Dementia with Lewy bodies often presents with cholinergic degeneration and varying degrees of cerebrovascular disease. There is a lack of radiological methods for evaluating cholinergic degeneration in dementia with Lewy bodies. We investigated the potential of the Cholinergic Pathway Hyperintensities Scale (CHIPS) in identifying cerebrovascular disease-related disruptions in cholinergic white matter pathways, offering a practical and accessible method for assessing cholinergic integrity in neurodegenerative diseases. We assessed the associations of CHIPS with regional brain atrophy, Alzheimer's disease co-pathology and clinical phenotype. Additionally, we compared its diagnostic performance to that of other manual and automated evaluation methods. We included 82 individuals (41 patients in the Lewy body continuum with either probable dementia with Lewy bodies or mild cognitive impairment with Lewy bodies, and 41 healthy controls) from the Sant Pau Initiative on Neurodegeneration cohort. We used CHIPS to assess cholinergic white matter signal abnormalities (WMSA) on MRI, while tractography mean diffusivity provided a complementary measure of cholinergic WMSA. For global WMSA evaluation, we used the Fazekas scale and FreeSurfer. CHIPS successfully identified cerebrovascular disease-related disruptions in cholinergic white matter pathways, as evidenced by its association with tractography and global WMSA markers (P < 0.005 for all associations). Lewy body patients showed a significantly higher degree of WMSA in the external capsule cholinergic pathway despite no significant differences in global WMSA compared to controls. CHIPS score in the posterior external capsule and the mean diffusivity in the external capsule and cingulum exceeded the threshold for an optimal biomarker (sensitivity and specificity values above 80%) in discriminating Lewy body patients from controls. Furthermore, higher CHIPS scores, Fazekas scale and tractography mean diffusivity were associated with more pronounced frontal atrophy in Lewy body patients but not in controls. No associations were found for the four WMSA and integrity methods with the core clinical features, clinical or cognitive measures, or CSF biomarkers. In conclusion, cholinergic WMSA were more pronounced in Lewy body patients compared to healthy controls, independently of global WMSA. Our findings indicate that cerebrovascular disease-related disruptions in cholinergic white matter may be linked to frontal atrophy in Lewy body patients. Clinically, we demonstrate the potential of CHIPS to assess cholinergic WMSA using widely available MRI sequences. Our data suggest cerebrovascular disease co-pathology could drive the cholinergic degeneration in Lewy body patients, opening opportunities for therapeutic interventions targeting vascular health from mild cognitive impairment with Lewy bodies through manifest dementia with Lewy bodies.

Center of Biomedical Investigation Network for Neurodegenerative Diseases 28029 Madrid Spain

Centre for Age Related Medicine Stavanger University Hospital 4068 Stavanger Norway

Department of Biomedical Engineering and Assistive Technology Czech Institute of Informatics Robotics and Cybernetics Czech Technical University Prague 160 00 Prague Czech Republic

Department of Neuroimaging Centre for Neuroimaging Sciences Institute of Psychiatry Psychology and Neuroscience King's College London SE5 8AF London UK

Department of Neurology Hospital de la Santa Creu i Sant Pau Biomedical Research Institute Sant Pau Universitat Autònoma de Barcelona 08025 Barcelona Spain

Department of Neurology University Medical Centre Ljubljana 1000 Ljubljana Slovenia

Department of Old Age Psychiatry Institute of Psychiatry Psychology and Neuroscience King's College London SE5 8AB London UK

Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institute 171 77 Stockholm Sweden

Division of Radiology Department for Clinical Science Intervention and Technology Karolinska Institutet 141 86 Stockholm Sweden

Facultad de Ciencias de la Salud Universidad Fernando Pessoa Canarias 35450 Las Palmas Spain

Faculty of Medicine University of Ljubljana 1000 Ljubljana Slovenia

Medical Radiation Physics and Nuclear Medicine Section for Nuclear Medicine Karolinska University Hospital Huddinge 14 186 Stockholm Sweden

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