Pedunculopontine-thalamic cholinergic projections in rapid eye movement sleep behaviour disorder

Cholinergic system degeneration is a hallmark of Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), but its involvement in prodromal stages, particularly regarding pedunculopontine-thalamic projections, remains unclear. This study investigated cholinergic pathway integrity in isolated REM sleep behaviour disorder (iRBD) and its relation to phenoconversion risk. We analyzed data from 146 iRBD patients and 102 controls from the Parkinson's Progression Markers Initiative using T1-weighted MRI for basal forebrain volume and diffusion-weighted imaging for three cholinergic pathways: lateral and medial nucleus basalis of Meynert (NBM)-cortical pathways and pedunculopontine nucleus (PPN)-thalamic pathways. Bayesian mixed models and Cox proportional hazards models assessed group differences, cognitive associations, and phenoconversion risk. Fractional anisotropy along PPN-thalamic pathways was reduced in iRBD, particularly in the left hemisphere. Within iRBD patients, medial NBM pathway integrity correlated with baseline cognitive performance. Reduced PPN-thalamic integrity predicted increased phenoconversion risk (hazard ratio=2.08). No group differences or associations with phenoconversion were found for NBM-cortical pathways or basal forebrain volume. These findings suggest that brainstem-thalamic cholinergic projections may be affected earlier than the basal forebrain system in Lewy body disease, potentially serving as a sensitive marker for phenoconversion risk in iRBD pending validation in longer follow-up studies.