A Comprehensive Description of the Roadmap to Identify and Validate a Myelin Biomarker.

Background: Demyelination and remyelination are major issues for scientists dealing with myelin disorders in both clinical and research fields. Despite that, rapid, reliable and convenient tools to monitor myelin changes still lack both in central and peripheral nervous system. Given that myelin is enriched in specific lipids and proteins, it is reasonable they could represent eligible candidates as structural damage biomarkers for this characteristic membrane. Among them, we focused on sphingomyelin (SM) due to the enrichment in myelin and because it is easily measurable in different biological matrices.

Objective: Depicting the roadmap to identify and validate SM dosage as a myelin biomarker useful for pre-clinical and clinical practice.

Design: This study adheres to STROBE guidelines for observational cross-sectional studies on human patients and to ARRIVE guidelines for animal models.

Method: Following the recommendations of the Society for CSF Analysis and Clinical Neurochemistry, we describe the stepwise process to validate SM as a myelin biomarker, starting from the optimization of the fluorescence-based assay and analytical validation in experimental models until clinical and pathological validation in biological fluids of neurological patients.

Results: SM dosage monitors myelination, demyelination, remyelination and even small myelin changes associated to myelin pathology and pharmacological treatments in experimental models. SM is detectable in human biological fluids and informative of myelin damage in the CSF of neurological patients. SM dosage identifies myelin breakdown in the CSF of patients affected by Guillain-Barrè Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), identifying disease activity, axonal from demyelinating variants, and avoiding misdiagnosis.

Conclusion: SM dosage displayed extremely promising real-word performances being able to identify, monitor and stage myelin pathology. Given that it is simple, inexpensive and easily adaptable to routine use in any hospital setting, it might rapidly progress to the implementation and impact on clinical outcomes.