Molecular-based diagnosis of Multiple Sclerosis and its progressive stage

Abstract Biomarkers aid diagnosis, allow inexpensive screening of therapies and guide selection of rational patient-specific polypharmacy regimens in most internal medicine disciplines. In contrast, there are no clinically-validated measurements of the physiological status, or dysfunction(s) of cellular components of the central nervous system (CNS). Accordingly, patients with chronic neurological diseases are generally treated with a single disease-modifying therapy without understanding patient-specific drivers of disability. Therefore, using multiple sclerosis (MS) as an example of a complex polygenic neurological disease, we sought to determine if cerebrospinal fluid (CSF) biomarkers are intra-individually stable, cell type-, disease- and/or process-specific and responsive to therapeutic intervention. Using DNA-aptamer-based multiplex assay, in-vitro- and statistical models, we developed in a training cohort (n=225) and validated in an independent-cohort (n=85) two biomarker-based classifiers that differentiate: 1. MS from CNS diseases that mimic MS clinically, pathophysiologically and on imaging, and 2. relapsing-remitting from progressive MS with ~90% accuracy. Treatment-induced changes in biomarkers greatly exceeded intra-individual-and technical variabilities of the assay. The observation that CNS biological processes reflected by combinatorial CSF biomarkers are robust, stable and disease- or even disease-stage specific opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders.

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