Cholinergic white matter pathways integrity in prodromal and early manifest Lewy body disease

Degeneration of the nucleus basalis of Meynert (NbM), the main cholinergic source to the cerebral cortex, has been demonstrated in advanced stages of Lewy body (LB) disorders. While the lateral and medial white matter pathways connecting the NbM to the cerebral cortex have been shown to be affected in LB patients with dementia, less is known regarding their vulnerability in prodromal and early manifest patients without significant cognitive impairment, and how their integrity relates to disease manifestation and progression. Here, we used diffusion MRI (dMRI) to examine whether changes in the microstructural integrity of the white matter tracts of the NbM are already evident in prodromal LB disease (namely, isolated rapid eye movement sleep behaviour disorder (iRBD), n = 67), and in patients with early manifest LB disease (Parkinson's disease (PD), n = 73), compared to healthy controls (n = 53). Furthermore, we examined whether the microstructural integrity of these pathways relates to cognitive function at baseline and longitudinal follow-up, and to the risk of phenoconverting from iRBD to manifest neurodegenerative disease (PD or dementia with LBs). Lastly, we examined the potential role of the NbM as a disease epicentre in the two patient groups by spatially correlating its cortical structural connectivity profile with disease-specific (i.e., iRBD or PD) cortical atrophy patterns. We found higher microstructural integrity at baseline of both the lateral and medial pathways to be associated with better verbal fluency performance at baseline (β = 3.29-3.52, P < 0.05). Higher microstructural integrity of the medial pathway was also associated with slower decline in Montreal Cognitive Assessment (MoCA) over time (β = 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). Furthermore, we found that cortical regions that are more anatomically connected to the NbM exhibited lower grey matter volumes 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, despite the associations observed at the subject-level, no evidence for differences in microstructural integrity of the NbM pathways was observed between patient cohorts and controls at baseline. Our findings suggest that the NbM white matter pathways have the potential to serve as non-invasive biomarkers indicating risk for clinical conversion and cortical pathology in iRBD and for baseline and longitudinal cognitive functioning in iRBD and early PD and therefore may potentially be used to stratify patients for clinical trials of disease-modifying and neuroprotective therapies.