Voxel‐by‐Voxel regression analysis identifies association between postmortem TDP‐43 and antemortem fractional anisotropy within white matter fibers connected to the hippocampus.

Background: TAR DNA‐binding protein 43 (TDP‐43), has been shown to be involved in various neurodegenerative disorders involving axonal damage including ALS, FTLD, and LATE. Studying the relationships between postmortem TDP‐43 and antemortem white matter (WM) structural integrity can allow for a better understanding of the disease, rather than exploring clinical presentations alone. Methods: In‐vivo diffusion‐weighted images were gathered on a 1.5T scanner from subjects from the Religious Orders Study and the Rush Memory and Aging Project. Images were processed using TORTOISE to calculate fractional anisotropy (FA). We utilized the IIT probabilistic WM atlas to identify voxels containing fibers that originate or terminate in the hippocampus. A semi‐quantitative rating of TDP‐43 severity was assessed in 5 brain regions. We utilized regression models to relate postmortem disease and antemortem FA within each voxel. Coexisting disease including β‐amyloid plaques, tau tangles, and cerebrovascular disease were used as covariates, along with demographic variables. Results: The 58 subjects were 91.10 (SD = 6.37) years old at death with a median interval from MRI to death of 2.8 years (SD = 1.19). Results revealed a significant negative relationship (p<0.05) between postmortem TDP‐43 and FA within fibers connecting the hippocampus to the parahippocampal and entorhinal cortices, fornix, and lingual gyrus. Preliminary results did not survive multiple comparisons correction. Conclusions: Our findings indicate that greater TDP‐43 disease burden is associated with lower white matter integrity within regions of the limbic system. These findings suggest the TDP‐43 disease process may contribute to reduced structural connectivity between the hippocampus and related regions, which may impact larger brain networks. [ABSTRACT FROM AUTHOR]