Abstract
Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na+ and Ca2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.
Highlights
Destructive, inflammatory demyelinating multiple sclerosis (MS) lesions can occur throughout the central nervous system (CNS) with preferential anatomical patterns forming
We found that the pThr555CRMP-2 form demonstrated during the peak stage of EAE can be reduced through the administration of a function blocking antibody against Nogo-A or alternatively, through the overexpression of the phosphomutant form of collapsin response mediator protein-2 (CRMP-2) by using an adeno-associated virus serotype 2 gene delivery system, could individually reduce the markers of degenerative axons appearing [135]
Permanent neurological deficits in MS are governed by CNS axonal degeneration of major fiber tracts but the molecular mechanisms, which contribute to this damage, are poorly understood
Summary
Destructive, inflammatory demyelinating multiple sclerosis (MS) lesions can occur throughout the central nervous system (CNS) with preferential anatomical patterns forming. These studies reflect the clinical relevance in measuring altered NAA levels during the course of MS as a biomarker for axonal damage in NAWM and both acute and chronic inflammatory lesions.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have