Paired CSF and plasma metabolomics reveals a robust CSF-centered metabolic phenotype in idiopathic normal-pressure hydrocephalus: an exploratory case-control study

Background: 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. Methods: 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| larger or equal to log2(1.5). Results: 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. Conclusions: 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.