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Metabolomics biomarker discovery in cerebrospinal fluid for cerebral amyloid angiopathy
Author(s) -
van den Berg Emma,
Kuiperij H. Bea,
Van Nostrand William E.,
Peters Tessa M.A.,
Coene Karlien L.M.,
Engelke Udo F.H.,
de Boer Siebolt,
Verbeek Marcel M.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041934
Subject(s) - cerebral amyloid angiopathy , metabolome , metabolite , metabolomics , biomarker , cerebrospinal fluid , biomarker discovery , amyloid (mycology) , pathology , medicine , chemistry , biology , computational biology , disease , dementia , bioinformatics , proteomics , biochemistry , gene
Background Cerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhages and contributes to cognitive decline. Probable diagnosis is currently determined using the modified Boston criteria. However, these in vivo imaging correlates only represent late‐stage disease manifestations, are unable to set definitive CAA diagnosis, and do not reflect disease progression or track severity. Thus there is an unmet need for an early‐stage CAA biomarker to bypass these limitations. Next to vascular amyloid‐ß accumulation and increased neuroinflammation, metabolite levels may also be altered due to changes induced by amyloid‐ß deposits. Method In the Cerebral Amyloid Angiopathy Fluid Biomarker Evaluation (CAFE) study, we aim to discover and validate new CAA‐specific biofluid markers. By using a transgenic rat model for small‐vessel CAA, the rTg‐DI model, we are able to study a genetically homogenous group, housed in an environment equal to wild‐type rats. An unbiased combined liquid chromatography‐mass spectrometry protocol to analyze cerebrospinal fluid (CSF) from these rats will be generated and optimized. With the obtained distinct metabolite profiles, we aim to identify novel CAA‐associated metabolite biomarkers. Result Next‐generation metabolic screening (NGMS) is our newly developed methodology to study the metabolome, using high‐resolution liquid chromatography quadrupole time‐of‐flight mass spectrometry. This high‐throughput unbiased NGMS approach enables us to detect >10,000 different features in one plasma sample, defined by their unique combination of accurate mass, specific retention time and intensity. In human CSF, 206 metabolites were annotated using the Human Metabolome Database. Application to rodent models requires only 25µL of CSF for analysis. Currently, we are analyzing CSF from 6‐months old rTg‐DI rats compared to age‐matched wild‐type rats (each n=10); the results will be presented during the conference. Conclusion We expect that our powerful innovative technology for untargeted and simultaneous analysis of a large number of metabolites in body fluids will be promising in discovering novel potential biomarkers for CAA. Using a robust animal model allows us to study biomarkers along the trajectory of disease progression. Furthermore, it will gain more insight in underlying processes and metabolic pathways that are involved in the pathophysiology of CAA. After the initial discovery phase, candidate markers will be validated in patient cohorts.