Cholinergic basal forebrain degeneration in isolated REM sleep behaviour disorder

Although growing evidence suggests that cholinergic basal forebrain degeneration is linked to cognitive impairment and axial motor symptoms in Lewy body disorders, the cholinergic contribution to their prodromal phase remains largely unknown. Herein, we aimed to address three important yet unresolved problems focusing on prodromal Lewy body disorders: (i) to examine whether and where basal forebrain degeneration begins; (ii) to determine how such alterations are related to other brain morphometric changes and monoaminergic deficits; and (iii) to investigate the extent to which basal forebrain atrophy contributes to the clinical picture. We included 93 patients with polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD), 33 with de novo Parkinson's disease (PD) with a premorbid history of RBD (dnPDRBD) and 36 healthy controls. Participants underwent baseline assessments including volumetric MRI, 18F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane PET scan, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale and neuropsychological evaluations. Regional volumes of cholinergic nuclei 1, 2 and 3 (Ch1-3) and cholinergic nucleus 4 (Ch4) were extracted using probabilistic maps, and voxel-based and surface-based morphometric analyses were applied to identify basal forebrain atrophy-associated cortical and subcortical regions. Subgroups of patients with iRBD underwent repeated motor and cognitive assessments (38 and 34 patients for 2 and 4 years, respectively). Among the basal forebrain complex, Ch4 volumes, but not Ch1-3 volumes, were significantly reduced in patients with iRBD. This reduction was positively correlated with limbic regions, including the amygdala and cingulate cortex, and, to a lesser extent, with the neocortical regions, particularly the frontal and temporal cortices. With respect to clinical symptoms, both Ch1-3 and Ch4 volume reductions were modestly associated with severe axial motor symptoms. Additionally, Ch1-3 volume reduction was associated with higher incidence of dementia and faster progression of memory impairment, whereas Ch4 volume reduction was associated with faster progression of limb bradykinesia. Using a multimodal imaging approach, we found that iRBD patients who later converted to PD showed predominant monoaminergic deficits but variable cholinergic involvement, and these patterns were similar to those observed in the dnPDRBD group. Conversely, iRBD patients who later converted to dementia with Lewy bodies showed predominant cholinergic deficits but variable monoaminergic involvement. This comprehensive analysis provides important implications for understanding how cholinergic basal forebrain degeneration is associated with brain morphometric changes, clinical outcomes and monoaminergic degeneration during the prodromal phase of Lewy body disorders.