Urine metabolomics signatures in reversible cerebral vasoconstriction syndrome

Abstract

Background The pathophysiology of reversible cerebral vasoconstriction syndrome is unclear. An unbiased systems-based approach might help to illustrate the metabolite profiling and underlying pathophysiology. Methods Urine samples were collected from reversible cerebral vasoconstriction syndrome patients and matched controls recruited in Taipei Veterans General Hospital. 1H-Nuclear magnetic resonance was used to initially explore the metabolic profile, and liquid chromatography tandem mass spectrometry was then used to identify metabolic alterations in reversible cerebral vasoconstriction syndrome. Untargeted metabolite screening was randomly performed on 10 reversible cerebral vasoconstriction syndrome patients and 10 control subjects in the discovery phase. The selected untargeted metabolites were further validated on 47 reversible cerebral vasoconstriction syndrome patients during their ictal stage (with 40 of them having remission samples) and 47 controls in the replication phase. Results and conclusion Six metabolites-hippurate, citrate, 1,3,7-trimethyluric acid, ascorbic acid, D-glucurono-6,3-lactone, and D- threo-isocitric acid-with t-test derived p-value < 0.05 and VIP score >1, were identified as potential urine signatures that can well distinguish reversible cerebral vasoconstriction syndrome subjects at ictal stage from controls. Among them, citrate, hippurate, ascorbic acid, and D-glucurono-6,3-lactone were significantly lower, and 1,3,7-trimethyluric acid and D- threo-isocitric acid were higher in reversible cerebral vasoconstriction syndrome patients. Of these, four selected metabolites, citrate, D-glucurono-6,3-lactone, ascorbic acid, and 1,3,7-trimethyluric acid, returned to normal levels in remission. These metabolites are related to pathways associated with free radical scavenging, with the hub molecules being associated with endothelial dysfunction or sympathetic overactivity. Whether these metabolites and their implicated networks play a role in the pathogenesis of reversible cerebral vasoconstriction syndrome remains to be confirmed.

Pathophysiology of reversible cerebral vasoconstriction syndrome

“…The urine level of 8-iso-PGF 2α was found to correlate with the severity of vasoconstriction, especially during the first week of disease course [ 52 ]. Consistent with the findings from urine samples, a recent study also demonstrated higher 8- iso -PGF 2α in the plasma in patients with RCVS during the acute stage [ 53 ].…”

“…Similar findings were also observed in another case-control study, which demonstrated not only impaired cerebrovascular reactivity during the acute stage but recovery of the impaired cerebrovascular reactivity in the remission stage in 70% of the cases who received follow-up [ 50 ]. Autonomic dysregulation [ 51 ], oxidative stress [ 52 , 53 ], impaired endothelial repairing capacity [ 54 ], and disruption of the BBB [ 55 , 56 ] might contribute to the altered cerebrovascular reactivity, which are detailed below. Moreover, a recent study identified a panel of microRNAs (miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p and let-7f-5p) that can be used to differentiate patients with RCVS (in acute stage) from controls with nearly 90% accuracy [ 57 ].…”

Metabolomic and proteomic characterization of sng and pain phenotypes in fibromyalgia

“…Untargeted metabolomes in urine and serum were performed as described by Hsu et al (Hsu et al, 2019 , 2020 ). Briefly, liquid chromatography tandem mass spectrometry (LC‐MS) analysis involved using an Agilent 1290 UPLC system (ACQUITY UPLC HSS T3 column, 2.1 × 100 mm; 1.8 µm; Waters) coupled with the 6540‐Quadrupole‐Time‐of‐Flight (QTOF) mass system (Agilent Technologies).…”

Oxidative stress, dysfunctional energy metabolism, and destabilizing neurotransmitters altered cerebral metabolic profile in a rat model of a simulated heliox saturation diving to 4.0 Mpa

“…Similarly, several studies have compared the amino acid neurotransmitter pro les of rats with high-pressure neurological syndrome to those of healthy individuals [2]. Illustrating the neurological metabolic ngerprint of CNS leisure might favor etiological hypotheses [9,10], prevention [11], and therapeutic approaches [12]. However, the integrated neurological metabolic perturbation induced by a great depth of heliox saturation diving has not been investigated.…”