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

Abstract

Background: 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.

Methods: 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.

Findings: 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<0·0001) than did those with amygdala-only TDP-43 (n=20, -3·29%, -4·11 to -2·46; p<0·0001; difference -1·10%, 95% CI -2·02 to -0·19; p=0·02) and those without TDP-43 (n=82, -3·11%, -3·54 to -2·68; p<0·0001; difference -1·28%, -1·88 to -0·67; p<0·0001). Among individuals with an intermediate likelihood of having Alzheimer's disease (neurofibrillary tangle stage B2; n=56), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=17, annual volume change -4·05%, 95% CI -5·09 to -2·99; p<0·0001) than did those with amygdala-only TDP-43 (n=6, -1·78%, -3·04 to -0·55; p=0·004; difference -2·27%, 95% CI -3·79 to -0·67; p=0·006) and those without TDP-43 (n=33, -1·63%, -2·43 to -0·83; p=0·0002; difference -2·43%, -3·66 to -1·18; p=0·0002). Hippocampal TDP-43 was not associated with the rate of hippocampal atrophy in individuals with a low likelihood of having Alzheimer's disease (neurofibrillary tangle stage B1; n=37). The trajectory analysis suggested that increased rates of TDP-43-associated hippocampal atrophy might occur at least 10 years before death. Results were similar for FreeSurfer and tensor-based morphometry.

Interpretation: TDP-43 should be considered as a potential factor related to increased rates of hippocampal atrophy in patients with Alzheimer's disease. Given the importance of hippocampal atrophy in Alzheimer's disease, it is imperative that techniques are developed for detection of TDP-43 in vivo.

Funding: US National Institute on Aging (National Institutes of Health).

Figure 1

Analyses of FreeSurfer hippocampal atrophy rates by TDP-43 and neurofibrillary tangle stages based on linear mixed effects regression modeling. (A) Shows hippocampal atrophy rates, expressed as an annual percent volume change, by TDP-43 stage separately for neurofibrillary tangles stages B1, B2, and B3. (B) Compares the rates of hippocampal atrophy, expressed as differences in annual percent volume change, between TDP-43 stages for each of the three neurofibrillary tangle stages. Annual percent volume changes and group-wise difference values are provided in Appendix, p8.

Figure 2

Analyses of FreeSurfer hippocampal atrophy rates by TDP-43 and amyloid stage (amyloid- (A0), and amyloid + (A1)) based on linear mixed effects regression modeling. (A) Shows hippocampal atrophy rates, expressed as an annual percent volume change, by TDP-43 stage separately for two amyloid stages. (B) Compares the rates of hippocampal atrophy, expressed as differences in annual percent volume change, between TDP-43 stages for each of the two amyloid stages. Annual percent volume changes and group-wise difference values are provided in Appendix, p8.

Figure 3

Trajectories of FreeSurfer hippocampal volumes for cases with and without hippocampal TDP-43 based on linear mixed effects regression modeling. The estimates assumed age at death of 80 years, MRI scan field strength of 1.5T, and a total intracranial volume of 1.4L. Note that cases with TDP-43 in the hippocampus (TDP+) had faster rates of hippocampal atrophy compared to cases without TDP-43 in the hippocampus (TDP−). The separation of the confidence intervals of the trajectories appears roughly a decade prior to death. Tick marks on the x-axis indicate available MRI data points in terms of years from death. Overall, on an annual basis and assuming death at age 80 years, mean decline was an estimated 0.19 cm3/year (95% CI, 0.17 to 0.20).

Figure 4

Models assessing the role of additional pathologies. (A) Analysis of the independent effect of each of multiple pathologies on hippocampal atrophy rates based on linear mixed effects regression modeling assuming no interactions among the effects. Estimates are from a mixed model with TDP-43, neurofibrillary tangle (NFT) stage, amyloid positivity, hippocampal sclerosis, and age at death. For reference, the estimated rate of decline for an individual who died at age 80 with TDP Stage 0, NFT Stage B1, no amyloid, and no hippocampal sclerosis is 0.7% per year (95% CI, −1.7 to +0.25). (B) FreeSurfer hippocampal atrophy rates in each TDP-43 stage contrasting those with neurofibrillary tangle stage B3 versus those with neurofibrillary tangle stage of B1 or B2. The atrophy rates are statistically significant in TDP-43 stages 0 and 1. Group-wise difference values are provided in Appendix, p8.