Cholinergic degeneration and early cognitive signs in prodromal Lewy body dementia

Abstract

Introduction: Isolated REM sleep behavior disorder (iRBD) is a strong prodromal marker of Lewy body diseases (LBDs) - Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Cholinergic loss is linked to cognitive decline in these conditions, but its trajectory remains unclear.

Methods: In a cohort of 92 iRBD participants with baseline MRI, cholinergic basal forebrain (cBF) volume was measured, with longitudinal changes analyzed in 49 with follow-up scans. Cross-sectional neuropsychological associations were examined across a broader RBD-LBD continuum, including the iRBD cohort plus 65 PD and 15 DLB patients with probable RBD.

Results: cBF volume declined at comparable rates in iRBD-to-PD and iRBD-to-DLB converters, but atrophy was more severe at DLB phenoconversion. cBF atrophy correlated with attention, executive, and memory deficits. In iRBD, baseline cBF z-score < -1.0 predicted dementia (hazard ratio = 9.57, p = .009).

Conclusion: cBF degeneration evolves from the prodromal iRBD stage of LBDs and predicts dementia, highlighting a window for cholinergic-targeted intervention.

Highlights: Basal forebrain links to attention, executive function, and memory in the RBD continuum. Basal forebrain atrophy progresses at similar rates in prodromal PD and prodromal DLB. At phenoconversion, basal forebrain atrophy is greater in DLB than in PD converters. Basal forebrain atrophy strongly predicts future dementia in iRBD. Executive dysfunction predicts faster basal forebrain degeneration in iRBD.

Keywords: Parkinson's disease; REM sleep behavior disorder; basal forebrain; cholinergic; cognition; dementia with Lewy bodies.

FIGURE 1

Longitudinal changes in cBF volume in prospective iRBD cohort with repeated MRI scans. (A) Estimated annual progression of cBF degeneration by phenoconversion outcome in prospective iRBD cohort. cBF volume progressively declines at a comparable rate in iRBD‐to‐PD and iRBD‐to‐DLB converters, with greater severity of cBF atrophy observed at the time of phenoconversion in DLB. Non‐converters exhibited no appreciable changes in cBF volumes over time. (B) Each line represents the individual cBF trajectory data of participants within each group. cBF, cholinergic basal forebrain; DLB, dementia with Lewy bodies; iRBD, isolated REM sleep behavior disorder; PD, Parkinson's disease; RBD, REM sleep behavior disorder.

FIGURE 2

Groupwise comparison of cBF volume across RBD–LBD continuum. (A) Cross‐sectional comparison of cBF volume shows significant reductions in DLB compared to controls. Within the RBD–LBD continuum, cBF volume is reduced in the order iRBD, PD, and DLB. (B) Among PD and DLB groups, no significant differences in cBF volumes are observed between subgroups with video PSG‐confirmed RBD and those with probable RBD identified through questionnaires. Subjects with video PSG‐confirmed RBD in each group represent individuals who converted from iRBD in the prospective cohort. cBF, cholinergic basal forebrain; DLB, dementia with Lewy bodies; iRBD, isolated REM sleep behavior disorder; LBD, Lewy body disease; PD, Parkinson's disease; PSG, polysomnography; pRBD, probable REM sleep behavior disorder; RBD, REM sleep behavior disorder. ^* p <  0.05, ^** p < 0.01, ^*** p < 0.001.

FIGURE 3

GM clusters associated with cBF degeneration across RBD–LBD continuum. Voxel‐based analyses of GM clusters associated with cBF volume are presented for each clinical group, categorized by clinical status at time of scan: (A) iRBD, (B) PD, and (C) DLB. Cluster size thresholds were set at k > 100 across all clinical groups. The p‐value thresholds applied were FWE‐corrected p < .05 for iRBD and PD and uncorrected p < .001 for DLB. The most prominent clusters – characterized by the highest peak T values and largest sizes – were consistently localized to limbic regions, including the olfactory cortex, amygdala, hippocampus, and parahippocampal gyrus, across all groups. Detailed information on these clusters can be found in the supplementary material. cBF, cholinergic basal forebrain; DLB, dementia with Lewy bodies; FWE, family‐wise error; GM, gray matter; iRBD, isolated REM sleep behavior disorder; LBD, Lewy body disease; PD, Parkinson's disease; RBD, REM sleep behavior disorder.