Spatial pattern of R 2 relaxation rate is associated with limbic‐predominant, age‐related, TDP‐43 encephalopathy neuropathological change (LATE‐NC)

Abstract

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) refers to the stereotypical accumulation of TDP-43 proteinopathy in older adults, and has been associated with lower memory, cognitive decline and increased likelihood of dementia. However, association of R2 with LATE-NC is still unclear. In this work, we examined the association and spatial profile of R2 alterations with LATE-NC in a large community cohort of older adults. This study included 797 individuals participating in three longitudinal studies: Rush Memory and Aging Project, Religious Orders Study, and Minority Aging Research Study (Fig. 1). Ex-vivo images were collected using a 2D multi-echo spin-echo (ME-SE) sequence. Afterwards, detailed neuropathologic examination was performed by a board-certified neuropathologist blinded to all data (Fig. 2). The R2 relaxation rate was quantified voxel-wise by fitting a monoexponential decay function S = S0 ∙exp(-R2 ∙t) to the ME-SE data. Images from one of the echoes were non-linearly registered to a brain template, and the resulting transformations were applied to the R2 -maps to enable voxel-wise analysis. Voxel-wise linear regression was used to investigate the association of R2 relaxation rate with LATE-NC controlling for Alzheimer's pathology, Lewy bodies, gross and microscopic infarcts, atherosclerosis, cerebral amyloid angiopathy, arteriolosclerosis, as well as age at death, sex, years of education, postmortem interval to fixation and postmortem interval to imaging, and scanner. Statistical significance was set at p<0.05. Voxel-wise analysis demonstrated lower R2 for greater LATE-NC burden in a number of brain regions in the temporal, frontal, occipital lobes and basal ganglia (Fig. 3). The strongest effects were observed in the amygdala, hippocampus, and neighboring temporal lobe regions. In addition, lower R2 with greater LATE-NC burden was demonstrated in the caudate, insular, frontal and occipital white matter regions. No brain regions showed positive associations of R2 with LATE-NC. The present study demonstrated a spatial pattern of lower R2 relaxation rate for greater LATE-NC burden in a large community cohort of older adults. This pattern involved mainly the temporal, frontal, occipital lobes and basal ganglia. The link between R2 and LATE-NC may be exploited towards the development of algorithms for the prediction of this devastating, recently recognized disease entity.