-
1.
Conducting dietary intervention trials in people with multiple sclerosis: Lessons learned and a path forward.
Fitzgerald, KC, Sand, IK, Senders, A, Spain, R, Giesser, B, Sullivan, P, Baer, DJ, LaRocca, N, Zackowski, K, Mowry, EM
Multiple sclerosis and related disorders. 2020;:101478
Abstract
Disease course in people with multiple sclerosis (MS) is heterogeneous. The impact of dietary and nutritional factors on MS prognosis is of interest to both patients and clinicians; differences in diet are hypothesized to contribute to disease evolution over time. However, studying diet, especially in people with MS, introduces methodologic complexity that should be recognized. In this review, we focus on methodological aspects relevant to the conduct of dietary interventions in people with MS, given our experience in leading such studies and the challenges we encountered in the realization of this work. We summarize key aspects of study design and important considerations, regardless of the specifics of the actual study (e.g. the particular diet of interest, target MS population, etc.). We discuss strategies for the design of the intervention as well as the selection of appropriate study endpoints. Finally, we provide an overview of strategies to improve the rigor of conducting dietary studies in people with MS.
-
2.
Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration.
Colombo, E, Bassani, C, De Angelis, A, Ruffini, F, Ottoboni, L, Comi, G, Martino, G, Farina, C
Frontiers in immunology. 2020;:635
Abstract
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of in vitro functional assays with astrocytes generated from human fibroblasts. These cells displayed the typical morphology and markers of astroglia, and were susceptible to the action of inflammatory mediators and BAF312, because expressing receptors for IL1, IL17, and S1P (namely S1P1 and S1P3). Targeting of S1P signaling by BAF312 inhibited NFκB translocation evoked by inflammatory cytokines, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Further, while glia cells exposed to IL1 or IL17 downregulated protein expression of glutamate transporters, BAF312-treated astrocytes maintained high levels of GLAST and GLT1 regardless of the presence of inflammatory mediators. Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors. Considering that NFκB-dependent responses are regulated by Nrf2, we measured activation of this critical transcription factor for anti-oxidant reactions, and observed that BAF312 rapidly induced nuclear translocation of Nrf2, but this effect was attenuated in the presence of an inflammatory milieu. Finally, in vitro experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of S1P or cytokine signaling in astrocytes via BAF312 prevented neurons from astrocyte-induced degeneration. Overall, these experiments on human astrocytes suggest that during neuroinflammation targeting of S1P1 via BAF312 may modulate key astrocyte functions and thereby attain neuroprotection indirectly.
-
3.
Epigenetics in Multiple Sclerosis.
Chan, VS
Advances in experimental medicine and biology. 2020;:309-374
Abstract
Multiple sclerosis (MS) is an aggravating autoimmune disease that cripples young patients slowly with physical, sensory and cognitive deficits. The break of self-tolerance to neuronal antigens is the key to the pathogenesis of MS, with autoreactive T cells causing demyelination that subsequently leads to inflammation-mediated neurodegenerative events in the central nervous system. The exact etiology of MS remains elusive; however, the interplay of genetic and environmental factors contributes to disease development and progression. Given that genetic variation only accounts for a fraction of risk for MS, extrinsic risk factors including smoking, infection and lack of vitamin D or sunshine, which cause changes in gene expression, contribute to disease development through epigenetic regulation. To date, there is a growing body of scientific evidence to support the important roles of epigenetic processes in MS. In this chapter, the three main layers of epigenetic regulatory mechanisms, namely DNA methylation, histone modification and microRNA-mediated gene regulation, will be discussed, with a particular focus on the role of epigenetics on dysregulated immune responses and neurodegenerative events in MS. Also, the potential for epigenetic modifiers as biomarkers and therapeutics for MS will be reviewed.
-
4.
Vitamin D receptor genetic polymorphisms and the risk of multiple sclerosis: A systematic review and meta-analysis.
Mohammadi, A, Azarnezhad, A, Khanbabaei, H, Izadpanah, E, Abdollahzadeh, R, Barreto, GE, Sahebkar, A
Steroids. 2020;:108615
Abstract
There are conflicting results regarding the exact effect of the vitamin D receptor (VDR) gene polymorphisms on the susceptibility to multiple sclerosis (MS). Therefore, we aimed to investigate the impact of four major studied VDR gene polymorphisms consisting of ApaI, BsmI, FokI, and TaqI on the risk of MS in the Iranian population. A literature search was performed in various databases to find case-control studies evaluating the association between VDR gene polymorphisms and MS risk in Iran. Data were extracted and odds ratios (OR) with 95% confidence intervals (CI) were calculated. Subgroup analyze was performed to detect potential sources of heterogeneity. A total of 1206 cases and 1402 controls in nine case-control studies were included. ApaI was the only variant which showed statistically significant relation in allelic (OR = 0.54 (95% CI: 0.37-0.79); P = 0.00), homozygote (OR = 3.48 (95% CI: 1.7-6.9); P = 0.00), dominant (OR = 0.56 (95% CI: 0.3-0.79); P = 0.01), and recessive (OR = 0.35 (95% CI: 0.18-0.66); P = 0.00) models. The TaqI polymorphism showed a significant negative association with MS only in the homozygote model (OR = 0.28 (95% CI: 0.08-0.9); P = 0.04). The BsmI polymorphism also showed significant relation in allelic (OR = 0.69 (95% CI: 0.51-0.94); P = 0.01), homozygote (OR = 0.46 (95% CI: 0.25-0.86); P = 0.01), and recessive OR = 0.56 (95% CI: 0.39-0.8); P = 0.00) models after performing sensitivity analysis. FokI polymorphism showed no significant association with MS risk. ApaI and TaqI TT genotype were found contributing to MS susceptibility and BsmI and FokI showed no relation with MS susceptibility in the Iranian population.
-
5.
Dalfampridine to Improve Balance in Multiple Sclerosis: Substudy from a Randomized Placebo-Controlled Trial.
Prosperini, L, Castelli, L, De Giglio, L, Bonanno, V, Gasperini, C, Pozzilli, C
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2020;(2):704-709
-
-
Free full text
-
Abstract
This was a substudy of a randomized, double-blind, placebo-controlled trial originally designed to explore the effect of dalfampridine on information processing speed (2013-002558-64 EU Clinical Trials Register) in patients with multiple sclerosis (MS). A total of 120 patients were originally randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. Here, we sought to explore the effect of dalfampridine on static balance in single-task and dual-task conditions in a subgroup of 41 patients. They underwent static posturography in quiet standing (single-task) and while performing the Stroop test (dual-task) at randomization (baseline), after 12 weeks and after a 4-week wash-out period. Baseline characteristics of active group (n = 27) did not differ from those of placebo group (n = 14). Dalfampridine treatment was associated with better balance control than placebo in both single-task (F = 4.80, p = 0.034) and dual-task (F = 6.42, p = 0.015) conditions, with small-to-moderate effect sizes (Cohen's f2 = 0.122-0.162). The beneficial effect of dalfampridine was not retained 4 weeks after its discontinuation. The rate of accidental falls per month did not differ between the two groups (p = 0.12). Our preliminary findings suggest that dalfampridine can be considered a potential option to treat balance impairment due to MS. Larger sample sizes are needed to verify if the beneficial effect of dalfampridine on balance can be translated into a reduced risk of accidental falls.
-
6.
The effect of emerging nutraceutical interventions for clinical and biological outcomes in multiple sclerosis: A systematic review.
Marx, W, Hockey, M, McGuinness, AJ, Lane, M, Christodoulou, J, van der Mei, I, Berk, M, Dean, OM, Taylor, B, Broadley, S, et al
Multiple sclerosis and related disorders. 2020;:101486
Abstract
BACKGROUND Due to the considerable burden of multiple sclerosis (MS)-related symptoms and the need to identify effective interventions to prevent disease progression, various nutraceutical interventions have been trialed as adjunctive treatments. The aim of this review was to investigate the efficacy and safety of nutraceutical interventions for clinical and biological outcomes in people with MS. METHODS In accordance with PRISMA reporting guidelines, a systematic literature search was conducted using three electronic literature databases. Risk of bias was assessed using the Jadad scale. RESULTS Thirty-seven randomized controlled trials, investigating fourteen nutraceuticals, were included in the review. Trials that investigated alpha lipoic acid (n = 4/6), ginkgo biloba (n = 3/5), vitamin A (n = 2/2), biotin (n = 1/2), carnitine (n = 1/2), green tea (n = 1/2), coenzyme Q10 (n = 1/1), probiotics (n = 1/1), curcumin (n = 1/1), Andrographis paniculata (n = 1/1), ginseng (n = 1/1), and lemon verbena (n = 1/1) were reported to improve biological (e.g. MRI brain volume change, antioxidant capacity) and/or clinical (e.g. fatigue, depression, Expanded Disability Status Scale) outcomes in multiple sclerosis compared to control. However, most trials were relatively small (average study sample size across included studies, n = 55) and there were few replicate studies per nutraceutical to validate the reported results. Furthermore, some nutraceuticals (e.g. green tea and inosine) should be used with caution due to reported adverse events. Risk of bias across most studies was low, with 31 studies receiving a score between 4 and 5 (out of 5) on the Jadad Scale. CONCLUSION The existing literature provides preliminary support for the use of a number of nutraceutical interventions in MS. However, sufficiently powered long-term trials are required to expand the currently limited literature and to investigate unexplored nutraceuticals that may target relevant pathways involved in MS such as the gut microbiome and mitochondrial dysfunction. Prospero ID: CRD42018111736.
-
7.
Vitamin B1 Intake in Multiple Sclerosis Patients and its Impact on Depression Presence: A Pilot Study.
Ortí, JER, Cuerda-Ballester, M, Drehmer, E, Carrera-Juliá, S, Motos-Muñoz, M, Cunha-Pérez, C, Benlloch, M, López-Rodríguez, MM
Nutrients. 2020;(9)
Abstract
Vitamin B1, or thiamine, is one of the most relevant vitamins in obtaining energy for the nervous system. Thiamine deficiency or lack of activity causes neurological manifestations, especially symptoms of depression, intrinsic to multiple sclerosis (MS) and related to its pathogenesis. On this basis, the aim of this study was to determine the possible relationship between the nutritional habits of patients with MS and the presence of depression. Therefore, a cross-sectional and observational descriptive study was conducted. An analysis of dietary habits and vitamin B1 consumption in a Spanish population of 51 MS patients was performed by recording the frequency of food consumption. Results showed a vitamin B1 intake within the established range, mainly provided by the consumption of ultra-processed products such as cold meats or pastries, and a total carbohydrate consumption lower than recommended, which stands out for its high content of simple carbohydrates deriving from processed foods such as dairy desserts, juice, snacks, pastries, chocolate bars, soft drinks and fermented alcohol. In addition, a significant negative correlation between depression and the intake of thiamine and total carbohydrates was observed. These findings could explain the influence of MS patients' eating habits, and consequently vitamin B1 activity, on depression levels.
-
8.
Safety and feasibility of various fasting-mimicking diets among people with multiple sclerosis.
Roman, SN, Fitzgerald, KC, Beier, M, Mowry, EM
Multiple sclerosis and related disorders. 2020;:102149
Abstract
BACKGROUND Fasting-mimicking diets have shown promise in experimental autoimmune encephalitis and are currently being investigated among people with multiple sclerosis (MS). Ensuring adherence to diet changes is critical to determining the efficacy of such interventions. OBJECTIVE Our primary aim was to evaluate the safety and feasibility of several fasting-mimicking diets and investigate whether various levels of clinical support improve diet adherence among people with MS. Secondarily, this study evaluated the impact of fasting-mimicking diets on weight and patient-reported outcomes (PROs). METHODS We conducted three pilot studies (two randomized controlled for 6 months; one randomized with transition to single arm) restricting either the amount or timing of calorie intake over 24 or 48 weeks. Interventions included calorie restriction (daily or intermittently) or time-restricted feeding. Adherence measures varied across studies but were collected at study visits along with weight and PRO data. RESULTS A total of 90 participants enrolled; 70 completed the studies, with no serious adverse events reported. Overall adherence to the calorie restriction diets was poor. When participants were tasked with maintaining a diet in a pragmatic setting, neither previously completed intense clinical support and education, nor weekly electronic communication throughout the diet period appeared to improve diet adherence. Participants who were able to adhere to a calorie restriction diet predictably lost weight. In contrast to calorie restriction, adherence to a time-restricted feeding (TRF) diet was relatively good. No statistically significant changes in PROs were observed in an intention-to-treat analysis. CONCLUSION The role diet may play in clinical outcomes in MS remains unknown, as class I evidence is lacking. Diet adherence remains a primary barrier to the feasible conduct of large, randomized controlled diet trials. Strict adherence to a TRF dietary change may be more feasible than calorie restriction and should be considered in future fasting-mimicking diet trials. ClinicalTrials.gov Registry:A Pilot Study of Intermittent Calorie Restriction in Multiple Sclerosis - NCT02647502. A Pragmatic Trial of Dietary Programs in People with Multiple Sclerosis (MS) - NCT02846558.
-
9.
Calling Out MS Fatigue: Feasibility and Preliminary Effects of a Pilot Randomized Telephone-Delivered Exercise Intervention for Multiple Sclerosis Fatigue.
Kratz, AL, Atalla, M, Whibley, D, Myles, A, Thurston, T, Fritz, NE
Journal of neurologic physical therapy : JNPT. 2020;(1):23-31
Abstract
BACKGROUND AND PURPOSE Fatigue is a common and debilitating symptom of multiple sclerosis (MS). Exercise therapy is effective in reducing MS-related fatigue; however, its feasibility, acceptability, and effectiveness when delivered over the telephone remain unknown. This randomized study aimed to determine the feasibility and acceptability of a telephone-delivered exercise intervention for MS-related fatigue. In addition, pre-/postchange in fatigue and secondary outcomes were compared with an otherwise identical in-person delivered exercise intervention. METHODS Twenty participants with MS and clinically significant fatigue were randomized to 8 sessions of either telephone (n = 10) or in-person (n = 10) delivered exercise therapy. Primary outcome measures concerned feasibility (number of sessions attended), acceptability (Client Satisfaction Questionnaire), and fatigue (Fatigue Severity Scale and two 11-point numeric rating scales: fatigue intensity and interference). Data on a range of secondary outcome measures were also collected. RESULTS There was no difference in average session attendance by group (telephone group: 7.6 ± 1.3 sessions; in-person 7.8 ± 0.42). Acceptability and reductions in fatigue were observed regardless of group, and improvements in a range of secondary outcomes were comparable. DISCUSSION AND CONCLUSIONS A telephone-delivered exercise intervention that targets MS-related fatigue is both feasible and acceptable. Primary and secondary outcome measures signaled that telephone-delivered exercise may be an effective mode of delivery that overcomes barriers to care in persons with MS and warrants testing in larger efficacy trials.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A293).
-
10.
Dietary interventions for multiple sclerosis-related outcomes.
Parks, NE, Jackson-Tarlton, CS, Vacchi, L, Merdad, R, Johnston, BC
The Cochrane database of systematic reviews. 2020;(5):CD004192
-
-
Free full text
-
Abstract
BACKGROUND Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system. Although the exact pathogenesis remains unknown, the leading theory is that it results from immune system dysregulation. Approved disease-modifying therapy appears to modulate the immune system to improve MS-related outcomes. There is substantial interest in the ability of dietary interventions to influence MS-related outcomes. This is an update of the Cochrane Review 'Dietary interventions for multiple sclerosis' (Farinotti 2003; Farinotti 2007; Farinotti 2012). OBJECTIVES To assess the effects of dietary interventions (including dietary plans with recommendations for specific whole foods, macronutrients, and natural health products) compared to placebo or another intervention on health outcomes (including MS-related outcomes and serious adverse events) in people with MS. SEARCH METHODS On 30 May 2019, we searched CENTRAL, MEDLINE, Embase, and Web of Science. We also searched ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (ICTRP), and Networked Digital Library of Theses and Dissertations (NDLTD). We checked reference lists in identified trials and requested information from trial authors to identify any additional published or unpublished data. SELECTION CRITERIA We included any randomized controlled trial (RCT) or controlled clinical trial (CCT) examining the effect of a dietary intervention versus placebo or another intervention among participants with MS on MS-related outcomes, including relapses, disability progression, and magnetic resonance imaging (MRI) measures. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Planned primary outcomes were number of participants experiencing relapse and change in disability progression, according to a validated disability scale at the last reported follow-up. Secondary outcomes included MRI activity, safety, and patient-reported outcomes. We entered and analysed data in Review Manager 5. MAIN RESULTS We found 41 full-text articles examining 30 trials following full-text review. Participants were adults with MS, defined by established criteria, presenting to MS clinics in Europe, North America, and the Middle East. Study design varied considerably, although all trials had at least one methodological issue leading to unknown or high risk of bias. Trials examined: supplementation to increase polyunsaturated fatty acids (PUFAs) (11 trials); a variety of antioxidant supplements (10 trials); dietary programmes (3 trials); and other dietary supplements (e.g. acetyl L-carnitine, biotin, creatine, palmitoylethanolamide, probiotic, riboflavin) (6 trials). In three trials comparing PUFAs with monounsaturated fatty acids (MUFAs), the evidence was very uncertain concerning difference in relapses (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; 3 studies, 217 participants; 75% in the PUFA group versus 74% in the MUFA group; very low-certainty evidence). Among four trials comparing PUFAs with MUFAs, there may be little to no difference in global impression of deterioration (RR 0.85, 95% CI 0.71 to 1.03; 4 studies, 542 participants; 40% in the PUFA group versus 47% in the MUFA group; low-certainty evidence). In two trials comparing PUFAs with MUFAs (102 participants), there was very low-certainty evidence for change in disability progression. None of the PUFA versus MUFA trials examined MRI outcomes. In one trial comparing PUFAs with MUFAs (40 participants), there were no serious adverse events; based on low-certainty evidence. In two trials comparing different PUFAs (omega-3 versus omega-6), there may be little to no difference in relapses (RR 1.02, 95% CI 0.62 to 1.66; 2 studies, 129 participants; 30% in the omega-3 versus 29% in the omega-6 group; low-certainty evidence). Among three trials comparing omega-3 with omega-6, there may be little to no difference in change in disability progression, measured as mean change in Expanded Disability Status Scale (EDSS) (mean difference (MD) 0.00, 95% CI -0.30 to 0.30; 3 studies, 166 participants; low-certainty evidence). In one trial comparing omega-3 with omega-6, there was likely no difference in global impression of deterioration (RR 0.99, 95% CI 0.51 to 1.91; 1 study, 86 participants; 29% in omega-3 versus 29% in omega-6 group; moderate-certainty evidence). In one trial comparing omega-3 with omega-6 (86 participants), there was likely no difference in number of new T1- weighted gadolinium-enhancing lesions, based on moderate-certainty evidence. In four trials comparing omega-3 with omega-6, there may be little to no difference in serious adverse events (RR 1.12, 95% CI 0.38 to 3.31; 4 studies, 230 participants; 6% in omega-3 versus 5% in omega-6 group; low-certainty evidence). In four trials examining antioxidant supplementation with placebo, there may be little to no difference in relapses (RR 0.98, 95% CI 0.59 to 1.64; 4 studies, 345 participants; 17% in the antioxidant group versus 17% in the placebo group; low-certainty evidence). In six trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning change in disability progression, measured as mean change of EDSS (MD -0.19, 95% CI -0.49 to 0.11; 6 studies, 490 participants; very low-certainty evidence). In two trials examining antioxidant supplementation with placebo, there may be little to no difference in global impression of deterioration (RR 0.99, 95% 0.50 to 1.93; 2 studies, 190 participants; 15% in the antioxidant group versus 15% in the placebo group; low-certainty evidence). In two trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning difference in gadolinium-enhancing lesions (RR 0.67, 95% CI 0.09 to 4.88; 2 studies, 131 participants; 11% in the antioxidant group versus 16% in the placebo group; very low-certainty evidence). In three trials examining antioxidant supplementation versus placebo, there may be little to no difference in serious adverse events (RR. 0.72, 95% CI 0.17 to 3.08; 3 studies, 222 participants; 3% in the antioxidant group versus 4% in the placebo group; low-certainty evidence). AUTHORS' CONCLUSIONS There are a variety of controlled trials addressing the effects of dietary interventions for MS with substantial variation in active treatment, comparator, and outcomes of interest. PUFA administration may not differ when compared to alternatives with regards to relapse rate, disability worsening, or overall clinical status in people with MS, but evidence is uncertain. Similarly, at present, there is insufficient evidence to determine whether supplementation with antioxidants or other dietary interventions have any impact on MS-related outcomes.