{"doi":"10.64898/2026.03.03.709452","title":"Diffusion MRI based biomarkers reveal a Prolonged Pre-Lesional Phase of Cerebral Small Vessel Disease","abstract":"<jats:title>Abstract</jats:title>\n                <jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI based biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and the risk factors associated with this progression have not been explored.</jats:p>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>\n                    We analyzed longitudinal neuroimaging data from 2,047 participants from a population-based cohort study (aged 49-101 years, 47% female). Using multi-output nonlinear mixed-effects models, we characterized the temporal progression of WMH and four diffusion MRI based biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS). Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education,\n                    <jats:italic>APOE ε4</jats:italic>\n                    status, and cardiometabolic conditions).\n                  </jats:p>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH, respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities.</jats:p>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Diffusion MRI based biomarkers capture microstructural injury at least a decade before appearance of WMH, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.</jats:p>\n                </jats:sec>","journal":null,"year":null,"id":633144,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1376670,"name":"Mingzhao Hu","orcid":null,"position":1,"is_corresponding":false},{"id":318778,"name":"Emily S. Lundt","orcid":"0000-0002-4754-8642","position":2,"is_corresponding":false},{"id":389157,"name":"Michael G. Kamykowski","orcid":"0000-0002-3108-7618","position":3,"is_corresponding":false},{"id":318670,"name":"Robert I. Reid","orcid":"0000-0003-2391-8650","position":4,"is_corresponding":false},{"id":176599,"name":"Terry M. Therneau","orcid":null,"position":5,"is_corresponding":false},{"id":318669,"name":"Sheelakumari Raghavan","orcid":"0000-0001-8652-7011","position":6,"is_corresponding":false},{"id":270813,"name":"Petrice M. Cogswell","orcid":"0000-0002-8128-4476","position":7,"is_corresponding":false},{"id":90099,"name":"Michael Griswold","orcid":"0000-0001-8106-5516","position":8,"is_corresponding":false},{"id":331917,"name":"B. Gwen Windham","orcid":"0000-0001-6240-5044","position":9,"is_corresponding":false},{"id":49956,"name":"Clifford R. Jack","orcid":"0000-0001-7916-622X","position":10,"is_corresponding":false},{"id":27599,"name":"Ronald C. Petersen","orcid":"0000-0002-8178-6601","position":11,"is_corresponding":false},{"id":253918,"name":"Jonathan Graff‐Radford","orcid":"0000-0003-2770-0691","position":12,"is_corresponding":false},{"id":226058,"name":"Prashanthi Vemuri","orcid":"0000-0003-4286-0589","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Diffusion MRI based biomarkers reveal a Prolonged Pre-Lesional Phase of Cerebral Small Vessel Disease","abstract":"<jats:title>Abstract</jats:title>\n                <jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI based biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and the risk factors associated with this progression have not been explored.</jats:p>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>\n                    We analyzed longitudinal neuroimaging data from 2,047 participants from a population-based cohort study (aged 49-101 years, 47% female). Using multi-output nonlinear mixed-effects models, we characterized the temporal progression of WMH and four diffusion MRI based biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS). Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education,\n                    <jats:italic>APOE ε4</jats:italic>\n                    status, and cardiometabolic conditions).\n                  </jats:p>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH, respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities.</jats:p>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Diffusion MRI based biomarkers capture microstructural injury at least a decade before appearance of WMH, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.</jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W7134109634","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.64898/2026.03.03.709452","host_type":"repository"},{"url":"https://doi.org/10.64898/2026.03.03.709452","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.64898/2026.03.03.709452","host_type":"publisher"}],"fields_of_study":["Advanced Neuroimaging Techniques and Applications","Dementia and Cognitive Impairment Research","Acute Ischemic Stroke Management"],"mesh_terms":[],"keywords":["Corpus callosum","Fractional anisotropy","Diffusion MRI","Hyperintensity","White matter","Neuroimaging","Population","Disease"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T11:05:58.324365Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}