Fluid biomarker and electrophysiological outcome measures for progressive MS trials

Abstract

Progressive multiple sclerosis (MS) is characterized by insidious clinical worsening that is difficult to accurately quantify and predict. Biofluid markers and electrophysiological measures are potential candidate outcome measures in clinical trials, allowing the quantification of nervous damage occurring in the disease. Neurofilaments are highly specific neuronal proteins. They may have come closest to such applications by their higher concentrations repeatedly demonstrated in cerebrospinal fluid (CSF) in all stages of MS, during relapses, their responsiveness to disease-modifying treatments in relapsing and progressive MS and their associations with measures of inflammatory and degenerative magnetic resonance imaging (MRI) outcomes. Digital single-molecule array (Simoa) technology improves accuracy of bioassays in the quantification of neurofilament light chain (NfL) in serum and plasma. NfL seems to mark a common final path of neuroaxonal injury independent of specific causal pathways. CSF and blood levels of NfL are highly correlated across various diseases including MS, suggesting that blood measurements may be useful in assessing response to treatment and predicting future disease activity. Other biomarkers like matrix metalloproteinases, chemokines, or neurotrophic factors have not been studied to a similar extent. Such measures, especially in blood, need further validation to enter the trial arena or clinical practice. The broadening armamentarium of highly sensitive assay technologies in the future may shed even more light on patient heterogeneity and mechanisms leading to disability in MS. Evoked potentials (EPs) are used in clinical practice to measure central conduction of central sensorimotor pathways. They correlate with and predict the severity of clinical involvement of their corresponding function. Their validation for use in multicenter studies is still lacking, with the exception of visual EPs. If further validated, EPs and fluid biomarkers would represent useful outcome measures for clinical trials, being related to specific mechanisms of the ongoing pathologic changes.

Evoked potentials as a biomarker of remyelination

“…It is likely that with longer follow-up, thin myelin sheaths will continue to accrue thicker myelin, accompanied by further reductions in VEP latency. The data presented here in a model characterized by ON demyelination and remyelination provide direct support to the suggestion that VEP recordings are true surrogate markers of remyelination (6,26,28,30,60) and will be a legitimate outcome measure in future clinical trials of remyelinating therapies in MS.…”

“…Thus, to date there has been a lack of models with reproducible optic neuropathy and lesions limited to demyelination and then remyelination that can be used to evaluate the myelin status by VEPs. This is a critical need in the development of definitive outcome measures in MS clinical trials of remyelination (25)(26)(27)(28)(29)(30)(31). Recently, 2 clinical trials in MS, testing the remyelination-promoting effect of 2 drugs, the first one a monoclonal antibody, opicinumab…”

Neurofilament Light Chain: Blood Biomarker of Neonatal Neuronal Injury

“…Neuronal injury marker NfL has proved a sensitive and specific biomarker in adult peripheral blood, serving as a promising adjunct to monitoring and decision-making in acute and chronic neurologic disease ( 16 , 17 ). Our study provides a first insight into neonatal NfL levels in term and preterm infants.…”

Validation of Quantitative Scores Derived From Motor Evoked Potentials in the Assessment of Primary Progressive Multiple Sclerosis: A Longitudinal Study

“…Development of therapies in primary progressive multiple sclerosis (PPMS) is hampered by the fact that detecting disease progression by clinical assessment needs considerable sample sizes and follow-up time to be meaningful ( 1 , 2 ). Biomarkers allowing shorter multicenter clinical trials in small patient groups are not well-established ( 3 , 4 ), and several candidate biomarkers have been proposed, including evoked potentials (EPs) ( 5 ).…”