Dysregulation of Amino Acid, Lipid, and Acylpyruvate Metabolism in Idiopathic Intracranial Hypertension: A Non-targeted Case Control and Longitudinal Metabolomic Study

Background: Idiopathic intracranial
hypertension
(IIH) is characterized by increased intracranial pressure occurring
predominantly in women with obesity. The pathogenesis is not understood.
We have applied untargeted metabolomic analysis using ultrahigh-performance
liquid chromatography–mass spectrometry to characterize the
cerebrospinal fluid (CSF) and serum in IIH compared to control subjects. Methods and findings: Samples were collected from IIH patients
(n = 66) with active disease at baseline and again
at 12 months following therapeutic weight loss. Control samples were
collected from gender- and weight-matched healthy controls (n = 20). We identified annotated metabolites in CSF, formylpyruvate
and maleylpyruvate/fumarylpyruvate, which were present at lower concentrations
in IIH compared to control subjects and returned to values observed
in controls following weight loss. These metabolites showed the opposite
trend in serum at baseline. Multiple amino acid metabolic pathways
and lipid classes were perturbed in serum and CSF in IIH alone. Serum
lipid metabolite pathways were significantly increased in IIH. Conclusions: We observed a number of differential metabolic
pathways related to amino acid, lipid, and acylpyruvate metabolism,
in IIH compared to controls. These pathways were associated with clinical
measures and normalized with disease remission. Perturbation of these
metabolic pathways provides initial understanding of disease dysregulation
in IIH.