AAIC 2022 Abstracts Basic Science and Pathogenesis Part 2

Background: Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is now recognized as a common neuropathological disorder of the aging brain and is associated with accelerated cognitive decline. However, the MRI signature of LATE-NC has not been fully determined. In this work, we hypothesized that abnormalities in whitematter (WM) structural integrity caused by LATE-NC may be detected by means of diffusion tensor imaging (DTI). Method: This study included 148 individuals participating in RushMemory and Aging Project, and Religious Orders Study (Fig.1). Ex-vivo DTI images were acquired using 3T scanners, followed by detailed histopathologic examination by a board-certified neuropathologist (Fig.2). As a post-processing step, fractional anisotropy (FA) maps generated from DTI imageswere aligned to an ex-vivo FA template and projected onto the correspondingWMskeleton. Voxel-wise analysis was performed on theWMskeleton to investigate the association of FA with LATE-NC, controlling for Alzheimer's disease, Lewy bodies, cerebral amyloid angiopathy, cerebral infarcts, atherosclerosis, arteriolosclerosis, age at death, sex, years of education, postmortem interval to fixation and imaging, total white matter hyperintensity volume, and scanner. Statistical significance was set at p<0.05. Using the voxels that showed significance in this analysis, (1) probableWMconnections passing through them were extracted, (2) FA values were compared between LATE-NC stages 1, 2, 3 and stage 0 (after adjusting for covariates). Result: Voxel-wise analysis revealed lower FA for greater LATE-NC burden in medial temporal lobeWM(Fig.3). The connections traversing thisWMregion included fibers connecting amygdala, temporal pole, hippocampus, entorhinal cortex, fusiform, insula, and putamen (Fig.4). No voxel showed positive association between FA and LATE-NC. Comparison of adjusted FA values inmedial temporal lobeWMacross LATE-NC stages revealed significant FA anomalies between stages 0 and 3 (.FA=-0.06, FDR-corrected p<10-6) (Fig.5). Conclusion: The present study in autopsied brains of community-based older adults showed lower diffusion anisotropy with greater LATE-NC burden involving WM con-nections between regions consistent with the known distribution of LATE-NC. Overall, this pattern may potentially contribute towards the development of an in-vivo tool for the prediction of this devastating, recently recognized disease entity.

Automated summary

This study investigated the impact of white matter structural abnormalities caused by LATE-NC using diffusion tensor imaging. The results showed that greater LATE-NC burden was associated with lower diffusion anisotropy in the medial temporal lobe white matter. These white matter connectivity anomalies may potentially contribute to the prediction of this disease.