{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T02:59:18Z","timestamp":1768445958041,"version":"3.49.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cognitive decline and gait disturbance are often observed simultaneously in patients with small vessel disease (SVD), also known as motoric cognitive dysfunction. However, it remains unknown whether cholinergic system disruption contributes to motoric cognitive dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>In this cross-sectional, single-center study conducted in the Netherlands, we included 213 patients with SVD between 2020 and 2021, all of whom had multimodal magnetic resonance imaging scans, gait assessments using the 6-meter walk test, and cognitive test battery data available. Cholinergic cortical (through external capsule and cingulum) and thalamic projections (pedunculopontine nucleus to thalamus) were reconstructed using probabilistic tractography on diffusion images, followed by the quantification of the disruption in these tracts with diffusion metrics derived from neurite orientation dispersion and density imaging model. Conventional magnetic resonance imaging markers for SVD were assessed.Covariates, including neurite orientation dispersion and density imaging metrics in the white matter control mask and SVD markers, were adjusted in linear regression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      A total of 213 patients with SVD were included, with a mean (SD) age of 74.6 (6.8) years, of whom 96 (45.1%) were women. Conventional SVD markers are differentially associated with disrupted cholinergic pathways, with white matter hyperintensities (WMH) being the main contributor (R\u00b2 highest for neurite density index, 0.38). WMH within the external capsule cholinergic pathway is more strongly associated with the neurite orientation dispersion and density imaging metrics in this tract compared with total WMH volume or WMH outside cholinergic projections. In contrast, WMH within the cingulum pathway contributes less to neurite orientation dispersion and density imaging variability (R\u00b2=0.18\u20130.33 versus 0.22\u20130.38). Disruption in cholinergic cortical pathways was associated with concurrent decline in performance of cognition and gait (external capsule pathway cerebrospinal fluid isotropic volume fraction, \u03b2=\u221210.77;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.004; cingulum pathway cerebrospinal fluid isotropic volume fraction, \u03b2=\u221213.38;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.011), adjusted for the covariates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Taken together, our findings suggest that disruption in cholinergic cortical pathways attributable to SVD, rather than cholinergic thalamic pathways, contributes to the motoric cognitive dysfunction in patients with SVD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.052256","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T09:00:49Z","timestamp":1761814849000},"page":"169-181","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Cholinergic Disruption Contributes to Motoric Cognitive Dysfunction in Cerebral Small Vessel Disease"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0927-2558","authenticated-orcid":true,"given":"Mengfei","family":"Cai","sequence":"first","affiliation":[{"name":"Guangdong Cardiovascular Institute (M.C.), Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China."},{"name":"Department of Neurology, Guangdong Neuroscience Institute (M.C., Y.Z.), Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China."},{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour (M.C., H.L., M.A.J., F.-E.d.L., A.M.T.), Radboud University Medical Center, Nijmegen, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2125-9092","authenticated-orcid":true,"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour (M.C., H.L., M.A.J., F.-E.d.L., A.M.T.), Radboud University Medical Center, Nijmegen, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-1354","authenticated-orcid":true,"given":"Milan","family":"Nemy","sequence":"additional","affiliation":[{"name":"Department of Cognitive Systems and Neurosciences (M.N.), Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University in Prague."},{"name":"Division of Clinical Geriatrics, Center for Alzheimer\u2019s Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden (M.N., D.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3018-4109","authenticated-orcid":true,"given":"Mina A.","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour (M.C., H.L., M.A.J., F.-E.d.L., A.M.T.), Radboud University Medical Center, Nijmegen, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3699-6917","authenticated-orcid":true,"given":"David G.","family":"Norris","sequence":"additional","affiliation":[{"name":"Centre for Cognitive Neuroimaging (D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2302-3136","authenticated-orcid":true,"given":"Marco","family":"Duering","sequence":"additional","affiliation":[{"name":"Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering, University of Basel, Switzerland (M.D.)."},{"name":"Institute for Stroke and Dementia Research, LMU University Hospital, Ludwig Maximilian University Munich, Germany (M.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Guangdong Neuroscience Institute (M.C., Y.Z.), Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9500-9793","authenticated-orcid":true,"given":"Roy P.C.","family":"Kessels","sequence":"additional","affiliation":[{"name":"Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center, Nijmegen, the Netherlands."},{"name":"Centre for Cognition (R.P.C.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands."},{"name":"Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands (R.P.C.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5722-6671","authenticated-orcid":true,"given":"Lenka","family":"Vyslouzilova","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Assistive Technology (L.V.), Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University in Prague."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-3194","authenticated-orcid":true,"given":"Stefan J.","family":"Teipel","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany (S.J.T.)."},{"name":"Department of Psychosomatic Medicine, Rostock University Medical Center, Germany (S.J.T.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9522-4338","authenticated-orcid":true,"given":"Daniel","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Center for Alzheimer\u2019s Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden (M.N., D.F.)."},{"name":"Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Santa Mar\u00eda de Gu\u00eda, Las Palmas, Spain (D.F.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2221-3026","authenticated-orcid":true,"given":"Frank-Erik","family":"de Leeuw","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour (M.C., H.L., M.A.J., F.-E.d.L., A.M.T.), Radboud University Medical Center, Nijmegen, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4815-2834","authenticated-orcid":true,"given":"Anil M.","family":"Tuladhar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour (M.C., H.L., M.A.J., F.-E.d.L., A.M.T.), Radboud University Medical Center, Nijmegen, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00131-X"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26615"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2016.02.012"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2021.102667"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glab247"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000470376.04336.ea"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.116607"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200930"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-024-00743-w"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13034"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00377-X"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac385"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad420"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab372"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13563"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.122.041687"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011213"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2377-11-29"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.038099"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.2214\/ajr.149.2.351"},{"key":"e_1_3_3_22_2","unstructured":"An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging - PubMed. Cited June 13 2024. https:\/\/pubmed.ncbi.nlm.nih.gov\/26481672\/"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.10.019"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.26054"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae145"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.03.072"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcab106"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-022-01319-6"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.24204"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/121.12.2249"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2007.05.050"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-132345"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.26311"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.09.011"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2007.06.004"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.09.018"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1177\/0898264314556987"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1037\/met0000074"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1037\/h0036316"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac265"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3539-11.2011"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr169"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2019.102048"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad220"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0014-y"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad226"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30153-X"},{"key":"e_1_3_3_48_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bpsgos.2021.12.012","article-title":"Neurite orientation dispersion and density imaging in psychiatric disorders: a systematic literature review and a technical note.","volume":"3","author":"Kraguljac NV","year":"2023","unstructured":"Kraguljac NV, Guerreri M, Strickland MJ, Zhang H. Neurite orientation dispersion and density imaging in psychiatric disorders: a systematic literature review and a technical note. Biological Psychiatry Global Open Science. 2023;3:10\u201321.","journal-title":"Biological Psychiatry Global Open Science"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.125.052256","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T16:07:25Z","timestamp":1768406845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.125.052256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":47,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1161\/STROKEAHA.125.052256"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.125.052256","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-05-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-15","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}