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DT‐01‐02: TEMPORAL NEOCORTICAL TAU DEPOSITION MEASURED WITH PET IS ASSOCIATED WITH LONGITUDINAL DECLINE IN MEMORY PERFORMANCE AMONG CLINICALLY NORMAL ELDERLY
Author(s) -
Johnson Keith A.,
Mormino Elizabeth,
Rentz Dorene M.,
Schultz Aaron,
Becker J. Alex,
Sepulcre Jorge,
Chhatwal Jasmeer,
Amariglio Rebecca,
Papp Kate,
Marshall Gad,
Shoup Timothy,
Yokell Daniel,
Brady Thomas,
Hyman Bradley,
Vasdev Neil,
Sperling Reisa
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.07.150
Subject(s) - entorhinal cortex , interquartile range , temporal cortex , neuroscience , recall , psychology , medicine , hippocampus , cognitive psychology
core pathological entities that define Alzheimer’s disease (AD). Little is known about the role of a third protein, the TAR DNA binding protein of 43kDa (TDP-43). The aim of this study was to determine whether TDP-43 independently has any effect on the clinical and neuroimaging characteristics typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Methods: Three-hundred forty-two subjects pathologically diagnosed with intermediate-high probability AD (Braak IV-VI) were screened for the presence, burden and distribution of TDP43. All cases had been classified as cognitively impaired or cognitively normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein e4, amyloid deposition, Lewy bodies, and vascular disease were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, mediation analysis was performed to determine whether the effects of TDP-43 were mediated by hippocampal sclerosis. Results: One-hundred ninety-five (57%) cases were TDP-positive. The TDP-positive cases could be divided into five stages (TDP-43 in AD (TAD) stages I-V), beginning in the amygdala. After accounting for potential confounders, TDP-43 had a strong effect on cognition, memory loss, and hippocampal atrophy in AD, particularly at lower Braak stages (Figure). These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10X more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and correlated with the TAD staging scheme. Conclusions: The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages. Importantly, TDP-43 amplifies memory loss and hippocampal atrophy in AD and also appears to be able to overpower what has been termed resilient cognition in AD. TDP-43 therefore is a key player in the AD neurodegenerative process and should be considered a potential therapeutic target for the treatment of AD.