Cholinergic degeneration and early cognitive signs in prodromal Lewy body dementia.

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.