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We aimed to shed light on IIH pathophysiology and identify disease\u2010specific biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This prospective cross\u2010sectional cohort study included patients with new\u2010onset IIH and age\u2010, body mass index\u2010, and sex\u2010matched healthy controls from 2 tertiary Danish Headache Centers (discovery cohort). Liquid chromatography coupled to tandem mass spectrometry analysis was used to measure reproducible proteomic profiles for paired serum and cerebrospinal fluid (CSF) samples. Results were validated using 3 validation cohorts comprising patients with IIH (pwIIH), cerebral sinus venous thrombosis (pwCSVT), and normal pressure hydrocephalus (pwNPH).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We included 53 pwIIH and 35 controls. PwIIH presented with papilledema and increased median lumbar puncture opening pressure (interquartile range [IQR]) (38.0 [33\u201346] vs 19.0 [17.0\u201323.0] cmH\n                      <jats:sub>2<\/jats:sub>\n                      O;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) compared to controls. Machine learning analysis identified 20 IIH\u2010predicting proteins for serum and CSF segregating pwIIH, but neither pwCSVT nor pwNPH, from controls with areas under the curve (AUC) of 0.84 and 0.92 (pwIIH, discovery cohort), 0.99 and 0.90 (pwIIH, validation cohort 1), 0.63 (plasma; pwCSVT), and 0.67 (CSF; pwNPH), respectively. Serum carbonic anhydrases (CA) 1 and 2 were upregulated and among the most IIH\u2010predicting proteins as were amyloid precursor protein (APP), S100P, and S100A12.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>We identified a panel of independently validated IIH\u2010specific candidate biomarkers. The serum candidate biomarkers pointed toward CA2 driven CSF hypersecretion in IIH providing a possible explanation for the therapeutic efficacy of CA inhibitors. The regulation of markers associated with neuronal impairment (APP, S100P\/S100A12) confirmed the non\u2010benign character of IIH. ANN NEUROL 2026;100:255\u2013267<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78261","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T11:56:16Z","timestamp":1779969376000},"page":"255-267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Idiopathic Intracranial Hypertension Is Characterized by a Distinct Proteomic Profile"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3841-452X","authenticated-orcid":false,"given":"Santosh D.","family":"Bhosale","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadiusz","family":"Nawrocki","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Southern Denmark  Odense 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