Association Between Improved Serum Fatty Acid Profiles and Cognitive Function During a Dietary Intervention Trial in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Cognitive impairment is a common multiple sclerosis (MS)-related symptom that impacts quality of life (QOL). Diet interventions are shown to be beneficial in managing QOL, and the intake of essential fatty acids is linked with improved cognitive function. However, the effect of diets on serum fatty acid profiles and cognitive function is unknown. METHODS: A previous randomized, parallel-arm trial recruited participants with relapsing-remitting MS (N = 77). Study visits included 4 time points: run-in, baseline, 12 weeks, and 24 weeks. During the run-in phase, participants followed their usual diet and were then randomly assigned to either a modified paleolithic (Wahls) or a low saturated fat (Swank) diet at baseline. Assessments at study visits included cognitive function assessed by Symbol Digit Modalities Test-Oral (SDMT-O) and Perceived Deficits Questionnaire (PDQ), and serum fatty acids, including eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic (ARA) acids. RESULTS: Both groups had significant improvements in all serum fatty acids (P < .01), except for ARA, as well as SDMT-O at 24-weeks (P < .05), total PDQ at 12 and 24 weeks (P < .01) compared with baseline values. The 12-week changes in ω-3 (EPA + DHA) index and EPA serum fatty acids were associated with SDMT-O changes (P ≤ .05); however, the changes in fatty acid levels did not mediate the effect of the diets on SDMT-O or PDQ (P > .05). CONCLUSIONS: Both diets led to improvements in serum fatty acid profiles and cognitive function, with associations between the 12-week ω-3 (EPA + DHA) index and EPA changes with SDMT-O.

The effect of dietary interventions on inflammatory biomarkers among people with multiple sclerosis: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system, characterized by demyelination and neurodegeneration, which has a profound impact on the quality of life. Dysregulated inflammatory processes are a major driver of MS progression, with many areas of research being dedicated to modulating inflammation in people with MS. Several dietary patterns have been associated with improvements in inflammatory biomarkers; although, the findings have been inconsistent. Thus, this study aims to evaluate the effects of dietary interventions on inflammatory markers in adults with MS. METHODS: Electronic databases, including PubMed/MEDLINE, Web of Science, Scopus, and Cochrane/Central, will be searched. Screening, selection, and extraction of data, along with quality assessment of included studies, will be done by two separate reviewers, and any potential conflicts will be settled through discussion. Two reviewers will independently assess the risk of bias in included studies using the Cochrane Risk of Bias Tool. If plausible, the results will be synthesized and pooled for meta-analysis. The overall quality of evidence of each study will be evaluated using the NutriGRADE tool, which is a modification to the Grading Recommendations Assessment, Development, and Evaluation (GRADE) developed specifically for nutrition research. DISCUSSION: Studies have demonstrated conflicting results regarding the effects of dietary interventions on serum levels of inflammatory biomarkers among people with MS. Thus, it is expected that the planned systematic review and meta-analysis will yield robust evidence on the effects of diet on inflammatory profile in the setting of MS.

Effects of a Remote Multimodal Intervention Involving Diet, Walking Program, and Breathing Exercise on Quality of Life Among Newly Diagnosed People with Multiple Sclerosis: A Quasi-Experimental Non-Inferiority Pilot Study.

Background: Interventions involving diet, physical activity, and breathing exercises are shown to be beneficial in managing both fatigue and quality of life (QoL) related to MS; however, the impact of such interventions among people newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) who decline disease-modifying therapies (DMTs) is unknown. Methods: A 12-month prospective quasi-experimental non-inferiority trial recruited people newly diagnosed with CIS or RRMS who voluntarily declined DMTs (health behavior group; HB, n = 29) or followed standard of care (SOC, n = 15). Participants in the HB group were remotely coached on the study diet, moderate-intensity walking, and breathing exercises. All participants completed questionnaires validated to assess MS symptoms, including perceived mental and physical QoL (MSQOL54); fatigue (Fatigue Severity Scale, FSS; and Modified Fatigue Impact Scale, MFIS); mood (Hospital Anxiety and Depression Scale, HADS); and cognitive function (Perceived Deficits Questionnaire, PDQ). Results: During the 12 months, the HB group experienced improvement in scores for mental QoL (MSQOL54 - Mental, 0.24, 95% CI 0.01, 0.47; p = 0.04), fatigue (Total MFIS, -7.26, 95% CI -13.3,-1.18; p = 0.02), and perceived cognitive function (Total PDQ, PDQ-Attention, PDQ-Promemory, and PDQ-Planning, p ≤ 0.03 for all). A between-group difference was observed only for PDQ-Planning (p = 0.048). Non-inferiority analysis revealed that the 12-month changes in means for the HB group were not worse than those for the SOC group with respect to fatigue (FSS, p = 0.02), mood (HDS-Anxiety, p = 0.02; HADS-Depression, p < 0.0001), physical QoL (MSQOL54 - Physical, p = 0.02), or cognitive dysfunction (Total PDQ, p = 0.01). Conclusion: The multimodal lifestyle intervention for individuals newly diagnosed with CIS or RRMS, who voluntarily decline DMTs, did not yield patient-reported outcomes worse than those observed in the SOC group regarding perceived mental quality of life, mood, fatigue, and cognitive function. Trial Registration: clinicaltrials.gov identifier: NCT04009005.

Diet-induced changes in functional disability are mediated by fatigue in relapsing-remitting multiple sclerosis: A secondary analysis of the WAVES randomized parallel-arm trial.

Background: People with multiple sclerosis (MS) often report dietary modifications; however, evidence on functional outcomes remains sparse. Objective: Evaluate the impact of the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets on functional disability among people with relapsing-remitting MS. Methods: Baseline-referenced MS functional composite (MSFC) scores were calculated from nine-hole peg-test (NHPT), timed 25-foot walk, and oral symbol digit modalities test (SDMT-O) collected at four study visits: (a) run-in, (b) baseline, (c) 12 weeks, and (d) 24 weeks. Participants were observed at run-in and then randomized at baseline to either the Swank (n = 44) or Wahls (n = 43) diets. Results: Among the Swank group, MSFC scores significantly increased from -0.13 ± 0.14 at baseline to 0.10 ± 0.11 at 12 weeks (p = 0.04) and 0.14 ± 0.11 at 24 weeks (p = 0.02). Among the Wahls group, no change in MSFC scores was observed at 12 weeks from 0.10 ± 0.11 at baseline but increased to 0.28 ± 0.13 at 24 weeks (p = 0.002). In both groups, NHPT and SDMT-O z-scores increased at 24 weeks. Changes in MSFC and NHPT were mediated by fatigue. Discussion: Both diets reduced functional disability as mediated by fatigue. Trial Registration: Clinicaltrials.gov Identifier: NCT02914964.

Evaluation of a web-based program for the adoption of wellness behaviors to self-manage fatigue and improve quality of life among people with multiple sclerosis: A randomized waitlist-control trial.

BACKGROUND: Wellness is a promising area of research in multiple sclerosis (MS); however, considerable questions remain regarding the efficacy of behavioral interventions to improve wellness and which delivery methods yield favorable results. OBJECTIVE: To evaluate the efficacy of a wellness intervention consisting of diet, stress reduction techniques, sleep hygiene, and exercise, delivered via a 7-week web-based program with no tailored intervention support (e.g., counseling or resources) from the study team, on quality of life (QoL) and fatigue among people with MS. METHODS: Individuals (n = 100) with self-reported physician's diagnosis of relapsing-remitting MS or clinically isolated syndrome were recruited to enroll in this randomized waitlist-control trial consisting of three timepoints at 0, 12, and 24 weeks. Participants were randomized to begin the intervention at baseline (INT; n = 51) or to a waitlist to begin the intervention after the 12-week timepoint (WLC; n = 49), and both groups were followed for 24 weeks. RESULTS: At 12-weeks, 95 participants (46 INT and 49 WLC) completed the primary endpoint and 86 (42 INT and 44 WLC) completed the 24-week follow-up. Compared to baseline, the INT group had a significant increase in physical QoL (5.43 ± 1.85; P = 0.003) at 12-weeks which was maintained at 24-weeks. Physical QoL values in the WLC group did not significantly increase between weeks 12 and 24 (3.24 ± 2.03; P = 0.11); however, physical QoL values significantly improved compared to week 0 values (4.00 ± 1.87; P = 0.033). Neither group had significant changes in mental QoL. The INT group had a mean baseline to 12-week change of ­5.06 ± 1.79 (P = 0.005) for MFIS and -0.68 ± 0.21 (P = 0.002) for FSS, both of which were maintained at 24-weeks. The 12- to 24-week changes for the WLC group were -4.50 ± 1.81 (P = 0.013) for MFIS and -0.44 ± 0.17 (P = 0.011) for FSS. At 12-weeks, the INT group had significantly greater reductions in fatigue compared to the WLC (P = 0.009 for both MFIS and FSS). There were no between-group mean differences for physical or mental QoL, but a significantly higher proportion of participants had clinically significant improvement in physical QoL in the INT group (50%) compared to the WLC group (22.5%) at 12-weeks (P = 0.006). The 12-week intervention effect was similar during the active intervention phase (i.e., baseline to 12 weeks for INT and 12 to 24 weeks for WLC) in each group. Course completion rates significantly differed between groups with 47.9% of the INT group and 18.8% of the WLC group completing the course (P = 0.01). CONCLUSION: A wellness intervention delivered via a web-based program, without tailored support, resulted in significant improvements in fatigue compared to control. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05057676.

Association of serum homocysteine, folate, and vitamin B12 and mood following the Swank and Wahls elimination dietary interventions in relapsing-remitting multiple sclerosis: Secondary analysis of the WAVES trial.

BACKGROUND: Depression and anxiety are common psychiatric comorbidities among people with multiple sclerosis (MS). Emerging data suggest abnormal serum homocysteine, vitamin B12, and folate levels in people with MS, which are related to a range of neurological disorders, including mood and mental illnesses. Evidence suggests that dietary interventions could affect mood disorders via several pathways. This study aimed to evaluate the impact of the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets, along with a supplement regimen, on mood as assessed by Hospital Anxiety and Depression Scale (HADS), and Mental Health Inventory (MHI). The secondary objective was to identify changes in serum levels of homocysteine, folate, and vitamin B12 and the association and mediation effects between their changes and HADS and MHI scores and their subscales among people with relapsing-remitting MS (RRMS). METHODS: In a previously conducted randomized parallel-arm trial, participants with RRMS (n = 77) were randomly allocated to either the Swank or Wahls diets at baseline and followed for 24 weeks. Blood was drawn at four study visits spaced 12 weeks apart: (1) run-in, (2) baseline, (3) 12 weeks, and (4) 24 weeks. Serum vitamin B12, folate, and homocysteine were analyzed. HADS and MHI questionnaires were also completed by participants at the four study visits to assess symptoms of depression and anxiety, behavioral control and positive affect respectively. RESULTS: Significant improvement in severity of depression (HADS-D) and anxiety (HADS-A) symptoms, MHI total, and MHI subscores were seen at 12 and 24 weeks in each diet group. Further, a significant within-group reduction in serum homocysteine and a significant increase in serum vitamin B12 level were observed in both groups at 12 and 24 weeks compared to corresponding baseline values (p ≤ 0.05 for all). All participants exceeded the analytical maximum threshold for folate of 20 nmol/L at 12 and 24 weeks. Changes in serum levels of homocysteine and vitamin B12 were not associated with and did not mediate changes in HADS depression, anxiety, MHI total and four subscales scores (p > 0.05). CONCLUSION: Participants on both Swank and Wahls dietary interventions, including folate and vitamin B12 supplements, showed significant improvement in mood. However, the favorable effects of both diets on mood were not associated with or mediated by the effect of the diets on serum levels of homocysteine, folate, and vitamin B12 (p > 0.05).

Effect of Paleolithic-based low-carbohydrate vs. moderate-carbohydrate diets with portion-control and calorie-counting on CTRP6, asprosin and metabolic markers in adults with metabolic syndrome: A randomized clinical trial.

OBJECTIVE: Several recent studies have been undertaken into carbohydrate-restricted diets. it has not been clearly demonstrated whether diets with different proportions of energy from carbohydrate exert distinct effects on metabolism and inflammation or not. The current randomized clinical trial (RCT) has been conducted to further elucidate the effects of severe and mild carbohydrate restriction on inflammation and cardiometabolic status in adults with metabolic syndrome (MetS). METHODS: Eighty adults with metabolic syndrome were randomized to one of the four carbohydrate restricted diets: Paleolithic-based low-carbohydrate diet with calorie-counting method (PLCD-CC) (n = 20), Paleolithic-based low-carbohydrate diet with portion-control method (PLCD-PC) (n = 20), moderate-carbohydrate diet with calorie-counting method (MCD-CC) (n = 20) and moderate-carbohydrate diet with portion-control method (MCD-PC) (n = 20) for 10 weeks. PLCD is defined as a diet consisting of 25-30% of energy from carbohydrate, 30% of energy from protein and 40-45% of energy from fat and encourages consumption of fruits, vegetables and lean meat. MCD is characterized as 40-45% carbohydrate, 30% protein and 30-35% fat. Body weight and composition, adipokines such as Asprosin, chemerin, leptin, hepatokines namely CTRP-6, FGF-21 and cardiovascular disease (CVD) risk factors were tested at baseline and at the end of 10 weeks. RESULTS: A total of 69 participants aged 42.95 (9.27) with metabolic syndrome completed the trial. At the end of current 10-week dietary intervention trial, significant reduction in weight, waist circumference, body fat, visceral fat and waist-hip ratio (WHR) was observed in all four intervention arms (P < 0.001). Also, the observed differences among groups did not reach statistical significance (P > 0.05). Moreover, we found significant reduction in CTRP6 and leptin in all intervention groups (P < 0.001). Reduction of Asprosin level was also marginally significant between intervention groups (P < 0.05). All four intervention groups were found to improve cardiometabolic markers such as FBS, TG, total cholesterol and LDL cholesterol compared to baseline. However, despite clinically significant difference, the within- and between-group changes were not statistically significant at the end of trial. CONCLUSIONS: The current RCT in Iranian adults with metabolic syndrome revealed that both moderate and Paleolithic-based low carbohydrate diets with both delivery approaches have comparable beneficial effects in terms of body weight and composition, cardiometabolic factors and metabolism-related adipokines and hepatokines. TRIAL REGISTRATION: Available at: https://en.irct.ir/trial/21157, identifier: (IRCT2016121925267N4), Registered on 26 July 2017.

Effect of low-carbohydrate diet on adiponectin level in adults: a systematic review and dose-response meta-analysis of randomized controlled trials.

BACKGROUND: To the best of our knowledge, no previous study has reported findings on the effects of low-carbohydrate diet (LCD) on adiponectin concentration. OBJECTIVE: The current systematic review and dose-response meta-analysis was carried out to systematically review the available controlled clinical trials about the effect of LCD on adiponectin level in adults. METHODS: Literature searches of PubMed/Medline, Scopus and Web of Sciences were conducted up to August 2019. Randomized controlled trials (RCTs) which assessed the effect of LCD on the adiponectin level were selected. RESULTS: Eleven studies, including 1047 participants (LCD = 534 and control = 513), were included in the meta-analysis. Proportion of carbohydrate from calorie was from 4 to 34%. Time of the follow-up varied between studies and ranged from 6 to 152 weeks. LCD intake mildly but significantly increased adiponectin (0.02 µg/ml, 95% CI: 0.01 to 0.03, P < 0.001). Dose-response analysis indicated a nonlinear association between the percentage of carbohydrate and change in adiponectin level from baseline (P = 0.04). After subgroup analysis based on the proportion of carbohydrate from calorie, there was a significant increase in adiponectin concentration in studies that prescribed <30% of calorie from carbohydrates (0.12 µg/ml, 95% CI: 0.07-0.18). In contrast, diets which consisted ≥30% of carbohydrates had no significant effect on adiponectin (0.50 µg/ml, 95% CI: -0.46 to 1.48). Also, meta-regression analysis revealed that age (ß = 0.04, P = 0.15), baseline BMI (ß= -0.15, P = 0.15), time of follow-up (ß = 0.01, P = 0.17), percentage of carbohydrates (ß = 0.004, P = 0.90), percentage of protein (ß= -0.12, P = 0.08), percentage of fat (ß = 0.20, P = 0.61) and baseline adiponectin (ß = 0.001, P = 0.97) are not sources of heterogeneity. CONCLUSION: This systematic review and meta-analysis demonstrated a mild but significant effect of LCD on adiponectin concentration compared to control groups.

Association between improved metabolic risk factors and perceived fatigue during dietary intervention trial in relapsing-remitting multiple sclerosis: A secondary analysis of the WAVES trial.

Background: Preliminary dietary intervention trials with the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets have shown favorable effects on fatigue among people with multiple sclerosis (MS); however, their impact on metabolic health is unknown. Objective: To evaluate the impact of the Swank and Wahls diets on markers of metabolic health and to determine the association and mediation effect between changes in metabolic health and perceived fatigue among people with relapsing-remitting MS (RRMS). Methods: As part of a randomized parallel-arm trial, vital signs, blood metabolic biomarkers, and the fatigue scale for motor and cognitive functions (FSMC) were collected from participants with relapsing-remitting MS (n = 77) at four study visits spaced 12 weeks apart: (1) run-in, (2) baseline, (3) 12-weeks, and (4) 24-weeks. Participants followed their usual diet at run-in, then were randomized at baseline to either the Swank or Wahls diets and followed for 24 weeks. Results: Both groups had significant reductions in weight, body mass index (BMI), total cholesterol, and low-density lipoprotein (LDL) at 12- and 24-weeks compared to respective baseline values (p ≤ 0.04 for all). The Swank group also had a significant reduction in high-density lipoprotein (HDL) at 12- and 24-weeks (p = 0.0001 and p = 0.02, respectively), while the Wahls group had significant reductions in diastolic blood pressure (DBP). In addition, both groups had significant reductions in FSMC total perceived fatigue and the motor and cognitive fatigue subscales at 12- and 24-weeks (p ≤ 0.01 for all); however, change in the cognitive subscale was not significant at 12-weeks in the Swank group (p = 0.06). Furthermore, the favorable effects, of both diets, on markers of metabolic health were not associated with and did not mediate the effect of the diets on perceived fatigue (p > 0.05 for all). Conclusion: Both diets lead to significant reductions in perceived fatigue, weight, BMI, total cholesterol, and LDL, but the significant reductions in perceived fatigue were independent of changes in markers of metabolic health.

Effects of modified-Paleo and moderate-carbohydrate diets on body composition, serum levels of hepatokines and adipocytokines, and flow cytometric analysis of endothelial microparticles in adults with metabolic syndrome: a study protocol for a randomized clinical trial.

BACKGROUND: Metabolic syndrome is a combination of metabolic risk factors causing a pathological condition that increases the risk of non-communicable diseases, such as diabetes and cardiovascular diseases. A variety of dietary approaches have been examined to halt this rapid trend; however, the effects of modified-Paleo diet and medium-carbohydrate diet on inflammation, adipokines, hepatokines, and the profile of endothelial microparticles in individuals with metabolic syndrome have not been investigated in detail. The present study is designed to examine the effect of modified-Paleo and moderate-carbohydrate diet with two delivery modes: "fixed diet plan" vs "calorie counting" on weight, body composition, serum levels of some hepatokines and adipocytokines, and flow cytometric analysis of endothelial microparticles in adults with metabolic syndrome. METHODS: Eighty metabolic syndrome patients will be recruited in this study. They will be randomly allocated to one of the following 4 groups: (1) receiving a modified-Paleo diet with calorie counting, (2) receiving a modified-Paleo diet with a fixed diet plan, (3) receiving a medium-carbohydrate diet with calorie counting, and (4) receiving a medium-carbohydrate diet with a fixed diet plan for 10 weeks. Weight, height, waist circumference, and body composition will be assessed at the study baseline and at the end of the trial. Serum insulin, asprosin, chemerin, FGF-21, CTRP-1, PYY, ghrelin, plasma EMPs (CD31+/CD42b- and CD144+/CD42b-), lipid profile, glycemic indices, hs-CRP, leptin, vitamin C, creatinine and satiety, hunger, fullness, and desire to eat (via visual analog scales) will be measured at the study baseline and at the end of the trial. Insulin resistance and insulin sensitivity will be determined using the HOMA-IR and QUICKI equations. DISCUSSION: To the best of our knowledge, this is the first randomized controlled trial that will determine the effect of modified-Paleo and moderate-carbohydrate diet on weight, body composition, serum levels of some hepatokines and adipocytokines, and the profile of EMPs in adults with metabolic syndrome. Moreover, the effects of different diet delivery modes, including "fixed diet plan" and "calorie counting" will also be analyzed. The results of this trial can provide clinical witnesses on the effectiveness of carbohydrate-restricted diets in ameliorating metabolic status and prevent the development of chronic diseases. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT2016121925267N4 . Registered on 26 July 2017.

Does Resveratrol Improve Insulin Signalling in HepG2 Cells?

OBJECTIVES: Diabetes mellitus is a common metabolic disorder with high global prevalence. It is characterized by a decrease in insulin secretion or a decrease in insulin sensitivity or both. The aim of the present study was to investigate the effects of resveratrol treatment on the expression of the genes involved in insulin signalling cascade, such as Forkhead box protein O1 (FoxO1), 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and mammalian target of rapamycin (mTOR). METHODS: HepG2 cells were cultured in serum-free medium with high concentrations of glucose and insulin and then were treated with resveratrol (5, 10 and 20 µM) for 24 and 48 hours. Complementary deoxyribonucleic acids (cDNAs) were synthesized followed by RNA extraction. Real-time quantitative reverse transcription polymerase chain reaction was used to analyze the expression of FoxO1, PDPK1 and mTOR. RESULTS: Resveratrol increased the expression of PDPK1, mTOR and FoxO1. No significant difference was seen among differing dosages of resveratrol, but treatments for 48 hours exerted the greatest effectiveness. CONCLUSIONS: Our results were consistent with other studies showing the beneficial effects of resveratrol on diabetes. However, considering the effects of resveratrol in increasing FoxO1 and gluconeogenic gene expression, long-term usage of resveratrol should be investigated in greater depth in future studies.