Rates of hippocampal atrophy and post-mortem TDP-43 in Alzheimer’s disease: a longitudinal retrospective study

BACKGROUND: Post-mortem studies have not identified an association between beta-amyloid or tau and rates of hippocampal atrophy in Alzheimer’s disease. TAR DNA binding protein of 43kDa (TDP-43) is another protein recently linked to Alzheimer’s disease. We aimed to determine whether hippocampal TDP-43 is associated with faster rates of hippocampal atrophy. METHODS: Two-hundred ninety-eight autopsied cases with Alzheimer’s spectrum disease that had antemortem head MRI scans between 1/1/1999–12/31/2012 recruited into the Mayo Clinic Alzheimer’s Disease Research Center or Patient Registry/Study of Aging were analyzed. TDP-43 immunohistochemistry was performed and cases classified as follows: no TDP-43; TDP-43 restricted to amygdala; and TDP-43 spreading into hippocampus. Eight-hundred sixteen MRI scans, spanning 1.0–11.2 years prior to death, were analyzed. We utilized longitudinal FreeSurfer and tensor-based morphometry with symmetric normalization to calculate hippocampal volume on all serial MRI and performed linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy, and determine the trajectory of TDP-43 associated atrophy. FINDINGS: One-hundred forty-one cases showed no TDP-43, 33 had TDP-43 restricted to the amygdala and 124 had TDP-43 in hippocampus. Cases with hippocampal TDP-43 had faster rates of hippocampal atrophy compared to cases with amygdala-only TDP-43 and those without TDP-43 in cases with an intermediate-high likelihood of having Alzheimer’s disease (N=261). Hippocampal TDP-43 was not associated with rate of hippocampal atrophy in cases with low likelihood of having Alzheimer’s disease (N=37). The trajectory analysis suggested that increased rates of TDP-43 associated hippocampal atrophy may be occurring at least 10-years before death. Results were similar for FreeSurfer and tensor-based morphometry. INTERPRETATION: In Alzheimer’s disease, TDP-43 should be considered a potential factor related to increased rates of hippocampal atrophy. Given the importance of hippocampal atrophy in Alzheimer’s disease, it is imperative that we develop techniques for detecting TDP-43 pathology in-vivo. FUNDING: National Institute of Aging