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, = 0.049) and presence of LB pathology (95% CI -0.54 to -0.06, = 0.015), as well as with the degree of LB pathology within the nucleus basalis Meynert (95% CI -0.54 to -0.07, = 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, = 0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI -0.49 to -0.01, = 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.