Molecular evidence of aquaporin-4 dysregulation and neuroinflammatory stress underlying blood-brain barrier dysfunction in idiopathic intracranial hypertension: A case-control study.

Objective

To evaluate aquaporins (AQP), heat shock proteins (HSP), and CD146 (cluster of differentiation) as molecular markers of blood-brain barrier (BBB) disruption and neuroinflammation in idiopathic intracranial hypertension (IIH).

Background

Emerging evidence implicates BBB dysfunction and neuroinflammation, yet their mechanistic basis in IIH is unclear.

Methods

In this case-control study with cross-sectional exposure ascertainment, conducted in Postgraduate Institute of Medical Education and Research, Chandigarh, India, from March 2023 to September 2024, newly diagnosed patients with IIH and age- and sex-matched healthy individuals undergoing spinal anesthesia for non-neurological disease anesthesia controls (AC) and age- and sex-matched healthy controls (HC) were enrolled. Protein levels of AQPs and gene expression of HSPs and CD146 were quantified in blood and cerebrospinal fluid (CSF) and correlated with clinical features and severity.

Results

Patients with IIH were predominantly female (87%), with mean body mass index (BMI) 28.1 ± 5.2 kg/m2 and mean CSF opening pressure 27.4 ± 4.8 cm CSF. Patients with IIH demonstrated reduced AQP4CSF levels as compared to AC group (2.65 [2.09, 3.70] vs. 3.07 [1.65, 7.15], p = 0.016) and increased gene expression of HSP70Blood as compared to AC and HC (3.86 [1.02, 5.61] vs. 1.08 [0.78, 2.91] vs. 1.77 [0.43, 2.27], p = 0.002); increased gene expression of HSP60CSF as compared to AC (1.28 [0.37, 2.44] vs. 0.52 [0.23, 1.26], p = 0.038); and increased gene expression of CD146Blood as compared to AC and HC (1.27 [0.50, 4.29] vs. 0.53 [0.35, 1.36] vs. 0.91 [0.58, 1.70], p = 0.008). HSP70CSF, HSP60Blood, and CD146Blood corelated positively with Headache Impact Test-6 (HIT-6) and MIDAS scores (ρ = 0.41, p = 0.01; ρ = 0.34, p = 0.032; ρ = 0.35, p = 0.029, ρ = 0.35) indicating an association with disease severity.

Conclusion

The findings provide molecular evidence of BBB disruption and neuroinflammatory pathway involved in the pathophysiology of IIH.