Idiopathic Intracranial Hypertension Is Characterized by a Distinct Proteomic Profile

OBJECTIVES: The pathophysiology of idiopathic intracranial hypertension (IIH) is poorly understood and disease-specific biomarkers are lacking. We aimed to shed light on IIH pathophysiology and identify disease-specific biomarkers. METHODS: This prospective cross-sectional cohort study included patients with new-onset IIH and age-, body mass index-, and sex-matched 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). RESULTS: O; p < 0.001) compared to controls. Machine learning analysis identified 20 IIH-predicting 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-predicting proteins as were amyloid precursor protein (APP), S100P, and S100A12. INTERPRETATION: We identified a panel of independently validated IIH-specific 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-benign character of IIH. ANN NEUROL 2026;100:255-267.