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lüll Variation in TMEM106B in chronic traumatic encephalopathy Cherry JD; Mez J; Crary JF; Tripodis Y; Alvarez VE; Mahar I; Huber BR; Alosco ML; Nicks R; Abdolmohammadi B; Kiernan PT; Evers L; Svirsky S; Babcock K; Gardner HM; Meng G; Nowinski CJ; Martin BM; Dwyer B; Kowall NW; Cantu RC; Goldstein LE; Katz DI; Stern RA; Farrer LA; McKee AC; Stein TDActa Neuropathol Commun 2018[Nov]; 6 (1): 115The 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.|Adolescent[MESH]|Adult[MESH]|Aged[MESH]|Aged, 80 and over[MESH]|Amyloid beta-Peptides/metabolism[MESH]|Antigens, CD/metabolism[MESH]|Antigens, Differentiation, Myelomonocytic/metabolism[MESH]|Chronic Traumatic Encephalopathy/*genetics/*pathology[MESH]|Disks Large Homolog 4 Protein/metabolism[MESH]|Football/injuries[MESH]|Genotype[MESH]|Humans[MESH]|Linkage Disequilibrium[MESH]|Male[MESH]|Membrane Proteins/*genetics[MESH]|Middle Aged[MESH]|Mutation/*genetics[MESH]|Nerve Tissue Proteins/*genetics[MESH]|Prefrontal Cortex/*metabolism/pathology[MESH]|Trauma Severity Indices[MESH]|Young Adult[MESH]|tau Proteins/metabolism[MESH] |