Paired CSF and plasma metabolomics reveals a robust CSF-centered metabolic phenotype in idiopathic normal-pressure hydrocephalus: an exploratory case–control study
The study found 56 altered metabolites in the CSF of patients with iNPH, indicating significant metabolic changes, but these findings need further validation in larger studies.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study analyzed paired cerebrospinal fluid (CSF) and plasma metabolomic profiles from 10 patients with idiopathic normal pressure hydrocephalus (iNPH) and 10 controls. The analysis revealed 56 altered CSF metabolites in iNPH patients, with 34 increased and 22 decreased. In plasma, 27 metabolites met significance criteria, but only a subset was consistent across analyses.
Abstract
<h4>Background</h4> Idiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable neurological disorder whose molecular basis remains incompletely understood. Metabolomic studies in iNPH are scarce and have focused largely on comparisons with other neurological disorders or on cerebrospinal fluid (CSF) alone. Consequently, the broader metabolic phenotype of iNPH and the extent to which CSF alterations are reflected in peripheral blood remain unclear. We therefore compared paired CSF and plasma metabolomic profiles from patients with iNPH and controls. <h4>Methods</h4> Paired CSF and plasma samples from 10 patients with iNPH and 10 controls were analyzed via hydrophilic interaction liquid chromatography–mass spectrometry. After quality control and deduplication, 134 CSF and 149 plasma metabolites were quantified. Protein-normalized abundances were log2-transformed and analyzed via age-adjusted ordinary least-squares regression as the primary model, with group-only regression and Mann–Whitney U tests used for sensitivity analyses. Significance was defined as Benjamini–Hochberg q < 0.05 and |log2-fold change| ≥ log2(1.5). <h4>Results</h4> Age-adjusted analysis revealed 56 altered CSF metabolites in iNPH patients, 34 of which were increased and 22 of which were decreased; 47 were also significantly altered according to the Mann–Whitney U test. The CSF phenotype encompassed energy and carnitine/acylcarnitine metabolism, redox and one-carbon/transsulfuration-associated metabolism, tryptophan–kynurenine metabolism, amino acid and nucleotide turnover, and neuronal- or membrane-associated metabolites. Prominent changes included increased succinate, 3-hydroxybutyrate, oxidized glutathione, cystathionine, kynurenine and kynurenic acid, together with decreased carnitine, short-chain acylcarnitines, methionine and ergothioneine. In plasma, 27 metabolites met the age-adjusted significance criteria, but only allantoin, N-formylmethionine, 3-hydroxybutyrate, N-acetylmethionine and kynurenic acid were also significant according to the Mann–Whitney U test. Global CSF–plasma effect–size concordance was moderate. The most consistent cross-compartment features were 3-hydroxybutyrate, N-formylmethionine and N-acetylmethionine. <h4>Conclusions</h4> iNPH was associated with a broad and comparatively consistent CSF-centered metabolic phenotype, whereas plasma showed a smaller, partial and model-sensitive reflection of these alterations. These findings support altered energy substrate handling, redox and sulfur-associated metabolism, tryptophan–kynurenine metabolism and neuronal or membrane-associated metabolite handling as components of iNPH biology. These exploratory findings require validation in larger, longitudinal cohorts.
Background
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder with an unclear molecular basis. Previous metabolomic studies have primarily focused on comparisons with other disorders or on CSF alone. This study aims to elucidate the broader metabolic phenotype of iNPH by comparing both CSF and plasma metabolomic profiles.
Methods
This exploratory case-control study analyzed paired CSF and plasma samples from 10 patients with iNPH and 10 controls using hydrophilic interaction liquid chromatography–mass spectrometry. A total of 134 CSF and 149 plasma metabolites were quantified, with analysis performed using age-adjusted ordinary least-squares regression and Mann–Whitney U tests for sensitivity.
Results
The age-adjusted analysis revealed 56 altered CSF metabolites in iNPH patients, with 34 increased and 22 decreased. According to the Mann–Whitney U test, 47 CSF metabolites were significantly altered. In plasma, 27 metabolites met the significance criteria, with only a few also significant in further testing.
Interpretation
The findings indicate a robust CSF-centered metabolic phenotype in iNPH, with moderate concordance in plasma metabolite alterations. While the study identifies significant changes, the clinical relevance of these findings remains uncertain due to the small sample size and the exploratory nature of the analysis.
Key findings
- 56 altered CSF metabolites in iNPH patients, n=10.
- 34 CSF metabolites increased and 22 decreased in iNPH patients.
- 27 plasma metabolites met age-adjusted significance criteria, n=10.
- Prominent CSF changes included increased succinate, 3-hydroxybutyrate, oxidized glutathione.
- Global CSF–plasma effect–size concordance was moderate.
Limitations
- small sample size n=10
- exploratory study design
- requires validation in larger cohorts
- model-sensitive results in plasma