Epigenetic associations of GPNMB rs199347 variant with alcohol consumption in Parkinson's disease.

Introduction: Alcohol consumption can induce a neuroinflammatory response and contribute to the progression of neurodegeneration. However, its association with Parkinson's disease (PD), the second most common neurodegenerative disorder, remains undetermined. Recent studies suggest that the glycoprotein non-metastatic melanoma protein B (GPNMB) is a potential biomarker for PD. We evaluated the association of rs199347, a variant of the GPNMB gene, with alcohol consumption and methylation upstream of GPNMB. Methods: We retrieved genetic and DNA methylation data obtained from participants enrolled in the Taiwan Biobank (TWB) between 2008 and 2016. After excluding individuals with incomplete or missing information about potential PD risk factors, we included 1,357 participants in our final analyses. We used multiple linear regression to assess the association of GPNMB rs199347 and chronic alcohol consumption (and other potential risk factors) with GPNMB cg17274742 methylation. Results: There was no difference between the distribution of GPNMB rs199347 genotypes between chronic alcohol consumers and the other study participants. A significant interaction was observed between the GPNMB rs199347 variant and alcohol consumption (p = 0.0102) concerning cg17274742 methylation. Compared to non-chronic alcohol consumers with the AA genotype, alcohol drinkers with the rs199347 GG genotype had significantly lower levels (hypomethylation) of cg17274742 (p = 0.0187). Conclusion: Alcohol consumption among individuals with the rs199347 GG genotype was associated with lower levels of cg17274742 methylation, which could increase expression of the GPNMB gene, an important neuroinflammatory-related risk gene for PD.

Fighting Against the Clock: Circadian Disruption and Parkinson's Disease.

Circadian disruption is being increasingly recognized as a critical factor in the development and progression of Parkinson's disease (PD). This review aims to provide an in-depth overview of the relationship between circadian disruption and PD by exploring the molecular, cellular, and behavioral aspects of this interaction. This review will include a comprehensive understanding of how the clock gene system and transcription-translation feedback loops function and how they are diminished in PD. The article also discusses the role of clock genes in the regulation of circadian rhythms, as well as the impact of clock gene dysregulation on mitochondrial function, oxidative stress, and neuroinflammation, including the microbiota-gut-brain axis, which have all been proposed as being crucial mechanisms in the pathophysiology of PD. Finally, this review highlights potential therapeutic strategies targeting the clock gene system and circadian rhythm for the treatment of PD.

Epigenetic regulation of Parkinson's disease risk variant GPNMB cg17274742 methylation by sex and exercise from Taiwan Biobank.

Background: Parkinson's disease (PD) is a complex neurodegenerative disease with an elusive etiology that involves the interaction between genetic, behavioral, and environmental factors. Recently, epigenetic modifications, particularly DNA methylation, have been recognized to play an important role in the onset of PD. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane protein crucial for immune cell activation and maturation, has emerged as a potential biomarker for the risk of PD. This research aims to investigate the influence of exercise and gender on the regulation of methylation levels of GPNMB cg17274742 in individuals. Methods: We analyze data from 2,474 participants in the Taiwan Biobank, collected from 2008 and 2016. Methylation levels at the GPNMB cg17274742 CpG site were measured using Illumina Infinium MethylationEPIC beads. After excluding individuals with incomplete data or missing information on possible risk factors, our final analysis included 1,442 participants. We used multiple linear regression models to assess the association between sex and exercise with adjusted levels of GPNMB cg17274742 for age, BMI, smoking, drinking, coffee consumption, serum uric acid levels, and hypertension. Results: Our results demonstrated that exercise significantly influenced the methylation levels of GPNMB cg17274742 in males (ß = -0.00242; p = 0.0026), but not in females (ß = -0.00002362; p = 0.9785). Furthermore, male participants who exercised showed significantly lower levels of methylation compared to the reference groups of the female and non-exercising reference groups (ß = -0.00357; p = 0.0079). The effect of the interaction between gender and exercise on the methylation of GPNMB cg17274742 was statistically significant (p = 0.0078). Conclusion: This study suggests that gender and exercise can modulate GPNMB cg17274742, with hypomethylation observed in exercise men. More research is needed to understand the underlying mechanisms and implications of these epigenetic changes in the context of risk and prevention strategies.

Case report: Steroid-responsive acute chorea as first presentation of the coexistence of Moyamoya and Graves' disease.

Background: Chorea is a movement disorder characterized by abrupt, rapid, and uncontrollable, random movements from one part of the body to another with motor impersistence. Sporadic chorea is rarely caused by either thyrotoxicosis or Moyamoya disease (MMD). Methods and results: In this case report, we describe a female patient with chorea with the rare coexistence of Graves' disease and Moyamoya disease. Tc-99m ethyl cysteinate dimer (ECD) brain perfusion single-photon emission computed tomography (SPECT) showed mild to moderate hypoperfusion in bilateral frontal and left temporal regions. After administering dexamethasone 20 mg for 5 days, her choreic movement symptoms recovered rapidly. Conclusion: Although uncommon, thyrotoxicosis and Moyamoya disease can co-occur, especially in Asian female adults. Excessive thyroid hormones contribute to the dysregulation of neurotransmitters in basal ganglia-thalamocortical circuits. Moyamoya disease is responsible for ischemic changes affecting the excitatory-inhibitory circuits between the basal ganglia and the neocortex. Under a state of coexistence, thyrotoxicosis exaggerates cerebral metabolism, aggravating the impaired cerebral perfusion induced by Moyamoya disease. Moreover, inflammatory reactions caused by thyroid autoantibodies may also promote the progression of Moyamoya disease. In our experience, treatment with steroids may not only synergize the anti-thyroid effect but may also be a way to modulate the neurotransmitters within the basal ganglia or restore cerebral perfusion. We suggest that evaluation of the thyroid function status in Moyamoya disease is essential.

Sustained response in early responders to safinamide in patients with Parkinson's disease and motor fluctuations: A post hoc analysis of the SETTLE study.

Safinamide is a selective, reversible, monoamine oxidase B inhibitor for the treatment of patients with Parkinson's disease (PD) and motor fluctuations. This was a post hoc analysis of the SETTLE study, in which patients with PD and motor fluctuations were randomly assigned to 24-week treatment with safinamide (50 mg/day for 2 weeks, increased to 100 mg/day if tolerated) or placebo. In the present analysis, responders were defined according to their treatment responses at Week 2 and Week 24 based on changes in ON-time without troublesome dyskinesia from baseline with cutoffs of 1 hour. It was found that 81% (103/127) of the responders at Week 2 maintained the response through Week 24 in the safinamide group. Other outcomes did not necessarily coincide with the ON-time response; however, "Early" responders who showed a treatment response at both Week 2 and Week 24 had substantial improvements from baseline in OFF-time, UPDRS Part II and III scores, and PDQ-39 summary index scores through Week 24. The safinamide group had a higher proportion of early responders than the placebo group (39% vs 20%, p < 0.0001). At baseline, early responders in the safinamide group had significantly higher UPDRS Part II and III scores, shorter ON-time, and longer OFF-time than the other responder populations. In conclusion, the results of the present post hoc analysis suggest that patients with a short ON-time, severe motor symptoms, and highly compromised activities of daily living can benefit from safinamide early in treatment and over the long term.

Safinamide as an Adjunct to Levodopa in Asian and Caucasian Patients With Parkinson's Disease and Motor Fluctuations: A Post Hoc Analysis of the SETTLE Study.

OBJECTIVE: Safinamide is a selective, reversible monoamine oxidase B inhibitor with demonstrated efficacy and tolerability in placebo-controlled studies and is clinically useful for patients with motor fluctuations. This study evaluated the efficacy and safety of safinamide as a levodopa adjunct therapy in Asian patients with Parkinson's disease. METHODS: Data from 173 Asian and 371 Caucasian patients from the international Phase III SETTLE study were included in this post hoc analysis. The safinamide dose was increased from 50 mg/day to 100 mg/day if no tolerability issues occurred at week 2. The primary outcome was the change from baseline to week 24 in daily ON-time without troublesome dyskinesia (i.e., ON-time). Key secondary outcomes included changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. RESULTS: Safinamide significantly increased daily ON-time relative to placebo in both groups (least-squares mean: 0.83 hours, p = 0.011 [Asians]; 1.05 hours, p < 0.0001 [Caucasians]). Motor function relative to placebo (UPDRS Part III) improved significantly in Asians (-2.65 points, p = 0.012) but not Caucasians (-1.44 points, p = 0.0576). Safinamide did not worsen Dyskinesia Rating Scale scores in either subgroup, regardless of the presence or absence of dyskinesia at baseline. Dyskinesia was largely mild for Asians and moderate for Caucasians. None of the Asian patients experienced adverse events leading to treatment discontinuation. CONCLUSION: Safinamide as a levodopa adjunct is well tolerated and effective in reducing motor fluctuations in both Asian and Caucasian patients. Further studies to investigate the real-world effectiveness and safety of safinamide in Asia are warranted.

Walking Exercise Reduces Postprandial Lipemia but Does Not Influence Postprandial Hemorheological Properties and Oxidative Stress.

A higher postprandial triglycerides response and hemorheological abnormalities may increase the incidence of metabolic disorders and negatively interfere with the aging process. A single session of preprandial endurance exercise was found to be effective in reducing triglyceride levels after a high-fat diet. However, whether the exercise-induced reduction in postprandial triglyceride levels influences hemorheological indicators remains unknown. This study aims to investigate the effects of postprandial lipemia on hemorheological properties and oxidative stress. Eight healthy young male participants completed two experimental trials. On day 1, the participants were randomly assigned to walk for 1 h at 50% VO2max (EE trial) or rest (CON trial). On day 2, participants rested and consumed a high-fat meal in the morning. Results: The postprandial area under the curve (AUC) of plasma TG concentration was significantly lower in EE compared to CON (EE: 9.2 ± 1.9; CON: 10.9 ± 1.7 mmol/L·h−1; p = 0.013; Cohen's d = 0.036). No significant difference was observed in hemorheological properties and MDA (p > 0.05). Endurance exercise effectively decreased postprandial TG concentration but did not influence the postprandial hemorheological properties and oxidative stress indicators.

Effects of modern technology (exergame and virtual reality) assisted rehabilitation vs conventional rehabilitation in patients with Parkinson's disease: a network meta-analysis of randomised controlled trials.

BACKGROUND: Modern technological applications, including exergames and virtual technology-assisted rehabilitation (VTAR) programmes, are promising for Parkinson's disease (PD) rehabilitation. However, evidence regarding their efficacy for rehabilitation is inconclusive. OBJECTIVES: This network meta-analysis (NMA) investigated the efficacy of exergames and VTAR on gait and balance outcomes and acceptability for patients with PD. DATA SOURCES: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, Web of Science and ClinicalTrials.gov. STUDY SELECTION: Randomised controlled trials (RCTs) investigating changes in gait or balance parameters were included in this study. STUDY APPRAISAL AND SYNTHESIS METHODS: In the NMA, standardised mean differences with 95% confidence intervals were calculated using a frequentist model. GRADE ratings were used to evaluate the quality of evidence in this study. RESULTS: Twenty-three RCTs with 949 participants were included. Exergames and VTAR were associated with significantly better improvements in balance and gait outcomes than usual treatment and other active control interventions. However, exergames were not associated with changes in depressive symptoms. The evaluation of acceptability results indicated that all exergames and VTAR were adequately tolerated, as indicated by the low drop-out rates. LIMITATIONS: Small sample sizes and heterogeneity were the key limitations of this study. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: This NMA confirmed that exergames are associated with more favourable gait and balance outcomes in patients with PD compared with usual treatment and other active control interventions. GRADE ratings revealed that most direct, indirect and overall network evidence was of low to medium quality. Larger-scale studies with longer follow-up periods are warranted.