Independent and additive contribution of white matter hyperintensities and Alzheimer’s disease pathology to basal forebrain cholinergic system degeneration

• Published in: NeuroImage clinical Vol. 39; p. 103477
• Main Authors: Kindler, Christine, Upadhyay, Neeraj, Bendella, Zeynep, Dorn, Franziska, Keil, Vera C., Petzold, Gabor C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2023; Elsevier
• Subjects: Alzheimer's disease; Cerebral small-vessel disease; Cholinergic basal forebrain nucleus; Nucleus basalis of Meynert; Regular; Voxel-based morphometry; White matter hyperintensities; Nucleus basalis of Meynert; Cerebral small-vessel disease; White matter hyperintensities; Cholinergic basal forebrain nucleus; Alzheimer's disease; Voxel-based morphometry
• ISSN: 2213-1582; 2213-1582
• DOI: 10.1016/j.nicl.2023.103477

•Cholinergic basal forebrain nuclei (CBFN) are smaller in AD compared to controls.•White matter hyperintensities in cholinergic projections are not correlated with CBFN volume in AD.•Cholinergic pathway hyperintensities are only weakly correlated with CBFN volume in non-AD subjects.•Cholinergic pathway hyperintensities correlate with gray matter atrophy in controls, but not in AD.•CBFN volumes correlate with distinct regional cortical atrophy patterns in both groups. Degeneration of the cholinergic basal forebrain nuclei (CBFN) system has been studied extensively in Alzheimer's disease (AD). White matter hyperintensities are a hallmark of aging as well as a common co-morbidity of AD, but their contribution to CBFN degeneration has remained unclear. Therefore, we explored the influence of white matter hyperintensities within cholinergic subcortical-cortical projection pathways on CBFN volumes and regional gray matter volumes in AD and age- and gender-matched controls. We analyzed magnetic resonance images (MRI) from 42 patients with AD and 87 age- and gender-matched control subjects. We assessed the white matter hyperintensity burden within the cholinergic projection pathways using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and applied probabilistic anatomical maps for the analysis of CBFN volumes, i.e. the Ch1-3 compartment and the Ch4 cell group (nucleus basalis of Meynert), by diffeomorphic anatomical registration using exponentiated lie algebra analysis of voxel-based morphometry. Using multiple linear regression analyses, we explored correlations between regional gray matter volumes and the extent of white matter hyperintensities or CBFN volumes in both groups. In AD, all CBFN volumes were significantly smaller than in controls, and white matter hyperintensity burden within the cholinergic projection pathways was not correlated with CBFN volume. In controls, white matter hyperintensity burden within the cholinergic projection pathways was inversely correlated with CBFN volume when corrected for sex and total intracranial volume, but this correlation was no longer significant after correction for age. Voxel-wise multiple linear regression analyses using threshold-free cluster enhancement revealed that in controls, cholinergic pathway hyperintensities correlated with gray matter loss in perisylvian areas, whereas the were no effects in AD. Moreover, we found that CBFN volumes correlated with distinct regional cortical atrophy patterns in both groups. Our results indicate that white matter hyperintensities and AD pathology contribute independently but additively to the degeneration of cholinergic basal forebrain structures. Whereas AD is primarily associated with CBFN volume loss, cholinergic degeneration associated with white matter hyperintensities appears to involve disruption of cholinergic cortical projection fibers with less pronounced effects on CBFN volumes.