期刊
BRAIN PATHOLOGY
卷 30, 期 2, 页码 364-372出版社
WILEY
DOI: 10.1111/bpa.12773
关键词
ABCC9; GRN; hippocampal sclerosis; LATE-NC; population study; TDP-43; TMEM106B
资金
- National Institute for Health Research (NIHR), Cambridge BioMedical Research Centre
- UK Medical Research Council (MRC) [G9901400]
- MRC
- Department of Health
- UK NIHR Biomedical Research Centre for Ageing and Age-related Disease Award
- Cambridgeshire and Peterborough NIHR CLAHRC
- Nottingham University Hospitals NHS Trust
- University of Sheffield
- Sheffield Teaching Hospitals NHS Foundation Trust
- Thomas Willis Oxford Brain Collection - Oxford Biomedical Research Centre
- Walton Centre NHS Foundation Trust, Liverpool
- Medical Research Council
- Alzheimer's Research Trust [ART PG2006/6]
- Academy of Finland [294817]
- Helsinki University Hospital Competitive fund
- Finska Lakaresallskapet
- Sigrid Juselius Foundation
- Liv och Halsa Foundation
- Australian NHMRC Project Grant [APP1042889]
- Addenbrooke's Charitable Trust
- Alzheimer's Research UK Scholarship [ARUK-PhD2014-19]
- Australian NHMRC Dementia Research Leadership Fellowship [GNT1135676]
- [MRC.U.1052.00.013]
- MRC [G1000691, G1100540, MR/L022656/1, MC_U105292687, G0400074, G0502157, G0900652, G9901400] Funding Source: UKRI
Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (chi(2)(2) = 20.61, P < 0.001) and T-allele (chi(2)(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A-allele (chi(2)(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.
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