White matter changes in the cholinergic system in Alzheimer’s disease and dementia with Lewy bodies

Abstract

AbstractBackgroundThe early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD.MethodsNBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data.ResultsFree water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls).ConclusionOur cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations.