Promise, Progress, and Pitfalls in the Search for Central Nervous System Biomarkers in Neuroimmunological Diseases: A Role for Cerebrospinal Fluid Immunophenotyping

Abstract

Biomarkers are central to the translational medicine strategic focus, though strict criteria need to be applied to their designation and utility. They are one of the most promising areas of medical research, but the “biomarker life-cycle” must be understood to avoid false-positive and false-negative results. Molecular biomarkers will revolutionize the treatment of neurological diseases, but the rate of progress depends on a bold, visionary stance by neurologists, as well as scientists, biotech and pharmaceutical industries, funding agencies, and regulators. One important tool in studying cell-specific biomarkers is multi-parameter flow cytometry. CSF immunophenotyping, or immune phenotypic subsets, captures the biology of intrathecal inflammatory processes, and has the potential to guide personalized immunotherapeutic selection and monitor treatment efficacy. Though data exist for some disorders, they are surprising lacking in many others, identifying a serious deficit to be overcome. Flow cytometric immunophenotyping provides a valuable, available, and feasible “window” into both adoptive and innate components of neuroinflammation that is currently underutilized.

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

“…C–C ligands ( 1 – 28 ), the largest group of CKs, correspond to C–C receptors (CCRs), just as C–X–C CKs ( 1 – 17 ), the second largest CK subgroup, do to C–X–C receptors (CXCRs), and there is functional relatedness between subgroup ligands ( 7 ). XCL (two types) and CX3C (one type) are smaller ligand subgroups.…”

“…Other small studies also have been reported, but with pitfalls in interpretation ( 1 ). In a study of Aicardi–Goutières syndrome (AGS), multiple CSF cytokine and CK abnormalities were shown ( 125 ), but would not have been significant if correction for multiple comparisons had been made.…”

“…The ultimate therapeutic goal is to gracefully overcome maladapted, disease-producing biologic processes, induce remission, and re-introduce immune tolerance without toxicity ( 1 ). Consistent with the definition of immunotherapy, biological response modifiers treat disease through induction, enhancement, or suppression of an immune response.…”

“…The era of “biomarker-guided therapy” has introduced a paradigm shift in immunotherapeutics based on the biological make-up of the individual patient ( 1 ). Integral to the concept of personalized medicine or “precision medicine” is the use of molecular biomarkers to improve detection of neuroinflammation and predict drug benefit or adverse effects ( 2 ).…”

Clinical trials in multiple sclerosis: potential future trial designs

“…43 The EDSS only registers overt deficits and misses the subtle clinical deteriorations in the course of the disease as it is inherently limited by the sensitivity of the clinical examinations that constitute this scale. 44 Finally, the EDSS records clinical information retrospectively, but yields no information on disease progression. 43,45…”