Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease

Objective To study the neuropathologic correlates of cholinergic basal forebrain (BF) atrophy as determined using antemortem MRI in the Alzheimer disease (AD) spectrum. Methods We determined associations between BF volume from antemortem MRI brain scans and postmortem assessment of neuropathologic features, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy body (LB) pathology, and TDP-43, in 64 cases of the Alzheimer's Disease Neuroimaging Initiative cohort. For comparison, we assessed neuropathologic features associated with hippocampal and parahippocampal gyrus atrophy. In addition to region of interest-based analysis, we determined the association of neuropathologic features with whole brain gray matter volume using regionally unbiased voxel-based volumetry. Results BF atrophy was associated with Thal amyloid phases (95% confidence interval [CI] -0.49 to -0.01,p= 0.049) and presence of LB pathology (95% CI -0.54 to -0.06,p= 0.015), as well as with the degree of LB pathology within the nucleus basalis Meynert (95% CI -0.54 to -0.07,p= 0.025). These effects were no longer significant after false discovery rate (FDR) correction. Hippocampal atrophy was significantly associated with the presence of TDP-43 pathology (95% CI -0.61 to -0.17,p= 0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI -0.49 to -0.01,p= 0.044; uncorrected). Voxel-based analysis confirmed spatially restricted effects of Thal phases and presence of LB pathology on BF volume. Conclusions These findings indicate that neuropathologic correlates of regional atrophy differ substantially between different brain regions that are typically involved in AD-related neurodegeneration, including different susceptibilities to common comorbid pathologies.