{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:06:20Z","timestamp":1792073180630,"version":"4.4.0"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AR050942"],"award-info":[{"award-number":["T32AR050942"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      X\u2010linked adrenoleukodystrophy (ALD) is caused by mutations in\n                      <jats:italic>ABCD1<\/jats:italic>\n                      , a peroxisomal gene. More than half of males with an\n                      <jats:italic>ABCD1<\/jats:italic>\n                      mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL\u201018]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in\n                      <jats:italic>Abcd1\u2010<\/jats:italic>\n                      knockout mice using a 2\u2010hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B\u2010cell infiltration, and astrogliosis. Compared to wild\u2010type controls,\n                      <jats:italic>Abcd1<\/jats:italic>\n                      \u2010knockout mice displayed more cerebral demyelination, blood\u2013brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL\u201018 immunoreactivity co\u2010localized with perivascular monocytes\/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL\u201018 levels correlated with MRI lesion severity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Our results suggest loss of\n                      <jats:italic>Abcd1<\/jats:italic>\n                      function in mice predisposes to more severe blood\u2013brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296\u2013312\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.27117","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T14:20:38Z","timestamp":1730125238000},"page":"296-312","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Novel Mouse Model for Cerebral Inflammatory Demyelination in X\u2010Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0868-4331","authenticated-orcid":false,"given":"Ezzat","family":"Hashemi","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Sciences Stanford University School of Medicine  Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha 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