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 43 kDa (TDP-43) and other common age-related pathologies, dementia, probable Alzheimer’s 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 CA1and/or subiculum. The severity and distribution of TDP-43 was 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 (LB) pathology; only TDP-43 pathology increased the odds of HS (OR=2.63; 95% 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 while HS without TDP-43 did not have statistically significant associations. TDP-43 without HS was separately related to lower episodic memory. Interpretation The combined role of hippocampal sclerosis and TDP-43 pathology are significant factors underlying global cognitive impairment and probable AD in older subjects.

Hippocampal Sclerosis and Epilepsy in Elderly Population

“…Noteworthy, TDP43-pathology has been reported to be relatively common in AD [4][5][6][7][8][9][10][11][12][13][14] and in line with this, TDP43-pathology was observed in as many as 88% of our cases with severe AD related pathology (Braak stages V-VI). It should be noted that clinical studies reporting that EP is common in AD include all subjects with AD diagnosis.…”

“…In AD, the hippocampal formation displays substantial pathology including AD related hallmark lesions such as neurofibrillary tangles and neuritic plaques [3]. Furthermore, many reports have indicated that a substantial number of AD subjects, in addition to the AD related lesions, also display TAR DNA binding protein 43 (TDP43) within the hippocampus [4][5][6][7][8][9][10][11][12][13][14]. TDP43 related pathology is primarily seen in subjects with frontotemporal lobar degeneration (FTLD) [15].…”

Patterns of Innovation in Alzheimer’s Disease Drug Development: A Strategic Assessment Based on Technological Maturity

“…42,43 Of particular interest is the technology growth curve for the transactive response DNA-binding protein of 43 kDa (TDP-43), a protein first identified for its association with amyotrophic lateral sclerosis and more recently associated with AD. [44][45][46] Growth of publications related to TDP-43 could not be modeled with the sigmoid function. Closer analysis suggests that this technology is still in the exponential, growing stage of the growth cycle and has not yet approached the established stage.…”

Mixed pathology is more likely in black than white decedents with Alzheimer dementia

“…The degree of atherosclerosis of the circle of Willis vessels was also recorded on a semiquantitative scale consisting of the following categories: none (0), mild (1), moderate (2), and severe (3), as previously described. 14 Statistical analysis. Descriptive statistical analyses were conducted to characterize differences between black and white decedents on postmortem interval (PMI) and clinical interval (number of months between last clinical examination and death).…”