distinctive pathology, the detail of which is reviewed in this article.

Dementia resulting from traumatic brain injury: what is the pathology?

Arch Neurol 2012; 69 (10): 1245-51

Traumatic brain injury (TBI) is among the earliest illnesses described in human history and remains a major source of morbidity and mortality in the modern era. It is estimated that 2% of the US population lives with long-term disabilities due to a prior TBI, and incidence and prevalence rates are even higher in developing countries. One of the most feared long-term consequences of TBIs is dementia, as multiple epidemiologic studies show that experiencing a TBI in early or midlife is associated with an increased risk of dementia in late life. The best data indicate that moderate and severe TBIs increase risk of dementia between 2- and 4-fold. It is less clear whether mild TBIs such as brief concussions result in increased dementia risk, in part because mild head injuries are often not well documented and retrospective studies have recall bias. However, it has been observed for many years that multiple mild TBIs as experienced by professional boxers are associated with a high risk of chronic traumatic encephalopathy (CTE), a type of dementia with distinctive clinical and pathologic features. The recent recognition that CTE is common in retired professional football and hockey players has rekindled interest in this condition, as has the recognition that military personnel also experience high rates of mild TBIs and may have a similar syndrome. It is presently unknown whether dementia in TBI survivors is pathophysiologically similar to Alzheimer disease, CTE, or some other entity. Such information is critical for developing preventive and treatment strategies for a common cause of acquired dementia. Herein, we will review the epidemiologic data linking TBI and dementia, existing clinical and pathologic data, and will identify areas where future research is needed.

Dementia pugilistica with clinical features of Alzheimer's disease.

Arq Neuropsiquiatr 2007; 65 (3B): 830-3 renataareza@yahoo.com.br

A 61-year-old ex-boxer presented with a three-year history of progressive memory decline. During a seven-year follow-up period, there was a continuous cognitive decline, very similar to that usually observed in Alzheimer's disease. Parkinsonian, pyramidal or cerebellar signs were conspicuously absent. Neuropathological examination revealed the typical features of dementia pugilistica: cavum septi pellucidi with multiple fenestrations, numerous neurofibrillary tangles in the cerebral isocortex and hippocampus (and rare senile plaques). Immunohistochemistry disclosed a high number of tau protein deposits and scarce beta-amyloid staining. This case shows that dementia pugilistica may present with clinical features practically undistinguishable from Alzheimer's disease.

Repeated Mild Closed Head Injuries Induce Long-Term White Matter Pathology and Neuronal Loss That Are Correlated With Behavioral Deficits.

ASN Neuro 2018; 10 (ä): 1759091418781921

An estimated 5.3 million Americans are living with a disability from a traumatic brain injury (TBI). There is emerging evidence of the detrimental effects from repeated mild TBIs (rmTBIs). rmTBI manifests its own unique set of behavioral and neuropathological changes. A subset of individuals exposed to rmTBI develop permanent behavioral and pathological consequences, defined postmortem as chronic traumatic encephalopathy. We have combined components of two classic rodent models of TBI, the controlled cortical impact model and the weight drop model, to develop a repeated mild closed head injury (rmCHI) that produces long-term deficits in several behaviors that correlate with neuropathological changes. Mice receiving rmCHI performed differently from 1-hit or sham controls on the elevated plus maze; these deficits persist up to 6 months postinjury (MPI). rmCHI mice performed worse than 1-hit and control sham mice at 2 MPI and 6 MPI on the Morris water maze. Mice receiving rmCHI exhibited significant atrophy of the corpus callosum at both 2 MPI and 6 MPI, as assessed by stereological volume analysis. Stereological analysis also revealed significant loss of cortical neurons in comparison with 1-hit and controls. Moreover, both of these pathological changes correlated with behavioral impairments. In human tau transgenic mice, rmCHI induced increases in hyperphosphorylated paired helical filament 1 tau in the hippocampus. This suggests that strategies to restore myelination or reduce neuronal loss may ameliorate the behavioral deficits observed following rmCHI and that rmCHI may model chronic traumatic encephalopathy in human tau mice.

Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions.

ASN Neuro 2011; 3 (1): e00051

Axonally specific microtubule-associated protein tau is an important component of neurofibrillary tangles found in AD (Alzheimer's disease) and other tauopathy diseases such as CTE (chronic traumatic encephalopathy). Such tau aggregate is found to be hyperphosphorylated and often proteolytically fragmented. Similarly, tau is degraded following TBI (traumatic brain injury). In the present study, we examined the dual vulnerability of tau to calpain and caspase-3 under neurotoxic and neurodegenerative conditions. We first identified three novel calpain cleavage sites in rat tau (four-repeat isoform) as Ser130 downward arrowLys131, Gly157 downward arrowAla158 and Arg380 downward arrowGlu381. Fragment-specific antibodies to target the major calpain-mediated TauBDP-35K (35 kDa tau-breakdown product) and the caspase-mediated TauBDP-45K respectively were developed. In rat cerebrocortical cultures treated with excitotoxin [NMDA (N-methyl-D-aspartate)], tau is significantly degraded into multiple fragments, including a dominant signal of calpain-mediated TauBDP-35K with minimal caspase-mediated TauBDP-45K. Following apoptosis-inducing EDTA treatment, tau was truncated only to TauBDP-48K/45K-exclusively by caspase. Cultures treated with another apoptosis inducer STS (staurosporine), dual fragmentation by calpain (TauBDP-35K) and caspase-3 (TauBDP-45K) was observed. Tau was also fragmented in injured rat cortex following TBI in vivo to BDPs of 45-42 kDa (minor), 35 kDa and 15 kDa, followed by TauBDP-25K. Calpain-mediated TauBDP-35K-specific antibody confirmed robust signals in the injured cortex, while caspase-mediated TauBDP-45K-specific antibody only detected faint signals. Furthermore, intravenous administration of a calpain-specific inhibitor SNJ-1945 strongly suppressed the TauBDP-35K formation. Taken together, these results suggest that tau protein is dually vulnerable to calpain and caspase-3 proteolysis under different neurotoxic and injury conditions.

Chronic traumatic encephalopathy and suicide: a systematic review.

Biomed Res Int 2013; 2013 (ä): 424280

Traumatic brain injury (TBI) is a global health concern, and the recent literature reports that a single mild TBI can result in chronic traumatic encephalopathy (CTE). It has been suggested that CTE may lead to death by suicide, raising important prevention, treatment, and policy implications. Thus, we conducted a systematic review of the medical literature to answer the key question: What is the existing evidence in support of a relationship between CTE and suicide? Systematic searches of CTE and suicide yielded 85 unique abstracts. Seven articles were identified for full text review. Only two case series met inclusion criteria and included autopsies from 17 unique cases, 5 of whom died by suicide. Neither studies used blinding, control cases, or systematic data collection regarding TBI exposure and/or medical/neuropsychiatric history. The identified CTE literature revealed divergent opinions regarding neuropathological elements of CTE and heterogeneity regarding clinical manifestations. Overall quality of evidence regarding a relationship between CTE and suicide was rated as very low using Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) criteria. Further studies of higher quality and methodological rigor are needed to determine the existence and nature of any relationship between CTE and suicide.

Visual fixation in the vegetative state: an observational case series PET study.

BMC Neurol 2010; 10 (ä): 35

BACKGROUND: Assessment of visual fixation is commonly used in the clinical examination of patients with disorders of consciousness. However, different international guidelines seem to disagree whether fixation is compatible with the diagnosis of the vegetative state (i.e., represents "automatic" subcortical processing) or is a sufficient sign of consciousness and higher order cortical processing. METHODS: We here studied cerebral metabolism in ten patients with chronic post-anoxic encephalopathy and 39 age-matched healthy controls. Five patients were in a vegetative state (without fixation) and five presented visual fixation but otherwise showed all criteria typical of the vegetative state. Patients were matched for age, etiology and time since insult and were followed by repeated Coma Recovery Scale-Revised (CRS-R) assessments for at least 1 year. Sustained visual fixation was considered as present when the eyes refixated a moving target for more than 2 seconds as defined by CRS-R criteria. RESULTS: Patients without fixation showed metabolic dysfunction in a widespread fronto-parietal cortical network (with only sparing of the brainstem and cerebellum) which was not different from the brain function seen in patients with visual fixation. Cortico-cortical functional connectivity with visual cortex showed no difference between both patient groups. Recovery rates did not differ between patients without or with fixation (none of the patients showed good outcome). CONCLUSIONS: Our findings suggest that sustained visual fixation in (non-traumatic) disorders of consciousness does not necessarily reflect consciousness and higher order cortical brain function.

Football's InfluencE on Lifelong health and Dementia risk (FIELD): protocol for a retrospective cohort study of former professional footballers.

BMJ Open 2019; 9 (5): e028654

INTRODUCTION: In the past decade, evidence has emerged suggesting a potential link between contact sport participation and increased risk of late neurodegenerative disease, in particular chronic traumatic encephalopathy. While there remains a lack of clear evidence to test the hypothesis that contact sport participation is linked to an increased incidence of dementia, there is growing public concern regarding the risk. There is, therefore, a pressing need for research to gain greater understanding of the potential risks involved in contact sports participation, and to contextualise these within holistic health benefits of sport. METHODS AND ANALYSIS: Football's InfluencE on Lifelong health and Dementia risk is designed as a retrospective cohort study, with the aim to analyse data from former professional footballers (FPF) in order to assess the incidence of neurodegenerative disease in this population. Comprehensive electronic medical and death records will be analysed and compared with those of a demographically matched population control cohort. As well as neurodegenerative disease incidence, all-cause, and disease-specific mortality, will be analysed in order to assess lifelong health. Cox proportional hazards models will be run to compare the data collected from FPFs to matched population controls. ETHICS AND DISSEMINATION: Approvals for study have been obtained from the University of Glasgow College of Medical, Veterinary and Life Sciences Research Ethics Committee (Project Number 200160147) and from National Health Service Scotland's Public Benefits and Privacy Panel (Application 1718-0120).

Study of Concussion in Rugby Union through MicroRNAs (SCRUM): a study protocol of a prospective, observational cohort study.

BMJ Open 2018; 8 (11): e024245

INTRODUCTION: The diagnosis of mild traumatic brain injury or sports-related concussion is a challenge for all clinicians, players, coaches and parents involved in contact sports. Currently, there is no validated objective biomarker available to assess the presence or severity of concussion in sport, and so it is necessary to rely on subjective measures like self-reporting of symptoms which depend on the cooperation of the athlete. There is a significant health risk associated with repetitive injury if the diagnosis is missed, and so there is great value in an objective biomarker to assist diagnostic and prognostic decisions. OBJECTIVE: To establish a panel of non-invasive MicroRNA biomarkers in urine and saliva for the rapid diagnosis of sports-related concussion and investigate the kinetics and clinical utility of these biomarkers in assisting diagnostic, prognostic and return-to-play decisions. METHODS AND ANALYSIS: Observational, prospective, multicentre cohort study recruiting between the 2017-2018 and 2018-2019 Rugby Union seasons. Professional rugby players in the two highest tiers of senior professional domestic rugby competition in England will be recruited prospectively to the study. During the season, three groups will be identified: athletes entering the World Rugby Head Injury Assessment (HIA) protocol, uninjured control athletes and control athletes with musculoskeletal injuries. Saliva and urine will be collected from these athletes at multiple timepoints, coinciding with key times in the HIA protocol and return-to-play process. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The compiled and analysed results will be presented at national and international conferences concerning the care of patients with traumatic brain injury. Results will also be submitted for peer review and publication in the subject journals/literature.

Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury.

Br J Pharmacol 2016; 173 (4): 681-91

Traumatic brain injury (TBI) has been linked to dementia and chronic neurodegeneration. Described initially in boxers and currently recognized across high contact sports, the association between repeated concussion (mild TBI) and progressive neuropsychiatric abnormalities has recently received widespread attention, and has been termed chronic traumatic encephalopathy. Less well appreciated are cognitive changes associated with neurodegeneration in the brain after isolated spinal cord injury. Also under-recognized is the role of sustained neuroinflammation after brain or spinal cord trauma, even though this relationship has been known since the 1950s and is supported by more recent preclinical and clinical studies. These pathological mechanisms, manifested by extensive microglial and astroglial activation and appropriately termed chronic traumatic brain inflammation or chronic traumatic inflammatory encephalopathy, may be among the most important causes of post-traumatic neurodegeneration in terms of prevalence. Importantly, emerging experimental work demonstrates that persistent neuroinflammation can cause progressive neurodegeneration that may be treatable even weeks after traumatic injury.

A systematic review of potential long-term effects of sport-related concussion.

Br J Sports Med 2017; 51 (12): 969-977

OBJECTIVE: Systematic review of possible long-term effects of sports-related concussion in retired athletes. DATA SOURCES: Ten electronic databases. STUDY SELECTION: Original research; incidence, risk factors or causation related to long-term mental health or neurological problems; individuals who have suffered a concussion; retired athletes as the subjects and possible long-term sequelae defined as >10 years after the injury. DATA EXTRACTION: Study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, neuroimaging findings and neuropathology results. Risk of bias and level of evidence were evaluated by two authors. RESULTS: Following review of 3819 studies, 47 met inclusion criteria. Some former athletes have depression and cognitive deficits later in life, and there is an association between these deficits and multiple prior concussions. Former athletes are not at increased risk for death by suicide (two studies). Former high school American football players do not appear to be at increased risk for later life neurodegenerative diseases (two studies). Some retired professional American football players may be at increased risk for diminishment in cognitive functioning or mild cognitive impairment (several studies), and neurodegenerative diseases (one study). Neuroimaging studies show modest evidence of macrostructural, microstructural, functional and neurochemical changes in some athletes. CONCLUSION: Multiple concussions appear to be a risk factor for cognitive impairment and mental health problems in some individuals. More research is needed to better understand the prevalence of chronic traumatic encephalopathy and other neurological conditions and diseases, and the extent to which they are related to concussions and/or repetitive neurotrauma sustained in sports.

A punch drunk jockey?

Br J Sports Med 2004; 38 (3): e3

The case is reported of a retired professional jockey with progressive memory loss. The concern is that he may be suffering from chronic traumatic encephalopathy or the "punch drunk syndrome".

Boxing and the brain. Revisiting chronic traumatic encephalopathy.

Br J Sports Med 2002; 36 (1): 2

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

Brain 2018; 141 (2): 422-458

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.

Computational modelling of traumatic brain injury predicts the location of chronic traumatic encephalopathy pathology.

Brain 2017; 140 (2): 333-343 m.ghajari@imperial.ac.uk.;

Traumatic brain injury can lead to the neurodegenerative disease chronic traumatic encephalopathy. This condition has a clear neuropathological definition but the relationship between the initial head impact and the pattern of progressive brain pathology is poorly understood. We test the hypothesis that mechanical strain and strain rate are greatest in sulci, where neuropathology is prominently seen in chronic traumatic encephalopathy, and whether human neuroimaging observations converge with computational predictions. Three distinct types of injury were simulated. Chronic traumatic encephalopathy can occur after sporting injuries, so we studied a helmet-to-helmet impact in an American football game. In addition, we investigated an occipital head impact due to a fall from ground level and a helmeted head impact in a road traffic accident involving a motorcycle and a car. A high fidelity 3D computational model of brain injury biomechanics was developed and the contours of strain and strain rate at the grey matter-white matter boundary were mapped. Diffusion tensor imaging abnormalities in a cohort of 97 traumatic brain injury patients were also mapped at the grey matter-white matter boundary. Fifty-one healthy subjects served as controls. The computational models predicted large strain most prominent at the depths of sulci. The volume fraction of sulcal regions exceeding brain injury thresholds were significantly larger than that of gyral regions. Strain and strain rates were highest for the road traffic accident and sporting injury. Strain was greater in the sulci for all injury types, but strain rate was greater only in the road traffic and sporting injuries. Diffusion tensor imaging showed converging imaging abnormalities within sulcal regions with a significant decrease in fractional anisotropy in the patient group compared to controls within the sulci. Our results show that brain tissue deformation induced by head impact loading is greatest in sulcal locations, where pathology in cases of chronic traumatic encephalopathy is observed. In addition, the nature of initial head loading can have a significant influence on the magnitude and pattern of injury. Clarifying this relationship is key to understanding the long-term effects of head impacts and improving protective strategies, such as helmet design.

Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections.

Brain 2016; 139 (Pt 9): 2441-55 m.thom@ucl.ac.uk.

SEE BERNASCONI DOI101093/AWW202 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Temporal lobe epilepsy, the most prevalent form of chronic focal epilepsy, is associated with a high prevalence of cognitive impairment but the responsible underlying pathological mechanisms are unknown. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer's disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy and explored this through clinico-pathological study. We first performed pathological examination on tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years to treat drug-refractory temporal lobe epilepsy. We identified hyperphosphorylated tau protein using AT8 immunohistochemistry and compared this distribution to Braak patterns of Alzheimer's disease and patterns of chronic traumatic encephalopathy. We quantified tau pathology using a modified tau score created specifically for analysis of temporal lobectomy tissue and the Braak staging, which was limited without extra-temporal brain areas available. Next, we correlated tau pathology with pre- and postoperative cognitive test scores and clinical risk factors including age at time of surgery, duration of epilepsy, history of secondary generalized seizures, history of head injury, handedness and side of surgery. Thirty-one of 33 cases (94%) showed hyperphosphorylated tau pathology in the form of neuropil threads and neurofibrillary tangles and pre-tangles. Braak stage analysis showed 12% of our epilepsy cohort had a Braak staging III-IV compared to an age-matched non-epilepsy control group from the literature (8%). We identified a mixture of tau pathology patterns characteristic of Alzheimer's disease and chronic traumatic encephalopathy. We also found unusual patterns of subpial tau deposition, sparing of the hippocampus and co-localization with mossy fibre sprouting, a feature of temporal lobe epilepsy. We demonstrated that the more extensive the tau pathology, the greater the decline in verbal learning (Spearman correlation, r = -0.63), recall (r = -0.44) and graded naming test scores (r = -0.50) over 1-year post-temporal lobe resection (P < 0.05). This relationship with tau burden was also present when examining decline in verbal learning from 3 months to 1 year post-resection (r = -0.54). We found an association between modified tau score and history of secondary generalized seizures (likelihood-ratio chi(2), P < 0.05) however there was no clear relationship between tau pathology and other clinical risk factors assessed. Our findings suggest an epilepsy-related tauopathy in temporal lobe epilepsy, which contributes to accelerated cognitive decline and has diagnostic and treatment implications.

The spectrum of disease in chronic traumatic encephalopathy.

Brain 2013; 136 (Pt 1): 43-64 ann.mckee@va.gov

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.

Prospective clinical biomarkers of caspase-mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration.

Brain Circ 2017; 3 (2): 87-108

Acute brain injuries, including ischemic and hemorrhagic stroke, as well as traumatic brain injury (TBI), are major worldwide health concerns with very limited options for effective diagnosis and treatment. Stroke and TBI pose an increased risk for the development of chronic neurodegenerative diseases, notably chronic traumatic encephalopathy, Alzheimer's disease, and Parkinson's disease. The existence of premorbid neurodegenerative diseases can exacerbate the severity and prognosis of acute brain injuries. Apoptosis involving caspase-3 is one of the most common mechanisms involved in the etiopathology of both acute and chronic neurological and neurodegenerative diseases, suggesting a relationship between these disorders. Over the past two decades, several clinical biomarkers of apoptosis have been identified in cerebrospinal fluid and peripheral blood following ischemic stroke, intracerebral and subarachnoid hemorrhage, and TBI. These biomarkers include selected caspases, notably caspase-3 and its specific cleavage products such as caspase-cleaved cytokeratin-18, caspase-cleaved tau, and a caspase-specific 120 kDa alphaII-spectrin breakdown product. The levels of these biomarkers might be a valuable tool for the identification of pathological pathways such as apoptosis and inflammation involved in injury progression, assessment of injury severity, and prediction of clinical outcomes. This review focuses on clinical studies involving biomarkers of caspase-3-mediated pathways, following stroke and TBI. The review further examines their prospective diagnostic utility, as well as clinical utility for improved personalized treatment of stroke and TBI patients and the development of prophylactic treatment chronic neurodegenerative disease.

Injury cascades in TBI-related neurodegeneration.

Brain Inj 2017; 31 (9): 1177-1182

Traumatic brain injury (TBI) is a widely recognized risk factor for neurodegenerative disease. The purpose of this review is to provide an update on the state of the science related to injury cascades in TBI-related neurodegeneration. Acute and chronic pathological outcomes of TBI are similar to those seen in several neurodegenerative conditions, suggesting common linking pathways. Initial research described severe TBI patients with post-mortem identification of abnormal proteins, such as amyloid deposits. History of mild TBI (mTBI) is less consistently associated with heightened risk of neurodegenerative outcomes, but specific populations with complicated medical histories and comorbidities may be more susceptible. Our understanding of a pathological signature associated with repetitive mTBI and/or subclinical brain trauma advanced significantly over the past decade, and is now commonly referred to as chronic traumatic encephalopathy. We discuss hypotheses linking TBI to neurodegenerative disease, and the importance of considering factors like injury severity, timing of injury (early life versus older age), injury frequency, and repetitive subclinical brain trauma when extrapolating results from current literature to certain populations. We describe the challenges to obtaining the data necessary for accurate epidemiological research and determination of true risk magnitude, and note the importance of developing treatment-based approaches to risk mitigation.

Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: A chronic effects of neurotrauma consortium study.

Brain Inj 2016; 30 (12): 1399-1413

OBJECTIVE: To test the hypothesis that the nucleus basalis of Meynert (nbM), a cholinergic basal forebrain (CBF) cortical projection system, develops neurofibrillary tangles (NFTs) during the progressive pathological stages of chronic traumatic encephalopathy (CTE) in the brain of athletes. METHOD: To characterize NFT pathology, tau-antibodies marking early, intermediate and late stages of NFT development in CBF tissue obtained at autopsy from eighteen former athletes and veterans with a history of repetitive mild traumatic brain injury (TBI) were used. RESULTS: Analysis revealed that cholinergic nbM neurons develop intracellular tau-immunoreactive changes progressively across the pathological stages of CTE. In particular, there was an increase in pre-tangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The nbM neurons also displayed pathologic TDP-43 inclusions and diffuse extracellular and vascular amyloid-beta (Abeta) deposits in CTE. A higher percentage of pS422/p75(NTR), pS422 and TNT1 labelled neurons were significantly correlated with age at symptom onset, interval between symptom onset and death and age at death. CONCLUSION: The development of NFTs within the cholinergic nbM neurons could contribute to an axonal disconnection in CTE. Further studies are needed to determine the mechanism driving NFT formation in the nbM neurons and its relation to chronic cognitive dysfunction in CTE.

Alzheimer's disease and chronic traumatic encephalopathy: Distinct but possibly overlapping disease entities.

Brain Inj 2016; 30 (11): 1279-1292

BACKGROUND: Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) have long been recognized as sharing some similar neuropathological features, mainly the presence of neurofibrilary tangles and hyperphosphorylated tau, but have generally been described as distinct entities. Evidence indicates that neurotrauma increases the risk of developing dementia and accelerates the progression of disease. Findings are emerging that CTE and AD may be present in the same patients. CLINICAL PRESENTATION: This study presents a series of previously unpublished cases, with one case demonstrating possible neurotrauma-related AD, one pure CTE, and an example of a case exhibiting features of both AD and CTE. The future significance of this work lies not only in the confirmation of AD-CTE co-existence, but, more importantly, ways of generating a hypothesis about the possibility that CTE may accelerate AD development. Understanding the relationship between neurotrauma and neurodegenerative disease will help elucidate how distinct disease entities can co-exist in the same patient. It will ultimately require the use of pre-clinical animal models and repeat injury paradigms to investigate clinically relevant injury mechanisms. These models should produce a CTE-like phenotype that must be both neuropathologically and behaviourally similar to human disease. CONCLUSION: This case series and review of the literature presents a discussion of AD and CTE in the context of neurotrauma. It highlights recent work from repetitive neurotrauma models with an emphasis on those exhibiting a CTE-like phenotype. Potential mechanisms of interest shared amongst AD and CTE are briefly addressed and future experiments are advocated for to enhance understanding of CTE pathophysiology and the relationship between CTE and AD.

Protein astrogliopathies in human neurodegenerative diseases and aging.

Brain Pathol 2017; 27 (5): 675-690

Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons associated with depositions of pathologically altered proteins showing hierarchical involvement of brain regions. The role of astrocytes in the pathogenesis of neurodegenerative diseases is explored as contributors to neuronal degeneration or neuroprotection pathways, and also as potential mediators of the transcellular spreading of disease-associated proteins. Protein astrogliopathy (PAG), including deposition of amyloid-beta, prion protein, tau, alpha-synuclein, and very rarely transactive response DNA-binding protein 43 (TDP-43) is not unprecedented or unusual in neurodegenerative diseases. Morphological characterization of PAG is considered, however, only for the neuropathological diagnosis and classification of tauopathies. Astrocytic tau pathology is seen in primary frontotemporal lobar degeneration (FTLD) associated with tau pathologies (FTLD-Tau), and also in the form of aging-related tau astrogliopathy (ARTAG). Importantly, ARTAG shares common features with primary FTLD-Tau as well as with the astroglial tau pathologies that are thought to be hallmarks of a brain injury-related tauopathy known as chronic traumatic encephalopathy (CTE). Supported by experimental observations, the morphological variability of PAG might reflect distinct pathogenic involvement of different astrocytic populations. PAG might indicate astrocytic contribution to spreading or clearance of disease-associated proteins, however, this might lead to astrocytic dysfunction and eventually contribute to the degeneration of neurons. Here, we review recent advances in understanding ARTAG and other related forms of PAG.

The neuropathology of chronic traumatic encephalopathy.

Brain Pathol 2015; 25 (3): 350-64

Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy (CTE). Most instances of CTE occur in association with the play of sports, but CTE has also been reported in association with blast injuries and other neurotrauma. Symptoms of CTE include behavioral and mood changes, memory loss, cognitive impairment and dementia. Like many other neurodegenerative diseases, CTE is diagnosed with certainty only by neuropathological examination of brain tissue. CTE is a tauopathy characterized by the deposition of hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles, astrocytic tangles and neurites in striking clusters around small blood vessels of the cortex, typically at the sulcal depths. Severely affected cases show p-tau pathology throughout the brain. Abnormalities in phosphorylated 43 kDa TAR DNA-binding protein are found in most cases of CTE; beta-amyloid is identified in 43%, associated with age. Given the importance of sports participation and physical exercise to physical and psychological health as well as disease resilience, it is critical to identify the genetic risk factors for CTE as well as to understand how other variables, such as stress, age at exposure, gender, substance abuse and other exposures, contribute to the development of CTE.

A review of neuroimaging findings in repetitive brain trauma.

Brain Pathol 2015; 25 (3): 318-49

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease confirmed at postmortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review, we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of injury and in more neurodegenerative phases of injury, as well as in military personnel exposed to repetitive head impacts. Finally, we discuss future directions for research that will likely lead to a better understanding of the underlying mechanisms separating those who recover from repetitive brain trauma vs. those who go on to develop CTE.

Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans.

Brain Pathol 2012; 22 (2): 142-9

While a history of a single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment such as Alzheimer's disease, the long-term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive/mild head injury. Here, post-mortem brains from long-term survivors of just a single TBI (1-47 years survival; n=39) vs. uninjured, age-matched controls (n=47) were examined for neurofibrillary tangles (NFTs) and amyloid-beta (Abeta) plaques using immunohistochemistry and thioflavine-S staining. Detailed maps of findings permitted classification of pathology using semiquantitative scoring systems. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one-third of TBI cases. In addition, Abeta-plaques were found in a greater density following TBI vs. controls. Moreover, thioflavine-S staining revealed that while all plaque-positive control cases displayed predominantly diffuse plaques, 64% of plaque-positive TBI cases displayed predominantly thioflavine-S-positive plaques or a mixed thioflavine-S-positive/diffuse pattern. These data demonstrate that widespread NFT and Abeta plaque pathologies are present in up to a third of patients following survival of a year or more from a single TBI. This suggests that a single TBI induces long-term neuropathological changes akin to those found in neurodegenerative disease.

Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy.

Brain Res 2016; 1630 (ä): 225-40 djanigro@flocel.com.

Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE.

A Proposed Mechanism for Development of CTE Following Concussive Events: Head Impact, Water Hammer Injury, Neurofilament Release, and Autoimmune Processes.

Brain Sci 2017; 7 (12): ä steve_kornguth@utexas.edu.;

During the past decade, there has been an increasing interest in early diagnosis and treatment of traumatic brain injuries (TBI) that lead to chronic traumatic encephalopathy (CTE). The subjects involved range from soldiers exposed to concussive injuries from improvised explosive devices (IEDs) to a significant number of athletes involved in repetitive high force impacts. Although the forces from IEDs are much greater by a magnitude than those from contact sports, the higher frequency associated with contact sports allows for more controlled assessment of the mechanism of action. In our study, we report findings in university-level women soccer athletes followed over a period of four and a half years from accession to graduation. Parameters investigated included T1-, T2-, and susceptibility-weighted magnetic resonance images (SWI), IMPACT (Immediate Post-Concussion Assessment and Cognitive Testing), and C3 Logix behavioral and physiological assessment measures. The MRI Studies show several significant findings: first, a marked increase in the width of sulci in the frontal to occipital cortices; second, an appearance of subtle hemorrhagic changes at the base of the sulci; third was a sustained reduction in total brain volume in several soccer players at a developmental time when brain growth is generally seen. Although all of the athletes successfully completed their college degree and none exhibited long term clinical deficits at the time of graduation, the changes documented by MRI represent a clue to the pathological mechanism following an injury paradigm. The authors propose that our findings and those of prior publications support a mechanism of injury in CTE caused by an autoimmune process associated with the release of neural proteins from nerve cells at the base of the sulcus from a water hammer injury effect. As evidence accumulates to support this hypothesis, there are pharmacological treatment strategies that may be able to mitigate the development of long-term disability from TBI.

Concussion diagnosis and management: Knowledge and attitudes of family medicine residents.

Can Fam Physician 2017; 63 (6): 460-466 aneet.mann@mail.utoronto.ca.;

OBJECTIVE: To assess the knowledge of, attitudes toward, and learning needs for concussion diagnosis and management among family medicine residents. DESIGN: E-mail survey. SETTING: University of Toronto in Ontario. PARTICIPANTS: Family medicine residents (N = 348). MAIN OUTCOME MEASURES: To describe relationships between awareness of concussion management and lifestyle, education background, and residency placement, t tests and (2) tests were used as appropriate. Linear regression was used to compare self-reported concussion knowledge with knowledge scores. Thematic analysis was used to interpret answers to the qualitative question asking residents to describe challenges they foresee physicians facing when diagnosing and managing concussion. RESULTS: The residents who responded (n = 73, response rate 21%) correctly answered an average of 5.2 questions out of 9 (58%) regarding the diagnosis and management of concussion. Postgraduate year, sex, personal history of concussion, and clinical exposure to concussion were not significant factors in predicting the number of correct answers. Several misconceptions and knowledge gaps were revealed. Of residents who responded, 71% did not recognize chronic traumatic encephalopathy and only 63% recognized second-impact syndrome as consequences of repetitive concussions. Moreover, 32% of residents did not think that every individual with a concussion should see a physician as part of management. Knowledge scores did not predict self-reported concussion knowledge. Thematic analysis revealed 4 themes related to the challenges of concussion diagnosis and management: the nonspecificity and vagueness of symptoms, lack of formal diagnostic criteria, patient compliance with management, and counseling patients with respect to return to play, work, or learning. CONCLUSION: We found substantial gaps in knowledge surrounding concussion diagnosis and management among family medicine residents. This lack of knowledge should be addressed at both the undergraduate medical education level and the residency training level to improve concussion-related care and patient outcomes.

Knowing What We Don't Know: Long-Term Psychiatric Outcomes following Adult Concussion in Sports.

Can J Psychiatry 2016; 61 (5): 270-6 chantel.debert@albertahealthservices.ca.

OBJECTIVE: Amidst a growing concern regarding concussion in sports, there is an emerging link between sport concussion and mental health outcomes. This review summarizes the current literature addressing long-term psychiatric sequelae associated with sport concussion in adults. METHOD: Several databases were searched using a broad list of keywords for each of concussion, sports, and mental health, with a resultant 311 studies for initial review. After limiting studies based on duplication, appropriateness of data, and relevance, 21 studies remained pertaining to depression, anxiety, substance use, and behavioural changes, including those highlighting chronic traumatic encephalopathy (CTE). RESULTS: Most studies identified suggested an increased prevalence of depressive symptoms related to concussion history. A conference abstract and qualitative study suggested increasing anxiety related to concussion history; however, a PhD dissertation found no relationship. In reviewing substance use, several studies mentioned use in athletes suspected of having concussion histories, although no link was established, while another noted undiagnosed concussion as leading to current substance misuse. Regarding behavioural changes, all studies identified occurrences of behaviour and/or cognitive changes in participants, with 2 studies suggesting a link with concussion history. With respect to CTE, concerns with mood, behaviour, cognition, and substance use were consistently highlighted, suggesting relations to previous sport concussion; however, the notion of different CTE subtypes and clear aetiology behind concussion severity or frequency was not consistently elucidated. CONCLUSION: There appears to be a growing body of evidence supporting the presence of long-term psychiatric and psychological sequelae following sport concussion in adults.

Concussion and Psychiatric Outcome in Adults and Children.

Can J Psychiatry 2016; 61 (5): 257-8 jmax@ucsd.edu.

Alzheimer's Dementia due to Suspected CTE from Subconcussive Head Impact.

Case Rep Neurol Med 2018; 2018 (ä): 7890269

Chronic traumatic encephalopathy (CTE) has been receiving increasing attention due to press coverage of professional football players. The devastating sequelae of CTE compel us to aim for early diagnosis and treatment. However, by current standards, CTE is challenging to diagnose. Clear clinical diagnostic criteria for CTE have not been established. Only recently, pathological diagnostic criteria have been recognized, but postmortem diagnosis is too late. Reliable biomarkers are not available. By imaging criteria, cavum septum pellucidum has been the only consistent identifiable MRI finding. Because of the imprecise nature of diagnosis based on clinical suspicion, physicians must become cognizant of the broad spectrum of presentations of CTE. With this awareness, appropriate workup can be initiated. CTE can present with early symptoms of emotional changes or late symptoms with memory decline and dementia. Here we present an unusual case of a patient with Alzheimer's disease secondary to suspected CTE that stems from subconcussive head impacts presenting with severe memory and MRI changes. Clinicians should be aware of this presentation and consider CTE in their differential diagnoses while undergoing workup of memory disorders.

Emotional Lability as a Unique Presenting Sign of Suspected Chronic Traumatic Encephalopathy.

Case Rep Neurol Med 2018; 2018 (ä): 2621416

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by head trauma. Diagnosis of this disease is difficult as reliable biomarkers have not been established and often this clinical entity is underappreciated with poor recognition of its clinical presentations (Lenihan and Jordan, 2015). The definitive diagnosis of CTE is determined by identification of neurofibrillary tangles in the perivascular space around the sulci in postmortem tissue (McKee et al., 2015). However, performing brain biopsies searching for neurofibrillary tangles is not a feasible option for early diagnosis. Thus, diagnosis of suspected CTE in the living has been based on clinical suspicion using proposed research criteria of clinical presentations. In addition, neuroimaging techniques have shown some promise in assisting diagnosis. Clinically, CTE is more commonly known to be associated with memory impairment and executive function disorder (Stern et al., 2013). However, here, we present two unique cases of prior professional football players where behavioral changes were the first identifying factors in clinical presentation and discuss possible neuroimaging options to help with CTE diagnosis. Because behavioral changes can be mistaken for other neuropsychological diseases, recognizing differing clinical constellations is critical to early diagnosis, early intervention, and improving patient care in suspected CTE.

Non-traumatic fractures following seizures: two case reports.

Cases J 2010; 3 (ä): 30 ines.slim@yahoo.fr.

INTRODUCTION: Seizures with or without trauma may cause fractures that occur commonly in epileptic seizures. Fracture risk is less reported in non-epileptic seizures. Some metabolic conditions leading to a decrease in bone mineral density may cause fractures secondary to non-epileptic seizure. CASE PRESENTATION: We describe two cases of non-traumatic acetabular and vertebrae fractures following seizures without history of epilepsy. They occurred in two male patients, 18 and 48 years old suffering respectively from hypercorticism and poorly controlled diabetes mellitus. Seizures, occurring inside hospital, were secondary to hypertensive encephalopathy crisis with hypokaliemia in the first case and severe hypoglycaemia in the second one. Fracture was promoted by a decrease in mineral bone density caused respectively by hypercorticism and diabetic chronic renal failure. CONCLUSION: These observations emphasize that fracture prevention among patients with decreased mineral bone density should include the avoidance of metabolic causes of seizure.

Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration.

Cell Biosci 2016; 6 (ä): 59

One of the two common hallmark lesions of Alzheimer's disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.

Hit parade: the future of the sports concussion crisis.

Cerebrum 2013; 2013 (ä): 2

While concussions have long been linked to brain and central nervous system issues, a new study suggests that repeated hits to the head-mild or otherwise-can lead to memory loss, depression, and dementia. This postmortem brain study, conducted at the Boston University Center for the Study of Traumatic Encephalopathy, provides new and troubling evidence about chronic traumatic encephalopathy (CTE), a long-term degenerative and incurable brain disease. Although military personnel and others are vulnerable to the disease, the highest risk is among athletes involved in contact sports in which hits to the head are considered "part of the game."

Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities.

Chin J Traumatol 2018; 21 (3): 137-151 yxiong1@hfhs.org.;

Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI.

Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma.

Clin Sports Med 2011; 30 (1): 179-88, xi

Chronic traumatic encephalopathy (CTE) is a form of neurodegeneration believed to result from repeated head injuries. Originally termed dementia pugilistica because of its association with boxing, the neuropathology of CTE was first described by Corsellis in 1973 in a case series of 15 retired boxers. CTE has recently been found to occur after other causes of repeated head trauma, suggesting that any repeated blows to the head, such as those that occur in American football, hockey, soccer, professional wrestling, and physical abuse, can also lead to neurodegenerative changes. These changes often include cerebral atrophy, cavum septi pellucidi with fenestrations, shrinkage of the mammillary bodies, dense tau immunoreactive inclusions (neurofibrillary tangles, glial tangles, and neuropil neurites), and, in some cases, a TDP-43 proteinopathy. In association with these pathologic changes, disordered memory and executive functioning, behavioral and personality disturbances (eg, apathy, depression, irritability, impulsiveness, suicidality), parkinsonism, and, occasionally, motor neuron disease are seen in affected individuals. No formal clinical or pathologic diagnostic criteria for CTE currently exist, but the distinctive neuropathologic profile of the disorder lends promise for future research into its prevention, diagnosis, and treatment.

The synergistic effect of concussions and aging in women? Disparities and perspectives on moving forward.

Concussion 2018; 3 (2): CNC55

Neuropsychiatric aspects of concussion: acute and chronic sequelae.

Concussion 2017; 2 (1): CNC29

Concussion - also known as mild traumatic brain injury - is a transient disturbance of neurological function resulting from traumatic forces imparted to the brain that often produce cognitive, behavioral and systemic symptoms. In this review of the literature, we discuss the pathophysiology of both acute and chronic neuropsychiatric sequelae of concussions, followed by a brief overview of evaluation and management of these sequelae.

Animal models of chronic traumatic encephalopathy.

Concussion 2017; 2 (2): CNC32

Repeated head impacts have been suggested to be associated with the development of the neurodegenerative disorder, chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau within the brain, with accompanying cognitive and behavioral deficits. How a history of repeated head impacts can lead to the later development of CTE is not yet known, and as such appropriate animal models are required. Over the last decade a number of rodent models of repeated mild traumatic brain injury have been developed that are broadly based on traditional traumatic brain injury models, in controlled cortical impact, fluid percussion and weight drop models, with adaptations to allow for better modeling of the mechanical forces associated with concussion.

Neuroenergetics of traumatic brain injury.

Concussion 2016; 1 (2): CNC9

A subset of traumatic brain injury (TBI) patients exhibit cognitive deficits later in life which may be due to the underlying pathology associated with Alzheimer's disease (AD) or chronic traumatic encephalopathy. The similarities between chronic traumatic encephalopathy and AD merit investigation of potentially similar mechanisms underlying the two diseases. Experimental and clinical studies of AD brains have revealed that insulin resistance links metabolic dysfunction to the neurodegeneration and cognitive deficits associated with AD. Recent work in experimental TBI has established that recovery is dependent on the return of normal brain metabolism and mounting evidence for a role of brain insulin in regulating central metabolism suggests that TBI, like AD, results in central insulin resistance. Here, we review the converging evidence from AD, TBI and diabetes research linking insulin insensitivity to neurodegeneration.

Summary of the 2015 University of Michigan Sport Concussion Summit.

Concussion 2016; 1 (4): CNC23

Discussions surrounding concussion have made their way into the public sphere over the previous decade with media attention and coverage of the injury fueling public debate. These conversations have devolved into discussions on banning contact and collision sports and raised legal questions surrounding injury management. Questions raised about concussion eclipse what science can answer, but the University of Michigan Injury Center (MI, USA) hosted a Concussion Summit in September 2015 as a means to condense, solidify and disseminate what is currently known on the topic. Areas for discussion included concussion incidence and prevention, diagnosis and management, legislation and education, legal and social aspects and future directions. A summary of those presentations are included within.

An introduction to sports concussions.

Continuum (Minneap Minn) 2014; 20 (6 Sports Neurology): 1545-51

PURPOSE OF REVIEW: Concussions are a major public health issue, and particularly so in the setting of sports. Millions of athletes of all ages may face the risks of concussion and repeat concussion. This article introduces the terminology, epidemiology, and underlying pathophysiology associated with concussion, focused on sports-related injuries. RECENT FINDINGS: Concussion is a clinical syndrome of symptoms and signs occurring after biomechanical force is imparted to the brain. Because of the subjective nature of symptom reporting, definitions of concussion differ slightly in different guidelines. Concussion nomenclature also includes mild traumatic brain injury, postconcussion symptoms, postconcussion syndrome, chronic neurocognitive impairment, subconcussive injury, and chronic traumatic encephalopathy. Between 1.6 and 3.8 million sports-related concussions are estimated in the United States annually, particularly in youth athletes. Rates of concussion are higher in sports such as football, rugby, ice hockey, and wrestling in males, and soccer and basketball in females. The underlying pathophysiology of concussion centers on membrane leakage, ionic flux, indiscriminate glutamate release, and energy crisis. These initial events then trigger ongoing metabolic impairment, vulnerability to second injury, altered neural activation, and axonal dysfunction. While the linkage between acute neurobiology and chronic deficits remains to be elucidated, activation of cell death pathways, ongoing inflammation, persistent metabolic problems, and accumulation of abnormal or toxic proteins have all been implicated. SUMMARY: Concussion is a biomechanically induced syndrome of neural dysfunction. Millions of concussions occur annually, many of them related to sports. Biologically, a complex sequence of events occurs from initial ionic flux, glutamate release, and axonal damage, resulting in vulnerability to second injury and possibly to longer-term neurodegeneration.

Chronic Traumatic Encephalopathy: The Impact on Athletes.

Cureus 2016; 8 (3): e532

Chronic traumatic encephalopathy (CTE) is a devastating neuropsychological condition afflicting a small percentage of athletes partaking in high-impact sports. The onset of symptoms lags years behind the inciting events. Repetitive minor head injuries are felt to be the main etiology behind CTE. Routine radiographic imaging generally is unremarkable in cases of CTE. Functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) are advanced MRI-based sequences that have shown promise in detecting early radiographic findings that may be reflective of CTE. Progressive neuronal loss is the histopathological hallmark of this neurodegenerative disease. Strategizing earlier detection techniques is paramount in delivering optimal care to athletes afflicted with CTE.

How to Rescue American Football.

Cureus 2016; 8 (4): e592

Blows to the head damage the brain. American football is a contact/collision sport that produces many injuries, including to the brain. Football has many supporters who cite important redeeming characteristics of the activity. Public attention to the hazards of children and adults playing football has heightend recently due to many new scientific discoveries, not least of which is the frequency with which players are seriously harmed and do not recover. It is now incumbent on all interested parties to invent and implement far better safety practices, equipment, rules, and processes or the sport must cease to exist in its current form. This paper presents several safety proposals for consideration and study.

Chronic traumatic encephalopathy: where are we and where are we going?

Curr Neurol Neurosci Rep 2013; 13 (12): 407 jessemez@bu.edu.

Chronic traumatic encephalopathy (CTE, previously called punch drunk and dementia pugilistica) has a rich history in the medical literature in association with boxing, but has only recently been recognized with other contact sports, such as football and ice hockey, as well as with military blast injuries. CTE is thought to be a neurodegenerative disease associated with repeated concussive and subconcussive blows to the head. There is characteristic gross and microscopic pathology found in the brain, including frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein 43 pathology. Clinically, there are characteristic progressive deficits in cognition (memory, executive dysfunction), behavior (explosivity, aggression), mood (depression, suicidality), and motor function (parkinsonism), which correlate with the anatomic distribution of brain pathology. While CTE shares clinical and neuropathological traits with other neurodegenerative diseases, the clinical syndrome and the neuropathology as a whole are distinct from other neurodegenerative diseases. Here we review the CTE literature to date. We also draw on the literature from mild traumatic brain injury and other neurodegenerative dementias, particularly when these studies provide guidance for future CTE research. We conclude by suggesting seven essential areas for future CTE research.

Concussion in Chronic Traumatic Encephalopathy.

Curr Pain Headache Rep 2015; 19 (10): 47 tdstein@bu.edu.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive mild traumatic brain injury. It is associated with a variety of clinical symptoms in multiple domains, and there is a distinct pattern of pathological changes. The abnormal tau pathology in CTE occurs uniquely in those regions of the brain that are likely most susceptible to stress concentration during trauma. CTE has been associated with a variety of types of repetitive head trauma, most frequently contact sports. In cases published to date, the mean length of exposure to repetitive head trauma was 15.4 years. The clinical symptoms of the disease began after a mean latency of 14.5 years with a mean age of death of 59.3 years. Most subjects had a reported history of concussions with a mean of 20.3. However, 16 % of published CTE subjects did not have a history of concussion suggesting that subconcussive hits are sufficient to lead to the development of CTE. Overall, the number of years of exposure, not the number of concussions, was significantly associated with worse tau pathology in CTE. This suggests that it is the chronic and repetitive nature of head trauma, irrespective of concussive symptoms, that is the most important driver of disease. CTE and exposure to repetitive head trauma is also associated with a variety of other neurodegenerations, including Alzheimer disease. In fact, amyloid beta peptide deposition is altered and accelerated in CTE and is associated with worse disease. Here, we review the current exposure, clinical, and pathological associations of CTE.

Does a Unique Neuropsychiatric Profile Currently Exist for Chronic Traumatic Encephalopathy?

Curr Sports Med Rep 2017; 16 (1): 30-35

There is evidence that repetitive mild traumatic brain injury leads to specific patterns of neuropathological findings, labeled chronic traumatic encephalopathy (CTE). However, questions remain about whether these neuropathological changes produce changes in behavior, cognition, and emotional status that are associated with a unique neuropsychiatric profile that can be assessed using currently available clinical tools. Our review of the literature indicates that insufficient evidence currently exists to suggest a distinct neuropsychiatric profile for CTE. Major limitations to the field presently include the relatively nascent nature of the topic, reliance on retrospective next-of-kin reporting, the lack of prospective studies, and similarities in neuropsychiatric symptoms between CTE, other neurodegenerative disorders and forms of psychopathology. Clinicians and researchers alike have a responsibility to adopt a cautious and balanced approach for antemortem assessments to minimize the potential unintended negative consequences of both overdiagnosing and underdiagnosing a clinical entity that has yet to be clearly established.

Current understanding of chronic traumatic encephalopathy.

Curr Treat Options Neurol 2014; 16 (9): 306

OPINION STATEMENT: Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease found in individuals with a history of repetitive head impacts. The neuropathology of CTE is increasingly well defined. Prospective, longitudinal studies with post-mortem neuropathologic validation as well as in vivo diagnostic techniques are needed in order to advance the understanding of CTE clinically. Given the large number of individuals who incur concussions and other forms of brain trauma, this is an important area for scientific and public health inquiry.

Extending the range of differential diagnosis of chronic traumatic encephalopathy of the boxer: Insights from a case report.

Dement Neuropsychol 2018; 12 (1): 92-96

Sports activities associated with repetitive cranial trauma have become a fad and are popular in gyms and even among children. It is important to consistently characterize the consequences of such sports activities in order to better advise society on the real risks to the central nervous system. We present the case of a former boxer reporting cognitive and behavioral symptoms that began six years after his retirement as a boxer, evolving progressively with parkinsonian and cerebellar features suggestive of probable chronic traumatic encephalopathy (CTE). Using our case as a paradigm, we extended the range of differential diagnosis of CTE, including corticobasal degeneration, multiple system atrophy, vitamin B12 deficiency, neurosyphilis, frontotemporal dementia and Alzheimer's disease.

Soccer (Football Association) and chronic traumatic encephalopathy: A short review and recommendation.

Dement Neuropsychol 2017; 11 (3): 218-220

Chronic traumatic encephalopathy (CTE) was initially described in boxers, but in recent years it has been reported in other settings, particularly in contact sports and military personnel. Soccer (football association) had previously been (and still is) considered relatively safe when compared to other sports, such as American football. However, a few cases of professional soccer players with CTE have been reported in the last few years. It is still unknown how frequent this condition is in soccer players, and the role played by heading the ball remains elusive. Other traumas to the head, face and neck caused by contact with another player's head, arm or other body parts are among the most frequent in soccer. In spite of the lack of more in-depth knowledge, there is reasonable evidence for recommending severe punishment (red card and suspension for several matches) for players causing avoidable trauma to another player's head.

Dementia resulting from traumatic brain injury.

Dement Neuropsychol 2015; 9 (4): 356-368

Traumatic brain injury (TBI) represents a significant public health problem in modern societies. It is primarily a consequence of traffic-related accidents and falls. Other recently recognized causes include sports injuries and indirect forces such as shock waves from battlefield explosions. TBI is an important cause of death and lifelong disability and represents the most well-established environmental risk factor for dementia. With the growing recognition that even mild head injury can lead to neurocognitive deficits, imaging of brain injury has assumed greater importance. However, there is no single imaging modality capable of characterizing TBI. Current advances, particularly in MR imaging, enable visualization and quantification of structural and functional brain changes not hitherto possible. In this review, we summarize data linking TBI with dementia, emphasizing the imaging techniques currently available in clinical practice along with some advances in medical knowledge.

Shaken baby syndrome: the quest for evidence.

Dev Med Child Neurol 2008; 50 (1): 10-4 Waney.Squier@clneuro.ox.ac.uk

Shaken baby syndrome (SBS), characterized by the triad of subdural haemorrhage, retinal haemorrhage, and encephalopathy, was initially based on the hypothesis that shaking causes tearing of bridging veins and bilateral subdural bleeding. It remains controversial. New evidence since SBS was first defined three decades ago needs to be reviewed. Neuropathology shows that most cases do not have traumatic axonal injury, but hypoxic-ischaemic injury and brain swelling. This may allow a lucid interval, which traumatic axonal injury will not. Further, the thin subdural haemorrhages in SBS are unlike the thick unilateral space-occupying clots of trauma. They may not originate from traumatic rupture of bridging veins but from vessels injured by hypoxia and haemodynamic disturbances, as originally proposed by Cushing in 1905. Biomechanical studies have repeatedly failed to show that shaking alone can generate the triad in the absence of significant neck injury. Impact is needed and, indeed, seems to be the cause of the majority of cases of so-called SBS. Birth-related subdural bleeds are much more frequent than previously thought and their potential to cause chronic subdural collections and mimic SBS remains to be established.

Juvenile Traumatic Brain Injury Results in Cognitive Deficits Associated with Impaired Endoplasmic Reticulum Stress and Early Tauopathy.

Dev Neurosci 2018; 40 (2): 175-188

The leading cause of death in the juvenile population is trauma, and in particular neurotrauma. The juvenile brain response to neurotrauma is not completely understood. Endoplasmic reticulum (ER) stress has been shown to contribute to injury expansion and behavioral deficits in adult rodents and furthermore has been seen in adult postmortem human brains diagnosed with chronic traumatic encephalopathy. Whether endoplasmic reticulum stress is increased in juveniles with traumatic brain injury (TBI) is poorly delineated. We investigated this important topic using a juvenile rat controlled cortical impact (CCI) model. We proposed that ER stress would be significantly increased in juvenile rats following TBI and that this would correlate with behavioral deficits using a juvenile rat model. A juvenile rat (postnatal day 28) CCI model was used. Binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP) were measured at 4 h in the ipsilateral pericontusion cortex. Hypoxia-inducible factor (HIF)-1alpha was measured at 48 h and tau kinase measured at 1 week and 30 days. At 4 h following injury, BiP and CHOP (markers of ER stress) were significantly elevated in rats exposed to TBI. We also found that HIF-1alpha was significantly upregulated 48 h following TBI showing delayed hypoxia. The early ER stress activation was additionally asso-ciated with the activation of a known tau kinase, glycogen synthase kinase-3beta (GSK-3beta), by 1 week. Tau oligomers measured by R23 were significantly increased by 30 days following TBI. The biochemical changes following TBI were associated with increased impulsive-like or anti-anxiety behavior measured with the elevated plus maze, deficits in short-term memory measured with novel object recognition, and deficits in spatial memory measured with the Morris water maze in juvenile rats exposed to TBI. These results show that ER stress was increased early in juvenile rats exposed to TBI, that these rats developed tau oligomers over the course of 30 days, and that they had significant short-term and spatial memory deficits following injury.

Fluid Biomarkers of Traumatic Brain Injury and Intended Context of Use.

Diagnostics (Basel) 2016; 6 (4): ä tanya.bogoslovsky.ctr@usuhs.edu.;

Traumatic brain injury (TBI) is one of the leading causes of death and disability around the world. The lack of validated biomarkers for TBI is a major impediment to developing effective therapies and improving clinical practice, as well as stimulating much work in this area. In this review, we focus on different settings of TBI management where blood or cerebrospinal fluid (CSF) biomarkers could be utilized for predicting clinically-relevant consequences and guiding management decisions. Requirements that the biomarker must fulfill differ based on the intended context of use (CoU). Specifically, we focus on fluid biomarkers in order to: (1) identify patients who may require acute neuroimaging (cranial computerized tomography (CT) or magnetic resonance imaging (MRI); (2) select patients at risk for secondary brain injury processes; (3) aid in counseling patients about their symptoms at discharge; (4) identify patients at risk for developing postconcussive syndrome (PCS), posttraumatic epilepsy (PTE) or chronic traumatic encephalopathy (CTE); (5) predict outcomes with respect to poor or good recovery; (6) inform counseling as to return to work (RTW) or to play. Despite significant advances already made from biomarker-based studies of TBI, there is an immediate need for further large-scale studies focused on identifying and innovating sensitive and reliable TBI biomarkers. These studies should be designed with the intended CoU in mind.

A derangement of the brain wound healing process may cause some cases of Alzheimer's disease.

Discov Med 2016; 22 (119): 43-6

A derangement of brain wound healing may cause some cases of Alzheimer's disease. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of Alzheimer's disease. Our hypothesis -- Alzheimer's disease is brain wound healing gone awry at least in some cases -- could be tested by measuring progression with biomarkers for the four stages of wound healing in humans or appropriate animal models. Autopsy studies might be done. Chronic traumatic encephalopathy might also result from the brain wound healing process.

Boxing-acute complications and late sequelae: from concussion to dementia.

Dtsch Arztebl Int 2010; 107 (47): 835-9 hans.foerstl@lrz.tu-muenchen.de

BACKGROUND: Boxing has received increased public attention and acceptance in recent years. However, this development has not been accompanied by a critical discussion of the early and late health complications. METHODS: We selectively review recent studies on the acute, subacute, and chronic neuropsychiatric consequences of boxing. RESULTS: Cerebral concussions ("knock-outs") are the most relevant acute consequence of boxing. The number of reported cases of death in the ring seems to have mildly decreased. Subacute neuropsychological deficits appear to last longer than subjective symptoms. The associated molecular changes demonstrate neuronal and glial injury correlated with the number and severity of blows to the head (altered total tau, beta-amyloid, neurofilament light protein, glial fibrillary acidic protein, and neuron-specific enolase). The risk of a punch-drunk syndrome (boxer's dementia, dementia pugilistica) as a late effect of chronic traumatic brain injury is associated with the duration of a boxer's career and with his earlier stamina. There are similarities (e.g. increased risk with ApoE4-polymorphism, beta-amyloid pathology) and differences (more tau pathology in boxers) compared with Alzheimer's disease. CONCLUSION: Protective gear has led to a remarkable reduction of risks in amateur boxing. Similar measures can also be used in professional boxing, but may decrease the thrill, which does appeal to many supporters.

Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link.

EBioMedicine 2018; 28 (ä): 21-30 Silvia.Fossati@nyumc.org.

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are devastating neurological disorders, whose complex relationship is not completely understood. Cerebrovascular pathology, a key element in both conditions, could represent a mechanistic link between Abeta/tau deposition after TBI and the development of post concussive syndrome, dementia and chronic traumatic encephalopathy (CTE). In addition to debilitating acute effects, TBI-induced neurovascular injuries accelerate amyloid beta (Abeta) production and perivascular accumulation, arterial stiffness, tau hyperphosphorylation and tau/Abeta-induced blood brain barrier damage, giving rise to a deleterious feed-forward loop. We postulate that TBI can initiate cerebrovascular pathology, which is causally involved in the development of multiple forms of neurodegeneration including AD-like dementias. In this review, we will explore how novel biomarkers, animal and human studies with a focus on cerebrovascular dysfunction are contributing to the understanding of the consequences of TBI on the development of AD-like pathology.

Do Patients With Temporal Lobe Epilepsy and Cognitive Decline Have Alzheimer's Disease or Chronic Traumatic Encephalopathy (CTE)?

Epilepsy Curr 2017; 17 (2): 96-98

Tau imaging in neurodegenerative diseases.

Eur J Nucl Med Mol Imaging 2016; 43 (6): 1139-50 paul.edison@imperial.ac.uk.

Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike beta-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [(18)F]THK523, [(18)F]THK5117, [(18)F]THK5105 and [(18)F]THK5351, [(18)F]AV1451(T807) and [(11)C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with beta - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future.

Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy.

Exp Mol Med 2017; 49 (5): e333

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE. The results showed that the genes related to the MAP kinase and calcium-signaling pathways were significantly downregulated in CTE. The altered expression of protein phosphatases (PPs) in these networks further suggested that the tauopathy observed in CTE involves common pathological mechanisms similar to Alzheimer's disease (AD). Using cell lines and animal models, we also showed that reduced PPP3CA/PP2B phosphatase activity is directly associated with increases in phosphorylated (p)-tau proteins. These findings provide important insights into PP-dependent neurodegeneration and may lead to novel therapeutic approaches to reduce the tauopathy associated with CTE.

An Autopsy Proven Child Onset Chronic Traumatic Encephalopathy.

Exp Neurobiol 2017; 26 (3): 172-177

Here we present an autopsy case of chronic traumatic encephalopathy (CTE) in a 36-year-old man. He had a history of febrile seizures at the age of four and was severely demented at age 10 when he was admitted to a mental hospital. He had suffered repetitive self-harm, such as frequent banging of the head on the wall in his hospital record, but he had no clear history between the ages of four and ten. Autopsy revealed global cerebral atrophy, including the basal ganglia, thalamus, hippocampus, amygdala, mammilary bodies and lateral geniculate bodies. This case showed typical pathological features of CTE. Phosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs) and neuropil threads (NT) we are widely distributed in the brain, especially in the depth of the cerebral sulci. NFT and NT were also found in the basal ganglia, thalamus, amygdala and brainstem. Scanty beta-amyloid deposits were found in the motor and sensory cortices, but alpha-synuclein was completely negative in the brain. This example showed that CTE can occur in young ages and that even children can experience CTE dementia.

Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury.

Exp Neurol 2018; 300 (ä): 167-178 elisa.zanier@marionegri.it.

There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: -30%) and external capsule (EC: -21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (-17%) and EC (-13%), corresponding to histopathological evidence of white matter loss (cl-CC: -68%; cl-EC: -30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

Exp Neurol 2016; 275 Pt 3 (ä): 381-388 mpb37@georgetown.edu.

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI.

Current status of fluid biomarkers in mild traumatic brain injury.

Exp Neurol 2016; 275 Pt 3 (ä): 334-352 jgeddes@uky.edu.

Mild traumatic brain injury (mTBI) affects millions of people annually and is difficult to diagnose. Mild injury is insensitive to conventional imaging techniques and diagnoses are often made using subjective criteria such as self-reported symptoms. Many people who sustain a mTBI develop persistent post-concussive symptoms. Athletes and military personnel are at great risk for repeat injury which can result in second impact syndrome or chronic traumatic encephalopathy. An objective and quantifiable measure, such as a serum biomarker, is needed to aid in mTBI diagnosis, prognosis, return to play/duty assessments, and would further elucidate mTBI pathophysiology. The majority of TBI biomarker research focuses on severe TBI with few studies specific to mild injury. Most studies use a hypothesis-driven approach, screening biofluids for markers known to be associated with TBI pathophysiology. This approach has yielded limited success in identifying markers that can be used clinically, additional candidate biomarkers are needed. Innovative and unbiased methods such as proteomics, microRNA arrays, urinary screens, autoantibody identification and phage display would complement more traditional approaches to aid in the discovery of novel mTBI biomarkers.

Research on the changes in balance motion behavior and learning, as well as memory abilities of rats with multiple cerebral concussion-induced chronic traumatic encephalopathy and the underlying mechanism.

Exp Ther Med 2018; 16 (3): 2295-2302

To study the effects of multiple cerebral concussion (MCC)-induced chronic traumatic encephalopathy on balance motion behavior learning and memory abilities of rats and its possible mechanism. 4MCC rat models were established by means of striking the head (4MCC group, n=15), while normal Sprague-Dawley (SD) rats were used as controls (C group, n=15). At 2 weeks after injury, balance beam (BB) test, beam walking (BW) test and Morris water maze (MWM) test were performed, respectively. The metabolites in brain tissues of rats, the number of glial fibrillary acidic protein (GFAP)-positive cells and apoptotic cells in brain slices of rats, and the expression levels of phosphorylated tau (p-tau) and Abeta1-40 proteins were detected. The score of rats in 4MCC group was significantly lower than that in C group (p<0.01). The escape latencies of rats in 4MCC group on the 4th-7th days during training and the time reaching the platform were significantly longer (p<0.05), but the residence time in the target quadrant was obviously shorter (p<0.01). Naphthalene acetic acid (NAA) and creatinine (Cr) values in septal coronal section in 4MCC group were significantly lower, but choline (Cho) and myo-inositol (MI) values were obviously higher (p<0.01). The number of GFAP-positive cells in the hippocampal and septal areas in 4MCC group were significantly larger (p<0.01). In the hippocampal and septal areas of 4MCC group, the number of apoptotic cells was obviously larger (p<0.01), and the expression levels of p-tau and Abeta1-40 proteins were significantly higher (p<0.01). Thus, MCC-induced chronic traumatic encephalopathy can increase the expressions of p-tau and Abeta1-40 proteins in the hippocampal and septal areas, leading to damage of hippocampal and septal neurons and increasing the number of astrocytes in the hippocampal and septal areas, ultimately damaging the balance motion behavior and learning, as well as memory abilities of rats.

Treating childhood traumatic brain injury with autologous stem cell therapy.

Expert Opin Biol Ther 2018; 18 (5): 515-524

INTRODUCTION: Neonatal traumatic brain injury (TBI) is a significant cause of developmental disorders. Autologous stem cell therapy may enhance neonatal brain plasticity towards repair of the injured neonatal brain. AREAS COVERED: The endogenous neonatal anti-inflammatory response can be enhanced through the delivery of anti-inflammatory agents. Stem cell therapy stands as a robust approach for sequestering the inflammation-induced cell death in the injured brain. Here, we discuss the use of umbilical cord blood cells and bone marrow stromal cells for acute and chronic treatment of experimental neonatal TBI. Autologous stem cell transplantation may dampen neuroinflammation. Clinical translation of this stem cell therapy will require identifying the therapeutic window post-injury and harvesting ample supply of transplantable autologous stem cells. Stem cell banking of cryopreserved cells may allow readily available transplantable cells and circumvent the unpredictable nature of neonatal TBI. Harnessing the anti-inflammatory properties of stem cells is key in combating the progressive neurodegeneration after the initial injury. EXPERT OPINION: Combination treatments, such as with hypothermia, may enhance the therapeutic effects of stem cells. Stem cell therapy has immense potential as a stand-alone or adjunctive therapy for treating neuroinflammation associated with neonatal TBI acutely and for preventing further progression of the injury.

An update on diagnostic and prognostic biomarkers for traumatic brain injury.

Expert Rev Mol Diagn 2018; 18 (2): 165-180

INTRODUCTION: Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (alphaII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.

Investigating possible retinal biomarkers of head trauma in Olympic boxers using optical coherence tomography.

Eye Brain 2018; 10 (ä): 101-110 c.childs@shu.ac.uk.;

Purpose: Changes to retina have been reported after a number of neurodegenerative conditions. The purpose of this study was to investigate retinal structures in Olympic boxers exposed to frequent head blows. Methods: Retinal imaging offers potential as a non-invasive biomarker of neuropathology. Macula and retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography (OCT) in UK Olympic boxers attending two mandatory eye screening programs, 18 months apart. Data from the two eye screenings provide longitudinal data of retinal change over time. Sedentary healthy subjects (controls) without past or present history of concussion were also screened at the time of the second boxer screening to provide comparison of cross-sectional data. Results: Sixteen Olympic boxers aged 20-33 years and 20 sedentary healthy controls, aged 24-45 years, were recruited. Significant macula thickening was observed over time (18 months) in 75% of right and 50% of left eye sectors. For RNFL, left eye quadrants thickened. For right eye RNFL quadrants, thickening and thinning of this layer were observed. Cross-sectional results showed thinner macula sectors and RNFL quadrants in Olympic boxers compared to controls. Conclusion: Significant change to macula and RNFL densities, occurring over an 18 month interval is an unexpected finding in otherwise heathy elite sportsmen. In addition, macula and RNFL were thinner than healthy sedentary controls. OCT may prove clinically useful as a candidate retinal biomarker of neuropathological change after mild traumatic brain injury and/or repeat head blows.

[18F]-T807 tauopathy PET imaging in chronic traumatic encephalopathy.

F1000Res 2014; 3 (ä): 229

A new molecular ligand for positron emission tomography (PET) of the human brain, [18F]-T807, is under investigation for the antemortem detection of pathological neurofibrillary aggregates, which are evidence of neurofibrillary tangle (NFT) diseases, also known as tauopathies. Repetitive mild traumatic brain injuries in athletes and battlefield veterans are associated with one such tauopathy, known as chronic traumatic encephalopathy (CTE). In a recent case report, a former NFL player with clinically probable CTE and a concurrent Progressive Supranuclear Palsy (PSP) -like syndrome was studied using [18F]-T807. The interpretation of this player's [18F]-T807 PET imaging was complicated by the overlap of tracer uptake in brain regions involved in CTE and PSP with regions associated with either nonspecific [18F]-T807 ligand binding or "aging-associated" binding of [18F]-T807 to authentic tauopathy known to be associated with aging and disease severity (i.e., NFT in the mesial temporal lobe). The implications of these data for the utility of [18F]-T807 in the pre-mortem detection of CTE are summarized.

A comparison of the spatial patterns of beta-amyloid (Abeta) deposits in five neurodegenerative disorders.

Folia Neuropathol 2018; 56 (4): 284-292

Alzheimer's disease neuropathologic change (ADNC) in the form of -amyloid (A) deposits is important not only in the pathogenesis of Alzheimer's disease (AD) and Down's syndrome (DS) but also as a 'co-pathology' in disorders such as dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). To compare cortical and hippocampal degeneration in different disorders, the spatial patterns of the diffuse, primi-tive, and classic A deposits were studied in regions of frontal and temporal cortex in five neurodegenerative disorders, viz. AD, DS, DLB, CBD, and CTE using spatial pattern analysis. In all disorders, the A deposits were clustered and in a proportion of brain regions, the clusters were regularly distributed parallel to the tissue boundary. Cluster dimensions in the cortex, measured parallel to the pia mater, were frequently in the range 400-800 m suggesting a spatial association with the cortico-cortical pathways. Differences were also observed among disorders, the diffuse A deposits being more frequently distributed in regular clusters in AD while cluster sizes of the diffuse and primitive deposits were significantly smaller in CTE. The data suggest considerable similarities in the spatial patterns of A deposits in different disorders, regardless of the clinical or pathological setting, which suggests that the spread of A via neuro-anatomical pathways may be common to several disorders.

Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis.

Free Radic Biol Med 2013; 65 (ä): 509-527 hm264@columbia.edu.

Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.

Brain injury, neuroinflammation and Alzheimer's disease.

Front Aging Neurosci 2013; 5 (ä): 26

With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries (Miller, 2012), traumatic brain injury (TBI) has garnered much recent attention. While the cause and severity of these injuries is variable, severe cases can lead to lifelong disability or even death. While aging is the greatest risk factor for Alzheimer's disease (AD), it is now becoming clear that a history of TBI predisposes the individual to AD later in life (Sivanandam and Thakur, 2012). In this review article, we begin by defining hallmark pathological features of AD and the various forms of TBI. Putative mechanisms underlying the risk relationship between these two neurological disorders are then critically considered. Such mechanisms include precipitation and 'spreading' of cerebral amyloid pathology and the role of neuroinflammation. The combined problems of TBI and AD represent significant burdens to public health. A thorough, mechanistic understanding of the precise relationship between TBI and AD is of utmost importance in order to illuminate new therapeutic targets. Mechanistic investigations and the development of preclinical therapeutics are reliant upon a clearer understanding of these human diseases and accurate modeling of pathological hallmarks in animal systems.

Molecular mechanisms of cognitive dysfunction following traumatic brain injury.

Front Aging Neurosci 2013; 5 (ä): 29

Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Abeta and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Abeta generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration.

Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability.

Front Cell Neurosci 2018; 12 (ä): 338

Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein. Tau is an amazing protein that plays a key role in cognitive processes, however, deposits of abnormal forms of tau are associated with several neurodegenerative diseases, including Alzheimer disease (AD), the most prevalent, and Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI), the most recently associated to abnormal tau. Tau post-translational modifications (PTMs) are responsible for its gain of toxic function. Alonso et al. (1996) were the first to show that the pathological tau isolated from AD brains has prion-like properties and can transfer its toxic function to the normal molecule. Furthermore, we reported that the pathological changes are associated with tau phosphorylation at Ser199 and 262 and Thr212 and 231. This pathological version of tau induces subcellular mislocalization in cultured cells and neurons, and translocates into the nucleus or accumulated in the perinuclear region of cells. We have generated a transgenic mouse model that expresses pathological human tau (PH-Tau) in neurons at two different concentrations (4% and 14% of the total endogenous tau). In this model, PH-Tau causes cognitive decline by at least two different mechanisms: one that involves the cytoskeleton with axonal disruption (at high concentration), and another in which the apparent neuronal morphology is not grossly affected, but the synaptic terminals are altered (at lower concentration). We will discuss the putative involvement of tau in proteostasis under these conditions. Understanding tau's biological activity on and off the microtubules will help shed light to the mechanism of neurodegeneration and of normal neuronal function.

Corrigendum: Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves.

Front Cell Neurosci 2014; 8 (ä): 404

[This corrects the article on p. 232 in vol. 8, PMID: 25165433.].

Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves.

Front Cell Neurosci 2014; 8 (ä): 232

Mild traumatic brain injury (mTBI) resulting from exposure to blast shock waves (BSWs) is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB). Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa) initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction (TJ) proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa) causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy (CTE) and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

Editorial: Brain Injury as a Neurodegenerative Disorder.

Front Hum Neurosci 2015; 9 (ä): 615

Chronic traumatic encephalopathy and other neurodegenerative proteinopathies.

Front Hum Neurosci 2014; 8 (ä): 30

"Chronic traumatic encephalopathy" (CTE) is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). The aim of this "perspective" is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.

Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology.

Front Hum Neurosci 2013; 7 (ä): 222

BACKGROUND: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown. METHODS: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline. RESULTS: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Moreover, the CTE cases showed co-morbid pathology of cancer, vascular disease, and AD. DISCUSSION: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE.

Cannabis Therapeutics and the Future of Neurology.

Front Integr Neurosci 2018; 12 (ä): 51

Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARgamma; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

Disrupted White Matter Microstructure of the Cerebellar Peduncles in Scholastic Athletes After Concussion.

Front Neurol 2019; 10 (ä): 518

Concussion, or mild traumatic brain injury (mTBI), is a major public health concern, linked with persistent post-concussive syndrome, and chronic traumatic encephalopathy. At present, standard clinical imaging fails to reliably detect traumatic axonal injury associated with concussion and post-concussive symptoms. Diffusion tensor imaging (DTI) is an MR imaging technique that is sensitive to changes in white matter microstructure. Prior studies using DTI did not jointly investigate white matter microstructure in athletes, a population at high risk for concussive and subconcussive head traumas, with those in typical emergency room (ER) patients. In this study, we determine DTI scalar metrics in both ER patients and scholastic athletes who suffered concussions and compared them to those in age-matched healthy controls. In the early subacute post-concussion period, athletes demonstrated an elevated rate of regional decreases in axial diffusivity (AD) compared to controls. These regional decreases of AD were especially pronounced in the cerebellar peduncles, and were more frequent in athletes compared to the ER patient sample. The group differences may indicate differences in the mechanisms of the concussive impacts as well as possible compound effects of cumulative subconcussive impacts in athletes. The prevalence of white matter abnormality in cerebellar tracts lends credence to the hypothesis that post-concussive symptoms are caused by shearing of axons within an attention network mediated by the cerebellum, and warrant further study of the correlation between cerebellar DTI findings and clinical, neurocognitive, oculomotor, and vestibular outcomes in mTBI patients.

Novel Mouse Tauopathy Model for Repetitive Mild Traumatic Brain Injury: Evaluation of Long-Term Effects on Cognition and Biomarker Levels After Therapeutic Inhibition of Tau Phosphorylation.

Front Neurol 2019; 10 (ä): 124

Traumatic brain injury (TBI) is a risk factor for a group of neurodegenerative diseases termed tauopathies, which includes Alzheimer's disease and chronic traumatic encephalopathy (CTE). Although TBI is stratified by impact severity as either mild (m), moderate or severe, mTBI is the most common and the most difficult to diagnose. Tauopathies are pathologically related by the accumulation of hyperphosphorylated tau (P-tau) and increased total tau (T-tau). Here we describe: (i) a novel human tau-expressing transgenic mouse model, TghTau/PS1, to study repetitive mild closed head injury (rmCHI), (ii) quantitative comparison of T-tau and P-tau from brain and plasma in TghTau/PS1 mice over a 12 month period following rmCHI (and sham), (iii) the usefulness of P-tau as an early- and late-stage blood-based biochemical biomarker for rmCHI, (iii) the influence of kinase-targeted therapeutic intervention on rmCHI-associated cognitive deficits using a combination of lithium chloride (LiCl) and R-roscovitine (ros), and (iv) correlation of behavioral and cognitive changes with concentrations of the brain and blood-based T-tau and P-tau. Compared to sham-treated mice, behavior changes and cognitive deficits of rmCHI-treated TghTau/PS1 mice correlated with increases in both cortex and plasma T-tau and P-tau levels over 12 months. In addition, T-tau, but more predominantly P-tau, levels were significantly reduced in the cortex and plasma by LiCl + ros approaching the biomarker levels in sham and drug-treated sham mice (the drugs had only modest effects on the T-tau and P-tau levels in sham mice) throughout the 12 month study period. Furthermore, although we also observed a reversal of the abnormal behavior and cognitive deficits in the drug-treated rmCHI mice (compared to the untreated rmCHI mice) throughout the time course, these drug-treated effects were most pronounced up until 10 and 12 months where the abnormal behavior and cognition deficits began to gradually increase. These studies describe: (a) a translational relevant animal model for TBI-linked tauopathies, and (b) utilization of T-tau and P-tau as rmCHI biomarkers in plasma to monitor novel therapeutic strategies and treatment regimens for these neurodegenerative diseases.

Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now?

Front Neurol 2018; 9 (ä): 445

Repetitive head trauma provides a favorable milieu for the onset of inflammatory and neurodegenerative processes. The result of long-lasting head trauma is chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, military personnel, and more recently, in American football players. CTE is a chronic neurodegenerative disease with hallmarks of hyperphosphorylated tau (p-tau) aggregates and intercellular lesions of neurofibrillary tangles. The criteria for CTE diagnosis requires at least 1-2 focal perivascular lesions of p-tau in the cerebral cortex, at the depth of the sulci. These pathognomonic lesions aggregate within neurons and glial cells such as astrocytes, and cell processes within the vicinity of small blood vessels. CTE presents in a distinct topographical distribution pattern compared to other tauopathies such as AD and other age-related astrogliopathies. CTE also has an insidious onset, years after repetitive head trauma. The disease course of CTE is characterized by cognitive dysfunction, behavioral changes, and can progress to altered motor function with parkinsonian-like manifestations in later stages. This short review aims to summarize CTE in professional football, epidemiology, diagnosis based on neuroanatomical abnormalities, cognitive degeneration, and adverse mental health effects, as well as gaps in the literature and future directions in diagnostics, therapeutics, and preventive measures.

Environmental Subconcussive Injury, Axonal Injury, and Chronic Traumatic Encephalopathy.

Front Neurol 2018; 9 (ä): 166

Brain injury occurs in two phases: the initial injury itself and a secondary cascade of precise immune-based neurochemical events. The secondary phase is typically functional in nature and characterized by delayed axonal injury with more axonal disconnections occurring than in the initial phase. Axonal injury occurs across the spectrum of disease severity, with subconcussive injury, especially when repetitive, now considered capable of producing significant neurological damage consistent with axonal injury seen in clinically evident concussion, despite no observable symptoms. This review is the first to introduce the concept of environmental subconcussive injury (ESCI) and sets out how secondary brain damage from ESCI once past the juncture of microglial activation appears to follow the same neuron-damaging pathway as secondary brain damage from conventional brain injury. The immune response associated with ESCI is strikingly similar to that mounted after conventional concussion. Specifically, microglial activation is followed closely by glutamate and calcium flux, excitotoxicity, reactive oxygen species and reactive nitrogen species (RNS) generation, lipid peroxidation, and mitochondrial dysfunction and energy crisis. ESCI damage also occurs in two phases, with the primary damage coming from microbiome injury (due to microbiome-altering events) and secondary damage (axonal injury) from progressive secondary neurochemical events. The concept of ESCI and the underlying mechanisms have profound implications for the understanding of chronic traumatic encephalopathy (CTE) etiology because it has previously been suggested that repetitive axonal injury may be the primary CTE pathogenesis in susceptible individuals and it is best correlated with lifetime brain trauma load. Taken together, it appears that susceptibility to brain injury and downstream neurodegenerative diseases, such as CTE, can be conceptualized as a continuum of brain resilience. At one end is optimal resilience, capable of launching effective responses to injury with spontaneous recovery, and at the other end is diminished resilience with a compromised ability to respond and/or heal appropriately. Modulating factors such as one's total cumulative and synergistic brain trauma load, bioavailability of key nutrients needed for proper functioning of restorative metabolic pathways (specifically those involved in the deactivation and clearance of metabolic by-products of brain injury) are key to ultimately determining one's brain resilience.

Considerations for Experimental Animal Models of Concussion, Traumatic Brain Injury, and Chronic Traumatic Encephalopathy-These Matters Matter.

Front Neurol 2017; 8 (ä): 240

Animal models of concussion, traumatic brain injury (TBI), and chronic traumatic encephalopathy (CTE) are widely available and routinely deployed in laboratories around the world. Effective animal modeling requires careful consideration of four basic principles. First, animal model use must be guided by clarity of definitions regarding the human disease or condition being modeled. Concussion, TBI, and CTE represent distinct clinical entities that require clear differentiation: concussion is a neurological syndrome, TBI is a neurological event, and CTE is a neurological disease. While these conditions are all associated with head injury, the pathophysiology, clinical course, and medical management of each are distinct. Investigators who use animal models of these conditions must take into account these clinical distinctions to avoid misinterpretation of results and category mistakes. Second, model selection must be grounded by clarity of purpose with respect to experimental questions and frame of reference of the investigation. Distinguishing injury context ("inputs") from injury consequences ("outputs") may be helpful during animal model selection, experimental design and execution, and interpretation of results. Vigilance is required to rout out, or rigorously control for, model artifacts with potential to interfere with primary endpoints. The widespread use of anesthetics in many animal models illustrates the many ways that model artifacts can confound preclinical results. Third, concordance between key features of the animal model and the human disease or condition being modeled is required to confirm model biofidelity. Fourth, experimental results observed in animals must be confirmed in human subjects for model validation. Adherence to these principles serves as a bulwark against flawed interpretation of results, study replication failure, and confusion in the field. Implementing these principles will advance basic science discovery and accelerate clinical translation to benefit people affected by concussion, TBI, and CTE.

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery.

Front Neurol 2015; 6 (ä): 223

Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology.

The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience.

Front Neurol 2015; 6 (ä): 222

Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p < 0.001) and AT270 (q = 4.03, p < 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05) and repeat blast (q = 4.21, p < 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22-27. During the probe trial, single blast (t = 6.44, p < 0.05) and repeat blast (t = 8.00, p < 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development.

Application of blood-based biomarkers in human mild traumatic brain injury.

Front Neurol 2013; 4 (ä): 44

Traumatic Brain Injury (TBI) is a global health concern. The majority of TBI's are mild, yet our ability to diagnose and treat mild traumatic brain injury (mTBI) is lacking. This deficiency results from a variety of issues including the difficulty in interpreting ambiguous clinically presented symptoms, and ineffective imaging techniques. Thus, researchers have begun to explore cellular and molecular based approaches to improve both diagnosis and prognosis. This has been met with a variety of challenges, including difficulty in relating biological markers to current clinical symptoms, and overcoming our lack of fundamental understanding of the pathophysiology of mTBI. However, recent adoption of high throughput technologies and a change in focus from the identification of single to multiple markers has given just optimism to mTBI research. The purpose of this review is to highlight a number of current experimental peripheral blood biomarkers of mTBI, as well as comment on the issues surrounding their clinical application and utility.

Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment?

Front Neurol 2012; 3 (ä): 186

The diagnosis of chronic traumatic encephalopathy (CTE) upon autopsy in a growing number of athletes and soldiers alike has resulted in increased awareness, by both the scientific/medical and lay communities, of the potential for lasting effects of repetitive traumatic brain injury. While the scientific community has come to better understand the clinical presentation and underlying pathophysiology of CTE, the diagnosis of CTE remains autopsy-based, which prevents adequate monitoring and tracking of the disease. The lack of established biomarkers or imaging modalities for diagnostic and prognostic purposes also prevents the development and implementation of therapeutic protocols. In this work the clinical history and pathologic findings associated with CTE are reviewed, as well as imaging modalities that have demonstrated some promise for future use in the diagnosis and/or tracking of CTE or repetitive brain injury. Biomarkers under investigation are also discussed with particular attention to the timing of release and potential utility in situations of repetitive traumatic brain injury. Further investigation into imaging modalities and biomarker elucidation for the diagnosis of CTE is clearly both needed and warranted.

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation.

Front Neurosci 2019; 13 (ä): 488

Tau-related dementias appear to involve specific to each disease aggregation pathways and morphologies of filamentous tau assemblies. To understand etiology of these differences, here we elucidate molecular mechanism of formation of tau PHFs based on the PMO theory of misfolding and aggregation of pleiomorphic proteins associated with neurodegenerative diseases. In this model, fibrillization of tau is initiated by the coupled binding and folding of the MTB domains that yields antiparallel homodimers, in analogy to folding of split inteins. The free energy of binding is minimized when the antiparallel alignment brings about backbone-backbone H-bonding between the MTBD segments of similar "strand" propensities. To assess these propensities, a function of the NMR shielding tensors of the C(alpha) atoms is introduced as the folding potential function FP i ; the C(alpha) tensors are obtained by the quantum mechanical modeling of protein secondary structure (GIAO//B3LYP/D95()). The calculated FP i plots show that the "strand" propensities of the MBTD segments, and hence the homodimer's register, can be affected by the relatively small changes in the environment's pH, as a result of protonation of MBTD's conserved histidines. The assembly of the antiparallel tau dimers into granular aggregates and their subsequent conversion into the parallel cross-beta structure of paired helical filaments is expected to follow the same path as the previously described fibrillization of Abeta. Consequently, the core structure of the nascent tau fibril is determined by the register of the tau homodimer. This model accounts for the reported differences in (i) fibril-core structure of in vivo and in vitro filaments, (ii) cross-seeding of isoforms, (iii) effects of reducing/non-reducing conditions, (iv) effects of PHF6 mutations, and (v) homologs' aggregation properties. The proposed model also suggests that in contrast to Alzheimer's and chronic traumatic encephalopathy disease, the assembly of tau prions in Pick's disease would be facilitated by a moderate drop in pH that accompanies e.g., transit in the endosomal system, inflammation response or an ischemic injury.

Neuron-Derived Exosome Proteins May Contribute to Progression From Repetitive Mild Traumatic Brain Injuries to Chronic Traumatic Encephalopathy.

Front Neurosci 2019; 13 (ä): 452

The recent recognition that Alzheimer disease-like pathology may be found in chronic traumatic encephalopathy (CTE) even after acute mild traumatic brain injury (mTBI) has increased the urgency of elucidating mechanisms, identifying biomarkers predictive of high risk of development of CTE, and establishing biomarker profiles indicative of impactful effects of treatments. Of the many proteins that are loaded into neuron-derived exosomes (NDEs) from damaged neurons after acute TBI, the levels of prion cellular protein (PRPc), coagulation factor XIII (XIIIa), synaptogyrin-3, IL-6, and aquaporins remain elevated for months. Prolonged heightened expression of aquaporins and IL-6 may account for the persistent central nervous system edema and inflammation of CTE. PRPc, XIIIa and synaptogyrin-3 bind and concentrate neurotoxic forms of oligomeric amyloid beta peptides or P-tau for delivery into neurons at or distant from the site of trauma. Our progression factor hypothesis of CTE asserts that physiological neuronal proteins, such as PRPc, XIIIa, synaptogyrin-3, IL-6 and aquaporins, that increase in concentration in neurons and NDEs for months after acute TBI, are etiological contributors to CTE by either direct actions or by recruiting neurotoxic forms of Abeta peptides or P-tau. Such progression factors also may be useful new targets for development of drugs to prevent CTE.

The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease.

Front Neurosci 2018; 12 (ä): 981

Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer's disease, Parkinson's disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.

Disruption in Brain Phospholipid Content in a Humanized Tau Transgenic Model Following Repetitive Mild Traumatic Brain Injury.

Front Neurosci 2018; 12 (ä): 893

Repetitive mild traumatic brain injury (mTBI) is a risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy typified by immunoreactive tau aggregates in the depths of the sulci. However, the underlying neurobiological mechanisms involved have not been largely explored. Phospholipids are important molecules which form membrane lipid bilayers; they are ubiquitous to every cell in the brain, and carry out a host of different functions. Imbalance in phospholipid metabolism, signaling and transport has been documented in some neurological conditions. However, not much is currently known about their roles in repetitive mTBI and how this may confer risk for the development of age-related neurodegenerative diseases. To address this question, we designed a longitudinal study (24 h, 3, 6, 9, and 12 months post-injury) to comprehensively investigate mTBI dependent brain phospholipid profiles compared to sham counterparts. We use our established mouse model of repetitive mTBI that has been extensively characterized up to 1-year post-injury in humanized tau (hTau) mice, which expresses all six human tau isoforms, on a null murine background. Our data indicates a significant increase in sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC), and derivative lysoPE and lysoPC at acute and/or sub-acute time points post-injury within the cortex and hippocampus. There was also a parallel increase at early time points in monounsaturated, polyunsaturated and saturated fatty acids. Omega-6 (arachidonic acid) to omega-3 (docosahexaenoic acid) fatty acid ratio for PE and PC species was increased also at 24 h and 3 months post-injury in both hippocampus and cortex. The long-term consequences of these early changes in phospholipids on neuronal and non-neuronal cell function is unclear, and warrants further study. Understanding phospholipid metabolism, signaling and transport following TBI could be valuable; they may offer novel targets for therapeutic intervention not only in TBI but other neurodegenerative diseases.

Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder (ALS-FTSD). A Review.

Front Neurosci 2018; 12 (ä): 259

Approximately 50-60% of all patients with amyotrophic lateral sclerosis (ALS) will develop a deficit of frontotemporal function, ranging from frontotemporal dementia (FTD) to one or more deficits of neuropsychological, speech or language function which are collectively known as the frontotemporal spectrum disorders of ALS (ALS-FTSD). While the neuropathology underlying these disorders is most consistent with a widespread alteration in the metabolism of transactive response DNA-binding protein 43 (TDP-43), in both ALS with cognitive impairment (ALSci) and ALS with FTD (ALS-FTD; also known as MND-FTD) there is evidence for alterations in the metabolism of the microtubule associated protein tau. This alteration in tau metabolism is characterized by pathological phosphorylation at residue Thr(175) (pThr(175) tau) which in vitro is associated with activation of GSK3beta (pTyr(216)GSK3beta), phosphorylation of Thr(231)tau, and the formation of cytoplasmic inclusions with increased rates of cell death. This putative pathway of pThr(175) induction of pThr(231) and the formation of pathogenic tau inclusions has been recently shown to span a broad range of tauopathies, including chronic traumatic encephalopathy (CTE) and CTE in association with ALS (CTE-ALS). This pathway can be experimentally triggered through a moderate traumatic brain injury, suggesting that it is a primary neuropathological event and not secondary to a more widespread neuronal dysfunction. In this review, we discuss the neuropathological underpinnings of the postulate that ALS is associated with a tauopathy which manifests as a FTSD, and examine possible mechanisms by which phosphorylation at Thr(175)tau is induced. We hypothesize that this might lead to an unfolding of the hairpin structure of tau, activation of GSK3beta and pathological tau fibril formation through the induction of cis-Thr(231) tau conformers. A potential role of TDP-43 acting synergistically with pathological tau metabolism is proposed.

Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms.

Front Neurosci 2017; 11 (ä): 572

Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.

Neuroimaging assessment of early and late neurobiological sequelae of traumatic brain injury: implications for CTE.

Front Neurosci 2015; 9 (ä): 334

Traumatic brain injury (TBI) has been increasingly accepted as a major external risk factor for neurodegenerative morbidity and mortality. Recent evidence indicates that the resultant chronic neurobiological sequelae following head trauma may, at least in part, contribute to a pathologically distinct disease known as Chronic Traumatic Encephalopathy (CTE). The clinical manifestation of CTE is variable, but the symptoms of this progressive disease include impaired memory and cognition, affective disorders (i.e., impulsivity, aggression, depression, suicidality, etc.), and diminished motor control. Notably, mounting evidence suggests that the pathology contributing to CTE may be caused by repetitive exposure to subconcussive hits to the head, even in those with no history of a clinically evident head injury. Given the millions of athletes and military personnel with potential exposure to repetitive subconcussive insults and TBI, CTE represents an important public health issue. However, the incidence rates and pathological mechanisms are still largely unknown, primarily due to the fact that there is no in vivo diagnostic tool. The primary objective of this manuscript is to address this limitation and discuss potential neuroimaging modalities that may be capable of diagnosing CTE in vivo through the detection of tau and other known pathological features. Additionally, we will discuss the challenges of TBI research, outline the known pathology of CTE (with an emphasis on Tau), review current neuroimaging modalities to assess the potential routes for in vivo diagnosis, and discuss the future directions of CTE research.

Suppression of Presymptomatic Oxidative Stress and Inflammation in Neurodegeneration by Grape-Derived Polyphenols.

Front Pharmacol 2018; 9 (ä): 867

Neurodegenerative disorders constitute a group of multifaceted conditions characterized by the progressive loss of neurons and synaptic connections consequent to a combination of specific genetic predispositions and stochastic stressors. The neuropathologies observed in both Alzheimer's and Parkinson's disease are in part attributed to compounding intrinsic and extrinsic environmental stressors, which we propose may be limited by the administration of specific grape derived phytochemicals and their metabolized derivatives, specifically polyphenols isolated from grape botanicals. Current therapies for neurodegenerative disorders are limited as they solely target the final disease pathologies including behavioral changes, cognitive deficits, proteinopathies and neuronal loss; however, this strategy is not a sustainable approach toward managing disease onset or progression. This review discusses the application of grape derived polyphenols as an adjunctive treatment paradigm for the prevention of neuropathologies associated with Alzheimer's disease, Parkinson's disease and Chronic Traumatic Encephalopathy by simultaneously ameliorating two stochastic stressors that facilitate their disease pathologies: inflammation and oxidative stress. The biophysical attributes of grape-derived polyphenols buffer against redox potential dependent peripheral and neuroinflammation and down regulate the activation of inflammasomes in microglia and astrocytes, which could provide a novel mechanism through which grape-derived polyphenols simultaneously suppress risk factors across pathologically distinct neurodegenerative conditions. This approach therefore offers a prophylactic mode, not feasible through current pharmacological agents, to target activity dependent risk factors for neurodegenerative disorders that manifest over an individual's lifetime.

Encephalitis, Mild Encephalitis, Neuroprogression, or Encephalopathy-Not Merely a Question of Terminology.

Front Psychiatry 2018; 9 (ä): 782

Background: Psychoneuroimmunology research has presented emerging evidence of the involvement of inflammatory and immune mechanisms in the pathogenesis of severe mental disorders. In this context, new terms with increasing clinical relevance have been proposed, challenging the existing terms, and requiring consensus definitions of the new ones. Method: From a perspective of longstanding personal involvement in clinical settings and research in psychoneuroimmunology, the new and the existing terms are critically reconsidered. Results: Meningoencephalitis and encephalitis are comparably well defined clinical terms in neuropsychiatry, although in the individual case approach diagnosis can be difficult, for example in some cases of encephalitis that are described with normal cerebrospinal fluid findings, or often in chronic encephalitis. Encephalopathy is also a widely accepted term, however, with a surprisingly broad meaning with regard to the assigned underlying pathophysiology, ranging from one-hit traumatic encephalopathy to inflammatory encephalopathy, the latter term addressing a type of brain dysfunction secondary to acute systemic inflammation without proven brain autochthonus inflammation (neuroinflammation). However, this latter assumption and term may be wrong as neuroinflammation is difficult to prove in vivo. With emerging insights into prevailing inflammatory and neuroinflammatory mechanisms that are involved in the pathogenesis of severe mental disorders, the interdependent aspects of sensitive assessment and potential clinical relevance of mild neuroinflammation are becoming more apparent and of increasing clinical interest. The new terms "mild encephalitis," "parainflammation," and "neuroprogression" show considerable overlap in addition to gaps and hardly defined borders. However, details are hard to discuss as available studies use many biomarkers, but most of these are done without an established categorical attribution to exclusive terms. Most important, the three new concepts (neruoprogression, parainflammation, and mild encephalitis) are not mutually exclusive, even at the individual case level, and therefore will require state-related individual assessment approaches beyond large confirmatory studies. Conclusion: The newly proposed terms of mild encephalitis, parainflammation, and neuroprogression have an emerging clinical relevance, but respective borders, gaps and overlap in between them remain unclear, and these concepts may even be seen as complementary. Categorical delineation of the new and reconsideration of the existing terms with respect to individualized psychiatric treatment is required for better clinical use, eventually requiring a consensus approach. Here, a critique based on available data and a focus on clinical perspective was outlined, which may help to enhance fruitful discussion. The idea followed here is in line with pillar number six as proposed for the Research Diagnostic Domains, i.e., to provide and follow new concepts in psychiatric research.

Beyond PubMed : called unfree

Interventions to evaluate fitness to drive among people with chronic conditions: Systematic review of literature.

Accid Anal Prev 2013; 50 (ä): 377-96 marta.marino@rm.unicatt.it

When an health condition has been identified, the question of whether to continue driving depends not on a medical diagnosis, but on the functional consequences of the illness. The complex nature of physical and mental impairments and their relationship with safe driving make the availability of evidence based tools necessary for health professionals. The review aims at identifying and summarizing scientific findings concerning the relationship between neuropsychological and clinical screening tests and fitness to drive among people with chronic conditions. Studies were searched for driving ability evaluation by road test or simulator, clinical/neuropsychological examinations of participants with chronic diseases or permanent disablement impairing driving performance, primary outcomes as fatal/non-fatal traffic injuries and secondary outcomes as fitness to drive assessment. Twenty-seven studies fulfilled the inclusion criteria. Some studies included more than one clinical condition. The illness investigated were Alzheimer Disease (n=6), Parkinson Disease (n=8), Cardiovascular Accident (n=4), Traumatic Brain Injuries (n=3), Sleep Apnea Syndrome (n=2), Narcolepsy (n=1), Multiple Sclerosis (n=1) and Hepatic Encephalopathy (n=1), comorbidities (n=3). No studies match inclusion criteria about Myasthenia Gravis, Diabetes Mellitus, Renal Diseases, Hearing Disorders and Sight Diseases. No studies referred to primary outcomes. The selected studies provided opposite evidences. It would be reasonable to argue that some clinical and neuropsychological tests are effective in predicting fitness to drive even if contrasting results support that driving performance decreases as a function of clinical and neuropsychological decline in some chronic diseases. Nevertheless we found no evidence that clinical and neuropsychological screening tests would lead to a reduction in motor vehicle crashes involving chronic disabled drivers. It seems necessary to develop tests with proven validity for identifying high-risk drivers so that physicians can provide guidance to their patients in chronic conditions, and also to medical advisory boards working with licensing offices.

Chronic Traumatic Encephalopathy (CTE): A Brief Historical Overview and Recent Focus on NFL Players.

ACS Chem Neurosci 2017; 8 (8): 1629-1631

Management of concussion in soccer.

Acta Neurochir (Wien) 2019; 161 (3): 425-433 peter.vajkoczy@charite.de.

BACKGROUND: When participating in contact sports, (mild) head trauma is a common incident-observed in both professional and amateur sports. When head trauma results in transient neurological impairment, a sports-related concussion has occurred. Acute concussion, repetitive concussions, as well as cumulative "sub-concussive" head impacts may increase the risk of developing cognitive and behavioral deficits for athletes, as well as accelerated cerebral degeneration. While this concept has been well established for classic contact sports like American Football, Rugby, or Boxing, there is still an awareness gap for the role of sports-related concussion in the context of the world's most popular sport-Soccer. METHODS: Here, we review the relevance of sport-related concussion for Soccer as well as its diagnosis and management. Finally, we provide insight into future directions for research in this field. RESULTS: Soccer fulfills the criteria of a contact sport and is characterized by a high incidence of concussion. There is ample evidence that these events cause functional and structural cerebral disorders. Furthermore, heading, as a repeat sub-concussive impact, has been linked to structural brain changes and neurocognitive impairment. As a consequence, recommendations for the diagnosis and management of concussion in soccer have been formulated by consensus groups. In order to minimize the risk of repetitive concussion in soccer the rapid and reliable side-line diagnosis of concussion with adoption of a strict remove-from-play protocol is essential, followed by a supervised, graduated return-to-play protocol. Recent studies, however, demonstrate that adherence to these recommendations by players, coaches, clubs, and officials is insufficient, calling for stricter enforcement. In addition, future research to solidify the pathophysiological relevance of concussion for soccer athletes seems to be needed. Advanced neuroimaging and neurochemical biomarker analyses (e.g. S100beta, tau and neurofilament light (NfL)) may assist in detecting concussion-related structural brain changes and selecting athletes at risk for irreversible damage. CONCLUSION: Sports-related concussion represents a genuine neurosurgical field of interest. Given the high socioeconomic relevance, neurosurgeons should get involved in prevention and management of concussion in soccer.

Altered beta-APP metabolism after head injury and its relationship to the aetiology of Alzheimer's disease.

Acta Neurochir Suppl 1996; 66 (ä): 96-102

There is increasing evidence of a link between head injury and the subsequent onset of Alzheimer's disease. Deposits of amyloid beta-protein (A beta) are found not only in cases of dementia pugilistica but in some 30% of patients dying after a single episode of severe head injury. Detailed clinicopathological studies have shown that A beta deposition is most likely, but not exclusively, to occur, the older the patient at the time of injury, and if the injury is the result of a fall. Distribution studies have shown that the A beta is widely deposited in the neocortex and there is no apparent association with any of the multiple primary or secondary pathologies of traumatic brain injury. There is an increased expression of beta-APP particularly in the pre-alpha cells of the entorhinal cortex and in areas of axonal damage. Recent molecular genetic studies have shown that there is a strong association between deposits of A beta and the apolipoprotein E genotype of the individual.

Does Swedish amateur boxing lead to chronic brain damage? 2. A retrospective study with CT and MRI.

Acta Neurol Scand 1990; 82 (5): 297-302

It is well known that professional boxers can develop chronic traumatic encephalopathy (dementia pugilistica) due to repeated head trauma. Beside CT findings indicating cerebral atrophy, the presence of a cavum septum pellucidum has been reported to indicate encephalopathy. CT findings in amateur boxers are not as well documented. The aim of this study was to find out if morphological changes could be demonstrated among former amateur boxers using CT and MRI. Two control groups of soccer players and track and field athletes in the same age-range were used for comparison. No significant differences in the width of the ventricular system, anterior horn index, width of cortical sulci, signs of vermian atrophy, or the occurrence of a cavum septum pellucidum were found between boxers and controls. A cavum septum pellucidum was found more often in the controls than in the boxers and is probably not a sign of earlier head trauma. MRI confirm no more findings than CT in this retrospective study.

Whiplash: chronic organic brain syndrome without hydrocephalus ex vacuo.

Acta Neurol Scand 1975; 51 (4): 268-84

Eleven patients who had sustained whiplash injuries to the neck were studied by pneumo-encephalography, by a variety of psychological tests, and by psychiatric evaluation with a view to assessing whether organic CNS changes might, in some cases, be a consequence of such injuries. Patients with traumatic encephalopathy, and age- and sex-matched groups of patients served as control groups. Pneumoencephalography showed normal findings in the whiplash group as a whole, the width of the ventricular system being significantly smaller than that of patients with traumatic encephalopathy. Psychological tests and psychiatric evaluation indicated that organic brain pathology was present in the whiplash patients, although to a lesser extent than in patients with traumatic encephalopathy.

The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments.

Acta Neuropathol 2019; 137 (5): 731-755 Cristina.morganti-kossmann@monash.edu.;

This review recounts the definitions and research evidence supporting the multifaceted roles of neuroinflammation in the injured brain following trauma. We summarise the literature fluctuating from the protective and detrimental properties that cytokines, leukocytes and glial cells play in the acute and chronic stages of TBI, including the intrinsic factors that influence cytokine responses and microglial functions relative to genetics, sex, and age. We elaborate on the pros and cons that cytokines, chemokines, and microglia play in brain repair, specifically neurogenesis, and how such conflicting roles may be harnessed therapeutically to sustain the survival of new neurons. With a brief review of the clinical and experimental findings demonstrating early and chronic inflammation impacts on outcomes, we focus on the clinical conditions that may be amplified by neuroinflammation, ranging from acute seizures to chronic epilepsy, neuroendocrine dysfunction, dementia, depression, post-traumatic stress disorder and chronic traumatic encephalopathy. Finally, we provide an overview of the therapeutic agents that have been tested to reduce inflammation-driven secondary pathological cascades and speculate the future promise of alternative drugs.

Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy.

Acta Neuropathol 2019; ä (ä): ä tdstein@bu.edu.;

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer's disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52-6.38, p < 0.001) adjusting for AD, APOE epsilon4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p's < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02-2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.

Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players.

Acta Neuropathol 2019; ä (ä): ä william.stewart@glasgow.ac.uk.;

Chronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugby players with dementia were assessed for neurodegenerative pathologies using established and preliminary consensus protocols. Thereafter, next of kin interviews were conducted to obtain detailed accounts of the patient's clinical presentation and course of disease to inform a final, integrated clinicopathological diagnosis. Neuropathologic change consistent with CTE (CTE-NC) was confirmed in five of seven former soccer and three of four former rugby players' brains, invariably in combination with mixed, often multiple neurodegenerative pathologies. However, in just three cases was the integrated dementia diagnosis consistent with CTE, the remainder having alternate diagnoses, with the most frequent integrated diagnosis Alzheimer's disease (AD) (four cases; one as mixed AD and vascular dementia). This consecutive autopsy series identifies neuropathologic change consistent with preliminary diagnostic criteria for CTE (CTE-NC) in a high proportion of former soccer and rugby players dying with dementia. However, in the majority, CTE-NC appears as a co-morbidity rather than the primary, dementia causing pathology. As such, we suggest that while CTE-NC might be common in former athletes with dementia, in many cases its clinical significance remains uncertain.

Astrocytic degeneration in chronic traumatic encephalopathy.

Acta Neuropathol 2018; 136 (6): 955-972 david.brody@usuhs.edu.;

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated head traumas. Using immunohistochemistry for glial fibrillary acidic protein as a marker, plus automated quantitative analysis, we examined the characteristics and extent of astrogliosis present in stage III and IV CTE, along with Alzheimer's disease (AD), and frontotemporal dementia (FTD) cases. Astrogliosis in CTE patients was more diffuse compared to that of AD and FTD patients, which was concentrated in the sulcal depths. Of 14 patients with CTE, 10 exhibited signs of a degenerating astrocyte pathology, characterized by beaded, broken astrocytic processes. This astrocytic degeneration was typically found to be diffuse throughout the white matter, although two cases demonstrated astrocytic degeneration in the gray matter. The degeneration was also observed in 2 of 3 AD and 2 of 3 FTD brains, with overall similar characteristics across diseases. There was minimal to no astrocytic degeneration in six age-matched controls with no neurodegenerative disease. We found that the extent of the white matter astrocytic degeneration was strongly correlated with the level of overall astrogliosis in both the white and gray matter. However, astrocytic degeneration was not correlated with the overall extent of tau pathology. Specifically, there was no correlation between levels of p-tau in the sulcal depths and astrocytic degeneration in the white matter adjacent to the sulcal depths. Thus, astrocytic degeneration and overall astrogliosis appear to represent distinct pathological features of CTE. Further investigation into these astroglial pathologies could provide new insights into underlying disease mechanisms and represent a potential target for in vivo assessment of CTE as well as other neurodegenerative disorders.

Axonal disruption in white matter underlying cortical sulcus tau pathology in chronic traumatic encephalopathy.

Acta Neuropathol 2017; 133 (3): 367-380 brodyd@neuro.wustl.edu.;

Chronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-mortem CTE studies have also reported myelin loss, axonal injury and white matter degeneration. Currently, the diagnosis of CTE is restricted to post-mortem neuropathological analysis. We hypothesized that high spatial resolution advanced diffusion MRI might be useful for detecting white matter microstructural changes directly adjacent to gray matter tau pathology. To test this hypothesis, formalin-fixed post-mortem tissue blocks from the superior frontal cortex of ten individuals with an established diagnosis of CTE were obtained from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank. Advanced diffusion MRI data was acquired using an 11.74 T MRI scanner at Washington University with 250 x 250 x 500 microm(3) spatial resolution. Diffusion tensor imaging, diffusion kurtosis imaging and generalized q-sampling imaging analyses were performed in a blinded fashion. Following MRI acquisition, tissue sections were tested for phosphorylated tau immunoreactivity in gray matter sulcal depths. Axonal disruption in underlying white matter was assessed using two-dimensional Fourier transform analysis of myelin black gold staining. A robust image co-registration method was applied to accurately quantify the relationship between diffusion MRI parameters and histopathology. We found that white matter underlying sulci with high levels of tau pathology had substantially impaired myelin black gold Fourier transform power coherence, indicating axonal microstructural disruption (r = -0.55, p = 0.0015). Using diffusion tensor MRI, we found that fractional anisotropy (FA) was modestly (r = 0.53) but significantly (p = 0.0012) correlated with axonal disruption, where lower FA was associated with greater axonal disruption in white matter directly adjacent to hyperphosphorylated tau positive sulci. In summary, our findings indicate that axonal disruption and tau pathology are closely associated, and high spatial resolution ex vivo diffusion MRI has the potential to detect microstructural alterations observed in CTE tissue. Future studies will be required to determine whether this approach can be applied to living people.

Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases.

Acta Neuropathol 2015; 130 (6): 891-3 h.ling@ucl.ac.uk.;

Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease.

Acta Neuropathol 2001; 101 (5): 518-24

Insights into mechanisms of familial Alzheimer's disease (AD) caused by genetic mutations have emerged rapidly compared to sporadic AD. Indeed, despite identification of several sporadic AD risk factors, it remains enigmatic how or why they predispose to neurodegenerative disease. For example, traumatic brain injury (TBI) predisposes to AD, and recurrent TBI in career boxers may cause a progressive memory disorder associated with AD-like brain pathology known as dementia pugilistica (DP). Although the reasons for this are unknown, repeated TBI may cause DP by mechanisms similar to those involved in AD. To investigate this possibility, we compared the molecular profile of tau pathologies in DP with those in AD and showed that the same tau epitopes map to filamentous tau inclusions in AD and DP brains, while the abnormal tau proteins isolated from DP brains are indistinguishable from the six abnormally phosphorylated brain tau isoforms in AD brains. Thus, these data suggest that recurrent TBI may cause DP by activating pathological mechanisms similar to those that cause brain degeneration due to accumulations of filamentous tau lesions in AD, and similar, albeit attenuated, activation of these processes by a single TBI may increase susceptibility to sporadic AD decades after the event.

Neuronal cytoskeletal changes are an early consequence of repetitive head injury.

Acta Neuropathol 1999; 98 (2): 171-8 j.f.geddes@mds.qmw.ac.uk

While neuropathological studies have established the pathology of dementia pugilistica to be similar to that of Alzheimer's disease, there is little information about the early histological changes caused by the repetitive trauma that eventually produces dementia pugilistica. We have examined the brains of four young men and a frontal lobectomy specimen from a fifth, age range 23-28 years, all of whom suffered mild chronic head injury. There were two boxers, a footballer, a mentally subnormal man with a long history of head banging, and an epileptic patient who repeatedly hit his head during seizures. The four autopsy cases were widely sampled; the lobectomy specimen was serially sliced after fixation. Routine stains were performed; inmmunostaining included beta-amyloid precursor protein, amyloid beta-protein (Abeta), tau and apolipoprotein E (apoE). Pathological findings in all five cases were of neocortical neurofibrillary tangles (NFTs) and neuropil threads, with groups of tangles consistently situated around blood vessels in the worst affected regions. No Abeta immunoreactivity was detected. The amount of neuronal apoE expression varied widely between the cases with no clear relation to the NFTs. The apoE genotype was determined in only two cases (both epsilon3/epsilon3). It appears that repetitive head injury in young adults is initially associated with neocortical NFT formation in the absence of Abeta deposition. The distribution of the tau pathology suggests that the pathogenesis of cytoskeletal abnormalities may involve damage to blood vessels or perivascular elements.

Relationship of amyloid beta/A4 protein to the neurofibrillary tangles in Guamanian parkinsonism-dementia.

Acta Neuropathol 1995; 90 (3): 287-98

The Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), which clinically resembles a mixture of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer disease (AD). The disease is characterized by the widespread development of neurofibrillary tangles in the central nervous system. These tangles have an immunohistochemical profile indistinguishable from that seen in AD. We studied by immunohistochemistry the occurrence of intracellular and extracellular neurofibrillary tangles in LB in the entorhinal cortex, hippocampus and substantia nigra using antibodies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its beta-amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequences. In advanced cases of LB, the development of neurofibrillary tangles was far more severe than in advanced cases of AD. Virtually all neurons of CA-1 and the subiculum were lost and only ghost tangles remained. In areas dominated by such extracellular tangles, BAP deposits were frequently observed developing around the fibers of ghost tangles. In some cases, the deposits covered only a few of the fibers, but in others, they seemed to envelope the complete tangle. The deposits were thioflavin S and Congo red positive, indicating that the BAP was in a consolidated form. We describe these entities as "tangle-associated amyloid deposits". Such BAP deposits have previously been described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas and in most cases in the substantia nigra. They do not evolve from diffuse BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracellular BAP deposits are formed.

Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders.

Acta Neuropathol 1994; 87 (5): 469-80

Alterations of the cerebral microvasculature have been reported in aging and in neurodegenerative disorders such as Alzheimer's disease. However, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cerebral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan protein core in normal aging controls. Alzheimer's disease, Down syndrome, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Pick's disease and dementia pugilistica. In all dementing illnesses, increased microvascular pathology was evident compared to normal controls. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These microvascular abnormalities demonstrated regional and laminar selectivity, and were primarily found in layers III and V of frontal and temporal cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimer's disease was statistically significant compared to age-matched controls. In addition, extracellular heparan sulfate proteoglycan deposits were observed which colocalized with thioflavine S-positive senile plaques in Alzheimer's disease, Down syndrome and selected Guam dementia cases. In some cases, heparan sulfate proteoglycan was seen in senile plaques that appeared to be diffuse or primitive plaques that stained weakly with thioflavine. Heparan sulfate proteoglycan-containing neurons were also observed in Alzheimer's disease, as well as in Down syndrome and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvascular pathology is found in aging and in Alzheimer's disease. The changes in Alzheimer's disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorders studied. Our studies further demonstrated that the microvascular pathology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally, we also found that heparan sulfate proteoglycan is present in senile plaques and neurons not only as previously reported in Alzheimer's disease, but also in Down syndrome and Guam cases. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or from degenerating neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases.

Acta Neuropathol 1992; 85 (1): 23-30

Head trauma has been associated with the occurrence of Alzheimer's disease and plays a clear role in the etiopathogenesis of the boxers encephalopathy referred to as dementia pugilistica. Neurofibrillary tangles (NFT), one of the pathological hallmarks of Alzheimer's disease are observed in very high densities in the brains of former professional boxers suffering from dementia pugilistica. In Alzheimer's disease, NFT display striking regional and laminar distribution patterns that have been correlated with the localization of neurons forming specific corticocortical connections. In dementia pugilistica cases, NFT were concentrated in the superficial layers in the neocortex, whereas in Alzheimer's disease they predominated in the deep layers. Thus, the association cortex of brains from dementia pugilistica patients demonstrated an inverse NFT distribution as compared to Alzheimer's disease. This finding suggests that a more circumscribed population of cortical pyramidal neurons might be affected in dementia pugilistica than in Alzheimer's disease.

Neuropathological observations in a case of autism presenting with self-injury behavior.

Acta Neuropathol 1991; 82 (4): 321-6

We report the neuropathological evaluation of a 24-year-old autistic woman suffering from a residual state of infantile autism and presenting with self-injury behavior since childhood. Her behavior included head-banging, eye-gouging and self-biting. All intended therapeutic measures remained without effect, including high doses of psychotropic drugs. At autopsy, numerous neurofibrillary tangles were found in the perirhinal and entorhinal cortex where they were frequently grouped in nests or clusters. A few neurofibrillary tangles were also observed in the amygdala and in the prepiriform and orbito-frontal cortex. In the cortex, tangles were located in both layers II and III. There were no neuritic plaques or amyloid deposits. Interestingly, neurofibrillary tangles have been described in brains of individuals who had experienced repeated head injuries such as boxers (dementia pugilistica) and soccer players, suggesting that in our case a similar mechanism induced tangle formation and resulted in the loss of selective neuronal populations.

Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein.

Acta Neuropathol 1991; 82 (4): 280-5

A histopathological study was carried out on the brains of eight ex-boxers (ages 56 to 83) using conventional histological staining methods and immunocytochemistry with antibodies to amyloid beta-protein and the PHF-related tau protein. All cases showed a large number of tau-immunoreactive neurofibrillary tangles and also beta-protein immunoreactive senile plaques in the cortex. In the areas with many neurofibrillary tangles, neuropil threads with tau-immunoreactivity were also observed, and some of the senile plaque lesions were surrounded by abnormal neurites with tau-immunoreactivity. Moreover, three cases revealed beta-protein-type cerebrovascular amyloid deposits on both leptomeningeal and cortical blood vessels. The present observations indicate that the cerebral pathology of dementia pugilistica is very similar to that of Alzheimer's disease and suggest that these two disorders share some common etiological and pathogenic mechanisms.

LES L'ESIONS ANATOMIQUES DE L'ENC'EPHALOPATHIE POST-TRAUMATIQUE. (COMAS PROLONG'ES ET "MORTS DU CERVEAU")

Acta Neuropathol 1963; 3 (ä): 313-27

[Clinical and pathogenetic characteristics of the craniocerebral trauma received by elderly patients after stroke].

Adv Gerontol 2010; 23 (1): 131-5

In 174 patients of elderly and senile age features of a clinical picture and pathogenesis of a craniocerebral trauma of a different severity occurred in different terms after the previous stroke and in different circumstances have been studied. The mutual relations of traumatic and vascular processes are complex, the vascular pathogenetic features of a trauma influence actively to the brain, earlier damaged by an ischemic stroke, increasing the probability of the heavy form of a combined cerebral pathology and the unfavourable forecast. However the vascular encephalopathy in these conditions "does not develop" in posttraumatic one and chronic vascular-brain frustration absolutely prevail in all cases above traumatic ones. This fact is to be taken into consideration to further treatment and rehabilitation.

Traumatic Brain Injury as a Trigger of Neurodegeneration.

Adv Neurobiol 2017; 15 (ä): 383-400 smithdou@mail.med.upenn.edu.

Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities. These include cavum septum pellucidum, brain atrophy and ventricular dilation, together with pathologies in tau, TDP-43, and amyloid-beta. However, the establishment and characterization of CTE as a distinct disease entity is in its infancy. Moreover, the relative "dose" of TBI, such as the frequency and severity of injury, associated with risk of CTE remains unknown. As such, there is a clear and pressing need to improve the recognition and diagnosis of CTE and to identify mechanistic links between TBI and chronic neurodegeneration.

Post-Traumatic Dizziness: Clinical and Medicolegal Aspects.

Adv Otorhinolaryngol 2019; 82 (ä): 111-118

Subjective complaints of dizziness after mild-to-moderate traumatic brain injury are common. Alterations in the mode of injury have changed the presentation symptoms. Evolutions in neuroimaging challenge conventional concepts regarding lack of evidence of injury following mild head trauma and provide hope for elucidating the site of lesion in patients with post-traumatic balance symptoms. Yet the vestibular clinician must maintain a healthy level of suspicion regarding potential exaggeration of symptoms and disability in patients with a financial incentive. Unique conditions warrant particular attention by the vestibular clinician, including chronic traumatic encephalopathy, catastrophization, and persistent postural and perceptual dizziness. The clinical significance of abnormalities, particularly on vestibular-evoked myogenic potential testing, needs to be better defined prior to their widespread application in the medical legal arena. The role of the medical expert is to provide opinion on matters requiring special knowledge to assist the court in reaching its findings. As such, this chapter provides an update on recent advances to consider in patients with dizziness after trauma.

Nerve growth factor and the basal forebrain cholinergic system: a link in the etiopathology of neurodegenerative dementias?

Alzheimer Dis Assoc Disord 1990; 4 (1): 1-13

The discovery of a specific association between nerve growth factor (NGF) and basal forebrain cholinergic neurons (BFCNs) marks the beginning of a new era of research into neurodegenerative diseases such as Alzheimer disease (AD). Degeneration of BFCNs appears to be one of the earliest and most prominent neuropathological features of a broad range of diseases of the human brain that give rise to loss of memory and dementia (including, in addition to Alzheimer disease, Parkinson disease, Lewy body dementia, progressive supranuclear palsy, dementia pugilistica, olivopontocerebellar atrophy, and Wernicke-Korsakoff syndrome). Selective localization of NGF receptors on BFCN, the relatively high levels of NGF mRNA in BFCN target areas, and numerous effects of exogenous NGF in vivo and in vitro provide overwhelming evidence that the structure and function of BFCNs in the adult brain are dependent on this molecule. The question then arises as to how this special relationship is disturbed in the diseased human brain? Initial investigations in AD have already indicated a normality of NGF mRNA and retention of receptors in the basal forebrain region. Interpretation of these results and the therapeutic relevance of NGF obviously depend upon future developments in understanding the role of NGF in the normal and pathological brain.

Cerebrospinal fluid tau, Abeta, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration.

Alzheimers Dement 2018; 14 (9): 1159-1170 bobstern@bu.edu.

INTRODUCTION: Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid beta1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy. METHODS: Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau181, amyloid beta1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI. RESULTS: No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P = .041), and higher sTREM2 levels were associated with higher t-tau concentrations (P = .009). DISCUSSION: In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.

Neuropsychological factors related to college ice hockey concussions.

Am J Alzheimers Dis Other Demen 2014; 29 (3): 201-4

We analyzed data from 74 male collegiate hockey players. Each athlete's season began with a baseline administration of the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) neuropsychology test battery. Fourteen athletes sustained a sport-related head injury and were readministered the test to assess the impact of the injury. A significant decrease in performance (compared to baseline) on immediate and delayed word recall and designs followed the first concussion. Following a second sport-related concussion, the 4 affected athletes showed significant decrease in visual motor speed. Performance improved on 2 response speed measures (Ps < .01). More errors occurred during a visual processing/discrimination task and immediate recall of designs declined (Ps < .05). We discuss the results in light of recent work related to the impact of early-life concussions and head injury on late-life consequences, such as chronic traumatic encephalopathy, and more immediate issues such as return-to-play decisions for athletes.

Mild head injury in pediatrics: algorithms for management in the ED and in young athletes.

Am J Emerg Med 2013; 31 (7): 1133-8 burkhard.simma@lkhf.at

Mild head injury is of interest because of a history of under diagnosis and underestimated clinical importance. Half of the patients with mild head injuries or concussions have sport-related injuries. Knowledge of symptoms and appropriate management can be improved and is a matter of practical interest. Several algorithms exist for discharge, admission or for cranial computed tomography (CT).These employ different risk factors and calculate their sensitivity of correctly identifying children with traumatic brain injury (TBI). In contrast, a multicenter, prospective study in the United States developed a prediction model to diagnose the absence of intracranial injury when certain symptoms are missing (negative prediction value). An acute concussion presents with a combination of physical, cognitive, and emotional symptoms, which are usually self-limited. In young athletes, a second impact before full recovery from the first may have deleterious consequences and should be avoided by strict "return to play" rules. Recent research suggests that repetitive minor hits may cause delayed brain damage (dementia pugilistica, "punch-drunk syndrome"). A link to neurodegenerative diseases such as dementia, Alzheimer's disease and parkinsonism (tauopathies) is described by amyloid beta plaques in the brain of such patients. A genetic predisposition (apolipoprotein) is discussed. This review focuses on the rules attempting to determine the need for cranial CT in the emergency department and the impact of mild head injuries in young athletes. We describe in detail standardized guidelines for appropriate diagnosis and treatment and discuss the association between repetitive minor injuries and chronic traumatic encephalopathy and neurodegenerative diseases.

Professional fighters brain health study: rationale and methods.

Am J Epidemiol 2013; 178 (2): 280-6 bernicc@ccf.org

Repetitive head trauma is a risk factor for Alzheimer's disease and is the primary cause of chronic traumatic encephalopathy. However, little is known about the natural history of, and risk factors for, chronic traumatic encephalopathy or about means of early detection and intervention. The Professional Fighters Brain Health Study is a longitudinal study of active professional fighters (boxers and mixed martial artists), retired professional fighters, and controls matched for age and level of education. The main objective of the Professional Fighters Brain Health Study is to determine the relationships between measures of head trauma exposure and other potential modifiers and changes in brain imaging and neurological and behavioral function over time. The study is designed to extend over 5 years, and we anticipate enrollment of more than 400 boxers and mixed martial artists. Participants will undergo annual evaluations that include 3-tesla magnetic resonance imaging scanning, computerized cognitive assessments, speech analysis, surveys of mood and impulsivity, and blood sampling for genotyping and exploratory biomarker studies. Statistical models will be developed and validated to predict early and progressive changes in brain structure and function. A composite fight exposure index, developed as a summary measure of cumulative traumatic exposure, shows promise as a predictor of brain volumes and cognitive function.

Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: the role of the forensic pathologist.

Am J Forensic Med Pathol 2010; 31 (2): 130-2

We present 5 cases of professional American contact sport athletes who committed parasuicides and suicides aged 50, 45, 44, 36, and 40 years old. Full forensic autopsies and immunohistochemical analyses of the brains revealed chronic traumatic encephalopathy (CTE). The brains appeared grossly normal at autopsy without gross evidence of remote traumatic injuries or neurodegenerative disease. Brain immunohistochemical analyses revealed widespread cerebral taupathy in the form of neurofibrillary tangles and neuritic threads without neuritic amyloid plaques. CTE refers to chronic cognitive and neuropsychiatric symptoms of chronic neurodegeneration following a single episode of severe traumatic brain injury or repeated episodes of mild traumatic brain injury. CTE can only be definitively diagnosed by direct tissue examination. Without full autopsies and immunohistochemical brain analyses these cases would never have been identified. Forensic pathologists will play a vital and central role in the emerging disease surveillance of CTE in professional American athletes, in the identification of CTE cases, and in the establishment of the epidemiology of CTE, with the goal of eventually developing preventive and interventional therapeutic protocols for CTE outcomes.

Concussion.

Am J Med 2017; 130 (8): 885-892 wmullally@bwh.harvard.edu.

Concussion has been recognized as a clinical entity for more than 1000 years. Throughout the 20th century it was studied extensively in boxers, but it did not pique the interest of the general population because it is the accepted goal of the boxer to inflict such an injury on their opponent. In 2002, however, the possibility that repetitive concussions could result in chronic brain damage and a progressive neurologic disorder was raised by a postmortem evaluation of a retired player in the most popular sports institution in the United States, the National Football League. Since that time concussion has been a frequent topic of conversation in homes, schools, and on television and has become a major focus of sports programs in communities and schools at all levels. Now all 50 states, the District of Columbia, and the National Collegiate Athletic Association have enacted laws and rules to protect the athlete.

Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy-Like Pathology in White Matter Despite Transient Behavioral Abnormalities.

Am J Pathol 2016; 186 (11): 2869-2886 dbriggs@med.wayne.edu.;

Repetitive mild traumatic brain injury (rmTBI), resulting from insults caused by an external mechanical force that disrupts normal brain function, has been linked to the development of neurodegenerative diseases, such as chronic traumatic encephalopathy and Alzheimer disease; however, neither the severity nor frequency of head injury required to trigger adverse behavioral outcomes is well understood. In this study, the administration of 30 head impacts using two different weights to lightly anesthetized, completely unrestrained mice established a paradigm that simulates the highly repetitive nature of sports- and military-related head injury. As the number of head impacts increases, the time to recover consciousness diminishes; however, both the sensorimotor function and behavioral outcomes of impacted mice evolve during the ensuing weeks. Postmortem analyses reveal robust Alzheimer disease and chronic traumatic encephalopathy-like conditions that manifest in a singular manner throughout the white matter concomitant with evidence of chronic oligodendrogenesis. Our data suggest that latency to recover the righting reflex may be an inadequate measure of injury severity and imply that exposure to repeated head impacts may mask the severity of an underlying and developing neuropathologic condition that does not manifest itself until long after head collisions cease. In addition, our data indicate that there is a cumulative and dose-dependent effect of repetitive head impacts that induces the neurobehavioral and neuropathologic outcomes seen in humans with a history of rmTBI.

Sports and Suicide.

Am J Sports Med 2016; 44 (10): 2483-2485

Concussions in the National Football League: A Current Concepts Review.

Am J Sports Med 2016; 44 (3): 801-11 aaron.m.yengo-kahn@vanderbilt.edu.;

BACKGROUND: Significant attention has been directed toward the immediate and long-term effects of sport-related concussions on athletes participating in contact sports, particularly football. The highest level of football, the National Football League (NFL), has received significant attention and criticism regarding player management and safety after mild traumatic brain injury (mTBI). Several review articles have reported data related to concussion in the NFL, but a succinct review and synthesis of data regarding NFL concussions is currently lacking. PURPOSE: To (1) review systematically the published data regarding concussion in the NFL and assess limitations of the studies, (2) elucidate areas where further research is needed, and (3) identify methods to improve future investigations of concussion in the NFL. STUDY DESIGN: Systematic review of literature. METHODS: English-language titles and abstracts published between 1900 and September 2014 were searched systematically across electronic databases, and a review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Peer-reviewed journal articles were included if they contained NFL concussion data with or without additional associated long-term effects. Reviews, editorials, letters to the editor, and comments were not included. RESULTS: Of the 344 records screened for review, 88 articles were assessed for eligibility. There were 31 studies that met the inclusion criteria and formed the basis of the evidence synthesis. Included in the current review were 8 case-control studies (Oxford Centre for Evidence-Based Medicine evidence level 3b), 6 descriptive epidemiological studies (level 4), 6 cross-sectional studies (level 4), 6 cohort studies (level 2b), and 5 case series (level 4). CONCLUSION: The study of concussions in the NFL has been limited by lack of recent empirical data, reliance on self-reported concussion history, and ascertainment bias of brains donated for autopsy studies. The scientific community as well as the public should be cautious in interpreting the current literature surrounding concussion.

Talking with parents of high school football players about chronic traumatic encephalopathy: a concise summary.

Am J Sports Med 2015; 43 (5): 1260-4 gary.solomon@vanderbilt.edu.

Over the past decade, athletic-related chronic traumatic encephalopathy (CTE) has garnered a great deal of attention in the popular press and, more recently, in the scientific press. With increasing frequency, sports medicine practitioners and providers are faced with questions from the parents of high school football players about CTE and the risk posed to children who participate in this or other contact or collision sports. The purpose of this review was to summarize the research on CTE in an attempt to provide some evidence-based answers to frequently asked questions in clinics from parents. Addressed are (1) the definitions of CTE and its symptoms, (2) the evidence for CTE in football, (3) abnormal tau protein, (4) the use of neuroimaging in CTE diagnosis, (5) risk for CTE, (6) CTE diagnosis in youth, (7) CTE and its relationship to suicide, and (8) contact and collision sports as a risk factor for permanent brain injury or death.

Acute and chronic brain injury in United States National Team soccer players.

Am J Sports Med 1996; 24 (2): 205-10

We designed a study to determine whether chronic encephalopathy occurs in elite, active soccer players resulting from repetitive heading of the soccer ball. Studies have suggested that the cumulative effects of heading a ball can cause a chronic brain syndrome similar to dementia pugilistica, which is seen in professional boxers. Twenty of 25 members of the U.S. Men's National Soccer Team training camp (average age, 24.9; average years of soccer, 17.7), who completed a questionnaire on head injury symptoms and had magnetic resonance imaging of the brain, were compared with 20 age-matched male elite track athletes. The soccer players were surveyed about playing position, teams, number of headers, acute head injuries, and years of playing experience. An exposure index to headers was developed to assess a dose-response effect of chronic heading. The soccer and track groups were questioned regarding alcohol use and history of acute head traumas. Questionnaire analysis and magnetic resonance imaging demonstrated no statistical differences between the two groups. Among the soccer players, symptoms and magnetic resonance imaging findings did not correlate with age, years of play, exposure index results, or number of headers. However, reported head injury symptoms, especially in soccer players, correlated with histories of prior acute head injuries (r = 0.63). These findings suggest that any evidence of encephalopathy in soccer players relates more to acute head injuries received playing soccer than from repetitive heading.

The Department of Veterans Affairs Biorepository Brain Bank: a national resource for amyotrophic lateral sclerosis research.

Amyotroph Lateral Scler Frontotemporal Degener 2013; 14 (7-8): 591-7

Our objective was to describe a unique national resource to facilitate amyotrophic lateral sclerosis (ALS) research, the Department of Veterans Affairs Biorepository Brain Bank. Enrolled veterans receive biannual telephone follow-up to collect clinical data until death including the ALS Functional Rating Scale-Revised (ALSFRS-R). A comprehensive post mortem examination is performed and a wide range of fixed and frozen brain and spinal cord samples are banked. As of December 2012, 240 veterans were enrolled from 47 states and post mortem tissue recoveries were performed on 100 veterans from 37 states. Average disease duration was 13.5 (range 3-45) years. Average follow-up for living subjects was 3.1 years and average ALSFRS-R score was 23.5 compared to 25.9 (12-24 months earlier), indicating slow disease progression. ALS was confirmed by post mortem examination in 97% of cases. Eighty-six percent of cases were TDP-43-positive. Additional neuropathological diagnoses include Lewy body disease (13%), frontotemporal lobar degeneration (6.3%), chronic traumatic encephalopathy with motor neuron disease (3.2%), and Alzheimer's disease (2.1%). Tissue RIN values were >/= 4.0 in 88% of cases. In conclusion, the availability of high quality fixed and frozen CNS tissue from this well characterized cohort is an important resource to facilitate research into genetic and environmental risk factors and clinical pathological relationships in ALS.

The Shrinking Brain: Cerebral Atrophy Following Traumatic Brain Injury.

Ann Biomed Eng 2018; ä (ä): ä ekuhl@stanford.edu.

Cerebral atrophy in response to traumatic brain injury is a well-documented phenomenon in both primary investigations and review articles. Recent atrophy studies focus on exploring the region-specific patterns of cerebral atrophy; yet, there is no study that analyzes and synthesizes the emerging atrophy patterns in a single comprehensive review. Here we attempt to fill this gap in our current knowledge by integrating the current literature into a cohesive theory of preferential brain tissue loss and by identifying common risk factors for accelerated atrophy progression. Our review reveals that observations for mild traumatic brain injury remain inconclusive, whereas observations for moderate-to-severe traumatic brain injury converge towards robust patterns: brain tissue loss is on the order of 5% per year, and occurs in the form of generalized atrophy, across the entire brain, or focal atrophy, in specific brain regions. The most common regions of focal atrophy are the thalamus, hippocampus, and cerebellum in gray matter and the corpus callosum, corona radiata, and brainstem in white matter. We illustrate the differences of generalized and focal gray and white matter atrophy on emerging deformation and stress profiles across the whole brain using computational simulation. The characteristic features of our atrophy simulations-a widening of the cortical sulci, a gradual enlargement of the ventricles, and a pronounced cortical thinning-agree well with clinical observations. Understanding region-specific atrophy patterns in response to traumatic brain injury has significant implications in modeling, simulating, and predicting injury outcomes. Computational modeling of brain atrophy could open new strategies for physicians to make informed decisions for whom, how, and when to administer pharmaceutical treatment to manage the chronic loss of brain structure and function.

Nano-Composite Foam Sensor System in Football Helmets.

Ann Biomed Eng 2017; 45 (12): 2742-2749 jakemerrell@gmail.com.;

American football has both the highest rate of concussion incidences as well as the highest number of concussions of all contact sports due to both the number of athletes and nature of the sport. Recent research has linked concussions with long term health complications such as chronic traumatic encephalopathy and early onset Alzheimer's. Understanding the mechanical characteristics of concussive impacts is critical to help protect athletes from these debilitating diseases and is now possible using helmet-based sensor systems. To date, real time on-field measurement of head impacts has been almost exclusively measured by devices that rely on accelerometers or gyroscopes attached to the player's helmet, or embedded in a mouth guard. These systems monitor motion of the head or helmet, but do not directly measure impact energy. This paper evaluates the accuracy of a novel, multifunctional foam-based sensor that replaces a portion of the helmet foam to measure impact. All modified helmets were tested using a National Operating Committee Standards for Athletic Equipment-style drop tower with a total of 24 drop tests (4 locations with 6 impact energies). The impacts were evaluated using a headform, instrumented with a tri-axial accelerometer, mounted to a Hybrid III neck assembly. The resultant accelerations were evaluated for both the peak acceleration and the severity indices. These data were then compared to the voltage response from multiple Nano Composite Foam sensors located throughout the helmet. The foam sensor system proved to be accurate in measuring both the HIC and Gadd severity index, as well as peak acceleration while also providing additional details that were previously difficult to obtain, such as impact energy.

Chronic traumatic encephalopathy: emergency physicians fielding more questions in the absence of evidence.

Ann Emerg Med 2012; 60 (4): 17A-21A

Initiation of antidepressant medication and risk of incident stroke: using the Adult Changes in Thought cohort to address time-varying confounding.

Ann Epidemiol 2019; ä (ä): ä maria.glymour@ucsf.edu.;

PURPOSE: Depression strongly predicts stroke incidence, suggesting that treating depression may reduce stroke risk. Antidepressant medications, however, may increase stroke risk via direct pathways. Previous evidence on antidepressant medication and stroke incidence is mixed. We evaluated associations between antidepressant use and incident stroke. METHODS: For 2302 Adult Changes in Thought cohort participants with no stroke at study entry, we characterized antidepressant use from pharmacy records, biennial depressive symptoms with a 10-item Centers for Epidemiologic Study-Depression scale, and incident strokes from ICD codes. We used discrete-time survival models with inverse probability weighting to compare stroke risk associated with filling antidepressant prescriptions and by medication category: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, or other. RESULTS: Over an average 8.4-year follow-up, 441 incident strokes occurred. Filling antidepressant medications 3+ times versus 0-2 times predicted 35% increased odds of stroke (OR = 1.35; 95% CI: 0.98, 1.66). Use of TCAs was associated with stroke onset (OR per 10 fills = 1.28; CI: 1.04, 1.57), but use of selective serotonin reuptake inhibitors (OR = 0.98; CI: 0.80, 1.20) or other antidepressants (OR = 0.99; CI: 0.67, 1.45) was not. CONCLUSIONS: Although patients who received antidepressant medication were at higher risk of stroke, this association appeared specific to TCA prescriptions.

Chief Concern: "I'm Worried I Have Chronic Traumatic Encephalopathy".

Ann Intern Med 2018; 168 (4): 285-286

Researchers take on a preventable dementia: brain bank is giving researchers new understanding of chronic traumatic encephalopathy.

Ann Neurol 2011; 70 (2): A11-4

Apolipoprotein E epsilon 4 and fatal cerebral amyloid angiopathy associated with dementia pugilistica.

Ann Neurol 1995; 38 (4): 698-9

Intercellular Spread of Protein Aggregates in Neurodegenerative Disease.

Annu Rev Cell Dev Biol 2018; 34 (ä): 545-568 holtzman@wustl.edu.;

Most neurodegenerative diseases are characterized by the accumulation of protein aggregates, some of which are toxic to cells. Mounting evidence demonstrates that in several diseases, protein aggregates can pass from neuron to neuron along connected networks, although the role of this spreading phenomenon in disease pathogenesis is not completely understood. Here we briefly review the molecular and histopathological features of protein aggregation in neurodegenerative disease, we summarize the evidence for release of proteins from donor cells into the extracellular space, and we highlight some other mechanisms by which protein aggregates might be transmitted to recipient cells. We also discuss the evidence that supports a role for spreading of protein aggregates in neurodegenerative disease pathogenesis and some limitations of this model. Finally, we consider potential therapeutic strategies to target spreading of protein aggregates in the treatment of neurodegenerative diseases.

Chronic traumatic encephalopathy: historical origins and current perspective.

Annu Rev Clin Psychol 2015; 11 (ä): 309-30 valmont@bu.edu

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is most often identified in postmortem autopsies of individuals exposed to repetitive head impacts, such as boxers and football players. The neuropathology of CTE is characterized by the accumulation of hyperphosphorylated tau protein in a pattern that is unique from that of other neurodegenerative diseases, including Alzheimer's disease. The clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition, frequently resulting in debilitating dementia. In some cases, motor features, including parkinsonism, can also be present. In this review, the historical origins of CTE are revealed and an overview of the current state of knowledge of CTE is provided, including the neuropathology, clinical features, proposed clinical and pathological diagnostic criteria, potential in vivo biomarkers, known risk factors, and treatment options.

Uncoupled Endothelial Nitric Oxide Synthase Enhances p-Tau in Chronic Traumatic Encephalopathy Mouse Model.

Antioxid Redox Signal 2019; 30 (13): 1601-1620

AIMS: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease thought to be caused by repetitive traumatic brain injury (TBI) and subconcussive injuries. While hyperphosphorylation of tau (p-Tau), which is attributed to astrocytic tangles (ATs) and neurofibrillary tangles, is known to be involved in CTE, there are limited neuropathological or molecular data. By utilizing repetitive mild TBI (rmTBI) mouse models, our aim was to examine the pathological changes of CTE-associated structures, specifically the ATs. RESULTS: Our rmTBI mouse models showed symptoms of depressive behavior and memory deficit, alongside an increased p-Tau expression in their neurons and astrocytes in both the hippocampus and cortex. rmTBI induced oxidative stress in endothelial cells and nitric oxide (NO) generation in astrocytes, which were mediated by hypoxia and increased hypoxia-inducible factor 1-alpha (HIF1alpha). There was also correlated decreased regional cerebral tissue perfusion units, mild activation of astrocytes and NFkappaB phosphorylation, increased expression of inducible nitric oxide synthase (iNOS), increased endothelial nitric oxide synthase (eNOS) uncoupling with decreased tetrahydrobiopterin, and increased expression of nitrotyrosine, NADPH oxidase 2 (Nox2)/nuclear factor (erythroid-derived 2) factor 2 (Nrf2) signaling proteins. Combined, these effects induced peroxynitrite formation and hyperphosphorylation of tau in the hippocampus and cortex toward the formation of ATs. INNOVATION: Our model features molecular pathogenesis events of CTE with clinically relevant latency periods. In particular, this is the first demonstration of an increased astrocytic iNOS expression in an in vivo model. CONCLUSION: We propose a novel mechanism of uncoupled eNOS and NO contribution to Tau phosphorylation and AT formation in rmTBI brain, toward an increased molecular understanding of the pathophysiology of human CTE.

Chronic traumatic encephalopathy is not a real disease.

Arch Clin Neuropsychol 2018; 33 (5): 644-648

There was a long-lasting debate during the first half of the 1900s about whether boxers suffered from a condition called "dementia pugilistica". This included arguments as to whether there was such a distinct clinical condition, whether it was static or progressive, and whether boxers were actually at any increased risk of any neurological issues at all. The debate was never resolved, but was resuscitated in 2005 with the speculation that a similar condition, dubbed "chronic traumatic encephalopathy (CTE)" existed in retired National Football League (NFL) players. A specific pattern of p-tau deposition has been identified in the brains of NFL retirees, and also identifiable in the brains of at least a percentage of individuals exposed to contact sports in general. Advocates of CTE as a disease describe it as presenting with behavioral disturbance, increased suicidality and neurodegeneration leading to dementia. The evidence to date, however, does not rise to the level of a verifiable disease, and remains at the level of case report. To assume that CTE pathology represents a neurodegenerative disease flies in the face of a number of facts, including that traumatic brain injury does not cause neurodegeneration, protein deposits in the brain are a poor predictor of behavioral symptoms, p-tau is not necessarily toxic or self-propagating, and retired NFL players are actually much physically and mentally healthier than men of their demographic background. They have an all-cause mortality rate that is 50% of that expected, and a suicide rate that is 40% of that expected. The most parsimonious explanation of the evidence to date is that repetitive head trauma may result in p-tau deposition, but that this isoform of p-tau is inert and has no toxic or self-propagating effects.

Current Public Knowledge Pertaining to Traumatic Brain Injury: Influence of Demographic Factors, Social Trends, and Sport Concussion Experience on the Understanding of Traumatic Brain Injury Sequelae.

Arch Clin Neuropsychol 2017; 32 (2): 155-167

Objective: The current study aimed to assess current broad traumatic brain injury (TBI)-related knowledge in the general public, as well as understanding regarding specific TBI-related conditions including post-concussive syndrome (PCS) and chronic traumatic encephalopathy (CTE). Methods: Data were collected from 307 domestic and 73 international individuals via online researcher-developed survey instrumentation utilizing the Amazon Mechanical Turk marketplace, a recently developed website that allows for a streamlined process of survey-based participant recruitment and data collection. Participants completed background demographics questions, a 31-item true/false questionnaire pertaining to TBI-related knowledge, and an inquiry related to willingness to allow (future) child(ren) to participate in several popular U.S. sports. Results: The overall accuracy rate of our U.S. sample was 61%. No accuracy differences were present for gender or geographic region (p's > .05). Participants who self-reported a prior concussion diagnosis, who reported receiving formal concussion training, and who endorsed participation in collegiate, semi-professional, or professional athletic competition, all exhibited lower accuracy rates than the respective comparison groups (p's < .001). Finally, individual item analysis revealed the presence of significant misconceptions pertaining to PCS and CTE. Conclusions: Misconceptions regarding TBI remain highly prevalent within the general public and may be explained, to some extent, by inefficiencies in current TBI-education practices. Moreover, misconceptions regarding PCS and CTE are also prevalent and likely reflect inconsistencies in the scientific literature, coupled with misleading media reports. To combat these trends, greater emphasis must be placed on construct definition within the field and streamlined, efficient communication with the general public.

The protective effect of education on cognition in professional fighters.

Arch Clin Neuropsychol 2014; 29 (1): 54-9

Education has a protective effect against cognitive deficits following various forms of brain insult. Professional fighting (boxing and mixed martial arts) provides a model for assessing the impact of cumulative brain injuries on cognition and brain health. In the current cross-sectional observational study, we explore whether education would be protective against cognitive loss in fighters. We tested 141 professional fighters using a computerized neurocognitive battery, in addition to structural MRI. We used automated segmentation software to compute the volumes of various brain structures. We found fighters with high school education or less to show more associations between fight exposure and cognitive test scores. The relationship between brain structure volume and exposure did not differ based on education. These results are interpreted as putatively showing a protective effect of education on functional integrity in fighters, although longitudinal data and a larger sample size are required to further understand this relationship.

Psychological, neuropsychological, and electrocortical effects of mixed mold exposure.

Arch Environ Health 2003; 58 (8): 452-63 bcbrain1@msn.com

The authors assessed the psychological, neuropsychological, and electrocortical effects of human exposure to mixed colonies of toxigenic molds. Patients (N = 182) with confirmed mold-exposure history completed clinical interviews, a symptom checklist (SCL-90-R), limited neuropsychological testing, quantitative electroencephalogram (QEEG) with neurometric analysis, and measures of mold exposure. Patients reported high levels of physical, cognitive, and emotional symptoms. Ratings on the SCL-90-R were "moderate" to "severe," with a factor reflecting situational depression accounting for most of the variance. Most of the patients were found to suffer from acute stress, adjustment disorder, or post-traumatic stress. Differential diagnosis confirmed an etiology of a combination of external stressors, along with organic metabolically based dysregulation of emotions and decreased cognitive functioning as a result of toxic or metabolic encephalopathy. Measures of toxic mold exposure predicted QEEG measures and neuropsychological test performance. QEEG results included narrowed frequency bands and increased power in the alpha and theta bands in the frontal areas of the cortex. These findings indicated a hypoactivation of the frontal cortex, possibly due to brainstem involvement and insufficient excitatory input from the reticular activating system. Neuropsychological testing revealed impairments similar to mild traumatic brain injury. In comparison with premorbid estimates of intelligence, findings of impaired functioning on multiple cognitive tasks predominated. A dose-response relationship between measures of mold exposure and abnormal neuropsychological test results and QEEG measures suggested that toxic mold causes significant problems in exposed individuals. Study limitations included lack of a comparison group, patient selection bias, and incomplete data sets that did not allow for comparisons among variables.

Neurologic aspects of boxing.

Arch Neurol 1987; 44 (4): 453-9

The assessment and prevention of potentially adverse neurologic consequences of boxing requires two important considerations. Acute neurologic injuries should be distinguished from chronic brain injuries and the level of competitive boxing (ie, amateur vs professional) must also be taken into account. Acute neurologic injuries such as concussion, post-concussion syndrome, intracranial hemorrhage, and brain contusion are more readily identified than chronic neurologic injuries because of their immediate devastation of the nervous system. In contrast, chronic neurologic injuries differ in their pathophysiologic mechanisms that are exemplified by an insidious onset and progression after the cessation of boxing. Accordingly, the chronic traumatic encephalopathy of boxing poses the most serious neurologic threat of boxing. Amateur boxing differs from professional boxing in the duration of fights, rules and regulatory policies, medical evaluation, and protective devices. These factors could produce a differential effect on the risk of injury to the brain. The prevention of neurologic injuries in boxing requires the integration of proper neurologic evaluation by qualified ring-side physicians, the design and utilization of effective protective devices, and the establishment of national regulatory agencies.

Posttraumatic premature Alzheimer's disease. Neuropathologic findings and pathogenetic considerations.

Arch Neurol 1982; 39 (9): 570-5

Dementia following head trauma is generally attributed to contusional injury or its complications. Dementia pugilistica and rare cases of classic Alzheimer's disease (AD) following head injury suggest that trauma may also play a provocative role in neurofibrillary change. The ages and clinical descriptions, however, allow other interpretations. A 38-year-old man died 16 years after substantial recovery from a single episode of severe head trauma. Pathologic study indicated that the clinical deterioration was due to classic AD. Ultrastructural evaluation demonstrated both paired helical and straight filaments in cortical neurons.

Driving safety after brain damage: follow-up of twenty-two patients with matched controls.

Arch Phys Med Rehabil 1990; 71 (2): 133-7

Driving after brain damage is a vital issue, considering the large number of patients who suffer from cerebrovascular and traumatic encephalopathy. The ability to operate a motor vehicle is an integral part of independence for most adults and so should be preserved whenever possible. The physician may estimate a patient's ability to drive safely based on his own examination, the evaluation of a neuropsychologist, and a comprehensive driving evaluation--testing, driving simulation, behind-the-wheel observation--with a driving specialist. This study sought to evaluate the ability of brain-damaged individuals to operate a motor vehicle safely at follow-up. These patients had been evaluated (by a physician, a neuropsychologist, and a driving specialist) and were judged able to operate a motor vehicle safely after their cognitive insult. Twenty-two brain-damaged patients who were evaluated at our institution were successfully followed up to five years (mean interval of 2.67 years). Patients were interviewed by telephone. Their driving safely was compared with a control group consisting of a close friend or spouse of each patient. Statistical analysis revealed no difference between patient and control groups in the type of driving, the incidence of speeding tickets, near accidents, and accidents, and the cost of vehicle damage when accidents occurred. The patient group was further divided into those who had, and those who had not experienced driving difficulties so that initial neuropsychologic testing could be compared. No significant differences were noted in any aspect of the neuropsychologic test battery. We conclude that selected brain-damaged patients who have passed a comprehensive driving assessment as outlined were as fit to drive as were their normal matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation.

Arch Toxicol 2017; 91 (4): 1623-1634 g.niedermayer@westernsydney.edu.au.;

Neuroinflammation is a pathophysiological process present in a number of neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, traumatic brain injury including chronic traumatic encephalopathy and other age-related CNS disorders. Although there is still much debate about the initial trigger for some of these neurodegenerative disorders, during the progression of disease, broad range anti-inflammatory drugs including cytokine suppressive anti-inflammatory drugs (CSAIDs) might be promising therapeutic options to limit neuroinflammation and improve the clinical outcome. One of the most promising CSAIDs is curcumin, which modulates the activity of several transcription factors (e.g., STAT, NF-kappaB, AP-1) and their pro-inflammatory molecular signaling pathways. However, normal curcumin preparations demonstrate low bioavailability in vivo. To increase bioavailability, preparations of high bioavailability curcumin have been introduced to achieve therapeutically relevant concentrations in target tissues. This literature review aims to summarize the pharmacokinetic and toxicity profile of different curcumin formulations.

Traumatic brain injury and chronic traumatic encephalopathy: a forensic neuropsychiatric perspective.

Behav Sci Law 2013; 31 (6): 721-38

Recent scientific reports and popular press describing chronic traumatic encephalopathy (CTE) collectively link this condition to a broad array of neuropsychiatric symptoms, including extremely rare and multi-determined behaviors such as murder-suicide. These reports are difficult to reconcile with several decades of research on the science of traumatic brain injury (TBI) and its consequences, especially the natural history and prognosis of mild TBI. This article attempts to reconcile these sources by reviewing the state of the science on CTE, with particular attention to case definitions and neuropathological criteria for this diagnosis. The evidence for links between TBI, CTE, and catastrophic clinical events is explored, and the complexity of attributing rare frequency behavioral events to CTE is highlighted. The clinical and medicolegal implications of the best available evidence are discussed, concluding with a cautionary note against prematurely generalizing current findings on CTE to entire populations of persons with, or at risk for, concussion exposures.

Amyloid-beta and tau pathology following repetitive mild traumatic brain injury.

Biochem Biophys Res Commun 2017; 483 (4): 1137-1142 Claudio.Soto@uth.tmc.edu.

Neurodegenerative diseases are characterized by distinctive neuropathological alterations, including the cerebral accumulation of misfolded protein aggregates, neuroinflammation, synaptic dysfunction, and neuronal loss, along with behavioral impairments. Traumatic brain injury (TBI) is believed to be an important risk factor for certain neurodegenerative diseases, such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). TBI represents a ubiquitous problem in the world and could play a major role in the pathogenesis and etiology of AD or CTE later in life. TBI events appear to trigger and exacerbate some of the pathological processes in these diseases, in particular, the formation and accumulation of misfolded protein aggregates composed of amyloid-beta (Abeta) and tau. Here, we describe the relationship between repetitive mild TBI and the development of Abeta and tau pathology in patients affected by AD or CTE on the basis of epidemiological and pathological studies in human cases, and a thorough overview of data obtained in experimental animal models. We also discuss the possibility that TBI may contribute to initiate the formation of misfolded oligomeric species that may subsequently spread the pathology through a prion-like process of seeding of protein misfolding.

Lithium treatment for chronic traumatic encephalopathy: A proposal.

Bipolar Disord 2019; 21 (2): 104-105

Large case series documents chronic brain damage in players of American football.

BMJ 2017; 358 (ä): j3602

Chronic traumatic encephalopathy is reported in 25 year old former American football player.

BMJ 2016; 352 (ä): h7027

Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study.

Br J Sports Med 2018; 52 (3): 192-198

BACKGROUND/AIM: To evaluate the association of genetic polymorphisms APOE, APOE G-219T promoter, microtubule associated protein(MAPT)/tau exon 6 Ser(53)Pro, MAPT/tau Hist(47)Tyr, IL-6572 G/C and IL-6R(Asp)358(Ala) with the risk of concussion in college athletes. METHODS: A 23-centre prospective cohort study of 1056 college athletes with genotyping was completed between August 2003 and December 2012. All athletes completed baseline medical and concussion questionnaires, and post-concussion data were collected for athletes with a documented concussion. RESULTS: The study cohort consisted of 1056 athletes of mean+/-SD age 19.7+/-1.5 years, 89.3% male, 59.4% Caucasian, 35.0% African-American, 5.6% other race. The athletes participated in American football, soccer, basketball, softball, men's wrestling and club rugby. A total of 133 (12.1% prevalence) concussions occurred during an average surveillance of 3 years per athlete. We observed a significant positive association between IL-6R CC (p=0.001) and a negative association between APOE4 (p=0.03) and the risk of concussion. Unadjusted and adjusted logistic regression analysis showed a significant association between IL-6R CC and concussion (OR 3.48; 95% CI 1.58 to 7.65; p=0.002) and between the APOE4 allele and concussion (OR 0.61; 95% CI 0.38 to 0.96; p=0.04), which persisted after adjustment for confounders. CONCLUSIONS: IL-6R CC was associated with a three times greater concussion risk and APOE4 with a 40% lower risk.

Sports concussion research, chronic traumatic encephalopathy and the media: repairing the disconnect.

Br J Sports Med 2017; 51 (24): 1732-1733

Chronic traumatic encephalopathy: how serious a sports problem is it?

Br J Sports Med 2014; 48 (2): 81-3

It is now recognised that there is a spectrum of concussion disorders ranging from acute concussion at one end to various forms of brain degeneration at the other end. The spectrum includes acute concussion, second impact syndrome or acute cerebral swelling, postconcussion syndrome, depression or anxiety, chronic traumatic encephalopathy (CTE) and possibly other forms of central nervous system degeneration. It is essential to carefully evaluate the clinical and neuropathological correlations of CTE that have been published. This has been accomplished in an excellent paper on this subject by Gardner and colleagues in this issue. There have been significant advances in our knowledge of the clinical and neuropathological features of CTE in athletes in the past 10 years. However, we are just at the beginning of our appreciation of this entity due to the paucity of research and the inability to diagnose CTE during life. At present, it is not possible to assess the validity of the proposed methods of classification and grading of the severity of the disease. Additional studies of large numbers of at-risk athletes are essential, especially prospective longitudinal studies. Obviously, such studies would be even more effective if reliable in vivo biomarkers were discovered, especially non-invasive ones such as advanced MRI or MR spectroscopy or invasive ones such as blood or cerebrospinal fluid tests. The major questions that remain unanswered include the frequency of CTE in various collision sports, the causal or otherwise relationship between concussions and CTE, the number of concussions that need to be involved and their management.

Chronic traumatic encephalopathy and risk of suicide in former athletes.

Br J Sports Med 2014; 48 (2): 162-5

BACKGROUND: In the initial autopsy case studies of chronic traumatic encephalopathy (CTE), some researchers have concluded that the proteinopathy associated with CTE is the underlying cause of suicidality and completed suicide in former athletes. METHODS: A review of the literature on contact sports and risk of completed suicide revealed only one epidemiological study with direct relevant data. RESULTS: There are no published cross-sectional, epidemiological or prospective studies showing a relation between contact sports and risk of suicide. One published epidemiological study suggests that retired National Football League players have lower rates of death by suicide than the general population. Outside of sports, there is a mature body of evidence suggesting that the causes of suicide are complex, multifactorial and difficult to predict in individual cases. CONCLUSIONS: Future research might establish a clear causal connection between the proteinopathy of CTE and suicide. At present, however, there is insufficient scientific evidence to conclude that there is a strong causal relationship between the presence of these proteinopathies and suicide in former athletes. Additional research is needed to determine the extent to which the neuropathology of CTE is a possible mediator or moderator variable associated with suicide.

Chronic traumatic encephalopathy: rugby's call for clarity, data and leadership in the concussion debate.

Br J Sports Med 2014; 48 (2): 76-9

Concussion and chronic traumatic encephalopathy: International Rugby Board's response.

Br J Sports Med 2014; 48 (2): 79-80

Chronic traumatic encephalopathy in sport: a systematic review.

Br J Sports Med 2014; 48 (2): 84-90

OBJECTIVE: To provide a critical review of chronic traumatic encephalopathy (CTE) by considering the range of clinical presentations, neuropathology and the strength of evidence for CTE as a distinct syndrome. DATA SOURCES: Seven electronic databases were searched using a combination of MeSH terms and key words to identify relevant articles. REVIEW METHODS: Specific inclusion and exclusion criteria were used to select studies for review. Data extracted where present included study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, investigation results and neuropathology results. RESULTS: The data from 158 published case studies were reviewed. Critical differences between the older descriptions of CTE (the 'classic' syndrome) and the recent descriptions (the 'modern' syndrome) exist in the age of onset, natural history, clinical features, pathological findings and diagnostic criteria, which suggests that modern CTE is a different syndrome. The methodology of the current studies does not allow determination of aetiology or risk factors. CONCLUSIONS: The clinicopathological differences between the 'classic' CTE syndrome and the 'modern' syndrome suggest that the new syndrome needs a different nomenclature. Further research is required to clearly define the clinical phenotype of the modern CTE syndrome and establish the underlying aetiology. Future research needs to address these issues through large-scale, prospective clinicopathological studies.

What is the evidence for chronic concussion-related changes in retired athletes: behavioural, pathological and clinical outcomes?

Br J Sports Med 2013; 47 (5): 327-30 paulmccr@bigpond.net.au

OBJECTIVE: The purpose of this paper was to review the current state of evidence for chronic traumatic encephalopathy (CTE) in retired athletes and to consider the potential differential diagnoses that require consideration when retired athletes present with cognitive and psychiatric problems. DATA SOURCES: MEDLINE, CINAHL, EMBASE, Mosby's Index, PsycEXTRA, PsycINFO and Scopus. Key words included CTE, dementia pugilistica, punch drunk syndrome, traumatic encephalopathy, CTE, repetitive head injury, sports concussion, multiple concussions, chronic concussions, subconcussive blow and sports-related traumatic brain injury. RESULTS: At present, there are no published epidemiological, cross-sectional or prospective studies relating to modern CTE. Owing to the nature of the published studies, being case reports or pathological case series, it is not possible to determine the causality or risk factors with any certainty. As such, the speculation that repeated concussion or subconcussive impacts cause CTE remains unproven. The extent to which age-related changes, psychiatric or mental health illness, alcohol/drug use or coexisting dementing illnesses contribute to this process is largely unaccounted for in the published literature. CONCLUSIONS: At present, the interpretation of causation in the modern CTE case studies should proceed cautiously. The causal assumptions require further prospective or longitudinal studies on the topic.

Induction of a transmissible tau pathology by traumatic brain injury.

Brain 2018; 141 (9): 2685-2699

Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naive mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans.

Is Huntington's disease a tauopathy?

Brain 2016; 139 (Pt 4): 1014-25 emmanuel@planel.org

Tauopathies are a subclass of neurodegenerative diseases typified by the deposition of abnormal microtubule-associated tau protein within the cerebral tissue. Alzheimer's disease, progressive supranuclear palsy, chronic traumatic encephalopathy and some fronto-temporal dementias are examples of the extended family of tauopathies. In the last decades, intermittent reports of cerebral tau pathology in individuals afflicted with Huntington's disease-an autosomal dominant neurodegenerative disorder that manifests by severe motor, cognitive and psychiatric problems in adulthood-have also begun to surface. These observations remained anecdotal until recently when a series of publications brought forward compelling evidence that this monogenic disorder may, too, be a tauopathy. Collectively, these studies reported that: (i) patients with Huntington's disease present aggregated tau inclusions within various structures of the brain; (ii) tau haplotype influences the cognitive function of Huntington's disease patients; and (iii) that the genetic product of the disease, the mutant huntingtin protein, could alter tau splicing, phosphorylation, oligomerization and subcellular localization. Here, we review the past and current evidence in favour of the postulate that Huntington's disease is a new member of the family of tauopathies.

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.

Brain Behav Immun 2017; 66 (ä): 31-44 marksundman@email.arizona.edu.;

As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury?

Brain Behav Immun 2017; 60 (ä): 369-382 lyndsey.collins-praino@adelaide.edu.au.;

A history of traumatic brain injury (TBI) is linked to an increased risk for the later development of dementia. This encompasses a variety of neurodegenerative diseases including Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE), with AD linked to history of moderate-severe TBI and CTE to a history of repeated concussion. Of note, both AD and CTE are characterized by the abnormal accumulation of hyperphosphorylated tau aggregates, which are thought to play an important role in the development of neurodegeneration. Hyperphosphorylation of tau leads to destabilization of microtubules, interrupting axonal transport, whilst tau aggregates are associated with synaptic dysfunction. The exact mechanisms via which TBI may promote the later tauopathy and its role in the later development of dementia are yet to be fully determined. Following TBI, it is proposed that axonal injury may provide the initial perturbation of tau, by promoting its dissociation from microtubules, facilitating its phosphorylation and aggregation. Altered tau dynamics may then be exacerbated by the chronic persistent inflammatory response that has been shown to persist for decades following the initial impact. Importantly, immune activation has been shown to play a role in accelerating disease progression in other tauopathies, with pro-inflammatory cytokines, like IL-1beta, shown to activate kinases that promote tau hyperphosphorylation. Thus, targeting the inflammatory response in the sub-acute phase following TBI may represent a promising target to halt the alterations in tau dynamics that may precede overt neurodegeneration and later development of dementia.

Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation.

Brain Behav Immun 2017; 64 (ä): 124-139 frances.corrigan@adelaide.edu.au.;

A history of repeated concussion has been linked to the later development of neurodegeneration, which is associated with the accumulation of hyperphosphorylated tau and the development of behavioral deficits. However, the role that exogenous factors, such as immune activation, may play in the development of neurodegeneration following repeated mild traumatic brain injury (rmTBI) has not yet been explored. To investigate, male Sprague-Dawley rats were administered three mTBIs 5days apart using the diffuse impact-acceleration model to generate approximately 100G. Sham animals underwent surgery only. At 1 or 5days following the last injury rats were given the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline. TLR4 activation had differential effects following rmTBI depending on the timing of activation. When given at 1day post-injury, LPS acutely activated microglia, but decreased production of pro-inflammatory cytokines like IL-6. This was associated with a reduction in neuronal injury, both acutely, with a restoration of levels of myelin basic protein (MBP), and chronically, preventing a loss of both MBP and PSD-95. Furthermore, these animals did not develop behavioral deficits with no changes in locomotion, anxiety, depressive-like behavior or cognition at 3months post-injury. Conversely, when LPS was given at 5days post-injury, it was associated acutely with an increase in pro-inflammatory cytokine production, with an exacerbation of neuronal damage and increased levels of aggregated and phosphorylated tau. At 3months post-injury, there was a slight exacerbation of functional deficits, particularly in cognition and depressive-like behavior. This highlights the complexity of the immune response following rmTBI and the need to understand how a history of rmTBI interacts with environmental factors to influence the potential to develop later neurodegeneration.

A magnetic resonance spectroscopy investigation in symptomatic former NFL players.

Brain Imaging Behav 2019; ä (ä): ä aplin@bwh.harvard.edu.

The long-term neurologic consequences of exposure to repetitive head impacts (RHI) are not well understood. This study used magnetic resonance spectroscopy (MRS) to examine later-life neurochemistry and its association with RHI and clinical function in former National Football League (NFL) players. The sample included 77 symptomatic former NFL players and 23 asymptomatic individuals without a head trauma history. Participants completed cognitive, behavior, and mood measures. N-acetyl aspartate, glutamate/glutamine, choline, myo-inositol, creatine, and glutathione were measured in the posterior (PCG) and anterior (ACG) cingulate gyrus, and parietal white matter (PWM). A cumulative head impact index (CHII) estimated RHI. In former NFL players, a higher CHII correlated with lower PWM creatine (r = -0.23, p = 0.02). Multivariate mixed-effect models examined neurochemical differences between the former NFL players and asymptomatic individuals without a history of head trauma. PWM N-acetyl aspartate was lower among the former NFL players (mean diff. = 1.02, p = 0.03). Between-group analyses are preliminary as groups were recruited based on symptomatic status. The ACG was the only region associated with clinical function, including positive correlations between glutamate (r = 0.32, p = 0.004), glutathione (r = 0.29, p = 0.02), and myo-inositol (r = 0.26, p = 0.01) with behavioral/mood symptoms. Other positive correlations between ACG neurochemistry and clinical function emerged (i.e., behavioral/mood symptoms, cognition), but the positive directionality was unexpected. All analyses controlled for age, body mass index, and education (for analyses examining clinical function). In this sample of symptomatic former NFL players, there was a direct effect between RHI and reduced cellular energy metabolism (i.e., lower creatine). MRS neurochemicals associated with neuroinflammation also correlated with behavioral/mood symptoms.

Limbic system structure volumes and associated neurocognitive functioning in former NFL players.

Brain Imaging Behav 2019; 13 (3): 725-734 ikoerte@bwh.harvard.edu.;

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 +/- 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 +/- 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.

Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma.

Brain Imaging Behav 2012; 6 (2): 244-54

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.

Chronic traumatic encephalopathy: what do parents of youth athletes know about it?

Brain Inj 2018; 32 (13-14): 1773-1779

INTRODUCTION/BACKGROUND: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused by repeated head impacts and associated with deficits in cognition. Despite research and media attention, there is little science-based information available for the public. Also unclear is what the public and particularly parents of youth athletes know about CTE. The U.S. Centers for Disease Control and Prevention (CDC) surveyed parents of young athletes to fill this gap. METHODS: CDC analysed 12 CTE-related questions that appeared in Porter Novelli Public Service's 2017 SummerStyles opinion survey. Analyses focused on 674 parents of children who play in a youth sports programme. RESULTS: Half of parents had at least one child who plays contact sports. About one-third of respondents reported being somewhat or very familiar with CTE. Most parents (81.7%) have not received educational materials on CTE from a school or sports programme. Healthcare providers were the preferred source of information about CTE (70%), followed by sports coaches (54%). DISCUSSION/CONCLUSION: This analysis identified information needs related to CTE among parents of young athletes. These findings can be used by health educators to tailor educational materials to meet information needs. Educational materials that emphasize potential prevention strategies and symptom onset may be beneficial.

Repeated mild traumatic brain injury produces neuroinflammation, anxiety-like behaviour and impaired spatial memory in mice.

Brain Inj 2018; 32 (1): 113-122

PRIMARY OBJECTIVE: Repeated traumatic brain injuries (rmTBI) are frequently associated with debilitating neuropsychiatric conditions such as cognitive impairment, mood disorders, and post-traumatic stress disorder. We tested the hypothesis that repeated mild traumatic brain injury impairs spatial memory and enhances anxiety-like behaviour. RESEARCH DESIGN: We used a between groups design using single (smTBI) or repeated (rmTBI) controlled cranial closed skull impacts to mice, compared to a control group. METHODS AND PROCEDURES: We assessed the effects of smTBI and rmTBI using measures of motor performance (Rotarod Test [RT]), anxiety-like behaviour (Elevated Plus Maze [EPM] and Open Field [OF] tests), and spatial memory (Morris Water Maze [MWM]) within 12 days of the final injury. In separate groups of mice, astrocytosis and microglial activation were assessed 24 hours after the final injury using GFAP and IBA-1 immunohistochemistry. MAIN OUTCOMES AND RESULTS: RmTBI impaired spatial memory in the MWM and increased anxiety-like behaviour in the EPM and OFT. In addition, rmTBI elevated GFAP and IBA-1 immunohistochemistry throughout the mouse brain. RmTBI produced astrocytosis and microglial activation, and elicited impaired spatial memory and anxiety-like behaviour. CONCLUSIONS: rmTBI produces acute cognitive and anxiety-like disturbances associated with inflammatory changes in brain regions involved in spatial memory and anxiety.

Suicide in professional American football players in the past 95 years.

Brain Inj 2016; 30 (13-14): 1718-1721

OBJECTIVE: To examine publicly-available information on all identified cases of suicide in active or former American professional football players between 1920 and the spring of 2015. DESIGN: Retrospective cohort study. SETTING: Professional American Football in the US. PARTICIPANTS: A cohort of 26 702 athletes who had died, retired or were currently playing in the NFL from nfl.com since 1920 was identified. MAIN OUTCOME MEASURES: Internet queries identifying 26 professional football players who completed suicide. Obituaries and news reports were reviewed. The primary outcome measures included mortality, demographic characteristics and life circumstances in professional American football players completing suicide. RESULTS: From 1920-2015, the median age of the 26 men who completed suicide was 39.5 years (range = 23-85). The median number of years after retirement was 6.5 (range = 0-63). Most of the deaths since 1920 have occurred in the past 15 years (58.7%) and a large percentage have occurred since 2009 (42.3%). Most of the men suffered from multiple life stressors prior to their deaths, such as retirement from sport, loss of steady income, divorce, failed business ventures, estrangement from family members and medical, psychiatric and/or substance abuse problems. CONCLUSIONS: A disproportionate number of completed suicides in current and former professional football players have occurred since 2009 (42.3%). It is well established in the literature that the causes of depression and suicidality are diverse, often multifactorial and treatable. Providing at-risk retired athletes with mental health treatment will likely reduce their suffering and improve their quality-of-life.

Chronic traumatic encephalopathy: contributions from the Boston University Center for the Study of Traumatic Encephalopathy.

Brain Inj 2015; 29 (2): 154-63

OBJECTIVE: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease associated with repetitive brain trauma (RBT). Initially described in boxers, CTE has now been found in other contact sport athletes with a history of RBT. In recent years, there has been tremendous media attention regarding CTE, primarily because of the deaths of high profile American football players who were found to have CTE upon neuropathological examination. However, the study of CTE remains in its infancy. This review focuses on research from the Centre for the Study of Traumatic Encephalopathy (CSTE) at Boston University. METHODS: This study reviews the formation of the CSTE, major CSTE publications and current ongoing research projects at the CSTE. RESULTS: The neuropathology of CTE has been well-described. Current research focuses on: methods of diagnosing the disease during life (including the development of biomarkers), examination of CTE risk factors (including genetic susceptibility and head impact exposure variables); description of the clinical presentation of CTE; development of research diagnostic criteria for Traumatic Encephalopathy Syndrome; and assessment of mechanism and pathogenesis. CONCLUSIONS: Current research at the BU CSTE is aimed at increasing understanding of the long-term consequences of repetitive head impacts and attempting to begin to answer several of the unanswered questions regarding CTE.

Chronic traumatic encephalopathy in professional sports: retrospective and prospective views.

Brain Inj 2015; 29 (2): 164-70

PRIMARY OBJECTIVE: The purposes of this paper are to review: (1) the history of chronic traumatic encephalopathy (CTE) in sports, (2) the similarities and differences between historic and current definitions of CTE, (3) recent epidemiology and cohort studies of CTE and (4) controversies regarding the current CTE positions. RESEARCH DESIGN: Not applicable. METHODS AND PROCEDURES: Selective review of published articles relevant to CTE. MAIN OUTCOME AND RESULTS: The current definitions of CTE have evolved from its original definition and now rely heavily on the post-mortem detection of hyperphosphorylated tau for diagnosis. As of 2013, there is a blended cohort of 110 professional athletes diagnosed with CTE. It is being assumed that concussions and/or sub-concussive impacts in contact sports are the sole cause of CTE. CONCLUSIONS: There are multiple causes of abnormal tau protein deposition in the human brain and the pathogenesis of CTE may not be related solely to concussion and/or sub-concussive injury. In all likelihood, the causes of CTE are a multivariate, as opposed to a univariate, phenomenon.

Exposure to sub-concussive head injury in boxing and other sports.

Brain Inj 2015; 29 (2): 171-4

BACKGROUND: Current characterizations of chronic traumatic brain injury (CTBI) in boxing, football and other sports are reviewed in the context of the history of research on sub-concussive brain trauma in athletes. METHODS: The utility of exposure models for understanding CTBI in boxers is examined and concerns regarding the paucity of findings supportive of an exposure model for CTBI in football players are discussed. RESULTS AND CONCLUSIONS: Recommendations for development of exposure models for sport-specific phenotypic characterizations of CTBI are presented.

The current role of decompressive craniectomy in the management of neurological emergencies.

Brain Inj 2013; 27 (9): 979-91 stephen.honeybul@health.wa.gov.au

Decompressive craniectomy has been used as a lifesaving procedure for many neurological emergencies, including traumatic brain injury, ischaemic stroke, subarachnoid haemorrhage, cerebrovenous thrombosis, severe intracranial infection, inflammatory demyelination and encephalopathy. The evidence to support using decompressive craniectomy in these situations is, however, limited. Decompressive craniectomy has only been evaluated by randomized controlled trials in traumatic brain injury and ischaemic stroke and, even so, its benefits and risks in these situations remain elusive. If one considers a modified Rankin Scale of 4 or 5 or dependency in daily activity as an unfavourable outcome, decompressive craniectomy is associated with an increased risk of survivors with unfavourable outcome (relative risk [RR] = 2.9, 95% confidence interval [CI] = 1.5-5.8, p = 0.002, I(2 )= 0%; number needed to operate to increase an unfavourable outcome = 3.5, 95% CI = 2.4-7.4), but not the number of survivors with a favourable outcome (RR = 1.5, 95% CI = 0.9-2.6, p = 0.13, I(2 )= 0%).

Acquired heterotopic ossification in the settings of cerebral anoxia and alternative therapy: two cases.

Brain Inj 2003; 17 (6): 535-44 karen_chua@ttsh.com.sg

Acquired Heterotopic Ossification (HO) has been well described in the literature as a recognized complication following spinal cord injury, traumatic brain injury and joint arthroplasty. Commonly, large proximal limb joints are affected. The underlying mechanisms for ectopic bone formation remain poorly elucidated. Post-stroke hemiplegia as a cause of neurogenic HO is rare, and no published reports of HO occurring after anoxic brain injury in adults have been documented. This study reports two unusual cases of acquired HO: (1) Polyarticular HO involving the ankle joint in a 24-year-old Chinese female who suffered severe anoxic encephalopathy following near drowning which resulted in persistent vegetative state; and (2) Elbow HO in chronic post-stroke hemiplegia occurring as a complication of alternative therapy following repeated forceful manipulation by a traditional practitioner in a 46 year-old male.

Panic disorder in a patient with traumatic brain injury: a case report and discussion.

Brain Inj 1999; 13 (9): 705-14 mscheutzow@msn.com

Individuals that may be especially susceptible to panic attacks in the rehabilitation setting are patients who have suffered traumatic brain injuries, post-concussion syndrome, lesions, or encephalopathy. An individual is described who suffered a traumatic brain injury and was determined to have suffered a panic attack during his rehabilitation stay. The manifestations of panic attacks are described, using the case report as an example. The psychological aetiology of panic disorders is also reviewed, and treatment options using four major classes of neuropharmacologic agents: benzodiazepines, tricyclic antidepressants, monoamide oxidase inhibitors, and serotonin reuptake inhibitors, are discussed. Given the increasing incidence and survival of patients with traumatic brain injuries, the complications of panic attacks and disorders will become more important; they are a serious condition that can affect an individual's lifestyle, employment, and relationships, and increase the risk of suicide. Rehabilitation specialists should be aware of the manifestations and management of panic attacks and come to appreciate that recognition of this treatable condition is important during all stages of rehabilitation.

Longitudinal changes in linguistic complexity among professional football players.

Brain Lang 2017; 169 (ä): 57-63 visar@asu.edu.;

Reductions in spoken language complexity have been associated with the onset of various neurological disorders. The objective of this study is to analyze whether similar trends are found in professional football players who are at risk for chronic traumatic encephalopathy. We compare changes in linguistic complexity (as indexed by the type-to-token ratio and lexical density) measured from the interview transcripts of players in the National Football League (NFL) to those measured from interview transcripts of coaches and/or front-office NFL executives who have never played professional football. A multilevel mixed model analysis reveals that exposure to the high-impact sport (vs no exposure) was associated with an overall decline in language complexity scores over time. This trend persists even after controlling for age as a potential confound. The results set the stage for a prospective study to test the hypothesis that language complexity decline is a harbinger of chronic traumatic encephalopathy.

[Late-onset Neurodegenerative Diseases Following Traumatic Brain Injury: Chronic Traumatic Encephalopathy (CTE) and Alzheimer's Disease Secondary to TBI (AD-TBI)].

Brain Nerve 2016; 68 (7): 849-57

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease, which is associated with mild repetitive traumatic brain injury (TBI). This long-term and progressive symptom due to TBI was initially called punch-drunk syndrome or dementia pugilistica, since it was believed to be associated with boxing. However, serial neuropathological studies of mild repetitive TBI in the last decade have revealed that CTE occurs not only in boxers but also in a wider population including American football players, wrestlers, and military personnel. CTE has gained large public interest owing to dramatic cases involving retired professional athletes wherein serious behavioral problems and tragic incidents were reported. Unlike mild repetitive TBI, a single episode of severe TBI can cause another type of late-onset neuropsychiatric disease including Alzheimer's disease (AD). Several epidemiological studies have shown that a single episode of severe TBI is one of the major risk factors of AD. Pathologically, both AD and CTE are characterized by abnormal accumulations of hyperphosphorylated tau proteins. However, recent neuropathological studies revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes, and accumulation of other misfolded proteins such as TDP-43. Currently, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can be made only via postmortem neuropathological examination. Development in neuroimaging techniques such as tau and amyloid positron emission tomography imaging might not only enable early diagnosis of CTE, but also contribute to the interventions for prevention of late-onset neurodegenerative diseases following TBI. Further studies are necessary to elucidate the mechanisms of neurodegeneration in the living brain of patients with TBI.

[Study of cumulative head injury in high shock avoider rat (THA rat)].

Brain Nerve 2009; 61 (3): 301-8

PURPOSE: Small but repeated head trauma, as represented by boxing-related punch-drunk syndrome and dementia pugilistica, occasionally cause dyskinesia and marked brain dysfunction following long-term post-traumatic follow-up, despite the absence of intracranial lesions, such as cerebral contusion and intracranial hemorrhage. We defined this condition as "cumulative head injury." To clarify its mechanism, we conducted an experiment involving appliciation of continuous head trauma of Tokai High Avoider (THA) rats, and examined subsequent marked function/histopathological changes. METHODS: THA rats were divided into 3 categories based on the frequency of impact exposure: a control group (Group A), a group exposed to 1 impact set (Group B), and a group exposed to 3 impact sets (Group C). In each group, histopathological, spontaneous motility, and learning tests were conducted. RESULTS: Histopathologically, no marked tissue destruction was observed in Group B or C. In Group C, the number of GFAP-positive cells were increased in acute-phase specimens of the hippocampus, cerebral cortex, and basilar cortex. With respect to chronic-phase histological changes, the numbers of GFAP-positive cells were increased in the hippocampus and the basilar cortex in Group C; however, these changes were less marked than in the acute stage. A marked function test identified emotional suppression in the acute stage and bimodal learning reduction in the acute to chronic stages in Group C. CONCLUSION: The results of this experiment revealed that the repetition of low-level trauma which did not lead to brain injury as revealed on pathological examination, induced emotional suppression and the bimodal reduction in learning results; further, this disorder exacerbated with an increase in impact frequency. The influence on marked brain function could be verified using a specific experimental system of THA rats. This model may be useful for evaluating the cumulative effects of repeated head trauma.

Association between contact sports participation and chronic traumatic encephalopathy: a retrospective cohort study.

Brain Pathol 2019; ä (ä): ä

Chronic traumatic encephalopathy is a debilitating neurodegenerative disorder associated with repetitive traumatic brain injuries often sustained through prior contact sport participation. The frequency of this disorder in a diverse population, including amateur athletes, is unknown. Primary historical obituary and yearbook records were queried for 2,566 autopsy cases in the Mayo Clinic Tissue Registry resulting in identification of 300 former athletes and 450 non-athletes. In these cases, neocortical tissue was screened for tau pathology with immunohistochemistry, including pathology consistent with chronic traumatic encephalopathy, blinded to exposure or demographic information. Using research infrastructure of the Rochester Epidemiology Project, a comprehensive and established medical records-linkage system of care providers in southern Minnesota and Western Wisconsin, medical diagnostic billing codes pertaining to head trauma, dementia, movement disorders, substance abuse disorders, and psychiatric disorders were recorded for cases and controls in a blinded manner. A total of 42 individuals had pathology consistent with, or features of, chronic traumatic encephalopathy. It was more frequent in athletes compared to non-athletes (27 cases versus 15 cases) and was largely observed in men (except for one woman). For contact sports, American football had the highest frequency of chronic traumatic encephalopathy pathology (15% of cases) and an odds ratio of 2.62 (P-value = 0.005). Cases with chronic traumatic encephalopathy pathology had higher frequencies of antemortem clinical features of dementia, psychosis, movement disorders, and alcohol abuse compared to cases without chronic traumatic encephalopathy pathology. Understanding the frequency of chronic traumatic encephalopathy pathology in a large autopsy cohort with diverse exposure backgrounds provides a baseline for future prospective studies assessing the epidemiology and public health impact of chronic traumatic encephalopathy and sports-related repetitive head trauma. This article is protected by copyright. All rights reserved.

Clinical features of repetitive traumatic brain injury and chronic traumatic encephalopathy.

Brain Pathol 2015; 25 (3): 304-17

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct pattern of hyperphosphorylated tau (p-tau). Thought to be caused by repetitive concussive and subconcussive injuries, CTE is considered largely preventable. The majority of neuropathologically confirmed cases have occurred in professional contact sport athletes (eg, boxing, football). A recent post-mortem case series has magnified concerns for the public's health following its identification in six high school level athletes. CTE is diagnosed with certainty only following a post-mortem autopsy. Efforts to define the etiology and clinical progression during life are ongoing. The goal of this article is to characterize the clinical concepts associated with short- and long-term effects of repetitive traumatic brain injury, with a special emphasis on new clinical diagnostic criteria for CTE. Utilizing these new diagnostic criteria, two cases of neuropathologically confirmed CTE, one in a professional football player and one in a professional boxer, are reported. Differences in cerebellar pathology in CTE confirmed cases in boxing and football are discussed.

The Study and Consequences of Repetitive Traumatic Brain Injury. Introduction.

Brain Pathol 2015; 25 (3): 287-8

Type and occurrence of serious complications in patients after mild traumatic brain injury.

Bratisl Lek Listy 2016; 117 (1): 22-5

Traumatic brain injury (TBI) remains a major public health and socio-economic problem, and 70-90% of all TBIs are classified as mild. Mild TBIs and concussions are mostly considered to be non-serious conditions with symptoms subsiding within a few days or weeks. However in 10-15% of patients, the symptoms persist one year after concussion and mostly include headache, fatigue, irritability, and cognitive problems (e.g. memory, concentration). These persisting symptoms negatively influence patient daily activities as postconcussion syndrome (PCS). Second-impact syndrome (SIS) is a very rare but usually fatal condition and occurs when repeated brain injuries lead to a catastrophic diffuse brain swelling. There is no scientific evidence on the incidence and risk of SIS. Chronic traumatic encephalopathy (CTE) is a progressive degenerative disease of the brain found in patients with a history of repetitive brain trauma. CTE presents with behavioural, cognitive, and motor symptoms. The literature to date lacks prospective epidemiological studies of the incidence of CTE. In recent medical literature, there is a description of 110 athletes with postmortem diagnosis of CTE (Tab. 1, Ref. 37).

Concussion knowledge among medical students and neurology/neurosurgery residents.

Can J Neurol Sci 2012; 39 (3): 361-8

BACKGROUND AND OBJECTIVES: Concussion is a prevalent brain injury in the community. While primary prevention strategies need to be enhanced, it is also important to diagnose and treat concussions expertly and expeditiously to prevent serious complications that may be life-threatening or long lasting. Therefore, physicians should be knowledgeable about the diagnosis and management of concussions. The present study assesses Ontario medical students' and residents' knowledge of concussion management. METHODS: A survey to assess the knowledge and awareness of the diagnosis and treatment of concussions was developed and administered to graduating medical students (n= 222) and neurology and neurosurgery residents (n = 80) at the University of Toronto. RESULTS: Residents answered correctly significantly more of the questions regarding the diagnosis and management of concussions than the medical students (mean = 5.8 vs 4.1, t= 4.48, p<0.01). Gender, participation in sports, and personal concussion history were not predictive of the number of questions answered correctly. Several knowledge gaps were identified in the sample population as a whole. Approximately half of the medical students and residents did not recognize chronic traumatic encephalopathy (n = 36) or the second impact syndrome (n = 44) as possible consequences of repetitive concussions. Twenty-four percent of the medical students (n = 18) did not think that "every concussed individual should see a physician" as part of management. CONCLUSIONS: A significant number of medical students and residents have incomplete knowledge about concussion diagnosis and management. This should be addressed by targeting this population during undergraduate medical education.

PLEDs: clinical correlates.

Can J Neurol Sci 2007; 34 (4): 443-50

OBJECTIVE: We reviewed our experience in 96 consecutive patients exhibiting periodic lateralized epileptiform discharges (PLEDs) on EEG. METHODS: EEG reports from January 1, 1999 to September 30, 2006 were screened for the term 'PLEDs' and its variants. A retrospective chart review, including examination of neuroimaging and other investigations, was conducted on each patient identified. RESULTS: Acute stroke, tumor and central nervous system infection were the most common etiologies, accounting for 26%, 12% and 12% of cases respectively. Acute hemorrhage and traumatic brain injury combined accounted for another 12%. Previously unreported etiologies included posterior reversible encephalopathy syndrome (PRES), familial hemiplegic migraine and cerebral amyloidosis. There were 9 cases of chronic PLEDs attributable to underlying cortical dysplasia or severe remote cerebral injury, all with an accompanying partial seizure disorder. A prominent role for alcohol withdrawal was noted, and in 6 cases was the sole etiological factor. Fever was present as a potential contributing factor in 40% of cases, and significant metabolic abnormalities in 35%. Seizure activity occurred in 85% of patients overall, but in 100% of patients with PLEDs Plus and BiPLEDs Plus. The overall mortality rate was 27%. Mortality among patients with BiPLEDs however was almost twice that, at 52%. CONCLUSIONS: This case series demonstrates the wide variety of potential PLED etiologies. It also emphasizes that despite advances in neurocritical care, the morbidity and mortality associated with PLEDs has changed little since their recognition four decades ago.

The nucleus basalis of Meynert.

Can J Neurol Sci 1986; 13 (1): 8-14

The nucleus basalis of Meynert has been studied extensively in the recent literature. Interest in this nucleus has resulted from the discovery that it is a major source of cortical cholinergic input and that there is neuronal loss in the nucleus basalis in some dementing illnesses. Consistent and severe involvement of the nucleus basalis of Meynert has been found in Alzheimer's disease and in the dementia accompanying Parkinson's disease. Occasional involvement is present in other dementing illnesses, such as progressive supranuclear palsy, Parkinsonism-Dementia complex of Guam, dementia pugilistica, Pick's disease, Korsakoff's syndrome, Down's Syndrome and Creutzfeldt-Jacob disease. Huntington's disease spares this nucleus. However, the role of the nucleus in cognitive function is as yet undetermined. Even its alteration with normal aging remains controversial. This review details the pathological studies of this region to date, with particular emphasis on the dementias. Its role in the dementias of Alzheimer's disease and Parkinson's disease is specifically addressed.

Dissemination of brain inflammation in traumatic brain injury.

Cell Mol Immunol 2019; 16 (6): 523-530 fshi66@gmail.com.;

Traumatic brain injury (TBI) is recognized as a global health problem due to its increasing occurrence, challenging treatment, and persistent impacts on brain pathophysiology. Neural cell death in patients with TBI swiftly causes inflammation in the injured brain areas, which is recognized as focal brain inflammation. Focal brain inflammation causes secondary brain injury by exacerbating brain edema and neuronal death, while also exerting divergent beneficial effects, such as sealing the damaged limitans and removing cellular debris. Recent evidence from patients with TBI and studies on animal models suggest that brain inflammation after TBI is not only restricted to the focal lesion but also disseminates to remote areas of the brain. The dissemination of inflammation has been detected within days after the primary injury and persists chronically. This state of inflammation may be related to remote complications of TBI in patients, such as hyperthermia and hypopituitarism, and may lead to progressive neurodegeneration, such as chronic traumatic encephalopathy. Future studies should focus on understanding the mechanisms that govern the initiation and propagation of brain inflammation after TBI and its impacts on post-trauma brain pathology.

The anatomy of concussion and chronic traumatic encephalopathy: A comprehensive review.

Clin Anat 2019; 32 (3): 310-318

Concussion is defined as a complex pathophysiological process that affects the brain as a result of traumatic biomechanical forces. Repeated unrecovered concussions can result in chronic brain injury syndrome which is referred to in the literature today as chronic traumatic encephalopathy." There is an exponential increase in public and political interest in this condition in the recent times resulting in a significant investment in research to improve the current understanding of the disease, ways to decrease its incidence and determine its prognosis. Broadly the research involves three main disciplines of medicine including neuropathology, neuroradiology and biological markers. Although progress has been made, to date there is no definite pathological, radiological or neurobiological marker which has shown consistent promise to make the diagnosis and prognosticate the disease. Possible reasons are multiple such as inconsistencies in the methods studies have used, different time periods in which the tests were conducted, the small numbers of subjects included in the studies, and inconsistencies in the definitions of concussion or mild traumatic brain injury. Herein, we present a comprehensive review of the current literature on this topic. Positron emission tomography scans with radioactive ligands such as T807 as an imaging biomarker, and neurofilament light and ubiquitin C-terminal hydrolase as serum biomarkers have shown some promise lately in diagnosing concussion and chronic traumatic encephalopathy and also determining their prognosis. Clin. Anat. 32:310-318, 2019. (c) 2018 Wiley Periodicals, Inc.

Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock.

Clin Chem Lab Med 2005; 43 (3): 259-68 thomas.mussack@med.uni-muenchen.de

Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with < or = 0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentrations in patients with hyperdynamic septic shock. For the first time, a similar extent of S-100B increase in serum of septic patients at the time of diagnosis was shown as reported for cardiac arrest or severe traumatic brain injury.

Traumatic Brain Injury, Chronic Traumatic Encephalopathy, and Alzheimer Disease.

Clin Geriatr Med 2018; 34 (4): 617-635 roula.aldahhak@health.slu.edu.;

Traumatic brain injury (TBI) is a major health and economic burden. With increasing aging population, this issue is expected to continue to rise. Neurodegenerative disorders are more common with aging population in general regardless of history of TBI. Recent evidence continues to support a relation between a TBI and neurocognitive decline later in life (such as in athletes and military). This article summarizes the pathologic and clinical effects of TBI (regardless of severity) on the later development of dementia in individuals 65 years or older.

Other neurologic diseases with dementia as a sequela.

Clin Geriatr Med 1988; 4 (4): 799-814

Less-common causes of dementia are briefly discussed. Disorders covered include Pick's disease, primary progressive aphasia, progressive supranuclear palsy, Huntington's disease, olivopontocerebellar atrophies, closed head injury, dementia pugilistica, and Creutzfeldt-Jakob disease. Pseudodementia is also discussed. These disorders are compared and contrasted with the more common etiologies of dementia that are reviewed in other articles in the issue. Topics covered include treatment, differential diagnosis, clinical features, and pathogenesis.

MRI findings in headbangers.

Clin Imaging 1997; 21 (6): 411-3

Magnetic resonance imaging (MRI) findings in a mentally retarded adult female who exhibits headbanging behavior are presented. Radiographic changes include enlargement of the diploic space in the parietal and occipital bones, and gray matter loss adjacent to the bony changes. This pattern of injury is compared with skull changes previously reported in headbangers, and neuronal injury seen in boxers (dementia pugilistica) and Minimata disease.

Neuroimaging in the Diagnosis of Chronic Traumatic Encephalopathy: A Systematic Review.

Clin J Sport Med 2017; ä (ä): ä

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repeated subconcussive and concussive head injury. Clinical features include cognitive, behavioral, mood, and motor impairments. Definitive diagnosis is only possible at postmortem. Here, the utility of neuroimaging in the diagnosis of CTE is evaluated by systematically reviewing recent evidence for changes in neuroimaging biomarkers in suspected cases of CTE compared with controls. DATA SOURCES: Providing an update on a previous systematic review of articles published until December 2014, we searched for articles published between December 2014 and July 2016. We searched PubMed for studies assessing neuroimaging changes in symptomatic suspected cases of CTE with a history of repeated subconcussive or concussive head injury or participation in contact sports involving direct impact to the head. Exclusion criteria were case studies, review articles, and articles focusing on repetitive head trauma from military service, head banging, epilepsy, physical abuse, or animal models. MAIN RESULTS: Seven articles met the review criteria, almost all of which studied professional athletes. The range of modalities were categorized into structural magnetic resonance imaging (MRI), diffusion MRI, and radionuclide studies. Biomarkers which differed significantly between suspected CTE and controls were Evans index (P = 0.05), cavum septum pellucidum (CSP) rate (P < 0.0006), length (P < 0.03) and ratio of CSP length to septum length (P < 0.03), regional differences in axial diffusivity (P < 0.05) and free/intracellular water fractions (P < 0.005), single-photon emission computed tomography perfusion abnormalities (P < 0.01), positron emission tomography (PET) signals from tau-binding, glucose-binding, and GABA receptor-binding radionuclides (P < 0.0001, P < 0.005, and P < 0.005, respectively). Important limitations include low specificity in identification of suspected cases of CTE across studies, the need for postmortem validation, and a lack of generalizability to nonprofessional athletes. CONCLUSIONS: The most promising biomarker is tau-binding radionuclide PET signal because it is most specific to the underlying neuropathology and differentiated CTE from both controls and patients with Alzheimer disease (P < 0.0001). Multimodal imaging will improve specificity further. Future research should minimize variability in identification of suspected cases of CTE using published clinical criteria.

A 9-year controlled prospective neuropsychologic assessment of amateur boxing.

Clin J Sport Med 2003; 13 (6): 339-52 mdporter@webone.com.au

OBJECTIVE: To test the hypothesis that there is an association between amateur boxing and chronic traumatic encephalopathy using neuropsychologic assessments. DESIGN: A prospective, controlled, blinded, observational, neuropsychologic study. SETTING: Amateur boxing clubs in Dublin, Ireland, March 1992 to April 2001. PARTICIPANTS: Twenty randomly selected, actively competing, male amateur boxers and 20 age-matched, socio-economic controls. INTERVENTIONS: The boxers participated in amateur competition and sparring. MAIN OUTCOME MEASURES: Raw scores and changes in scores over time were recorded in the following neuropsychologic tests: Trail Making Tests A and B, Digit Symbol, Finger Tapping (dominant and nondominant hands), modified versions of the Finger Tapping Tests, Paired-Associate Learning, Digit Span, Rey-Osterrieth Complex Figure Tests A and B, and Serial Addition. Raw scores and changes in scores for the two groups were compared, and a regression analysis was performed to detect any association between these values and exposure to boxing. RESULTS: The boxers showed superior performance in the Trail Making Tests A and B at all time points and an inferior performance in both standard Finger Tapping Tests at all time points except baseline for the dominant hand. This inferior performance was not found in the modified versions of the tests. The controls showed significant deterioration in their performance in the Rey-Osterrieth Complex Figure Tests A and B. CONCLUSIONS: In this small controlled, prospective study of competitive amateur boxers, there was no evidence of neuropsychologic deterioration over 9 years. The amateur boxers demonstrated relative preservation and/or improvement of some neuropsychologic skills relative to the socioeconomic controls.

Controlled prospective neuropsychological assessment of active experienced amateur boxers.

Clin J Sport Med 1996; 6 (2): 90-6

OBJECTIVE: To use a practical battery of eight neuropsychological tests for the detection of an association between amateur boxing and chronic traumatic encephalopathy. DESIGN: A controlled prospective neuropsychological study over a 15-18-month period. SETTING: Dublin, Ireland. March 1992 to September 1993. PARTICIPANTS: Twenty experienced actively competing amateur boxers and 20 controls matched for age and socioeconomic status. INTERVENTIONS: Participation in competitive amateur boxing and training. MAIN OUTCOME MEASURES: Absolute scores, and changes in scores, in the neuropsychological tests. RESULTS: At the end of the study period, the boxers performed significantly better then the controls in both the Trail-Making Tests A and B (TMT-A, TMT-B), whereas the control group's scores for the Finger Tapping Tests (FTT) were significantly higher than those of the boxers. The boxer's scores for the dominant-hand FTT showed a significant deterioration, but there was no association between this change and boxing exposure. CONCLUSIONS: There was no evidence of neuropsychological impairment in the boxers as compared with socioeconomically, educationally and age-matched controls, and there was no association between boxing exposure and performances in any of the neuropsychological tests used. There is accumulating evidence that amateur boxing is not associated with chronic traumatic encephalopathy but longer term prospective studies are needed.

Frequency, magnitude, and distribution of head impacts in Pop Warner football: the cumulative burden.

Clin Neurol Neurosurg 2014; 118 (ä): 1-4 wong.ricky@gmail.com.;

BACKGROUND: A growing body of research suggests that subconcussive head impacts or repetitive mild Traumatic Brain Injury (mTBI) can have cumulative and deleterious effects. Several studies have investigated head impacts in football at the professional, collegiate, and high school levels, in an attempt to elucidate the biomechanics of head impacts among football players. Youth football players, generally from 7 to 14 years of age, constitute 70% of all football players, yet burden of, and susceptibility to, head injury in this population is not well known. METHODS: A novel impact sensor utilizing binary force switches (Shockbox((R))) was used to follow an entire Pop Warner football team consisting of twenty-two players for six games and five practices. The impact sensor was designed to record impacts with linear accelerations over 30g. In addition, video recording of games and practices were used to further characterize the head impacts by type of position (skilled versus unskilled), field location of impact (open field versus line of scrimmage), type of hit (tackling, tackled, or hold/push), and whether the impact was a head-to-head impact or not. RESULTS: We recorded a total of 480 head impacts. An average of 21.8 head impacts occurred per practice, while 61.8 occurred per game. Players had an average of 3.7 head impacts per game and 1.5 impacts per practice (p<0.001). The number of high magnitude head impacts (>80g) was 11. Two concussions were diagnosed over the course of the season. However, due to technical reasons the biomechanics of those hits resulting in concussions were not captured. CONCLUSION: Despite smaller players and slower play when compared to high school, collegiate or professional players, those involved in youth football sustain a moderate number of head impacts per season with several high magnitude impacts. Our results suggest that players involved in open-field, tackling plays that have head-to-head contact sustain impacts with the highest linear accelerations. Our data supports previously published data that suggests changes to the rules of play during practice can reduce the burden of hits.

Blood-brain barrier dysfunction in a boxer with chronic traumatic encephalopathy and schizophrenia.

Clin Neuropathol 2019; 38 (2): 51-58

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition characterized by the perivascular deposition of phosphorylated tau (p-tau) protein aggregates resulting from repetitive mild traumatic brain injury (rTBI). Advances in the field have revealed the significance of repetitive head trauma in the pathogenesis of CTE in contact sports as well as military veterans. In this study we provide evidence of blood-brain barrier (BBB) disruption in regions of intense perivascular p-tau deposition in a former professional boxer diagnosed with CTE and schizophrenia. P-tau deposition was associated with loss of the tight junction protein claudin-5 and enhanced extravasation of endogenous blood components such as fibrinogen and IgG. We also provide evidence of tight junction disruption in individuals with schizophrenia, with discontinuous claudin-5 immunoreactivity in the parietal cortex. This data highlights a common phenotype of a dysfunctional BBB in individuals with CTE and schizophrenia and may represent a novel correlate of neural dysfunction in individuals at risk of developing CTE and schizophrenia..

Dementia pugilistica: a severe tribute to a career.

Clin Neuropathol 2015; 34 (4): 193-8

A 59-year-old man, ex-professional boxer, met clinical criteria for probable Alzheimer's disease. The patient agreed to be included in a clinico-pathological study with donation to the brain bank, and he died at 71. The brain was grossly atrophic, with a prominent atrophy of the entorhinal cortex and hippocampus, and with pallor of the substantia nigra. Immunohistochemistry with anti-tau A4 revealed abundant and diffuse deposits in the neo-cortex, whereas amyloid angiopathy was absent. Coupled anti-tau AT8 immunohistochemistry and Congo red staining showed no neuritic plaques. tau-AT8-positive glial tangles and neurofibrillary tangles involved preferentially the superficial cortical layers, and were irregularly concentrated in the depth of cortical sulci and near vessels. Neurofibrillary degeneration was marked in amygdala, hippocampus, substantia nigra, and locus ceruleus. Enlarged and/or distorted axons were numerous in hippocampus and mid-brain. TDP 43-positive neuronal inclusions were numerous in amygdala and hippocampus. There was no synucleinopathy. These observations are in accordance with the previously reported data on chronic traumatic encephalopathy. The discussion is focused on professional boxing as it becomes evident that repetitive trauma on the brain provokes the deposition of abnormal proteins involved in neurodegeneration.

Dementia in a retired world boxing champion: case report and literature review.

Clin Neuropathol 2009; 28 (4): 275-80

OBJECTIVE: Dementia in retired boxers, also referred to as "dementia pugilistica" (DP), is usually attributed to repeated concussive and subconcussive blows to the head. We report the case of a former world boxing champion whose progressive cognitive decline could be ascribed to DP, cerebral infarcts and Wernicke-Korsakoff syndrome. This case demonstrates that dementia in retired boxers may be caused and/or exacerbated by etiologic factors other than DP. MATERIALS AND METHODS: We correlated the clinical features with the histochemical and immunohistochemical changes observed on autopsy brain material from a retired boxer, reviewed the literature on boxing-related dementia, and compared our findings with previous reports on DP. RESULTS: Neuropathologic examination revealed numerous neurofibrillary tangles (NFTs), rare neuritic plaques (NPs), multiple cerebral infarcts, fenestrated septum pellucidum, atrophic and gliotic mamillary bodies, and pale substantia nigra and locus ceruleus. CONCLUSIONS: Our neuropathologic data confirmed the notion that dementia in retired boxers could be due to several factors such as DP, multiple cerebral infarcts and Wernicke-Korsakoff syndrome. Our findings illustrate the need to comprehensively examine former boxers with dementia as well as carefully evaluate the neuropathologic changes that may cause or contribute to the patient's cognitive and behavioral symptoms. Such an approach is crucial in order to provide prompt and more definitive therapies.

The pathology of the human locus ceruleus.

Clin Neuropathol 1983; 2 (1): 1-7

The number of nerve cells of locus ceruleus and their nucleolar volume were determined in 63 normally aged individuals and in 41 cases with neurologic diseases. Pathologic alterations, such as a severe nerve cell loss and atrophy with or without extensive neurofibrillary degeneration or Lewy body formation, were generally seen in the nucleus locus ceruleus in Alzheimer's disease, Down's syndrome, dementia pugilistica, Parkinson's disease, and progressive supranuclear palsy, but such changes were only slight in normally aged individuals and minimal in motor neuron disease. Protein synthetic capacity was substantially reduced in the remaining nerve cells of the locus ceruleus, in Alzheimer's disease, Down's syndrome, and dementia pugilistica, but was unaltered in normally aged individuals (even in extreme old age), in motor neuron disease, and in the few remaining cells in Parkinson's disease and progressive supranuclear palsy. It is suggested that the pathologic alterations in the locus ceruleus found in these diseases, in conjunction with changes in the hypothalamus, lead to impairment of mental ability with eventual dementia through disturbance of the function of those pathways regulating homeostasis within the central nervous system.

Historical perspectives on evolving operational definitions of concussive brain injury: From railway spine to sport-related concussion.

Clin Neuropsychol 2019; ä (ä): 1-18

Objective: Concussion is a clinical syndrome of biomechanically induced alteration in brain function. The historical derivation of current operational definitions of uncomplicated concussive brain injury based on acute injury variables especially posttraumatic amnesia (PTA) vs. symptom presence (no PTA) are reviewed. Methods: Major milestones from 150 plus years of concussion research include (a) railway spine; (b) traumatic neurosis; (c) duration of loss of consciousness predicting severity of brain injury; (d) early neuropsychological studies; (e) sport related concussion; and (f) chronic traumatic encephalopathy. Results: After initial organic explanations proved untenable, 19th century conceptions of concussion were operationally defined from symptom presence, attributed primarily to psychogenic (emotional, motivational, and/or predispositional) causes. In the 1930s, duration of PTA was linked to brain injury severity via outcome studies. Concussion (as defined by PTA < 1 h) was later found to cause a transient lowering of neuropsychological test scores in memory and executive function. In the 1990s, organizational definitions of sport-related concussion began to include biomechanical events without PTA that produced symptoms. Such events have not been linked to neuropsychological impairment. Conclusions: Two differing operational definitions of concussion are in the current use, involving the presence vs. absence of PTA. These two groupings are not clinically similar, although they are currently being widely treated as such. Operational definitions of concussion should address both minimum and maximums for duration of PTA, initial Glasgow Coma Scale score, complications, and symptom presence.

Current issues in pediatric sports concussion.

Clin Neuropsychol 2011; 25 (6): 1042-57 pschatz@sju.edu

This article reviews current issues in the following areas of pediatric sports-related concussion: incidence of concussion, potential long-term effects, return to play, and the emergence of legislation regarding concussion education and management programs. Incidence of concussion is presented in context of emergency room visits, as well as under-reporting of concussions. The literature on history of concussion is reviewed, for high school, collegiate, and professional athletes, with respect to potential long-term effects of cerebral concussion. Specific discussions of effects include: decreased cognition and increased symptom reporting following multiple concussions, and recent diagnoses of chronic traumatic encephalopathy in non-professional and youth athletes. Recent legislative and advocacy efforts are reviewed, including mandated programs in specific states.

Neuropsychology of sports-related head injury: Dementia Pugilistica to Post Concussion Syndrome.

Clin Neuropsychol 1999; 13 (2): 193-209 d.erlanger@worldnet.att.net

This article reviews the existing literature in the following areas of sports neuropsychology: Dementia Pugilistica, concussion and Post Concussion Syndrome, Second Impact Syndrome, and the emerging role of the sports neuropsychologist regarding return to play decisions. Dementia Pugilistica is discussed as a condition that exists along a continuum: Although many boxers will develop mild neurocognitive deficits, it is not yet known what percent of these mild presentations will progress to diagnosable Dementia Pugilistica. Factors contributing to both increased and reduced risk are detailed. The role of neuropsychological assessment in research and clinical management is reviewed. Existing studies of concussion incurred during contact sports provide evidence of an important role for neuropsychology in assessment and management of mild head injuries. Issues in clinical assessment of concussion are reviewed. The importance of grading of concussions, monitoring of postconcussive symptom resolution, and the use of neuropsychological test results in return to play decisions is detailed. The Second Impact Syndrome is discussed with regard to return to play decisions. Recommendations are proposed for research and for clinical application of findings in sports neuropsychology.

Chronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation?

Cold Spring Harb Perspect Med 2018; 8 (2): ä

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. There is often a long latency period between an individual's exposure to repetitive brain trauma and the clinical symptoms of CTE. The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebral cortex to a widespread tauopathy that involves diffuse cortical and medial temporal lobe regions. We hypothesize that the spread of tau from focal perivascular lesions to a widespread tauopathy occurs as a result of intraneuronal and intrasynaptic prion-like protein templating, as well as tau secretion and propagation along glymphatic and cerebrospinal fluid pathways.

The Prion-Like Behavior of Assembled Tau in Transgenic Mice.

Cold Spring Harb Perspect Med 2017; 7 (10): ä

Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system. In chronic traumatic encephalopathy, tauopathy appears to spread from the neocortex to the brainstem. These findings implicate neuron-to-neuron propagation of tau aggregates. Isoform compositions and morphologies of tau filaments can differ between tauopathies, which is consistent with the existence of distinct tau strains. Here, we review recent findings that support prion-like mechanisms in the pathogenesis of tauopathies through the experimental use of transgenic mice.

Chronic Traumatic Encephalopathy.

Continuum (Minneap Minn) 2019; 25 (1): 187-207

PURPOSE OF REVIEW: This article provides a discussion on the current state of knowledge of chronic traumatic encephalopathy (CTE), with an emphasis on clinical features and emerging biomarkers of the condition. RECENT FINDINGS: The results of several large brain bank case series among subjects with a history of contact sports or repetitive head trauma have indicated that a high frequency of CTE may exist in this population. However, the true prevalence of CTE among individuals with a history of head trauma remains unknown, given that individuals who experienced cognitive, behavioral, and mood symptoms during life are more likely to have their brains donated for autopsy at death and epidemiologic studies of the condition are lacking. Neuropathologic consensus criteria have been published. Research-based clinical criteria have been proposed and are beginning to be applied, but the definitive diagnosis of CTE in a living patient remains impossible without effective biomarkers for the condition, which is an active area of study. SUMMARY: The field of CTE research is rapidly growing and parallels many of the advances seen for other neurodegenerative conditions, such as Alzheimer disease decades ago.

Chronic traumatic encephalopathy and other long-term sequelae.

Continuum (Minneap Minn) 2014; 20 (6 Sports Neurology): 1588-604

PURPOSE OF REVIEW: Growing public health concern exists over the incidence of chronic traumatic brain injury (TBI) in athletes participating in contact sports. Chronic TBI represents a spectrum of disorders associated with long-term consequences of single or repetitive TBI and includes chronic traumatic encephalopathy (CTE), chronic postconcussion syndrome, and chronic neurocognitive impairment. Neurologists should be familiar with the different types of chronic TBI and their diagnostic criteria. RECENT FINDINGS: CTE is the most severe chronic TBI and represents the neurologic consequences of repetitive mild TBI. It is particularly noted among boxers and football players. CTE presents with behavioral, cognitive, and motor symptoms, and can only be definitively diagnosed postmortem. Chronic postconcussion syndrome is defined as postconcussion symptoms that last longer than 1 year and do not appear to resolve; it may develop after a single concussive event. Chronic neurocognitive impairment is an all-encompassing clinical term denoting long-term neurologic sequelae secondary to sports-related trauma and can present either within the postconcussion syndrome or years after a symptom-free interval. SUMMARY: This article discusses the diagnostic evaluation of chronic TBI, including clinical history, neurologic examination, neuropsychological testing, neuroimaging, and laboratory testing, as well as the distinctions between CTE, chronic postconcussion syndrome, and chronic neurocognitive impairment. Neurologic impairment among athletes exposed to repetitive brain injury appears to be a real phenomenon. Because CTE has no established treatment, prevention is of paramount importance for athletes participating in contact sports.

Induced hypothermia in critical care medicine: a review.

Crit Care Med 2003; 31 (7): 2041-51 s.bernhard@southernhealth.org.au

BACKGROUND: Clinical trials of induced hypothermia have suggested that this treatment may be beneficial in selected patients with neurologic injury. OBJECTIVES: To review the topic of induced hypothermia as a treatment of patients with neurologic and other disorders. DESIGN: Review article. INTERVENTIONS: None. MAIN RESULTS: Improved outcome was demonstrated in two prospective, randomized, controlled trials in which induced hypothermia (33 degrees C for 12-24 hrs) was used in patients with anoxic brain injury following resuscitation from prehospital cardiac arrest. In addition, prospective, randomized, controlled trials have been conducted in patients with severe head injury, with variable results. There also have been preliminary clinical studies of induced hypothermia in patients with severe stroke, newborn hypoxic-ischemic encephalopathy, neurologic infection, and hepatic encephalopathy, with promising results. Finally, animal models have suggested that hypothermia that is induced rapidly following traumatic cardiac arrest provides significant neurologic protection and improved survival. CONCLUSIONS: Induced hypothermia has a role in selected patients in the intensive care unit. Critical care physicians should be familiar with the physiologic effects, current indications, techniques, and complications of induced hyperthermia.

Imaging Chronic Traumatic Encephalopathy: A Biomedical Engineering Perspective.

Crit Rev Biomed Eng 2016; 44 (6): 473-492

A disease initially associated with boxers ninety years ago, chronic traumatic encephalopathy (CTE) is now recognized as a significant risk to boxers, American football players, ice hockey players, military personnel or anyone to whom recurrent head injuries are a distinct possibility. Diagnosis is currently confirmed at autopsy, although CTE's presumed sufferers have symptoms of depression, suicidal thoughts, mood and personality changes, and loss of memory. CTE sufferers also complain of losing cognitive ability, dysfunction in everyday activities, inability to keep regular employment, violent tendencies and marital strife. Dementia may develop over the long term. Unfortunately, there is no clear consensus in regards to pathology, with both number and severity of head injuries being linked to disease progression. Despite the slow advancement of this disease, there are no clinical methods to diagnose or monitor prognosis in presumed patients, limiting clinicians' efforts to symptom management. The lack of diagnostic tools fuels the need for biomedical engineers to develop techniques for in vivo detection of CTE. This review examines efforts made with various magnetic resonance and nuclear imaging techniques, with a view towards improving the sensitivity and specificity of diagnostic imaging for CTE.

Chronic Traumatic Encephalopathy and Movement Disorders: Update.

Curr Neurol Neurosci Rep 2016; 16 (5): 46 Carmela.tartaglia@uhn.ca.;

Association of repetitive brain trauma with progressive neurological deterioration has been described since the 1920s. Punch drunk syndrome and dementia pugilistica (DP) were introduced first to explain symptoms in boxers, and more recently, chronic traumatic encephalopathy (CTE) has been used to describe a neurodegenerative disease in athletes and military personal with a history of multiple concussions. Although there are many similarities between DP and CTE, a number of key differences are apparent especially when comparing movement impairments. The aim of this review is to compare clinical and pathological aspects of DP and CTE with a focus on disorders of movement.

Update on TBI and Cognitive Impairment in Military Veterans.

Curr Neurol Neurosci Rep 2015; 15 (10): 68 gregory.elder@va.gov.

Traumatic brain injury (TBI) is a common cause of morbidity and mortality in military life. Interest in military TBI has increased recently due to the conflicts in Iraq and Afghanistan. Certain types of TBI are relatively unique to the military, the most prominent being blast-related TBI. Blast-related mild TBI has been of particular concern in veterans from the most recent conflicts although controversy remains concerning its separation from post-traumatic stress disorder. TBI is also a risk factor for the later development of neurodegenerative diseases in which cognitive impairment is prominent putting veterans at risk for disorders including Alzheimer's disease and chronic traumatic encephalopathy. Recent evidence associating TBI with chronic cognitive impairment is reviewed in the context of its relevance to military veterans.

The clinical presentation of chronic traumatic encephalopathy.

Curr Neurol Neurosci Rep 2015; 15 (5): 23 mlenihan@nycap.rr.com.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder attributed to repetitive mild traumatic brain injury. The diagnosis in a living individual can be challenging and can be made definitively only at autopsy. The symptoms are often nonspecific and overlap with neurodegenerative disorders such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Higher exposure to repetitive head trauma increases the risk of CTE. Genetic risk factors such as presence of an apolipoprotein E epsilon4 allele may be important. Individuals have varying degrees of cognitive, behavioral, and motor decline. Limitations in the manner in which data have been obtained over the years have led to different clinical descriptions of CTE. At present, there are no biomarkers to assist in the diagnosis. Standard neuroimaging may show nonspecific atrophic changes; however, newer imaging modalities such as positron emission tomography (PET) and diffusion tensor imaging (DTI) show promise. Neuropsychological testing may be helpful in determining the pattern of cognitive or behavioral decline.

Hypothermia for brain protection and resuscitation.

Curr Opin Anaesthesiol 2006; 19 (5): 487-91 ramachandran.ramani@yale.edu

PURPOSE OF REVIEW: Clinicians are actively looking for an effective brain protection technique. With pharmacologic agents, several phase III trials in stroke, severe traumatic brain injury, and post-cardiac arrest survivors have failed. Hence there is renewed interest in mild to moderate hypothermia for brain protection. Phase III clinical trials with hypothermia have been successful only in post-cardiac arrest survivors and neonatal hypoxic encephalopathy. This review focuses on the possible reasons for our inability to translate into positive clinical trials what is observed consistently in laboratory models. RECENT FINDINGS: Several factors have been identified for the failure of successive hypothermia clinical trials. Patients with severe traumatic brain injury with Glasgow Coma Score of 4-7 on admission and those less than 45 years of age and neonates with hypoxic encephalopathy are more responsive to hypothermia. Similarly, early and effective cooling techniques and titration of hypothermia to a defined endpoint are likely to be more effective. New techniques such as local cooling of the brain and the combination of hypothermia with drugs are being evaluated. SUMMARY: Hypothermia can at present be recommended only for post-cardiac arrest survivors and in neonatal hypoxic encephalopathy.

Tau imaging in the study of ageing, Alzheimer's disease, and other neurodegenerative conditions.

Curr Opin Neurobiol 2016; 36 (ä): 43-51 victorlv@unimelb.edu.au.;

In vivo tau imaging allows a deeper understanding of tau deposition in the brain, providing insights into the causes, diagnosis and treatment of primary and secondary tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. The cross-sectional and longitudinal assessment of the temporal and spatial patterns of tau deposition in the brain will allow a better understanding of the role tau plays in ageing as well as its relationship with cognition, genotype, and neurodegeneration. It is likely that selective tau imaging could be used as a diagnostic and prognostic biomarker of disease progression, as well as a surrogate marker for monitoring of efficacy and patient recruitment for disease-specific therapeutic trials.

Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions.

Curr Opin Neurol 2011; 24 (6): 525-31

PURPOSE OF REVIEW: There are currently no consensus-based clinical diagnostic criteria for chronic traumatic encephalopathy (CTE). This review provides an update on recent literature pertaining to clinically relevant procedures that--presently or in the future--may be useful for the in-vivo detection, characterization, and/or prediction of CTE. RECENT FINDINGS: Preliminary evidence about the clinical manifestations of CTE has been accumulating via post-mortem medical record review and interviews of friends or family members of individuals with neuropathologically documented CTE. This evidence suggests that CTE is manifested clinically by changes in cognition (especially memory and executive functioning, with dementia later in the disease course), mood (especially, depression, apathy, and suicidality), personality and behavior (especially poor impulse control and behavioral disinhibition), and movement (including parkinsonism and signs of motor neuron disease). At the present time, evidence regarding CTE has not been confirmed in a prospective study of a cohort at risk for CTE. SUMMARY: On the basis of recent research in the fields of dementia and traumatic brain injury, several in-vivo procedures (including neurological examination, neuropsychological assessment, neuroimaging techniques, and blood and cerebrospinal fluid biomarkers) each have the potential to contribute unique information about the manifestations of CTE, including clinical and preclinical stages. More research is needed to develop a set of consensus diagnostic criteria that provide a reliable and valid indicator of neuropathologically verified CTE. Until such criteria are developed, the clinical assessment of CTE should be informed by modern research that is of relevance to traumatic brain injury and neurodegenerative diseases.

The Pathophysiology of Concussion.

Curr Pain Headache Rep 2016; 20 (6): 42 mchoe@mednet.ucla.edu.

Concussion is a significant issue in medicine and the media today. With growing interest on the long-term effects of sports participation, it is important to understand what occurs in the brain after an impact of any degree. While some of the basic pathophysiology has been elucidated, much is still unknown about what happens in the brain after traumatic brain injury, particularly with milder injuries where no damage can be seen at the structural level on standard neuroimaging. Understanding the chain of events from a cellular level using studies investigating more severe injuries can help to drive research efforts in understanding the symptomatology that is seen in the acute phase after concussion, as well as point to mechanisms that may underlie persistent post-concussive symptoms. This review discusses the basic neuropathology that occurs after traumatic brain injury at the cellular level. We also present the pathology of chronic traumatic encephalopathy and its similarities to other neurodegenerative diseases. We conclude with recent imaging and biomarker findings looking at changes that may occur after repeated subconcussive blows, which may help to guide efforts in understanding if cumulative subconcussive mechanical forces upon the brain are detrimental in the long term or if concussive symptoms mark the threshold for brain injury.

Evaluation and Management of Concussion in Young Athletes.

Curr Probl Pediatr Adolesc Health Care 2018; 48 (5-6): 139-150 jkosoy@northwell.edu.;

Learning about concussion diagnosis and management is important for all individuals who will be taking care of young athletes. There are about 1.7million reported concussions per year, and, of these, about 20% are sports related. There are risks in all sports, but the highest rates of concussions are from football, rugby, and hockey, with soccer being the highest cause for girls. An on-field assessment includes evaluating airway, breathing, and circulation, followed by cervical spine assessment. Then, concussion evaluation tools can be used to aid in making the diagnosis. While concussion symptoms for the majority of youth resolve within a few weeks, some individuals may have persistence of symptoms for 3 months or more, referred to as postconcussive syndrome. Providers should consider ongoing symptoms in assessing when an athlete may safely return to sports and to learning. A major concern that has become more apparent in recent years is the possibility that concussions may have a longitudinal effect on health, such as in the development of chronic traumatic encephalopathy. Research has shown that there is an increase in the number of patients presenting to their primary care physician with concussions. Knowing how best to prevent, diagnose, and manage concussions will help to minimize risks to young athletes.

Neurologic Care in Concussion and Post-Concussive Encephalopathy.

Curr Probl Pediatr Adolesc Health Care 2016; 46 (2): 52-7 CHADEHUMBM@EMAIL.CHOP.EDU.

Concussion has become a more recent "medical fad" with a lot of media coverage and hence an increasing incidence. According to the Center for Disease Control (CDC) and Prevention there are estimates of as many as 3.8 million sport-related traumatic brain injuries occurring annually (Centers for Disease Control and Prevention, 2007). Given these numbers, concussion care will require that both primary and specialist physicians feel comfortable in its management. This article will discuss the pathophysiology, epidemiology, clinical evaluation, therapies and prognosis in patients with concussion. The complex and chronic symptoms after a concussion and their management will be highlighted. Appropriate concussion care is essential for improving both the long and short term outcomes in adolescent athletes. There is an important role for the neurologist in improving the outcome in these athletes.

VA's National PTSD Brain Bank: a National Resource for Research.

Curr Psychiatry Rep 2017; 19 (10): 73 Matthew.J.Friedman@Dartmouth.edu.;

The National PTSD Brain Bank (NPBB) is a brain tissue biorepository established to support research on the causes, progression, and treatment of PTSD. It is a six-part consortium led by VA's National Center for PTSD with participating sites at VA medical centers in Boston, MA; Durham, NC; Miami, FL; West Haven, CT; and White River Junction, VT along with the Uniformed Services University of Health Sciences. It is also well integrated with VA's Boston-based brain banks that focus on Alzheimer's disease, ALS, chronic traumatic encephalopathy, and other neurological disorders. This article describes the organization and operations of NPBB with specific attention to: tissue acquisition, tissue processing, diagnostic assessment, maintenance of a confidential data biorepository, adherence to ethical standards, governance, accomplishments to date, and future challenges. Established in 2014, NPBB has already acquired and distributed brain tissue to support research on how PTSD affects brain structure and function.

The Impact of Traumatic Brain Injury on the Aging Brain.

Curr Psychiatry Rep 2016; 18 (9): 81 jonathan.hobbs@uchospitals.edu.;

Traumatic brain injury (TBI) has come to the forefront of both the scientific and popular culture. Specifically, sports-related concussions or mild TBI (mTBI) has become the center of scientific scrutiny with a large amount of research focusing on the long-term sequela of this type of injury. As the populace continues to age, the impact of TBI on the aging brain will become clearer. Currently, reports have come to light that link TBI to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as certain psychiatric diseases. Whether these associations are causations, however, is yet to be determined. Other long-term sequelae, such as chronic traumatic encephalopathy (CTE), appear to be associated with repetitive injuries. Going forward, as we gain better understanding of the pathophysiological process involved in TBI and subclinical head traumas, and individual traits that influence susceptibility to neurocognitive diseases, a clearer, more comprehensive understanding of the connection between brain injury and resultant disease processes in the aging brain will become evident.

Athletic Suicide - Separating Fact From Fiction and Navigating the Challenging Road Ahead.

Curr Sports Med Rep 2018; 17 (3): 83-84

Ice Hockey Summit II: zero tolerance for head hits and fighting.

Curr Sports Med Rep 2015; 14 (2): 135-44

This study aimed to present currently known basic science and on-ice influences of sport-related concussion (SRC) in hockey, building upon the Ice Hockey Summit I action plan (2011) to reduce SRC. The prior summit proceedings included an action plan intended to reduce SRC. As such, the proceedings from Summit I served as a point of departure for the science and discussion held during Summit II (Mayo Clinic, Rochester, MN, October 2013). Summit II focused on (1) Basic Science of Concussions in Ice Hockey: Taking Science Forward, (2) Acute and Chronic Concussion Care: Making a Difference, (3) Preventing Concussions via Behavior, Rules, Education, and Measuring Effectiveness, (4) Updates in Equipment: Their Relationship to Industry Standards, and (5) Policies and Plans at State, National, and Federal Levels To Reduce SRC. Action strategies derived from the presentations and discussion described in these sectors were voted on subsequently for purposes of prioritization. The following proceedings include the knowledge and research shared by invited faculty, many of whom are health care providers and clinical investigators. The Summit II evidence-based action plan emphasizes the rapidly evolving scientific content of hockey SRC. It includes the most highly prioritized strategies voted on for implementation to decrease concussion. The highest-priority action items identified from the Summit include the following: (1) eliminate head hits from all levels of ice hockey, (2) change body checking policies, and (3) eliminate fighting in all amateur and professional hockey.

Is chronic traumatic encephalopathy a real disease?

Curr Sports Med Rep 2014; 13 (1): 33-7

Chronic traumatic encephalopathy (CTE) has received widespread media attention and is treated in the lay press as an established disease, characterized by suicidality and progressive dementia. The extant literature on CTE is reviewed here. There currently are no controlled epidemiological data to suggest that retired athletes are at increased risk for dementia or that they exhibit any type of unique neuropathology. There remain no established clinical or pathological criteria for diagnosing CTE. Despite claims that CTE occurs frequently in retired National Football League (NFL) players, recent studies of NFL retirees report that they have an all-cause mortality rate that is approximately half of the expected rate, and even lower suicide rates. In addition, recent clinical studies of samples of cognitively impaired NFL retirees have failed to identify any unique clinical syndrome. Until further controlled studies are completed, it appears to be premature to consider CTE a verifiable disease.

Chronic traumatic encephalopathy.

Curr Sports Med Rep 2013; 12 (1): 28-32

Sports-related concussion has gained increased prominence, in part due to media coverage of several well-known athletes who have died from consequences of chronic traumatic encephalopathy (CTE). CTE was first described by Martland in 1928 as a syndrome seen in boxers who had experienced significant head trauma from repeated blows. The classic symptoms of impaired cognition, mood, behavior, and motor skills also have been reported in professional football players, and in 2005, the histopathological findings of CTE were first reported in a former National Football League (NFL) player. These finding were similar to Alzheimer's disease in some ways but differed in critical areas such as a predominance of tau protein deposition over amyloid. The pathophysiology is still unknown but involves a history of repeated concussive and subconcussive blows and then a lag period before CTE symptoms become evident. The involvement of excitotoxic amino acids and abnormal microglial activation remain speculative. Early identification and prevention of this disease by reducing repeated blows to the head has become a critical focus of current research.

Public knowledge of late-life cognitive decline and dementia in an international sample.

Dementia (London) 2018; ä (ä): 1471301218805923

Background and objectives One method of mitigating global increases in dementia prevalence involves assessing public knowledge and then educating laypeople. We measured knowledge of late-life pathological cognitive decline in a diverse, international sample using a standardized, validated instrument. RESEARCH DESIGN AND METHODS: We assessed 3619 international respondents recruited through Amazon's Mechanical Turk with a 44-item dementia knowledge survey and 18 sociodemographic items. Results Results suggested that the following sociodemographic variables are associated with less overall knowledge: young age, male gender, low educational attainment, born in a developing nation, of ethnic minority status, not married, and less prior dementia experience. Specific knowledge gaps emerged in cerebrovascular disease, delirium versus dementia, treatment of behavioral dementia symptoms, Alzheimer's disease genetics, Parkinson's disease symptoms, and characteristics of chronic traumatic encephalopathy and subjective cognitive decline. Discussion and implications: Findings may facilitate effective multinational dementia education initiatives by providing specific recommendations as to which sociodemographic populations and content knowledge domains will benefit the most from limited resources.

Chronic traumatic encephalopathy in sports: a historical and narrative review.

Dev Neuropsychol 2018; 43 (4): 279-311

My objectives are to review: 1) a brief history of sport-related concussion (SRC) and chronic traumatic encephalopathy (CTE), 2) the evolution of CTE in American professional football, 3) the data regarding SRC/CTE as they relate to depression and suicide, 4) the data on the neurocognitive effects of subconcussion/repetitive head trauma (with emphases on heading the ball in soccer and early exposure to football), 5) the evidence related to SRC and neurodegenerative diseases, 6) the published studies of CTE, 7) the NINDS neuropathological criteria for CTE, 8) public beliefs about SRC/CTE, and 9) the scientific questions regarding CTE.

Chronic traumatic encephalopathy.

Dis Mon 2019; ä (ä): ä jbailes@northshore.org.;

Electroencephalographic findings in 186 cases of chronic post-traumatic encephalopathy.

Electroencephalogr Clin Neurophysiol 1951; 3 (1): 9-14

Special Considerations in Trauma Patients.

Emerg Med Clin North Am 2015; 33 (4): 853-61 mabraham@umem.org.;

The emergent management of a traumatic injury can be an extremely intense situation. These assessments can be even more difficult when patients have an underlying psychiatric condition. After a protocoled evaluation of the traumatic injuries, the psychological manifestation of diseases can be addressed. The appropriate use of physical or chemical restraints to facilitate the work-up is paramount in the ability of the provider to protect patients and staff from agitated and traumatized patients. The emergency medicine provider should have a low threshold for including psychiatry in the treatment plans, as the long-term sequelae of these entities require specialized treatment.

Maladie d'Alzheimer et la theorie du zinc.

Encephale 1990; 16 (4): 231-9

UNLABELLED: In Alzheimer's disease, the Primum Movens is amyloid production on precapillaries: dysphoric angiopathy, and capillaries: senile plaques. Cerebral amyloid alone may be asymptomatic. Clinical symptoms of amnesia appear when amyloid induces neighbouring neuritic alterations: paired helical filaments and distant neuronal body lesions: neurofibrillary tangles. HYPOTHESIS: the amyloid induces zinc deficiency which produces the tangles. In Alzheimer's disease, cerebral zinc decreases particularly in the hippocampus. Without amyloid, neurofibrillary tangles are produced by metalotoxicity and therefore probably brain zinc displacement: by lead: encephalopatia saturnica, by calcium deficiency: Guam's encephalopathy, by aluminium, by blood-brain-barrier disturbances probably leading to an abnormal entry of metals in the brain (dementia pugilistica, viral encephalitides). Neurofibrillary tangles may be produced by deficiency of the following zinc enzymes: 1) those of DNA metabolism inducing abnormal DNA and therefore abnormal protein synthesis: paired helical filaments and neurofibrillary tangles; 2) of glutamate-dehydrogenase resulting in an excitotoxic increase of glutamate, which may produce neurofibrillary tangles, particularly in the hippocampus rich in glutamate pathways; 3) those of neuronal detoxication: superoxide-dismutase, carbonic anhydrase, lactate-dehydrogenase leading to neuronal toxicity particularly in the hippocampus normally rich in superoxide dismutase; 4) those of neurotransmitters metabolisms (opioid peptides, GABA, acetylcholine). Therapeutic implication: a non-toxic zinc complex crossing the Blood-Brain-Barrier should be useful.

No difference in the prevalence of Alzheimer-type neurodegenerative changes in the brains of suicides when compared with controls: an explorative neuropathologic study.

Eur Arch Psychiatry Clin Neurosci 2018; 268 (5): 509-517 matschke@uke.de.;

Suicide ranks among the leading causes of death for individuals of all ages with highest rates in the elderly. The cause of suicide is considered a multifactorial phenomenon. A variety of neurodegenerative diseases, notably Alzheimer's disease, or, more recently, tauopathies as frontotemporal lobar degeneration or chronic traumatic encephalopathy, has been suggested as risk factor for suicide. Accordingly, we hypothesized that neurodegenerative changes typical of these diseases should be more prevalent in the brains of suicides when compared with controls. Suicides from the German federal state of Hamburg (n = 162) were compared with age- and sex-matched controls who died of other cause. Neuropathological assessment included semiquantitative analysis of neuritic plaques and neurofibrillary tangles visualized with silver stains; in addition, quantitative immunohistochemical analysis of beta-amyloid load and counts of tau-positive neurofibrillary tangles and neuropil threads was done. Univariate analysis and multivariable conditional logistic regression models did not show an effect of any parameter associated with the odds of committing suicide. On the contrary, after stratification for age, older suicide victims (over 48 years) showed lower beta-amyloid loads when compared to controls in the univariate analysis (suicides: 4.7 +/- 12.9; controls: 9.9 +/- 20.9; p = 0.031; r = - 0.17). In conclusion, neuropathological characteristics of Alzheimer's disease and common tauopathies associated with age seem to be of limited relevance for suicides. However, intact cognition when planning and carrying out complex acts may be of importance in the context of suicide.

Sport specificity of mental disorders: the issue of sport psychiatry.

Eur Arch Psychiatry Clin Neurosci 2013; 263 Suppl 2 (ä): S205-10 Karl-Juergen.Baer@med.uni-jena.de.

The prevalence of psychiatric conditions among elite athletes is still under debate. More and more evidence has accumulated that high-performance athletes are not protected from mental disorders as previously thought. The authors discuss the issue of the sport specificity of selected mental diseases in elite athletes. Specific aspects of eating disorders, exercise addiction, chronic traumatic encephalopathy and mood disorders in the context of overtraining syndrome are examined. In particular, the interrelationship between life and work characteristics unique to elite athletes and the development of mental disorders are reviewed. Differences of clinical presentation and some therapeutic consequences are discussed. The authors suggest that the physical and mental strains endured by elite athletes might influence the onset and severity of their psychiatric disorder. Beside the existing research strategies dealing with the amount of exercise, its intensity and lack of recreation experienced by athletes, further research on psycho-social factors is needed to better understand the sport-specific aetiology of mental disorders in high-performance athletes.

A laser microprobe mass analysis of brain aluminum and iron in dementia pugilistica: comparison with Alzheimer's disease.

Eur Neurol 1997; 38 (1): 53-8

We report a laser microprobe mass analysis of aluminum and iron content in the hippocampus and in the inferior temporal cortex in 2 cases of dementia pugilistica (DP), 4 cases of Alzheimer's disease (AD), and 3 controls. There was a predominant accumulation of Al and Fe within neurofibrillary tangles (NFT) in both DP and AD cases. High levels of Al and Fe were also detected in the nuclei of NFT-free and NFT-containing neurons, as well as in neuropil probe sites in these cases. In both regions, NFT contained substantially higher levels of Al and Fe in DP compared to AD cases. These findings suggest the existence of an association between the deposition of Al and Fe and NFT formation, and support the possibility of a global dysregulation of Al and Fe transport in DP and AD.

Diagnosis makes a difference: Perceptions of older persons with dementia symptoms.

Exp Aging Res 2018; 44 (2): 148-161

Background/Study Context: Employing the stereotype content model and terror management theory, we examined whether stereotypes and feelings about persons with dementia vary depending on the type of dementia diagnosis and purported causes of the dementia. METHODS: Participants were randomly assigned to read one of four vignettes that depicted a man who consulted his doctor because of memory problems. All vignettes described the same symptoms and diagnostic tests, but each of four groups read a different result: all tests normal (Normal); Alzheimer's disease (AD); Wernicke-Korsakoff Syndrome (WKS) associated with alcohol abuse; and chronic traumatic encephalopathy (CTE) associated with head injuries from playing football in high school and college. Measures included a word fragment completion task, a stereotype content scale, and an emotions scale. RESULTS: Results showed no differences in the number of death-related words generated in the word fragment completion task and no differences in assessment of competence across the four groups. Those in the Normal, AD, and CTE groups evaluated the man as warmer than those in the WKS group. Participants in the AD condition showed more empathy than those in the WKS group. There were no differences in pity or fear but the CTE condition produced more envy and admiration and the WKS condition produced more contempt. CONCLUSION: These results suggest that different forms of dementia elicit varying emotional and cognitive responses.

Repetitive closed-head impact model of engineered rotational acceleration (CHIMERA) injury in rats increases impulsivity, decreases dopaminergic innervation in the olfactory tubercle and generates white matter inflammation, tau phosphorylation and degeneration.

Exp Neurol 2019; 317 (ä): 87-99 cole.vonderhaar@mail.wvu.edu.;

Traumatic brain injury (TBI) affects at least 3M people annually. In humans, repetitive mild TBI (rmTBI) can lead to increased impulsivity and may be associated with chronic traumatic encephalopathy. To better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology, we used CHIMERA (Closed-Head Injury Model of Engineered Rotational Acceleration) to deliver five TBIs to rats, which were continuously assessed for trait impulsivity using the delay discounting task and for neuropathology at endpoint. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. Histological analyses revealed reduced dopaminergic innervation from the ventral tegmental area to the olfactory tubercle, consistent with altered impulsivity neurocircuitry. Consistent with diffuse axonal injury generated by CHIMERA, white matter inflammation, tau immunoreactivity and degeneration were observed in the optic tract and corpus callosum. Finally, pronounced grey matter microgliosis was observed in the olfactory tubercle. Our results provide insight into the mechanisms by which rTBI leads to post-traumatic psychiatric-like symptoms in a novel rat TBI platform.

Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men.

Exp Neurol 2016; 275 Pt 3 (ä): 389-404 bojo@roskampinstitute.net.;

Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field.

Cerebral Vascular Injury in Traumatic Brain Injury.

Exp Neurol 2016; 275 Pt 3 (ä): 353-366 ramon.diaz-arrastia@usuhs.edu.

Traumatic cerebral vascular injury (TCVI) is a very frequent, if not universal, feature after traumatic brain injury (TBI). It is likely responsible, at least in part, for functional deficits and TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive cerebral microvascular injury in humans and experimental animal, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI, and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences (MRI-ASL), Transcranial Doppler (TCD), and Near InfraRed Spectroscopy (NIRS). Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for the development of novel therapies for TBI.

Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury.

Exp Neurol 2015; 273 (ä): 168-76 lxu9@jhmi.edu.;

Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI.

Commentary on Kamper et. al., juvenile traumatic brain injury evolves into a chronic brain disorder: The challenges in longitudinal studies of juvenile traumatic brain injury.

Exp Neurol 2014; 261 (ä): 434-9 jlifshitz@email.arizona.edu.

Juvenile traumatic brain injury (TBI) leaves survivors facing a potential lifetime of cognitive, somatic and emotional symptoms. A recent study published in Experimental Neurology (Kamper et al., 2013) explored the chronic consequences of focal brain injury induced in the juvenile animal, extending their previous observations out to 6months post-injury. The results demonstrate transient, persistent, and late onset behavioral dysfunction, which are associated with subtle evidence for enduring histopathology. In line with investigations about chronic traumatic encephalopathy from brain injury initiated in the adult, juvenile TBI establishes signs of a chronic brain disorder, with unique considerations relative to ongoing developmental processes. This commentary discusses the challenges in evaluating aging with injury in the juvenile population, the current methods of juvenile TBI, and what can be anticipated for the future of the field.

How far have biological therapies come in regenerative sports medicine?

Expert Opin Biol Ther 2018; 18 (7): 785-793

INTRODUCTION: Regular engagement in sports produces many health benefits, but also exposes to increased injury risk. The quality of medical care available is crucial not only for sports trauma but also to avoid overuse syndromes and post-traumatic degenerative conditions. AREAS COVERED: We provide background information on some clinical needs in sport injuries and describe the main families of biological products used in clinical practice. We also discuss limitations of the current clinical experience. EXPERT OPINION: Sport and exercise impairment affects different segments of the population with different needs. The exceptional demands of elite athletes and subsequent media coverage have created hype around regenerative therapies. Statistical evidence, whether weak (cell products) or moderate (PRPs), is not enough to drive medical decisions because of the heterogeneity of the biological products available and their application procedures. Moreover, the specific needs of the different segments of the population along with the available clinical evidence for each musculoskeletal condition should be considered in the decision-making process. There is urgent need to develop regenerative protocols combined with post-intervention rehabilitation, and gather meaningful clinical data on the safety and efficacy of these interventions in the different populations segments.

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro-injuries.

Expert Opin Ther Targets 2017; 21 (6): 627-638

INTRODUCTION: Since its discovery as a major CNS-abundant protein 25 years ago, Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has emerged as an important enzyme in regulating brain protein metabolism, by coupling to the proteasome pathway of protein degradation. Areas covered: UCH-L1 is implicated in both familial and sporadic Parkinson disease and other chronic neurodegenerative diseases. Also, UCH-L1 has been recently emerging as a biofluid-based biomarker for various forms of acute neurotrauma and CNS injury. Expert opinion: The loss of UCH-L1 activity coupled with the gain of proteinopathy function are linked to neurodegeneration such as Parkinsonism and Alzheimer's disease. In addition, certain post-translational modifications of UCH-L1 might promote the conversion of the cytosolic UCH-L1(C) to the membrane-associated UCH-L1(M) form, which seems to play a role in alpha-synucleinopathy formation. Thus, targeting the conversion of UCH-L1(C) to the UCH-L1(M) form might be the key to developing therapies for neurodegenerative diseases linked to UCH-L1. In parallel, UCH-L1 is also emerging as a promising neuron-derived biomarker for traumatic brain injury, ischemic and homographic stroke, pediatric hypoxic-ischemic encephalopathy, spinal cord injury, epileptic seizure and cardiac arrest. This shows that UCH-L1 has strong potential as a robust and universal biomarker target for various forms of CNS injury.

Management of chronic traumatic encephalopathy.

Expert Rev Neurother 2019; ä (ä): ä

Introduction Chronic Traumatic Encephalopathy (CTE) is a neuropathological disease defined by perivascular hyperphosphorylated tau protein depositions in a patchy distribution at the depths of cortical sulci in the brain. Presently, in living individuals, it cannot be precisely diagnosed or differentiated from other neurodegenerative diseases nor are there treatments for the underlying disease process. There are non-pharmacologic and pharmacologic treatments for the symptoms of CTE that improve the quality of daily life. That is the primary focus of this review article that used Pub Med and other standard data bases but drew heavily from the authors personal experience managing patients at risk for CTE. Areas covered The history and pathology of CTE, aiding the clinician diagnosing CTE as unlikely, possible, or probable in the living, and symptom treatment are the major areas discussed. Expert Opinion Diagnosing CTE during life with sensitive and specific biomarkers is the next critical step and only then will its incidence and prevalence, risk factors, and clinical features due to tauopathy versus axonopathy or other features be known.