Central cholinergic white matter pathways in prodromal and early manifest Lewy body disease

Background and ObjectivesDegeneration of the nucleus basalis of Meynert (NbM) has been reported in Lewy body (LB) disorders. However, while structural changes in the white matter system connecting the NbM to the cerebral cortex have been shown in LB dementia, less is known regarding its vulnerability in prodromal and early manifest patients without cognitive impairment, and its relationship with clinical manifestation and disease progression. MethodsHere, we used diffusion MRI (dMRI) data from the Oxford Parkinsons Discovery Cohort (OPDC) to examine whether differences in the microstructural integrity of the lateral and medial white matter pathways of the NbM are already evident in prodromal (isolated REM-sleep behaviour disorder (iRBD), n=67), and early manifest (Parkinsons disease (PD), n=73) LB disease compared to matched controls (n=53). Furthermore, we examined its relationship with baseline and longitudinal cognitive function, and future risk of phenoconverting from iRBD to manifest neurodegenerative disease (PD or dementia with Lewy bodies). Lastly, we examined the potential role of the NbM as a syndrome-specific epicenter in each of the two patient groups by spatially correlating its cortical connectivity profile with cortical atrophy pattern. ResultsWe found higher microstructural integrity of both pathways to be associated with better verbal fluency performance at baseline ({beta}=3.29-3.52, p<0.05). Higher baseline medial pathway integrity was also associated with slower decline in MoCA score over time ({beta}=0.05, p<0.05). In addition, higher integrity of both pathways at baseline was associated with reduced future risk of phenoconversion in iRBD (HR<0.51, p<0.05). Lastly, we found reduced grey matter volumes in cortical regions that are more anatomically connected to the NbM in iRBD (r=-0.31, p<0.05), but not PD (r=-0.08, p=0.29), suggesting its potential role in shaping cortical pathology in iRBD. Interestingly, no evidence for differences in NbM pathways integrity between patient cohorts and controls at baseline was observed. ConclusionsOur findings suggest that the NbM white matter system may serve as a non-invasive biomarker, indicating risk for clinical conversion and cortical pathology in iRBD and for baseline and longitudinal cognitive functioning in iRBD and early PD. Hence, it may potentially be used to stratify patients for clinical trials of disease-modifying and neuroprotective therapies.