Degeneration In Multiple Sclerosis Research Articles

Explainable artificial intelligence toward usable and trustworthy computer-aided diagnosis of multiple sclerosis from Optical Coherence Tomography.

Several studies indicate that the anterior visual pathway provides information about the dynamics of axonal degeneration in Multiple Sclerosis (MS). Current research in the field is focused on the quest for the most discriminative features among patients and controls and the development of machine learning models that yield computer-aided solutions widely usable in clinical practice. However, most studies are conducted with small samples and the models are used as black boxes. Clinicians should not trust machine learning decisions unless they come with comprehensive and easily understandable explanations. A total of 216 eyes from 111 healthy controls and 100 eyes from 59 patients with relapsing-remitting MS were enrolled. The feature set was obtained from the thickness of the ganglion cell layer (GCL) and the retinal nerve fiber layer (RNFL). Measurements were acquired by the novel Posterior Pole protocol from Spectralis Optical Coherence Tomography (OCT) device. We compared two black-box methods (gradient boosting and random forests) with a glass-box method (explainable boosting machine). Explainability was studied using SHAP for the black-box methods and the scores of the glass-box method. The best-performing models were obtained for the GCL layer. Explainability pointed out to the temporal location of the GCL layer that is usually broken or thinning in MS and the relationship between low thickness values and high probability of MS, which is coherent with clinical knowledge. The insights on how to use explainability shown in this work represent a first important step toward a trustworthy computer-aided solution for the diagnosis of MS with OCT.

The macular retinal ganglion cell layer as a biomarker for diagnosis and prognosis in multiple sclerosis: A deep learning approach.

The macular ganglion cell layer (mGCL) is a strong potential biomarker of axonal degeneration in multiple sclerosis (MS). For this reason, this study aims to develop a computer-aided method to facilitate diagnosis and prognosis in MS. This paper combines a cross-sectional study of 72 MS patients and 30 healthy control subjects for diagnosis and a 10-year longitudinal study of the same MS patients for the prediction of disability progression, during which the mGCL was measured using optical coherence tomography (OCT). Deep neural networks were used as an automatic classifier. For MS diagnosis, greatest accuracy (90.3%) was achieved using 17 features as inputs. The neural network architecture comprised the input layer, two hidden layers and the output layer with softmax activation. For the prediction of disability progression 8 years later, accuracy of 81.9% was achieved with a neural network comprising two hidden layers and 400 epochs. We present evidence that by applying deep learning techniques to clinical and mGCL thickness data it is possible to identify MS and predict the course of the disease. This approach potentially constitutes a non-invasive, low-cost, easy-to-implement and effective method.

Prophylactic Glatiramer Acetate Treatment Positively Attenuates Spontaneous Opticospinal Encephalomyelitis.

Background: Glatiramer acetate (GA) is a well-established treatment option for patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS) with few side effects. The double transgenic mouse model spontaneous opticospinal encephalomyelitis (OSE), based on recombinant myelin oligodendrocyte glycoprotein35-55 reactive T and B cells, mimicks features of chronic inflammation and degeneration in MS and related disorders. Here, we investigated the effects of prophylactic GA treatment on the clinical course, histological alterations and peripheral immune cells in OSE. Objective: To investigate the effects of prophylactic glatiramer acetate (GA) treatment in a mouse model of spontaneous opticospinal encephalomyelitis (OSE). Methods: OSE mice with a postnatal age of 21 to 28 days without signs of encephalomyelitis were treated once daily either with 150 µg GA or vehicle intraperitoneally (i. p.). The animals were scored daily regarding clinical signs and weight. The animals were sacrificed after 30 days of treatment or after having reached a score of 7.0 due to animal care guidelines. We performed immunohistochemistry of spinal cord sections and flow cytometry analysis of immune cells. Results: Preventive treatment with 150 µg GA i. p. once daily significantly reduced clinical disease progression with a mean score of 3.9 ± 1.0 compared to 6.2 ± 0.7 in control animals (p < 0.01) after 30 d in accordance with positive effects on weight (p < 0.001). The immunohistochemistry showed that general inflammation, demyelination or CD11c+ dendritic cell infiltration did not differ. There was, however, a modest reduction of the Iba1+ area (p < 0.05) and F4/80+ area upon GA treatment (p < 0.05). The immune cell composition of secondary lymphoid organs showed a trend towards an upregulation of regulatory T cells, which lacked significance. Conclusions: Preventive treatment with GA reduces disease progression in OSE in line with modest effects on microglia/macrophages. Due to the lack of established prophylactic treatment options for chronic autoimmune diseases with a high risk of disability, our study could provide valuable indications for translational medicine.

Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis.

Animal models of multiple sclerosis (MS), specifically experimental autoimmune encephalomyelitis (EAE), have been used extensively to develop anti-inflammatory treatments. However, the similarity between MS and one particular EAE model does not end at inflammation. MS and chronic EAE induced in C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 share many neuropathologies. Beyond both having white matter lesions in spinal cord, both also have widespread neuropathology in the cerebral cortex, hippocampus, thalamus, striatum, cerebellum, and retina/optic nerve. In this review, we compare neuropathologies in each of these structures in MS with chronic EAE in C57BL/6 mice, and find evidence that this EAE model is well suited to study neuroaxonal degeneration in MS.

Retinal layer thinning as a biomarker of long-term disability progression in multiple sclerosis

Background: Peripapillary retinal nerve fibre layer and macular ganglion cell plus inner plexiform layer thinning are markers of neuroaxonal degeneration in multiple sclerosis. Objective: We aimed to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning for prediction of long-term disability. Methods: This is a 6-year prospective longitudinal study on 93 multiple sclerosis patients. Optical coherence tomography scans were performed at baseline, after 1, 2 and 6 years. Primary endpoint was disability progression after 6 years, defined as expanded disability status scale worsening and/or cognitive deterioration. Univariate and multivariate analysis was used to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer to predict the primary endpoint. Results: A total of 57 (61.3%) patients had disability worsening, 40 (43.0%) expanded disability status scale worsening and 34 (36.6%) cognitive deterioration. Mean peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness were 93.0 and 75.2 µm, and mean annualised peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning rates over 6 years were 1.3 and 1.6 µm, respectively. Univariate and multivariate analysis revealed lower peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness and higher annualised thinning rates in patients with disability progression after 6 years. Effects were more pronounced for ganglion cell plus inner plexiform layer and expanded disability status scale worsening than for peripapillary retinal nerve fibre layer models and cognitive deterioration. Conclusion: Ganglion cell plus inner plexiform layer and peripapillary retinal nerve fibre layer measurements depict neurodegeneration and predict disability progression in multiple sclerosis.

Promising Treatment for Multiple Sclerosis: Mitochondrial Transplantation.

In recent years, several studies have examined the multifaceted role of mitochondria in Multiple Sclerosis (MS), suggesting that, besides inflammation and demyelination, mitochondrial aberration is a crucial factor in mediating axonal degeneration, the latter being responsible for persistent disabilities in MS patients. Therefore, mitochondria have been recognized as a possible multiple sclerosis therapeutic target. Recently, mitochondrial transplantation has become a new term for the transfer of live mitochondria into damaged cells for the treatment of various diseases, including neurodegenerative diseases. In this hypothesis, we propose mitochondrial transplantation as a new, potentially applicable approach to counteract axonal degeneration in multiple sclerosis.

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy.

Microglia are the resident macrophages of the central nervous system (CNS) acting as the first line of defense in the brain by phagocytosing harmful pathogens and cellular debris. Microglia emerge from early erythromyeloid progenitors of the yolk sac and enter the developing brain before the establishment of a fully mature blood–brain barrier. In physiological conditions, during brain development, microglia contribute to CNS homeostasis by supporting cell proliferation of neural precursors. In post-natal life, such cells contribute to preserving the integrity of neuronal circuits by sculpting synapses. After a CNS injury, microglia change their morphology and down-regulate those genes supporting homeostatic functions. However, it is still unclear whether such changes are accompanied by molecular and functional modifications that might contribute to the pathological process. While comprehensive transcriptome analyses at the single-cell level have identified specific gene perturbations occurring in the “pathological” microglia, still the precise protective/detrimental role of microglia in neurological disorders is far from being fully elucidated. In this review, the results so far obtained regarding the role of microglia in neurodegenerative disorders will be discussed. There is solid and sound evidence suggesting that regulating microglia functions during disease pathology might represent a strategy to develop future therapies aimed at counteracting brain degeneration in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

Thalamic nuclei degeneration in multiple sclerosis

ObjectivesTo define both the severity and extent of structural alteration in certain thalamic nuclei by means of MR morphometry and to compare these findings with clinical performance in different phenotypes of multiple sclerosis (MS). MethodsWe comparatively measured the thalamus nuclei volumes of patients with remitting-relapsing (RRMS) and secondary-progressive (SPMS) phenotypes of multiple sclerosis and healthy control subjects (HC). The evaluation of neurological performance was based on the results of Expanded Disability Status Scale and Multiple Sclerosis Severity Scale. Cognitive and mental state was rated according to the results of Mini-Mental State Examination, Frontal Assessment Battery, Montreal Cognitive Assessment and Symbol Digit Modalities Test. Freesurfer 6.0 was used for thalamic nuclei volumes calculation. ResultsThe median volume decline in thalamic pulvinar nuclei in RRMS group on the left side (anterior nucleus − 186,6 mm3, posterior nucleus – 149,4 mm3, medial nucleus 852,4 mm3) compared to HC (anterior nucleus – 229,2 mm3, posterior nucleus – 187,5 mm3, medical nucleus – 1081,3 mm3). Same group, right side – anterior nucleus – 219,5 mm3, posterior nucleus 187,1 mm3, medial nucleus – 989,6 mm3; HC group – anterior nucleus 261,1 mm3, posterior nucleus 240,5 mm3, medial nucleus – 1196,7 mm3 (p < 0,05). The highest correlation of the written section of SDMT was observed with the left ventral anterior nucleus (r = 0,71). ConclusionThese findings indicate the credible correlation between clinical progression of neurological and cognitive impairment in MS patients with asymmetry left-sided thalamic nuclei atrophy and may be considered a potential predicting tool of MS progression.

Chronic Demyelination and Axonal Degeneration in Multiple Sclerosis: Pathogenesis and Therapeutic Implications.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). Inflammatory attacks in MS lead to both demyelination and axonal damage. However, due to incomplete remyelination most MS lesions remain chronically demyelinated. In parallel, there is axonal degeneration in the CNS of MS patients, contributing to progressive disability. There are currently no approved therapies that adequately restore myelin or protect axons from degeneration. In this review, we will discuss the pathophysiology of axonal loss and chronic demyelination in MS and how understanding this pathophysiology is leading to the development of new MS therapeutics. Ongoing research into the function of oligodendrocytes and myelin has revealed the importance of their relationship with neuronal health. Demyelination in MS leads to a number of pathophysiologic changes contributing to axonal generation. Among these are mitochondrial dysfunction, persistent neuroinflammation, and the effects of reactive oxygen and nitrogen species. With this information, we review currently approved and investigational therapies designed to restore lost or damaged myelin and protect against neuronal degeneration. The development of therapies to restore lost myelin and protect neurons is a promising avenue of investigation for the benefit of patients with MS.

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis.

Background and purposePeripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) thinning are markers of neuroaxonal degeneration in multiple sclerosis (MS), which is reduced by disease‐modifying treatment (DMT). We aimed to investigate the potential of pRNFL and GCIPL thinning for prediction of DMT failure in relapsing MS (RMS).MethodsIn this 4‐year prospective observational study on 113 RMS patients, pRNFL and GCIPL were measured at DMT initiation and after 12 months (M12) and 24 months (M24). Treatment failure was defined as 6‐month confirmed Expanded Disability Status Scale (EDSS) progression and/or Symbol Digit Modalities Test (SDMT) worsening. Optimal cutoff values for predicting treatment failure were determined by receiver operating characteristic analyses and hazard ratios (HRs) by multivariable Cox regression adjusting for age, sex, disease duration, EDSS/SDMT, and DMT class.ResultsThinning of GCIPL >0.5 μm/year at M24 showed superior value for treatment failure prediction (HR: 4.5, 95% confidence interval [CI]: 1.8–7.6, p < 0.001; specificity 91%, sensitivity 81%), followed by GCIPL >0.5 μm at M12 (odds ratio [OR]: 3.9, 95% CI: 1.4–6.9, p < 0.001; specificity 85%, sensitivity 78%), and pRNFL ≥2 μm/year at M24 (OR: 3.7, 95% CI: 1.1–6.5, p = 0.023; specificity 84%, sensitivity 69%), whereas pRNFL at M12 was not predictive.ConclusionsGCIPL, and to a lesser degree pRNFL, thinning predicts disability progression after DMT initiation and may be a useful and accessible biomarker of treatment failure in RMS.

Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis.

BackgroundPIRA (progression independent of relapse) has emerged as a term to quantify the proportion of disability worsening due to non-inflammatory neurodegenerative processes in multiple sclerosis (MS).ObjectiveTo determine the impact of PIRA on retinal thinning, a biomarker of neuroaxonal degeneration in MS, in comparison to traditional disability worsening and relapse.MethodsIn a 4-year, prospective observational study including 171 relapsing MS (RMS) patients, retinal thinning was determined by annual spectral-domain optical coherence tomography measuring macular ganglion-cell-and-inner-plexiform-layer (GCIPL) and peripapillary-retinal-nerve-fibre-layer (pRNFL). PIRA was defined as an expanded disability status scale (EDSS) or symbol digit modalities test (SDMT) worsening confirmed after 24 weeks with no relapse in the 30 days before or after the disability worsening.ResultsEach PIRA event was associated with a mean additional loss of GCIPL (1.8 µm) and pRNFL (1.9 µm), similar to the impact of EDSS and SDMT worsening. Overall relapse and relapse without subsequent EDSS worsening did not influence retinal thinning, while a relapse with EDSS worsening was associated with an additional loss of GCIPL (1.3 µm) and pRNFL (1.4 µm).ConclusionsPIRA is associated with retinal thinning, likely reflecting neurodegenerative processes, not directly associated with focal inflammation. It might be a clinical measure to identify MS patients with ongoing MS-associated neurodegeneration.

The Role of Cerebral Hypoperfusion in Multiple Sclerosis (ROCHIMS) Trial in Multiple Sclerosis: Insights From Negative Results.

Background: Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan.Objective: To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms.Methods: 27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients.Results: Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms.Conclusions: Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood.

Macular ganglion cell–inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis

Background: Macular ganglion cell–inner plexiform layer (mGCIPL) is an emerging biomarker of neuroaxonal degeneration in multiple sclerosis (MS). Objective: We aimed to determine cut-off values of mGCIPL thinning for discriminating between progressing and stable patients in relapsing multiple sclerosis (RMS). Methods: This is a 3-year prospective longitudinal study on 183 RMS patients with annual optical coherence tomography. Best possible cut-off values of baseline mGCIPL and annual loss of macular ganglion cell–inner plexiform layer (aLmGCIPL) for discriminating clinically progressing (physical progression or cognitive decline) from stable patients were defined by receiver operating characteristics analysis and tested using multivariate regression models. Results: Baseline mGCIPL thickness <77 µm was associated with an increased risk (hazard ratio: 2.7, 95% confidence interval (CI): 1.5–4.7, p < 0.001) of disability progression. An aLmGCIPL cut-off ⩾1 µm accurately identified clinically progressing patients (87% sensitivity at 90% specificity) and was a strong predictor of clinical progression (odds ratio: 18.3, 95% CI: 8.8–50.3). Conclusion: We present evidence that cross-sectionally measured mGCIPL thickness and annualized thinning rates of mGCIPL are able to identify clinically progressing RMS with high accuracy.

Stem Cells Therapy for Multiple Sclerosis.

Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS) associated with inflammatory plaques of white matter demyelination, oligodendrocyte destruction, reactive gliosis and axonal degeneration. In this chapter, we first review the pathological process of axonal degeneration in MS and discuss how these changes cause clinical symptoms of MS. We then discuss the pharmacological treatment to improve the clinical symptoms. Finally, we highlight how the autologous hematopoietic stem cell transplantation (AHSCT) can be effective for aggressive MS patients, who fail to respond to drug therapies, and also propose the future challenges of AHSCT.

Mitochondrial Dysfunction in Multiple Sclerosis: A Systematic Review

Abstract- Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) and is characterized by a high degree of heterogeneity in progression and treatment response. Mitochondrial dysfunction is increasingly recognized as an important feature of MS pathology and may be relevant for clinical disease progression. This paper systematically reviews published evidence concerning the role of mitochondrial abnormalities with MS. Literature searched using the Web of Science, PMC/Medline via PubMed and Scopus databases up to May 2017 with no time and language limitation. After quality assessment, 9 articles were included in the study. All data extraction was conducted by two reviewers independently. Based on the results of the studies, it seems that mitochondrial DNA abnormality and mitochondrial dysfunction may be due to primary inflammation in MS or may be occurred itself before any inflammation, but definitely contributes to axonal degeneration and disease progression. Mitochondrial abnormality contributes to axonal degeneration in MS and disease progression.

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial

Background: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). Objective: To determine whether fluoxetine slows accumulation of disability in progressive MS. Methods: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). Results: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test (p = 0.258) and Cox regression analysis (p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. Conclusion: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.

Diffusion tensor imaging identifies aspects of therapeutic estrogen receptor β ligand-induced remyelination in a mouse model of multiple sclerosis

Diffusion tensor imaging (DTI) has been shown to detect white matter degeneration in multiple sclerosis (MS), a neurodegenerative autoimmune disease that presents with diffuse demyelination of the central nervous system. However, the utility of DTI in evaluating therapeutic remyelination has not yet been well-established. Here, we assessed the ability of DTI to distinguish between remyelination and neuroprotection following estrogen receptor β ligand (Indazole chloride, IndCl) treatment, which has been previously shown to stimulate functional remyelination, in the cuprizone (CPZ) diet mouse model of MS. Adult C57BL/6 J male and female mice received a normal diet (control), demyelination-inducing CPZ diet (9wkDM), or CPZ diet followed by two weeks of a normal diet (i.e., remyelination period) with either IndCl (RM + IndCl) or vehicle (RM + Veh) injections. We evaluated tissue microstructure of the corpus callosum utilizing in vivo and ex vivo DTI and immunohistochemistry (IHC) for validation. Compared to control mice, the 9wkDM group showed decreased fractional anisotropy (FA), increased radial diffusivity (RD), and no changes in axial diffusivity (AD) both in vivo and ex vivo. Meanwhile, RM + IndCl groups showed increased FA and decreased RD ex vivo compared to the RM + Veh group, in accordance with the evidence of remyelination by IHC. In conclusion, the DTI technology used in the present study can identify some changes in myelination and is a valuable translational tool for evaluating MS pathophysiology and therapeutic efficacy.

Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan

BackgroundAxonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS.MethodsThe ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.DiscussionWe hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism.Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest.Trial registrationClinical Trials Register, EudraCT 2017-001253-13. Registered on 15 February 2018.

Peripapillary retinal nerve fibre layer thinning rate as a biomarker discriminating stable and progressing relapsing-remitting multiple sclerosis.

Peripapillary retinal nerve fibre layer (pRNFL) thickness is a strong candidate as a biomarker of axonal degeneration in multiple sclerosis (MS). The aim was to determine a cut-off value of pRNFL thinning rates in relapsing-remitting MS (RRMS) to discriminate between stable and progressing patients. In this 3-year prospective longitudinal study on 141 RRMS patients, annual pRNFL thinning rates (aLpRNFL) were determined by individual linear regression models. The best possible cut-off value discriminating clinically progressing (physical progression or cognitive decline) and stable patients was defined by receiver operating characteristic analysis. Cut-off values were validated using a multivariate logistic regression model. Average aLpRNFL in progressing patients (2.4μm, SD 2.1) was significantly higher compared to stable patients (0.5μm, SD 1.2, P<0.001). At a predefined specificity of 90%, aLpRNFL >1.5μm was able to distinguish between stable and progressing RRMS with a sensitivity of 76.1%. aLpRNFL >1.5μm was associated with a 15-fold increased risk of clinically progressing MS (P<0.001). A cut-off of aLpRNFL discriminating clinically progressing and stable RRMS was identified. After validation in independent cohorts, this cut-off could be used as a biomarker of axonal degeneration supporting disease monitoring in daily clinical routine.