{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:53:31Z","timestamp":1792274011038,"version":"4.4.0"},"reference-count":32,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:p>Biological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated with the burden of cSVD provides leads on underlying biological processes. In 494 participants (mean age 67.6\u2009\u00b1\u20098.7\u2009years; 36% female; 75% cardiovascular diseases; 25% reference participants) we assessed the relation between 92 blood-based biomarkers from the OLINK cardiovascular III panel and cSVD, using cluster-based analyses. We focused particularly on white matter hyperintensities (WMH). Nineteen biomarkers individually correlated with WMH ratio (r range: 0.16\u20130.27, Bonferroni corrected p-values &lt;0.05), of which sixteen biomarkers formed one biomarker cluster. Pathway analysis showed that this biomarker cluster predominantly reflected coagulation processes. This cluster related also significantly to other cSVD manifestations (lacunar infarcts, microbleeds, and enlarged perivascular spaces), which supports generalizability beyond WMHs. To study possible causal effects of biological processes reflected by the cluster we performed a mediation analysis that showed a mediation effect of the cluster on the relation between age and WMH ratio (proportion mediated 17%), and hypertension and WMH-volume (proportion mediated 21%). In conclusion, we identified a cluster of blood-based biomarkers reflecting coagulation, that is related to manifestations of cSVD, corroborating involvement of coagulation abnormalities in the etiology of cSVD.<\/jats:p>","DOI":"10.1177\/0271678x221077339","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T01:40:13Z","timestamp":1643334013000},"page":"1282-1293","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":25,"title":["A cluster of blood-based protein biomarkers reflecting coagulation relates to the burden of cerebral small vessel disease"],"prefix":"10.1177","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3839-4311","authenticated-orcid":false,"given":"Sanne","family":"Kuipers","sequence":"first","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7086-0864","authenticated-orcid":false,"given":"L Malin","family":"Overmars","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"},{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram","family":"van Es","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"de Bresser","sequence":"additional","affiliation":[{"name":"Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther E","family":"Bron","sequence":"additional","affiliation":[{"name":"Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imo E","family":"Hoefer","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L Jaap","family":"Kappelle","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte E","family":"Teunissen","sequence":"additional","affiliation":[{"name":"Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, VrijeUniversiteit Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert Jan","family":"Biessels","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Haitjema","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"bibr1-0271678X221077339","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.04.003"},{"key":"bibr2-0271678X221077339","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30079-1"},{"key":"bibr3-0271678X221077339","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2019.100916"},{"key":"bibr4-0271678X221077339","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2015.116"},{"key":"bibr5-0271678X221077339","doi-asserted-by":"publisher","DOI":"10.1159\/000480738"},{"key":"bibr6-0271678X221077339","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.592"},{"key":"bibr7-0271678X221077339","unstructured":"Olink proteomics. 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