{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T11:04:53Z","timestamp":1784718293675,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,20]]},"group-title":"Neurology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["U54NS121688"],"award-info":[{"award-number":["U54NS121688"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS122184"],"award-info":[{"award-number":["R01NS122184"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R33NS120249"],"award-info":[{"award-number":["R33NS120249"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Neuroinflammation is a key component of the response to injury after concussion, but direct links between diffusion MRI metrics and specific plasma inflammatory pathways in human concussion have not been established.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To examine associations between diffusion MRI metrics and pathway-level inflammatory proteomic signatures in adolescents during the subacute period after concussion.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design, Setting, and Participants<\/jats:title>\n                  <jats:p>Cross-sectional analysis of data from the CARE4Kids Consortium, a six-site prospective study. Participants were English-speaking adolescents ages 11\u201317.99 with concussion and symptoms at 7\u201335 days post-injury. Data were collected between 2022-2024. Of 370 enrolled participants, 122 had both diffusion MRI and plasma proteomics available for analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposure<\/jats:title>\n                  <jats:p>Advanced diffusion MRI metrics were converted to z-scores and participants were grouped by the spatial extent of outlier values (potholes and peaks) across 15 white matter regions of interest. Nine non-redundant groupings were selected for primary analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>Pathway-level inflammatory profiles derived from gene set enrichment analysis (GSEA) of \u223c5,400 plasma proteins measured by Olink proximity extension assay, targeting nine hallmark inflammatory pathways spanning initiation through resolution. Persistent symptoms were assessed 64-115 days post-injury.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Diffusion metrics reflecting tissue disorganization were associated with upregulation of the coagulation pathway, consistent with hemostatic-inflammatory signaling. Metrics reflecting reduced tissue complexity and neurite density were associated with upregulation of interferon-\u03b1 and interferon-\u03b3 response pathways, consistent with microstructural remodeling driven by cellular immune activation. Elevated free water content was associated with downregulation of most inflammatory pathways and trend-level transforming growth factor - \u03b2 upregulation, reflecting inflammatory resolution. Time since injury did not differ between groups based on free water (Kolmogorov-Smirnov p = 0.97), suggesting these differences reflect individual variability in recovery pace. Exploratory analyses showed a trend toward lower odds of persistent symptoms in the group with elevated free water content (odds ratio = 0.51,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.18).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>Multiple diffusion MRI metrics are differentially sensitive to distinct neuroinflammatory states in the subacute period after adolescent concussion. These findings suggest that diffusion imaging could serve as a non-invasive tool for inflammatory phenotyping, with potential implications for identifying patients who may benefit from targeted immunomodulatory intervention.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Question<\/jats:title>\n                    <jats:p>Are specific diffusion MRI metrics sensitive to distinct inflammatory pathway signatures in adolescents during the subacute period after concussion?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>In this cross-sectional study of 122 adolescents with concussion, multimodal diffusion MRI metrics were associated with mechanistically distinct proteomic signatures rather than a uniform inflammatory response. Metrics reflecting tissue disorganization were associated with hemostatic-inflammatory pathway upregulation, metrics reflecting reduced tissue complexity and neurite density were associated with interferon signaling and coagulation suppression, and elevated free water content was associated with inflammatory pathway downregulation and trend-level resolution-phase signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>Different diffusion MRI metrics are sensitive to qualitatively different neuroinflammatory processes, suggesting that multimodal diffusion imaging may enable non-invasive profiling of the post-injury inflammatory state and inform targeted therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                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