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Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated in these phenotypes. Combining CSF and brain, we identified 71 metabolite-trait associations, such as glycerophosphocholines with Alzheimer's disease, O-sulfo-L-tyrosine with Parkinson's disease, glycine, xanthine with waist-to-hip ratio and ergothioneine with inflammatory bowel disease. Our study expanded the knowledge of MQTLs in the central nervous system, providing insights into human traits., Competing Interests: Competing interests: C.C. has received research support from GSK and EISAI and is a member of the advisory board of Circular Genomics and owns stocks. A.R. and M.B. have received research support from Grifols, Roche, Araclon and Janssen. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. All other authors have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown., Objective: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men)., Methods: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015)., Results: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences., Conclusion: Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

Diminished nigrostriatal dopaminergic neurotransmission is a biochemical hallmark of Parkinson's disease. Despite this, a reliable trait biomarker of sporadic Parkinson's disease has not emerged from measurements of cerebrospinal fluid dopamine metabolites. Previous studies have highlighted strong neurochemical relationships between dopamine and various purine compounds. In this study, we analyzed cerebrospinal fluid concentrations of homovanillic acid (the major catabolite of dopamine) and the purine compound xanthine for a comparison of 217 unmedicated Parkinson's disease subjects and 26 healthy controls. These compounds were highly correlated for both the Parkinson's disease subjects (r=0.68) and for controls (r=0.73; both groups, p<0.001). While neither homovanillic acid nor xanthine concentrations differentiated Parkinson's disease from controls, their ratio did. For controls, the mean [xanthine]/[homovanillic acid] quotient was 13.1±5.5 as compared to the Parkinson's disease value of 17.4±6.7 at an initial lumbar CSF collection (p=0.0017), and 19.7±8.7 (p<0.001) at a second CSF collection up to 24 months later. The [xanthine]/[homovanillic acid] ratio in the Parkinson's disease subjects differed as a function of disease severity, as measured by the sum of Unified Parkinson's Disease Rating Scale Activities of Daily Living and Motor Exam ratings. The [xanthine]/[homovanillic acid] ratio also increased between the first and second CSF collections, suggesting that this quotient provides both a state and trait biomarker of Parkinson's disease. These observations add to other neurochemical evidence that links purine metabolism to Parkinson's disease., (Copyright © 2011. Published by Elsevier B.V.)

Aim: The aim of this study was to evaluate the usefulness of cerebral blood flow velocity in the middle cerebral artery measured by transcranial Doppler as criteria to therapeutic action in communicating hydrocephalic children., Methods: In eight non-tumoral communicating hydrocephalic infants, ranging from five to 18 months of age, monitored from 18 to 36 months (mean time of follow-up: 24.25 months), cerebrospinal fluid (CSF) oxypurines (hypoxanthine and xanthine) and uric acid levels were compared by means of the Evans' index, the mean weekly increase in cranial circumference, and the transcranial Doppler measurements., Results: Results indicate that clinical (mean weekly increase in head circumference), radiological (Evans' index), biochemical (oxypurines and uric acid in the CSF), and hemodynamic (transcranial Doppler) criteria have the same role in monitoring infantile hydrocephalus., Conclusion: In conclusion the transcranial Doppler measurement can be done noninvasively and examinations can be repeated when needed, obtaining immediate, Results: Hence, it is the most adequate monitoring technique in clinical practice.

Background: Insufficient cerebral O2 supply leads to cellular energy failure and loss of brain cell function. The relationship between the severity of cellular energy failure due to hemorrhagic hypotension and the loss of electrocortical brain activity (ECBA), as a measure of brain cell function, is not yet fully elucidated in near-term born lambs., Objectives: To study the relationship between cerebral purine and pyrimidine metabolism, as a measure of brain cell energy failure, and brain cell function after hemorrhagic hypotension in near-term born lambs., Methods: Eight near-term lambs (term 147 days) were delivered at 131 days of gestation. After a stabilization period, mean arterial blood pressure was reduced till 30% of baseline by withdrawal of blood. Cerebrospinal fluid (CSF) was obtained at the end of the hypotensive period (2.5 h). CSF from 8 siblings was used for comparison. HPLC was used to determine purine and pyrimidine metabolites in CSF, as a measure of cellular energy failure. ECBA was calculated as the root mean square value of a band-filtered (2-16 Hz) one-channel EEG., Results: Values of guanosine, inosine, hypoxanthine, xanthine and uridine were significantly higher, while ECBA was significantly lower after hemorrhagic hypotension than control values. The concentrations of inosine, hypoxanthine, xanthine and uridine were significantly negatively linearly related to ECBA., Conclusions: Brain cell function is negatively related to concentrations of inosine, hypoxanthine, xanthine and uridine in the CSF after hemorrhagic hypotension in near-term born lambs., (Copyright (c) 2006 S. Karger AG, Basel.)

Object: Identification of new therapeutic agents aimed at attenuating posttraumatic brain edema formation remains an unresolved challenge. Among others, activation of bradykinin B2 receptors is known to mediate the formation of brain edema. The purpose of this study was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist, LF 16-0687Ms, in brain-injured rats., Methods: Focal contusion was produced by controlled cortical impact injury. Five minutes after trauma, the rats received a single dose of no, low- (3 mg/kg body weight), or high- (30 mg/kg) dose LF 16-0687Ms. After 24 hours, the amount of brain swelling and hemispheric water content were determined. Low and high doses of LF 16-0687Ms significantly reduced brain swelling by 25% and 27%, respectively (p < 0.03). Hemispheric water content tended to be increased in the nontraumatized hemisphere. In a subsequent series of 10 rats, cisternal cerebrospinal fluid (CSF) samples were collected to determine whether changes in substances associated with edema formation could clarify why LF 16-0687Ms increases water content. For this, the volume regulator amino acid taurine, the excitatory transmitter glutamate, and the adenosine triphosphate degradation products hypoxanthine and xanthine were measured. In CSF, the levels of taurine, hypoxanthine, and xanthine were significantly decreased following a single administration of LF 16-0687Ms (p < 0.005); the level of glutamate, however, was double that found in control animals (p < 0.05)., Conclusions: Using the present study design, a single administration of LF 16-0687Ms successfully reduced posttraumatic brain swelling. The decreased levels of taurine, hypoxanthine, and xanthine may reflect reduced posttraumatic brain edema, whereas the increased level of glutamate could account for the elevated water content observed in the nontraumatized hemisphere.

Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase. Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls. Lactate is only elevated in meningitis. Normal lactate dehydrogenase (LDH) levels and absent correlation between the albumin ratio and neurochemical parameters exclude an artificial increase due to cell lysis and barrier damage. Absent correlation between neurochemical parameters within each patient group is most likely related to preserved glial and neuronal uptake mechanisms. CSF hypoxanthine, xanthine, and uric acid levels appear superior to lactate in reflecting glutamate-mediated excitotoxicity in neurological patients.