Cerebrovascular co-pathology and cholinergic white matter pathways along the Lewy body continuum

Background: Dementia with Lewy Bodies (DLB) often presents with cholinergic degeneration and varying degrees of cerebrovascular disease (CVD). Radiological methods for assessing cholinergic degeneration in DLB are limited. We investigated the potential of the radiological Cholinergic Pathway Hyperintensities Scale (CHIPS) in identifying CVD-related disruptions in cholinergic white matter pathways. We compared the utility of CHIPS to other radiological and automated methods of evaluation. Methods: We included 82 individuals (41 patients along the clinical continuum of Lewy body (LB) disease and 41 healthy controls) from the Sant Pau Initiative on Neurodegeneration cohort. We evaluated white matter signal abnormalities (WMSA) and cholinergic pathways integrity on MRI using two clinical radiological methods (CHIPS, Fazekas) and two automated methods (tractography mean diffusivity, FreeSurfer WMSA volume). Between and within study groups, we investigated associations among those measures, as well as regional atrophy, cerebrospinal fluid (CSF) biomarkers of AD co-pathology, core clinical features, and cognitive measures. Results: Cholinergic white matter methods (CHIPS and tractography) showed a strong correlation, as did global WMSA methods (FreeSurfer WMSA volume and Fazekas). LB patients showed a significantly higher degree of WMSA in the external capsule cholinergic pathway compared to controls, without global WMSA differences. Receiver operating characteristic (ROC) analysis revealed that the CHIPS score in the posterior external capsule and the mean diffusivity in both external capsule and cingulum exceeded the threshold for an optimal biomarker in discriminating LB patients from controls. Higher CHIPS scores, Fazekas scores, and mean diffusivity from tractography were associated with more pronounced frontal atrophy in LB patients. No significant associations were found between the four WMSA and integrity methods and any of the core clinical features, cognitive measures, or CSF biomarkers in the LB group. Conclusions: Cholinergic WMSA were more pronounced in LB patients than in healthy controls, above and beyond global WMSA. Mechanistically, CVD in cholinergic white matter may be implicated in frontal atrophy along the LB continuum. Clinically, we demonstrate the potential of CHIPS to assess cholinergic WMSA. Our findings show that CVD co-pathology may contribute to the well-known cholinergic degeneration in DLB, allowing for vascular health-focused therapies from prodromal DLB onwards.