Purine Metabolism Profiling Reveals Distinct Associations of Uric Acid, Xanthine, and Hypoxanthine with Neurological Severity and Functional Outcome After Acute Ischemic Stroke.
Roman-Filip I, Farczadi L, et al. • International journal of molecular sciences • 2026
Simultaneous assessment of uric acid together with xanthine and hypoxanthine may provide additional insight into stroke severity and neurological recovery, supporting the potential role of purine metabolism profiling as a complementary biomarker approach in acute ischemic stroke.
Key Findings
Results
Hypoxanthine concentrations varied significantly according to admission NIHSS severity categories, with lower values observed among patients presenting severe neurological deficits.
The association between hypoxanthine and NIHSS severity categories was statistically significant (p = 0.022)
The study included 143 consecutive patients admitted with acute ischemic stroke in a tertiary neurological center
Neurological severity was assessed using the National Institutes of Health Stroke Scale (NIHSS)
Plasma hypoxanthine concentrations were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology
Results
Plasma xanthine concentrations demonstrated a significant association with unfavorable long-term functional outcome and exhibited the highest predictive performance among purine biomarkers in ROC analysis.
The association between xanthine and unfavorable long-term functional outcome was statistically significant (p = 0.033)
Xanthine achieved an AUC of 0.614 in ROC curve analysis, the highest among the purine biomarkers assessed
Functional outcome was evaluated using the modified Rankin Scale (mRS) at discharge and at 3-month follow-up
Plasma xanthine concentrations were quantified using validated LC-MS/MS methodology
Results
Serum uric acid concentrations were numerically lower in patients with poorer functional outcomes at discharge and at 3 months, but these differences were not statistically significant.
Lower uric acid was observed in patients with worse functional outcomes at both discharge and 3-month follow-up timepoints
The differences in uric acid across functional outcome groups did not reach statistical significance
Uric acid was noted to have dual antioxidant and pro-oxidant properties, which has driven prior extensive investigation
The study design was a prospective observational cohort study
Results
Admission NIHSS remained the main independent predictor of unfavorable 3-month functional outcome in the adjusted multivariable logistic regression model, while xanthine and other purine biomarkers did not retain statistically significant independent associations.
Multivariable logistic regression models were used to evaluate independent predictive performance of purine metabolism biomarkers
After adjustment, xanthine, hypoxanthine, and uric acid did not retain statistically significant independent associations with unfavorable 3-month functional outcome
Admission NIHSS score was identified as the dominant independent predictor
ROC curve analysis and multivariable logistic regression were both performed to evaluate predictive performance
Methods
The study used a prospective observational cohort design with 143 consecutive acute ischemic stroke patients and LC-MS/MS quantification of purine metabolites.
143 consecutive patients admitted with acute ischemic stroke were enrolled at a tertiary neurological center
Plasma xanthine and hypoxanthine concentrations were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology
Neurological severity was assessed using NIHSS and functional outcome using mRS at discharge and at 3-month follow-up
Statistical methods included Shapiro-Wilk and Kolmogorov-Smirnov normality testing, Student's t-test, Mann-Whitney U test, Kruskal-Wallis test, Spearman's rank correlation, ROC curve analysis, and multivariable logistic regression
Correlations were visualized using a heatmap
Background
Purine metabolism and oxidative stress are recognized as important contributors to ischemic brain injury, but comparatively limited data existed on the prognostic relevance of upstream purine metabolites such as xanthine and hypoxanthine prior to this study.
Uric acid has been extensively investigated due to its dual antioxidant and pro-oxidant properties
The study aimed to fill a gap regarding xanthine and hypoxanthine, which are upstream purine metabolites
The authors note that the underlying biological mechanisms linking purine biomarkers to outcomes were not directly assessed in this study
The study framed purine metabolism profiling as a potential complementary biomarker approach in AIS
What This Means
This research examined whether measuring three related compounds involved in purine metabolism — uric acid, xanthine, and hypoxanthine — in the blood of stroke patients could help predict how severely they would be affected and how well they would recover. The study followed 143 patients admitted to a hospital with acute ischemic stroke (the type caused by a blood clot blocking blood flow to the brain), measuring these compounds at admission and tracking patients' neurological function and ability to perform daily activities both at discharge and three months later.
The researchers found that hypoxanthine levels were significantly different depending on how severe a patient's stroke symptoms were at admission, with lower hypoxanthine seen in patients with more severe deficits. Xanthine levels were significantly associated with worse long-term functional outcomes at three months and had the best predictive ability of the three compounds tested, though this predictive ability was modest (AUC of 0.614, where 1.0 would be perfect prediction). Uric acid showed a numerical trend toward lower levels in patients with worse outcomes, but this did not reach statistical significance. Importantly, when all factors were analyzed together in a statistical model, the initial stroke severity score (NIHSS) remained the strongest predictor of poor outcome, and none of the purine compounds independently added statistically significant predictive value after accounting for stroke severity.
This research suggests that measuring xanthine and hypoxanthine alongside uric acid — rather than uric acid alone as has been common in prior research — may provide a more complete picture of what is happening in the brain after a stroke. However, these findings are exploratory, the biological reasons for the associations were not directly tested, and the purine compounds did not independently predict outcomes beyond what stroke severity scores already capture. Future research could investigate whether these metabolite profiles change over time and whether they reflect specific aspects of brain injury or recovery.
Roman-Filip I, Farczadi L, Roman-Filip C, Bajko Z, Moțățăianu A, Maier S, et al.. (2026). Purine Metabolism Profiling Reveals Distinct Associations of Uric Acid, Xanthine, and Hypoxanthine with Neurological Severity and Functional Outcome After Acute Ischemic Stroke.. International journal of molecular sciences. https://doi.org/10.3390/ijms27198486