Decreased purine metabolite levels in cerebrospinal fluid of transgenic cerebral amyloid angiopathy rats.

Background: Cerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhages and contributes to cognitive decline. The currently applied modified Boston criteria fall short in detecting early‐stage disease and biomarkers to track disease progression are lacking. In the CAA Fluid Biomarker Evaluation (CAFE) study we aim to identify novel CAA‐specific biomarkers. We hypothesize that levels of metabolites in cerebrospinal fluid (CSF) are altered due to amyloid‐β deposits. Method: High‐resolution liquid chromatography quadrupole time‐of‐flight mass spectrometry was used to analyze metabolite levels in an untargeted fashion (Coene et al., 2018; Peters et al., 2020) in CSF derived from small‐vessel CAA transgenic (rTg‐DI) and wild‐type (WT) rats. Candidate features identified in a discovery study (n=8 WT; n=10 rTg; 6 months old) were validated in larger groups of rats including various ages (n=30 WT; n=29 rTg; 3‐6‐12 months old). Features were annotated based on accurate mass, specific retention time and semi‐quantitative intensity by comparison with reference standard compounds and online database matching. Result: Of the 48 significantly different features discovered in the pilot, 27 could be validated in the second study. Several features corresponded with reference compounds of metabolites involved in the purine metabolism pathway, which included guanosine, guanine, inosine, xanthine and hypoxanthine. All these levels were significantly decreased in all groups of the rTg rats compared to WT, some progressing with older age (Figure 1). An additional n=605 features were identified with significantly different levels between the various groups. Molecular formulas for other possible interesting features could be computed, whose metabolite identities are currently being confirmed by using standard compounds. Conclusion: Metabolomics analyses of the CSF of transgenic rats shows promise in discovering novel potential biomarkers for CAA. Using a robust animal model allows us to study biomarkers along the trajectory of disease progression. Our results suggest a global down‐regulation of the purine pathway (Figure 2), a finding previously observed in early‐stage Alzheimer’s disease (Alonso‐Andrés et al., 2017). [ABSTRACT FROM AUTHOR]