Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study

Post-mortem studies have not identified an association between β-amyloid or tau and rates of hippocampal atrophy in patients with Alzheimer's disease. TAR DNA binding protein 43 (TDP-43) is another protein linked to Alzheimer's disease. We aimed to investigate whether hippocampal TDP-43 is associated with increased rates of hippocampal atrophy. In this longitudinal retrospective study, we analysed post-mortem brain tissue of all individuals with an Alzheimer's disease spectrum pathological diagnosis who had antemortem head MRI scans between Jan 1, 1999, and Dec 31, 2012, and who had been recruited into the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. We did TDP-43 immunohistochemistry and classified individuals as follows: no TDP-43 in the amygdala or hippocampus; TDP-43 restricted to the amygdala; and TDP-43 spreading into the hippocampus. Each individual was also assigned a neurofibrillary tangle stage (B1–B3), relating to the likelihood of having Alzheimer's disease. We used longitudinal FreeSurfer software and tensor-based morphometry with symmetric normalisation to calculate hippocampal volume on all serial MRI scans and used linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy and to assess the trajectory of TDP-43-associated atrophy. We identified 298 individuals meeting the inclusion criteria, with 816 usable MRI scans (spanning 1·0–11·2 years of the disease) available for analysis. 141 individuals showed no TDP-43 in the amygdala or hippocampus, 33 had TDP-43 restricted to the amygdala, and 124 had TDP-43 in the hippocampus. Among individuals with a high likelihood of having Alzheimer's disease (neurofibrillary tangle stage B3; n=205), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=103, annual volume change −4·39%, 95% CI −4·82 to −3·95; p