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We hypothesized that white matter interstitial fluid accumulation, estimated via magnetic resonance imaging (MRI) free water (FW), would explain the associations between elevated PlGF, white matter hyperintensities (WMH), and cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>MarkVCID consortium participants \u226555 years old with plasma PlGF and brain MRI were included. We tested cross\u2010sectionally whether FW mediated the associations between PlGF and WMH, or PlGF and cognition, measured using the Clinical Dementia Rating (CDR) scale and an executive function (EF) composite (Uniform Data Set version 3 [UDS3]\u2010EF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>For 370 participants (mean age 72), a higher PlGF was associated with higher FW, higher WMH, and higher CDR, but not UDS3\u2010EF. Higher FW was associated with higher WMH, higher CDR, and lower UDS3\u2010EF. FW explained 26% of the association between PlGF and CDR and 73% of the association between PlGF and WMH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Elevated PlGF may contribute to WMH and cognitive impairment through white matter FW accumulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CLINICAL TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>NCT06284213<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>PlGF is a promising blood\u2010based biomarker for vascular cognitive impairment.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In MarkVCID, higher PlGF was associated with accumulated white matter FW on MRI.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>FW mediated the association between higher PlGF and MRI\u2010visible white matter injury.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>FW mediated the association between PlGF and worse CDR scale.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PlGF may contribute to cognitive dysfunction via accumulated interstitial fluid.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14408","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T07:00:58Z","timestamp":1734505258000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["White matter free water mediates the associations between placental growth factor, white matter hyperintensities, and cognitive status"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-7669","authenticated-orcid":false,"given":"Kyle C.","family":"Kern","sequence":"first","affiliation":[{"name":"Department of Neurology University of California Los Angeles  Los Angeles California USA"},{"name":"Department of Neurology West Los Angeles Veterans Affairs Medical Center  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manu","family":"Vohra","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa L.","family":"Thirion","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny J. 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