Limbic Predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC) is Associated with Lower Diffusion Anisotropy in Medial Temporal Lobe White Matter

Abstract

AbstractBackgroundLimbic 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 white matter (WM) structural integrity caused by LATE‐NC may be detected by means of diffusion tensor imaging (DTI).MethodThis study included 148 individuals participating in Rush Memory 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 images were aligned to an ex‐vivo FA template and projected onto the corresponding WM skeleton.Voxel‐wise analysis was performed on the WM skeleton 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) probable WM connections passing through them were extracted, (2) FA values were compared between LATE‐NC stages 1, 2, 3 and stage 0 (after adjusting for covariates).ResultVoxel‐wise analysis revealed lower FA for greater LATE‐NC burden in medial temporal lobe WM (Fig.3). The connections traversing this WM region 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 in medial temporal lobe WM across LATE‐NC stages revealed significant FA anomalies between stages 0 and 3 (ΔFA=‐0.06, FDR‐corrected p<10‐6) (Fig.5).ConclusionThe present study in autopsied brains of community‐based older adults showed lower diffusion anisotropy with greater LATE‐NC burden involving WM connections 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.