Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease

• Published in: Annals of neurology Vol. 77; no. 6; pp. 942 - 952
• Main Authors: Nag, Sukriti, Yu, Lei, Capuano, Ana W., Wilson, Robert S., Leurgans, Sue E., Bennett, David A., Schneider, Julie A.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.06.2015; Wiley Subscription Services, Inc
• Subjects: Age; Aged; Aged, 80 and over; Aging - metabolism; Aging - pathology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Cognitive ability; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Confidence intervals; DNA-Binding Proteins - metabolism; Female; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Pathology; Religious orders; Sclerosis - pathology
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.24388

Objective To investigate the association of hippocampal sclerosis (HS) with TAR‐DNA binding protein of 43kDa (TDP‐43) and other common age‐related pathologies, dementia, probable Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive domains in community‐dwelling older subjects. Methods Diagnoses of dementia, probable AD, and MCI in 636 autopsied subjects from the Religious Order Study and the Rush Memory and Aging Project were based on clinical evaluation and cognitive performance tests. HS was defined as severe neuronal loss and gliosis in the hippocampal CA1 and/or subiculum. The severity and distribution of TDP‐43 were assessed, and other age‐related pathologies were also documented. Results HS was more common in those aged >90 years (18.0%) compared to younger subjects (9.2%). HS cases commonly coexisted with TDP‐43 pathology (86%), which was more severe (p < 0.001) in HS cases. Although HS also commonly coexisted with AD and Lewy body pathology; only TDP‐43 pathology increased the odds of HS (odds ratio [OR] = 2.63, 95% confidence interval [CI] = 2.07–3.34). In logistic regression models accounting for age, TDP‐43, and other common age‐related pathologies, HS cases had higher odds of dementia (OR = 3.71, 95% CI = 1.93–7.16), MCI, and probable AD (OR = 3.75, 95% CI = 2.01–7.02). In linear regression models, including an interaction term for HS and TDP‐43 pathology, HS with coexisting TDP‐43 was associated with lower function in multiple cognitive domains, whereas HS without TDP‐43 did not have statistically significant associations. TDP‐43 without HS was separately related to lower episodic memory. Interpretation The combined roles of HS and TDP‐43 pathology are significant factors underlying global cognitive impairment and probable AD in older subjects. Ann Neurol 2015;77:942–952