Positive association of Cerebral Amyloid Angiopathy (CAA) with R2 Relaxation rate: A study of ex‐vivo MRI and pathology

Abstract

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid‐β in the walls of cortical and leptomeningeal small vessels. CAA is common in older adults and has been associated with cognitive decline and dementia. In this work, the association of CAA with the transverse relaxation rate R2 values in a large community‐based cohort of older adults was investigated.MethodCerebral hemispheres from 797 participants of three cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, and the Religious Orders Study (Figure 1) were included in this work. All hemispheres were imaged ex‐vivo at approximately 30 days postmortem using 3T clinical MRI scanners. Each scan included a multi‐echo spin‐echo sequence, and in each voxel, the signals from the different echoes were used to fit a mono‐exponential T2 decay equation (R2 is the reciprocal of T2). The resulting R2 maps were registered to an ex‐vivo brain hemisphere template using ANTS. Following the MRI scan, each hemisphere underwent thorough neuropathologic evaluation (Figure 2). The assessed pathologies were: CAA, Alzheimer’s pathology, LATE‐NC, hippocampal sclerosis (HS), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts.Voxel‐wise linear regression was conducted to test the association of R2 with CAA, controlling for all other neuropathologies listed above, demographics (age at death, sex, education), and other variables (postmortem interval to immersion in fixative, postmortem interval to ex‐vivo MRI, scanners). Statistical analysis was done using PALM with tail‐accelerated 1000 permutations, threshold‐free cluster enhancement, and family‐wise error rate correction. Statistical significance was set at p<0.05.ResultThe voxel‐wise analysis revealed a spatial pattern of higher R2 values for higher CAA burden (Figure 3). The pattern included subcortical structures such as the caudate, putamen, nucleus accumbens, hippocampus, regions in the insula, anterior cingulate cortex, orbitofrontal cortex, and superior frontal cortex (Figure 3). No voxel showed a negative association between R2 values and CAA burden.ConclusionOur work showed that CAA is associated with higher R2 among older adults, independent of other neuropathologies and demographic factors. The spatial pattern for this association derived from the voxel‐wise analysis included subcortical and frontal lobe structures.