{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T07:23:22Z","timestamp":1787556202561,"version":"build-2736575974"},"reference-count":9,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Colony stimulating factor\u20101 receptor\u2013related disorder (CSF1R\u2010RD) is a rare, autosomal dominant neurodegenerative disease caused by loss\u2010of\u2010function variants in the CSF1R gene, leading to microglial dysfunction and progressive white matter degeneration. Therapeutic strategies targeting microglial pathways, including activation of triggering receptor expressed on myeloid cells 2 (TREM2), have been proposed to compensate for impaired CSF1R signaling. Iluzanebart (VGL101), a monoclonal antibody TREM2 agonist, has shown promise in preclinical models. We report a longitudinal clinical course, neuroimaging findings, genetic analysis, and postmortem neuropathological examination of a 52\u2010year\u2010old patient with genetically confirmed CSF1R\u2010RD (c.2507G&gt;A, p.Ser836Asn). The patient received iluzanebart as part of a Phase 2 clinical trial. Clinical progression, MRI changes, and histopathological features at autopsy were systematically analyzed. Despite treatment, the patient experienced progressive cognitive decline, neuropsychiatric symptoms, motor impairment, and seizures, culminating in death. Serial neuroimaging demonstrated worsening white matter degeneration and brain atrophy without evidence of therapeutic response. Neuropathological examination revealed characteristic features of CSF1R\u2010RD, including severe myelin loss, axonal spheroids, infiltration of Iba1\u2010positive cells with macrophage\u2010like morphology, and cortical neuronal abnormalities. There was no histological evidence of treatment\u2010related benefit or harm. This case represents the first clinicopathological assessment of iluzanebart in CSF1R\u2010RD and demonstrates no observable clinical, radiological, or neuropathological improvement. These findings highlight the challenges of targeting microglial dysfunction in advanced disease and suggest that TREM2 activation alone may be insufficient to alter disease progression.<\/jats:p>","DOI":"10.1111\/neup.70066","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:01:25Z","timestamp":1782194485000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Colony Stimulating Factor\u20101 Receptor\u2010Related Disorder Treated With Ilunazebart"],"prefix":"10.1111","volume":"46","author":[{"given":"Lukasz","family":"Milanowski","sequence":"first","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"},{"name":"Department of Neurology, Faculty of Health Sciences Medical University of Warsaw  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delaney","family":"Liskey","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"},{"name":"Regenerative Sciences Ph.D. Program, Mayo Clinic Graduate School of Biomedical Sciences  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey J.","family":"Strongosky","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Gelfand","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":false,"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5487-1053","authenticated-orcid":false,"given":"Zbigniew K.","family":"Wszolek","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"e_1_2_13_2_1","volume-title":"GeneReviews","author":"Dulski J.","year":"1993"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.5603\/pjnns.108495"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.70033"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-025-03346-1"},{"key":"e_1_2_13_6_1","unstructured":"ClinicalTrials.gov \u201cA Study of VGL101 in Patients With Adult\u2010Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia \u201daccessed May 2 2026 https:\/\/clinicaltrials.gov\/study\/NCT05677659."},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14171387"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02193-z"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.003"},{"issue":"3","key":"e_1_2_13_10_1","first-page":"416","article-title":"A TREM2\u2010Activating Antibody With a Blood\u2010Brain Barrier Transport Vehicle Enhances Microglial Metabolism in Alzheimer's Disease Models","volume":"26","author":"Lengerich B.","year":"2023","journal-title":"Nature 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