{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:51:19Z","timestamp":1791161479832,"version":"4.1.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013301","name":"Parkinson\u2019s Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J Fox Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>White matter lesions are associated with cognitive impairment in Parkinson\u2019s disease, but the underlying neurobiological mechanisms remain unclear. One hypothesis is that strategically located white matter lesions disrupt long-range white matter pathways crucial for cognitive functioning, particularly cholinergic projections from the basal forebrain, contributing to cognitive decline. Using volumetric measures of basal forebrain nuclei (T1 MRI proxy for brain cholinergic projection nuclei), quantitative white matter lesion assessments (fluid-attenuated inversion recovery MRI) and a presynaptic cholinergic marker (18F-FEOBV PET), we tested a mechanistic model of white matter lesion effects on basal forebrain cholinergic projections and nuclei, and how these disruptions relate to cognition.<\/jats:p>\n                  <jats:p>We analysed data from 127 mid-to-advanced-stage patients with Parkinson\u2019s disease without dementia. Periventricular and deep white matter lesion burdens were quantified with the UBO Detector pipeline. Cognitive function was assessed across five domains using z-scores from a control group matched for age and education. Voxel-wise analyses examined associations between white matter lesion burden and cholinergic synaptic density, followed by mediation analyses testing whether cholinergic alterations mediated the relationship between white matter lesions and cognition, while correcting for sex, levodopa equivalent dose and disease duration.<\/jats:p>\n                  <jats:p>Voxel-wise analyses revealed that higher periventricular lesions burden was associated with reduced 18F-FEOBV uptake in an insular\u2013limbic\u2013frontal\u2013cingulum cluster, while deep lesions showed more topographically limited associations that disappeared after adjusting for periventricular burden. Periventricular lesions affected lateral and external Ch4 cholinergic projection pathways (81%\u201388% of patients), more frequently than deep white matter lesions (25%\u201347% of patients), except for the external capsule, which was equally affected by both. Cognitive performance (global cognition, memory, executive function and attention) was associated with both periventricular lesion burden and 18F-FEOBV uptake within the insular\u2013limbic\u2013frontal\u2013cingulum cluster, as well as with basal forebrain volume. Mediation analyses indicated that periventricular lesions had a direct effect on cortical terminal integrity (18F-FEOBV) and an indirect, presumably retrograde degeneration effect via basal forebrain atrophy. The effect of periventricular lesions on insular\u2013limbic\u2013frontal\u2013cingulum cholinergic terminal density was a strong mediator of the association between lesion burden and cognitive performance. A weaker mediation effect via the basal forebrain emerged for global cognition, whereas mediation was more robust for memory and executive functioning.<\/jats:p>\n                  <jats:p>Our findings indicate that periventricular white matter lesions contribute to cognitive vulnerability in Parkinson\u2019s disease without dementia through impacts on basal forebrain cholinergic projections. White matter lesion burden may represent a mechanistically meaningful biomarker for predicting cognitive trajectories and informing targeted interventions in Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awag172","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T11:43:50Z","timestamp":1778327030000},"page":"3495-3508","source":"Crossref","is-referenced-by-count":1,"title":["White matter lesions disrupt cholinergic pathways important for cognition in Parkinson\u2019s disease"],"prefix":"10.1093","volume":"149","author":[{"given":"Giulia","family":"Carli","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Morris K. Udall Center of Excellence for Parkinson\u2019s Disease Research, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Brown","sequence":"additional","affiliation":[{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotini","family":"Michalakis","sequence":"additional","affiliation":[{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Biddix","sequence":"additional","affiliation":[{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stiven","family":"Roytman","sequence":"additional","affiliation":[{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Vangel","sequence":"additional","affiliation":[{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"August","family":"Van Hout","sequence":"additional","affiliation":[{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabesh","family":"Kanel","sequence":"additional","affiliation":[{"name":"Morris K. Udall Center of Excellence for Parkinson\u2019s Disease Research, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Parkinson\u2019s Foundation Research Center of Excellence, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J H","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger L","family":"Albin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Morris K. Udall Center of Excellence for Parkinson\u2019s Disease Research, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Parkinson\u2019s Foundation Research Center of Excellence, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"VA Ann Arbor Healthcare System Neurology Service and GRECC, , Ann Arbor, MI 48105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0352-6414","authenticated-orcid":false,"given":"Nicolaas I","family":"Bohnen","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Morris K. Udall Center of Excellence for Parkinson\u2019s Disease Research, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan , Ann Arbor, MI 48106 ,","place":["USA"]},{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Parkinson\u2019s Foundation Research Center of Excellence, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"VA Ann Arbor Healthcare System Neurology Service and GRECC, , Ann Arbor, MI 48105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"2026100419580041700_awag172-B1","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.parkreldis.2017.07.033","article-title":"Neuropathology of Parkinson disease","volume":"46(Suppl 1)","author":"Dickson","year":"2018","journal-title":"Parkinsonism Relat Disord."},{"key":"2026100419580041700_awag172-B2","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1093\/brain\/awab446","article-title":"Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state","volume":"145","author":"Smaji\u0107","year":"2022","journal-title":"Brain"},{"key":"2026100419580041700_awag172-B3","doi-asserted-by":"crossref","DOI":"10.1038\/s41531-023-00592-z","article-title":"White matter changes in Parkinson\u2019s disease","volume":"9","author":"Yang","year":"2023","journal-title":"NPJ Parkinsons Dis."},{"key":"2026100419580041700_awag172-B4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/S1474-4422(13)70124-8","article-title":"Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration","volume":"12","author":"Wardlaw","year":"2013","journal-title":"Lancet Neurol."},{"key":"2026100419580041700_awag172-B5","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1136\/jnnp.2009.204685","article-title":"Heterogeneity of small vessel disease: A systematic review of MRI and histopathology correlations","volume":"82","author":"Gouw","year":"2011","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"2026100419580041700_awag172-B6","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1747-4949.2011.00725.x","article-title":"Cerebral small vessel disease: A review of clinical, radiological, and histopathological phenotypes","volume":"7","author":"Moran","year":"2012","journal-title":"Int J Stroke."},{"key":"2026100419580041700_awag172-B7","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1161\/01.STR.28.3.652","article-title":"Pathogenesis of leukoaraiosis: A review","volume":"28","author":"Pantoni","year":"1997","journal-title":"Stroke"},{"key":"2026100419580041700_awag172-B8","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.114.001140","article-title":"What are white matter hyperintensities made of? 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