Degeneration In Multiple Sclerosis Research Articles

β-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration.

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein β-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of β-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, β-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of β-synuclein in provoking T-cell-mediated pathology of the central nervous system.

Optical coherence tomography as a means to characterize visual pathway involvement in multiple sclerosis.

Optical coherence tomography (OCT) is a noninvasive in-vivo imaging tool that enables the quantification of the various retinal layer thicknesses. Given the frequent involvement of the visual pathway in multiple sclerosis, OCT has become an important tool in clinical practice, research and clinical trials. In this review, the role of OCT as a means to investigate visual pathway damage in multiple sclerosis is discussed. Evidence from recent OCT studies suggests that the peripapillary retinal nerve fibre layer (pRNFL) appears to be an ideal marker of axonal integrity, whereas the macular ganglion cell and inner plexiform layer (GCIP) thickness enables early detection of neuronal degeneration in multiple sclerosis. The thickness of the macular inner nuclear layer (INL) has been suggested as a biomarker for inflammatory disease activity and treatment response in multiple sclerosis. OCT parameters may also be used as an outcome measure in clinical trials evaluating the neuroprotective or regenerative potential of new treatments. OCT provides insights into multiple sclerosis beyond the visual pathway. It is capable of quantifying the major pathological hallmarks of the disease, specifically inflammation and neuroaxonal degeneration. OCT, therefore, has the potential to become another mainstay in the monitoring of multiple sclerosis patients.

Involvement of Mitochondria in Neurodegeneration in Multiple Sclerosis.

Functional disruption and neuronal loss followed by progressive dysfunction of the nervous system underlies the pathogenesis of numerous disorders defined as "neurodegenerative diseases". Multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system resulting in serious neurological dysfunctions and disability, is one of the most common neurodegenerative diseases. Recent studies suggest that disturbances in mitochondrial functioning are key factors leading to neurodegeneration. In this review, we consider data on mitochondrial dysfunctions in multiple sclerosis, which were obtained both with patients and with animal models. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. The genetic studies analyzing association of mitochondrial DNA polymorphic variants in multiple sclerosis suggest the participation of mitochondrial genome variability in the development of this disease, although questions of the involvement of individual genomic variants are far from being resolved.

The Effect of Glatiramer Acetate on Retinal Nerve Fiber Layer Thickness in Patients with Relapsing-Remitting Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study.

Optical coherence tomography (OCT) is a technique that allows for the assessment of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV), which reflect neuroaxonal integrity within the retina. As such it has been used in multiple sclerosis (MS) to study neurodegeneration. Glatiramer acetate (GA) is a widely used treatment for MS, which is suggested to have a possible neuroprotective role. The aim of this study was to assess RFNLT and TMV changes in relapsing-remitting MS (RRMS) patients who started treatment with GA and were followed for a 24-month period. A cohort of 60 RRMS patients and 40 healthy controls (HCs) were imaged with OCT at baseline and follow-up. All subjects also underwent clinical and neurological examination. Measurements were compared between the RRMS patients and HCs as well as between optic neuritis (ON)-affected and ON-unaffected eyes. At baseline, MS patients showed lower average RNFLT (p = 0.046) and TMV (p = 0.013) when compared with HCs. No significant differences in the evolution of OCT measures were detected over the follow-up between MS patients and HCs. MS patients with both affected and unaffected eyes showed significantly lower average RNFLT, temporal inferior RNFLT, and TMV at baseline, compared with HCs. No significant differences between ON-affected and ON-unaffected eyes in MS patients were detected over the follow-up, except for the nasal superior RNFLT (p = 0.019). This study suggests a beneficial role of GA on retinal axonal degeneration in MS, and further confirms the utility of OCT to monitor the neuroprotective effect of disease-modifying treatment.

Characterizing Microstructural Tissue Properties in Multiple Sclerosis with Diffusion MRI at 7 T and 3 T: The Impact of the Experimental Design

The recent introduction of advanced magnetic resonance (MR) imaging techniques to characterize focal and global degeneration in multiple sclerosis (MS), like the Composite Hindered and Restricted Model of Diffusion, or CHARMED, diffusional kurtosis imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI) made available new tools to image axonal pathology non-invasively in vivo. These methods already showed greater sensitivity and specificity compared to conventional diffusion tensor-based metrics (e.g., fractional anisotropy), overcoming some of its limitations.While previous studies uncovered global and focal axonal degeneration in MS patients compared to healthy controls, here our aim is to investigate and compare different diffusion MRI acquisition protocols in their ability to highlight microstructural differences between MS and control tissue over several much used models. For comparison, we contrasted the ability of fractional anisotropy measurements to uncover differences between lesion, normal-appearing white matter (WM), gray matter and healthy tissue under the same imaging protocols. We show that: (1) focal and diffuse differences in several microstructural parameters are observed under clinical settings; (2) advanced models (CHARMED, DKI and NODDI) have increased specificity and sensitivity to neurodegeneration when compared to fractional anisotropy measurements; and (3) both high (3 T) and ultra-high fields (7 T) are viable options for imaging tissue change in MS lesions and normal appearing WM, while higher b-values are less beneficial under the tested short-time (10 min acquisition) conditions.

Chemical hypoxia-induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2).

The extent of remyelination in multiple sclerosis lesions is often incomplete. Injury to oligodendrocyte progenitor cells can be a contributing factor for such incomplete remyelination. The precise mechanisms underlying insufficient repair remain to be defined, but oxidative stress appears to be involved. Here, we used immortalized oligodendrocyte cell lines as model systems to investigate a causal relation of oxidative stress and endoplasmic reticulum stress signaling cascades. OLN93 and OliNeu cells were subjected to chemical hypoxia by blocking the respiratory chain at various levels. Mitochondrial membrane potential and oxidative stress levels were quantified by flow cytometry. Endoplasmic reticulum stress was monitored by the expression induction of activating transcription factor 3 and 4 (Atf3, Atf4), DNA damage-inducible transcript 3 protein (Ddit3), and glucose-regulated protein 94. Lentiviral silencing of nuclear factor (erythroid-derived 2)-like 2 or kelch-like ECH-associated protein 1 was applied to study the relevance of NRF2 for endoplasmic reticulum stress responses. We demonstrate that inhibition of the respiratory chain induces oxidative stress in cultured oligodendrocytes which is paralleled by the expression induction of distinct mediators of the endoplasmic reticulum stress response, namely Atf3, Atf4, and Ddit3. Atf3 and Ddit3 expression induction is potentiated in kelch-like ECH-associated protein 1-deficient cells and absent in cells lacking the oxidative stress-related transcription factor NRF2. This study provides strong evidence that oxidative stress in oligodendrocytes activates endoplasmic reticulum stress response in a NRF2-dependent manner and, in consequence, might regulate oligodendrocyte degeneration in multiple sclerosis and other neurological disorders.

Peripapillary retinal nerve fibre layer as measured by optical coherence tomography is a prognostic biomarker not only for physical but also for cognitive disability progression in multiple sclerosis

Background: Peripapillary retinal nerve fibre layer (pRNFL) thickness is emerging as a marker of axonal degeneration in multiple sclerosis (MS). Objective: We aimed to prospectively assess the predictive value of pRNFL for progression of physical and cognitive disability in relapsing-remitting MS (RRMS). Methods: In this 3-year longitudinal study on 151 RRMS patients, pRNFL was measured by spectral-domain optical coherence tomography (OCT). We used proportional hazard models, correcting for age, sex, disease duration, Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) at baseline, to test a pRNFL thickness ≤88 µm at baseline for prediction of EDSS progression and cognitive decline. We also evaluated the decrease in pRNFL thickness from baseline to year 3 in a multivariate linear regression model. Results: pRNFL thickness ≤88 µm was independently associated with a threefold increased risk of EDSS progression (p < 0.001) and a 2.7-fold increased risk of cognitive decline within the subsequent 3 years (p < 0.001). Mean pRNFL delta was −5.3 µm (SD, 4.2). It was significantly negatively impacted by EDSS progression, cognitive decline, higher age and disease duration, while positively impacted by disease-modifying therapy (DMT). Conclusion: Cross-sectional and longitudinal monitoring of pRNFL is useful as a biomarker for prediction of physical and cognitive disability progression in patients with RRMS in everyday clinical practice.

Fibre-specific white matter changes in multiple sclerosis patients with optic neuritis.

Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross-section, that can be estimated for each fibre direction in each voxel (termed a “fixel”). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 ± 10.2 years, 11 females) and 14 healthy controls (32.7 ± 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS.

Heterogeneous pathological processes account for thalamic degeneration in multiple sclerosis: Insights from 7 T imaging

Background: Thalamic degeneration impacts multiple sclerosis (MS) prognosis. Objective: To investigate heterogeneous thalamic pathology, its correlation with white matter (WM), cortical lesions and thickness, and as function of distance from cerebrospinal fluid (CSF). Methods: In 41 MS subjects and 17 controls, using 3 and 7 T imaging, we tested for (1) differences in thalamic volume and quantitative T2* (q-T2*) (2) globally and (3) within concentric bands originating from the CSF/thalamus interface; (4) the relation between thalamic, cortical, and WM metrics; and (5) the contribution of magnetic resonance imaging (MRI) metrics to clinical scores. We also assessed MS thalamic lesion distribution as a function of distance from CSF. Results: Thalamic lesions were mainly located next to the ventricles. Thalamic volume was decreased in MS versus controls (p < 10−2); global q-T2* was longer in secondary progressive multiple sclerosis (SPMS) only (p < 10−2), indicating myelin and/or iron loss. Thalamic atrophy and longer q-T2* correlated with WM lesion volume (p < 0.01). In relapsing-remitting MS, q-T2* thalamic abnormalities were located next to the WM (p < 0.01 (uncorrected), p = 0.09 (corrected)), while they were homogeneously distributed in SPMS. Cortical MRI metrics were the strongest predictors of clinical outcome. Conclusion: Heterogeneous pathological processes affect the thalamus in MS. While focal lesions are likely mainly driven by CSF-mediated factors, overall thalamic degeneration develops in association with WM lesions.

Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase.

Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate (DMF) is an effective oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. DMF activates the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) leading to increased synthesis of the major cellular antioxidant glutathione (GSH) and prominent neuroprotection in vitro. We previously demonstrated that DMF is capable of raising GSH levels even when glutathione synthesis is inhibited, suggesting enhanced GSH recycling. Here, we found that DMF indeed induces glutathione reductase (GSR), a homodimeric flavoprotein that catalyzes GSSG reduction to GSH by using NADPH as a reducing cofactor. Knockdown of GSR using a pool of E. coli RNase III-digested siRNAs or pharmacological inhibition of GSR, however, also induced the antioxidant response rendering it impossible to verify the suspected attenuation of DMF-mediated neuroprotection. However, in cystine-free medium, where GSH synthesis is abolished, pharmacological inhibition of GSR drastically reduced the effect of DMF on glutathione recycling. We conclude that DMF increases glutathione recycling through induction of glutathione reductase.

Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis.

Counteracting the progressive neurological disability caused by neuronal and axonal loss is the major unmet clinical need in multiple sclerosis therapy. However, the mechanisms underlying irreversible neuroaxonal degeneration in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are not well understood. A long-standing hypothesis holds that the distribution of voltage-gated sodium channels along demyelinated axons contributes to neurodegeneration by increasing neuroaxonal sodium influx and energy demand during CNS inflammation. Here, we tested this hypothesis in vivo by inserting a human gain-of-function mutation in the mouse NaV1.2-encoding gene Scn2a that is known to increase NaV1.2-mediated persistent sodium currents. In mutant mice, CNS inflammation during EAE leads to elevated neuroaxonal degeneration and increased disability and lethality compared with wild-type littermate controls. Importantly, immune cell infiltrates were not different between mutant EAE mice and wild-type EAE mice. Thus, this study shows that increased neuronal NaV1.2 activity exacerbates inflammation-induced neurodegeneration irrespective of immune cell alterations and identifies NaV1.2 as a promising neuroprotective drug target in multiple sclerosis.

Vascular Disease in Patients with Multiple Sclerosis: A Review

Background: despite major advances in immunology and molecular biology, Multiple Sclerosis is poorly understood with regards to etiology and its immune trigger and causal pathways are substantially unknown. In recent years, vascular abnormalities associated with Multiple Sclerosis have been investigated, opening the doors to the hypothesis that in the pathogenesis of multiple sclerosis a vascular component could be important. Different forms of vascular abnormalities have been associated with MS: increased risk for ischemic disease, cerebral hypoperfusion, abnormalities of endothelial cells and impaired venous drainage. The aim of this review was to describe literature evidence concerning the correlation between Multiple Sclerosis and vascular dysfunction, cardiovascular risk factors and major cardiovascular events. Methods: A literature review was performed using the following databases and web search engines: PubMed – US National Library of Medicine; Google Scholar; and Ovid MEDLINE. The search included the following combination of terms: “multiple sclerosis” and endothelial dysfunction or vascular dysregulation or vascular hypothesis or risk factors or cardiovascular disease or venous thromboembolism or epidemiology. The selected articles were divided into six macro-groups according to the topic of the paper: cardiovascular risk; cardiovascular diseases; microcirculation factors; venous alterations; infectious pathogens; and vascular adverse effects of therapy. Results: patients with Multiple Sclerosis seem to have more cardiovascular risk factors and an increased risk for ischemic stroke. Several studies have demonstrated cerebral perfusion abnormalities. The relationship between the disturbances in cerebral venous outflow and neurological disorders remains an open issue that requires further studies. Conclusion: Recent evidence suggests that vascular components may be initiating triggers for neuronal pathology and subsequent neurological manifestations of the disease. The high degree of comorbidity between vascular disease and Multiple Sclerosis suggests that vascular pathology may be an important factor causing neuronal dysfunction or degeneration in multiple sclerosis.

Association of multiple sclerosis with lateral olfactory tract usher substance (LOTUS), a possible endogenous inhibitor of axonal degeneration

AbstractNeuronal regeneration in the adult mammalian central nervous system (CNS) is restricted after brain injury, and some of myelin components and their common receptor, Nogo receptor‐1 (NgR1), have been identified as the key molecules for limiting axonal regeneration in the CNS. They have been widely studied as therapeutic targets to overcome the limitation of neuronal regeneration, and strategies using antagonism to NgR1 are expected for the development of the most promising therapies. Recently signaling through NgR1 was shown to be an underlying mechanism of axonal degeneration in multiple sclerosis (MS). Although MS is generally considered an autoimmune demyelinating disorder, axonal degeneration has recently attracted attention as an important pathological feature and one of the mechanisms leading to progressive neurological disability. These pathological and clinical features of MS suggest that molecules involved in limitation of axonal growth can be potential candidates for MS biomarker and therapeutic target, and recent studies have supported these hypotheses. We have previously identified a novel endogenous NgR1 antagonist and named it lateral olfactory tract usher substance (LOTUS). Our data showed that LOTUS promotes axonal growth through blocking of NgR1 signaling, suggesting that LOTUS could be an endogenous inhibitor of axonal degeneration. Furthermore, our recent study demonstrated an interesting variation of LOTUS level in the cerebrospinal fluid of MS patients that was well correlated with disease activity. Here, we review the association of MS with the molecules related to axonal growth including LOTUS, and discuss the clinical application of LOTUS as a promising biomarker and therapeutic target.

Axonal degeneration in multiple sclerosis: defining therapeutic targets by identifying the causes of pathology.

Current therapeutics in multiple sclerosis (MS) target the putative inflammation and immune attack on CNS myelin. Despite their effectiveness in blunting the relapse rate in MS patients, such therapeutics do not prevent MS disease progression. Importantly, specific clinical dilemma arises through inability to predict MS progression and thereby therapeutically target axonal injury during MS, limiting permanent disability. The current review identifies immune and neurobiological principles that govern the sequelae of axonal degeneration during MS disease progression. Defining the specific disease arbiters, inflammatory and autoimmune, oligodendrocyte dystrophy and degenerative myelin, we discuss a basis for a molecular mechanism in axons that may be targeted therapeutically, in spatial and temporal manner to limit axonal degeneration and thereby halt progression of MS.

The impact of isolated lesions on white-matter fiber tracts in multiple sclerosis patients.

Infratentorial lesions have been assigned an equivalent weighting to supratentorial plaques in the new McDonald criteria for diagnosing multiple sclerosis. Moreover, their presence has been shown to have prognostic value for disability. However, their spatial distribution and impact on network damage is not well understood. As a preliminary step in this study, we mapped the overall infratentorial lesion pattern in relapsing–remitting multiple sclerosis patients (N = 317) using MRI, finding the pons (lesion density, 14.25/cm3) and peduncles (13.38/cm3) to be predilection sites for infratentorial lesions. Based on these results, 118 fiber bundles from 15 healthy controls and a subgroup of 23 patients showing lesions unilaterally at the predilection sites were compared using diffusion tensor imaging to analyze the impact of an isolated infratentorial lesion on the affected fiber tracts. Fractional anisotropy, mean diffusion as well as axial and radial diffusivity were investigated at the lesion site and along the entire fiber tract. Infratentorial lesions were found to have an impact on the fractional anisotropy and radial diffusivity not only at the lesion site itself but also along the entire affected fiber tract. As previously found in animal experiments, inflammatory attack in the posterior fossa in multiple sclerosis impacts the whole affected fiber tract. Here, this damaging effect, reflected by changes in diffusivity measures, was detected in vivo in multiple sclerosis patients in early stages of the disease, thus demonstrating the influence of a focal immune attack on more distant networks, and emphasizing the pathophysiological role of Wallerian degeneration in multiple sclerosis.

Chemotactic signaling and beyond: link between interleukin-16 and axonal degeneration in multiple sclerosis.

Multiple sclerosis (MS) is a progressive inflammatory, and chronic demyelinating, neurodegenerative disease of central nervous system (CNS). Autoimmune responses to myelin and other CNS antigens mediated by cluster of differentiation 4 (CD4+) T cells are critical for initiation and progression of disease. Migration of autoimmune T cells from the peripheral lymph organs into CNS parenchyma leads to inflammation, demyelination and damage of axonal cytoskeleton, which manifest in decreased impulse conduction velocity of motor and sensory nerves. Myelin and axonal pathology causes motor, sensory and autonomic nerve dysfunction, including optic nerve damage leading to double or distorted vision; paresis and paralysis of extremities, painful sensations, and bladder sphincter dysfunction, manifested as bladder incontinence. Gray matter pathology in cortical and subcortical regions, including cerebellum and hippocampus underlies cognitive and behavioral dysfunction consisting of memory deficits, depression, and ataxic gait and tremor.

Myelin morphology and axon pathology in demyelination during experimental autoimmune encephalomyelitis.

Myelin morphology and axon pathology in demyelination during experimental autoimmune encephalomyelitis.

Multicontrast MRI Quantification of Focal Inflammation and Degeneration in Multiple Sclerosis.

Introduction. Local microstructural pathology in multiple sclerosis patients might influence their clinical performance. This study applied multicontrast MRI to quantify inflammation and neurodegeneration in MS lesions. We explored the impact of MRI-based lesion pathology in cognition and disability. Methods. 36 relapsing-remitting MS subjects and 18 healthy controls underwent neurological, cognitive, behavioural examinations and 3 T MRI including (i) fluid attenuated inversion recovery, double inversion recovery, and magnetization-prepared gradient echo for lesion count; (ii) T1, T2, and T2* relaxometry and magnetisation transfer imaging for lesion tissue characterization. Lesions were classified according to the extent of inflammation/neurodegeneration. A generalized linear model assessed the contribution of lesion groups to clinical performances. Results. Four lesion groups were identified and characterized by (1) absence of significant alterations, (2) prevalent inflammation, (3) concomitant inflammation and microdegeneration, and (4) prevalent tissue loss. Groups 1, 3, 4 correlated with general disability (Adj-R 2 = 0.6; P = 0.0005), executive function (Adj-R 2 = 0.5; P = 0.004), verbal memory (Adj-R 2 = 0.4; P = 0.02), and attention (Adj-R 2 = 0.5; P = 0.002). Conclusion. Multicontrast MRI provides a new approach to infer in vivo histopathology of plaques. Our results support evidence that neurodegeneration is the major determinant of patients' disability and cognitive dysfunction.

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

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.

A dam for retrograde axonal degeneration in multiple sclerosis?

ObjectiveTrans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic...