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

Abstract

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.

Figure 1

Photomicrographs showing the CA1 and subiculum in cases without (A) and with (B) HS in which sclerosis involves CA1 (starting below the arrowhead) and the subiculum (right of the *) in continuity. Higher magnification shows preservation of pyramidal neurons in the CA1 in the absence of sclerosis (C) and astrogliosis with few residual neurons (arrowheads) in the case with HS (D). Hematoxylin-eosin stain, Scale bar = 500 μm (A,B) and 200 μm (C, D).

Figure 2

Blue shades represent the pathologic diagnosis of AD with or without coexisting HS and/or TDP-43 pathology, while the pink shades represent the pathologic diagnosis of HS and/or TDP without pathologic AD.

Figure 3

The probability of a clinical diagnosis of AD (green line) with increasing burden of AD pathology and the additive influences of HS (black line) and TDP-43 pathology (red line) was predicted for a female aged 88 years with 16 years of education controlling for Lewy body pathology, macro and microinfarcts. The probability of a clinical diagnosis of AD was about 30 % per one unit of global AD pathology score (AD pathology score range 0-3.2 units). Concurrence of HS further increased the probability of the clinical diagnosis of AD to about 70 %, and the further addition of TDP-43 pathology increased the probability to about 75%.