Objective: To study the neuropathological correlates of cholinergic basal forebrain atrophy as determined using ante-mortem MRI in the Alzheimer’s disease (AD) spectrum.

Methods: We determined associations between basal forebrain (BF) volume from antemortem MRI brain scans and post-mortem assessment of neuropathological features, including neuritic plaques, neurofibrillary tangles (NFT), Lewy body (LB) pathology, and TDP-43, in 64 cases of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. For comparison, we assessed neuropathological features associated with hippocampal and parahippocampal gyrus atrophy. In addition to region of interest-based analysis, we determined the association of neuropathological features with whole brain grey matter volume using regionally unbiased voxel-based volumetry.

Results: BF atrophy was associated with Thal amyloid phases (95% confidence interval -0.49 - -0.01, p=0.049) and presence of LB pathology (95% CI -0.54 - -0.06, p=0.015), as well as with the degree of LB pathology within the Nucleus basalis Meynert (NbM) (95% CI -0.54 - -0.07, p=0.025). These effects were no more significant after false discovery rate (FDR) correction. Hippocampal atrophy was significantly associated with the presence of TDP-43 pathology (95% CI 0.61 - -0.17, p=0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI -0.49 - 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 neuropathological correlates of regional atrophy differ substantially between different brain regions that are typically involved in AD-related neurodegeneration, including different susceptibilities to common co-morbid pathologies.

Supplementary Material Section describing the neuropathological assessments of the ADNI Neuropathology Core