Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

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 Ca 2+ 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.

Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

“…Quantitative analysis of g-ratios (the inner axonal diameter to the total outer diameter) confirmed that mutant Htt significantly increased this ratio in PLP-150Q mice in an age-dependent manner (Figure 5C). It is well known that demyelination can lead to axonal degeneration (Rodriguez and Scheithauer, 1994; Sathornsumetee et al, 2000; Lee et al, 2014). Consistently, electron microscopy also revealed a number of degenerated axons, which appear swollen and dark, in PLP-150Q mice at 5 months of age (Figure 5D).…”

Limiting Neuronal Nogo Receptor 1 Signaling during Experimental Autoimmune Encephalomyelitis Preserves Axonal Transport and Abrogates Inflammatory Demyelination

“…In contrast to the original research focus defining the autoimmune mechanisms that are operative in multiple sclerosis (MS) and the therapeutic developments that have achieved substantive reductions in relapse rates, axonal degeneration and neural tissue injury still remain the arbiter of profound neurological deficit in individuals living with this severe disease (for review, see Lee et al, 2014). Two models of axonopathy/demyelination have been suggested in MS pathology; primary axonal degeneration or oligodendrocyte dystrophy followed by demyelination (inside-out), or demyelination leading to secondary axonal degeneration (outside-in; Trapp and Nave, 2008).…”

The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

“…Elevated neurofilament light chain (NfL) is a more recently discovered biomarker of neurodegenerative diseases, including AD, frontotemporal dementia, amyotrophic lateral sclerosis, and multiple sclerosis (Chatterjee et al, ; Gille et al, ; Goossens et al, ; Siller et al, ). An increase in NfL in CSF and blood is interpreted as an indication of ongoing axonal damage (Lee, Taghian, & Petratos, ). Although both tau and NfL are both markers of neurodegeneration, they represent different degenerative processes in the brain.…”