{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:49:47Z","timestamp":1791402587520,"version":"4.3.3"},"reference-count":51,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R61HD109748"],"award-info":[{"award-number":["R61HD109748"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K23HL155898"],"award-info":[{"award-number":["K23HL155898"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This study sought to evaluate proteomic, metabolomic, and immune signatures in the cerebrospinal fluid of individuals with Down Syndrome Regression Disorder (DSRD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A prospective case\u2013control study comparing proteomic, metabolomic, and immune profiles in individuals with DSRD was performed. Samples were obtained from a biorepository of affected individuals and compared to clinically available data and previously obtained neurodiagnostic studies. Individuals with DSRD were compared to individuals with established neuroinflammatory conditions (e.g., multiple sclerosis), and neurotypical controls undergoing a lumbar puncture for headaches. Samples underwent high\u2010throughput proteomic, metabolomic, and immune marker profiling. Data was compared across groups and clinical phenotypes. Gene set enrichment analysis and pathway analyses were utilized to analyze the data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In total, 34 individuals with DSRD, 22 neuroinflammatory controls, and 27 neurotypical controls were enrolled in the study. We observed a highly significant concordance in dysregulated proteomics signatures in DSRD and neuroinflammatory controls versus healthy controls, most prominently upregulation of many immunoglobulin sequences. In addition, individuals with DSRD displayed strong upregulation of liver\u2010derived plasma proteins and erythrocyte proteins in the CSF, indicating poor blood\u2013brain barrier integrity. The immune marker profile of DSRD is clearly similar to other neuroimmunological conditions, including strong elevation of MIP3\u2010\u03b1, eotaxin, and IFN\u2010\u03b3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Individuals with DSRD have unique CSF proteomic and metabolomic signatures consistent with neuroinflammation and increased blood\u2013brain barrier permeability. The CSF of individuals with DSRD was more comparable to individuals with neuroinflammatory disorders than neurotypical controls, indicating the potential for an immune etiology of disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52299","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T06:42:19Z","timestamp":1740552139000},"page":"805-820","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Evidence of blood\u2013brain barrier dysfunction and <scp>CSF<\/scp> immunoglobulin synthesis in Down Syndrome Regression Disorder"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-8234","authenticated-orcid":false,"given":"Jonathan D.","family":"Santoro","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Pediatrics Children's Hospital Los Angeles  Los Angeles California USA"},{"name":"Department of Neurology Keck School of 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