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

Abstract

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.

Progress and recognition of idiopathic intracranial hypertension: A narrative review

“… 190 Individuals with IIH have an abnormal metabolome, unique androgen signature, and dysregulated glucocorticoid phenotype. 113 , 191 Growing evidence suggests that IIH may not be purely idiopathic but is related to systemic metabolic and hormonal disturbances. The early diagnosis and treatment of IIH still pose challenges.…”

Idiopathic intracranial hypertension: expanding our understanding

“…Several exploratory untargeted metabolomic studies, involving female patients with active IIH:WT study showed dysregulation of amino acid and lipid metabolism in CSF and serum samples. Mechanistically how this relates to IIH is uncertain [25]. A similar study by the same group employed nuclear magnetic resonance spectroscopy demonstrating lower urea, raised lactate:pyruvate ratio and acetate levels in the CSF at baseline.…”