Clinical correlates of serum 25-hydroxyvitamin D in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients have lower levels of serum 25-hydroxyvitamin D (25(OH)D) than the general population. Previous studies have suggested a negative association between 25(OH)D and clinical features of PD, but the data are inconsistent. MATERIALS AND METHODS: We conducted a cross-sectional, observational study. Serum 25(OH)D, disease (Hoehn-Yahr stage [HY]) and clinical symptom (Unified Parkinson Disease Rating Scale [UPDRS]) severity and global cognitive functions (Mini-Mental State Examination [MMSE]) were studied in 500 consecutive PD patients not using vitamin D supplements. Information on sunlight exposure and dietary intakes (using a 66-item food frequency questionnaire) were also collected. A convenient sample of age and sex-matched community healthy controls (N = 100) was included as a control group. RESULTS: PD patients had lower 25(OH)D serum levels than controls. Deficiency status (<20 ng/mL) was found in 65.6% of patients. 25(OH)D levels were independently correlated to sunlight exposure (P = .002) and vitamin D intake (P = .009). In multivariate models, using a Mendelian randomization approach, lower serum 25(OH)D was associated with more severe disease (HY, P = .035), worse clinical symptoms (UPDRS Part-III total score [P = .006] and dopaminergic [P = .033] and non-dopaminergic subscores [P = .001]) and greater global cognitive function impairment (P = .041). Neither cognitive functions nor clinical features were associated with reduced intake of vitamin D and sunlight exposure. CONCLUSION: : Serum 25(OH)D was negatively correlated with disease and symptoms severity, as well as with global cognitive functions. Our study adds to the evidence that low 25(OH)D may affect the progression of PD negatively. Intervention studies in this area are required.

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

COVID-19 in Parkinson's Disease Patients Living in Lombardy, Italy.

BACKGROUND: It is unknown whether patients with PD are at greater risk of COVID-19, what their risk factors are, and whether their clinical manifestations differ from the general population. OBJECTIVES: The study aimed to address all these issues. METHODS: In a case-controlled survey, we interviewed 1,486 PD patients attending a single tertiary center in Lombardy, Italy and 1,207 family members (controls). RESULTS: One hundred five (7.1%) and 92 controls (7.6%) were identified as COVID-19 cases. COVID-19 patients were younger, more likely to suffer from chronic obstructive pulmonary disease, to be obese, and vitamin D nonsupplemented than unaffected patients. Six patients (5.7%) and 7 family members (7.6%) died from COVID-19. Patients were less likely to report shortness of breath and require hospitalization. CONCLUSIONS: In an unselected large cohort of nonadvanced PD patients, COVID-19 risk and mortality did not differ from the general population, but symptoms appeared to be milder. The possible protective role of vitamin D supplementation warrants future studies. © 2020 International Parkinson and Movement Disorder Society.

Could Mucuna pruriens be the answer to Parkinson's disease management in sub-Saharan Africa and other low-income countries worldwide?

Parkinson's disease (PD) is a progressive, disabling, neurodegenerative disease that requires long term care and pharmaceutical treatment. Levodopa remains the gold standard treatment for PD globally, although it is largely unavailable and unaffordable for the majority of patients in many sub-Saharan African and other low-income countries (LICs). We suggest the potential for Mucuna pruriens (MP), a leguminous plant, to replace or supplement levodopa-based medicines in countries where levodopa is unaffordable and inaccessible due to its low costs of preparation and high natural availability. MP has been shown to induce a great improvement of motor symptoms with few adverse events in recent studies. However, caution is important until more robust data on the long-term safety of MP are available. We believe that MP could potentially be part of the answer to affordable, symptomatic treatment of PD in LICs worldwide.

Muscle-targeted nutritional support for rehabilitation in patients with parkinsonian syndrome.

OBJECTIVE: We evaluated the efficacy of muscle-targeted nutritional support on the functional outcomes of multidisciplinary intensive rehabilitation treatment (MIRT) in patients with Parkinson disease (PD) or parkinsonism. METHODS: We conducted a pragmatic, bicentric, randomized (1:1), assessor-blind controlled trial (Protein, Leucine and Vitamin D Enhancing Rehabilitation [PRO-LEADER]; April 2017 to January 2018) in cognitively intact patients with PD or parkinsonism and undergoing a 30-day MIRT. Patients (n = 150) received a standard hospital diet with or without a whey protein-based nutritional supplement enriched with leucine and vitamin D twice daily. The primary efficacy endpoint was the increase in the distance walked during a 6-minute walking test (6MWT). Secondary endpoints were changes in 4-meter walking speed, Timed Up and Go test (TUG), Berg balance scale, handgrip strength, Self-assessment Parkinson's Disease Disability Scale, body weight, and skeletal muscle mass (SMM). RESULTS: Nutritional support resulted in greater increase in the distance walked during 6MWT (mean 69.6 meters [95% confidence interval (CI) 60.7-78.6]) than no support (51.8 meters [95% CI 37.0-66.7]): center-adjusted mean difference, 18.1 meters (95% CI 0.9-35.3) (p = 0.039). Further adjustment for changes in dopaminergic therapy and SMM yielded consistent results: mean difference, 18.0 meters (95% CI 0.7-35.2) (p = 0.043). A meaningful effect was also found for the following secondary endpoints: 4-meter walking speed (p = 0.032), TUG (p = 0.046), SMM, and SMM index (p = 0.029). Six patients discontinued the nutritional therapy due to mild side effects. CONCLUSION: The consumption of a whey protein-based nutritional formula enriched with leucine and vitamin D with MIRT improved lower extremity function and preserved muscle mass in patients with PD or parkinsonism.Clinicaltrials.gov IDENTIFIER: NCT03124277. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with parkinsonism undergoing intensive rehabilitation, a whey protein-based nutritional formula enriched with leucine and vitamin D increased distance walked on the 6MWT.

Nutritional characterisation of Zambian Moringa oleifera: acceptability and safety of short-term daily supplementation in a group of malnourished girls.

In Zambia, chronic malnutrition still is one of the most common problem among children. To fight against malnutrition, the easiest short-term solution could be to combine specific types of food with affordable local plants. A large variety of natural food resources grow in Zambia, such as Moringa oleifera (MO), whose leaves are known for their health benefits, but are not consumed much by local populations. We analysed Zambian MO powder obtained from dried leaves and found that it contains large amounts of protein, minerals and vitamins, such as iron, calcium and carotenoids. These characteristics make MO a good and sustainable complementary solution to malnutrition. We also evaluated the acceptability and the safety of dietary supplementation with MO powder in malnourished children for 30 days. A daily dose of 14 g daily was safe and well accepted. Its regular use in the menu of local populations may be viable proposition.

Phase matters: A role for the subthalamic network during gait.

The role of the subthalamic nucleus in human locomotion is unclear although relevant, given the troublesome management of gait disturbances with subthalamic deep brain stimulation in patients with Parkinson's disease. We investigated the subthalamic activity and inter-hemispheric connectivity during walking in eight freely-moving subjects with Parkinson's disease and bilateral deep brain stimulation. In particular, we compared the subthalamic power spectral densities and coherence, amplitude cross-correlation and phase locking value between resting state, upright standing, and steady forward walking. We observed a phase locking value drop in the ß-frequency band (≈13-35Hz) during walking with respect to resting and standing. This modulation was not accompanied by specific changes in subthalamic power spectral densities, which was not related to gait phases or to striatal dopamine loss measured with [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane and single-photon computed tomography. We speculate that the subthalamic inter-hemispheric desynchronization in the ß-frequency band reflects the information processing of each body side separately, which may support linear walking. This study also suggests that in some cases (i.e. gait) the brain signal, which could allow feedback-controlled stimulation, might derive from network activity.

Daily intake of Mucuna pruriens in advanced Parkinson's disease: A 16-week, noninferiority, randomized, crossover, pilot study.

BACKGROUND: Thousands of individuals with Parkinson's disease (PD) in low-income countries have limited access to marketed levodopa preparations. Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in tropical areas, may be a sustainable alternative therapy for indigent patients. Single-dose intake of MP proved noninferior to marketed levodopa preparations. METHODS: Fourteen PD patients with motor fluctuations and dyskinesias received MP powder (obtained from roasted seeds) and marketed levodopa/carbidopa (LD/CD) in a randomized order and crossover design over a 16-week period. Efficacy measures were changes in quality of life, motor and non-motor symptoms, and time with good mobility without troublesome dyskinesias. Safety measures included tolerability, frequency of adverse events, changes in laboratory indices and electrocardiogram. RESULTS: Daily intake of MP was associated with a variable clinical response, especially in terms of tolerability. Seven patients (50%) discontinued MP prematurely due to either gastrointestinal side-effects (n = 4) or progressive worsening of motor performance (n = 3), while nobody discontinued during the LD/CD phase. In those who tolerated MP, clinical response to MP was similar to LD/CD on all efficacy outcome measures. Patients who dropped out entered a study extension using MP supernatant water (median[IQR], 16 [7-20] weeks), which was well tolerated. CONCLUSIONS: The overall benefit provided by MP on the clinical outcome was limited by tolerability issues, as one could expect by the relatively rapid switch from LD/CD to levodopa alone in advanced PD. Larger parallel-group studies are needed to identify appropriate MP formulation (e.g. supernatant water), titration scheme and maintenance dose to minimize side-effects in the long-term. CLINICAL TRIALS. GOV IDENTIFIER: NCT02680977.

Mucuna pruriens in Parkinson disease: A double-blind, randomized, controlled, crossover study.

OBJECTIVE: To investigate whether Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in all tropical areas worldwide, may be used as alternative source of levodopa for indigent individuals with Parkinson disease (PD) who cannot afford long-term therapy with marketed levodopa preparations. METHODS: We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD-DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias. RESULTS: When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD-DDCI. No differences in cardiovascular response were recorded. CONCLUSION: Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile. CLINICALTRIALSGOV IDENTIFIER: NCT02680977.

Mucuna pruriens for Parkinson's disease: Low-cost preparation method, laboratory measures and pharmacokinetics profile.

BACKGROUND: Parkinson's disease (PD) is a progressive neurological condition. Levodopa (LD) is the gold standard therapy for PD patients. Most PD patients in low-income areas cannot afford long-term daily Levodopa therapy. The aim of our study was to investigate if Mucuna pruriens (MP), a legume with high LD content that grows in tropical regions worldwide, might be potential alternative for poor PD patients. METHODS: We analyzed 25 samples of MP from Africa, Latin America and Asia. We measured the content in LD in various MP preparations (dried, roasted, boiled). LD pharmacokinetics and motor response were recorded in four PD patients, comparing MP vs. LD+Dopa-Decarboxylase Inhibitor (DDCI) formulations. RESULTS: Median LD concentration in dried MP seeds was 5.29%; similar results were obtained in roasted powder samples (5.3%), while boiling reduced LD content up to 70%. Compared to LD+DDCI, MP extract at similar LD dose provided less clinical benefit, with a 3.5-fold lower median AUC. CONCLUSION: Considering the lack of a DDCI, MP therapy may provide clinical benefit only when content of LD is at least 3.5-fold the standard LD+DDCI. If long-term MP proves to be safe and effective in controlled clinical trials, it may be a sustainable alternative therapy for PD in low-income countries.

Low-protein and protein-redistribution diets for Parkinson's disease patients with motor fluctuations: a systematic review.

The American Academy of Neurology suggests advising the redistribution of daily protein meal content to every Parkinson's disease (PD) patient with motor fluctuations during levodopa treatment. However, no comprehensive evaluation of this complementary therapy has been performed. A systematic review of intervention studies investigating the neurologic outcome of low-protein (<0.8 g/kg of ideal weight/day) and protein-redistribution diets in patients with PD experiencing motor fluctuations during levodopa treatment. All studies (uncontrolled or randomized) investigating a low-protein and/or a protein-redistribution diet (LPD and PRD) and involving patients with PD with motor fluctuations were included, provided that sufficient information on dietary protein content and neurologic outcome measures was available. We identified 16 eligible studies, but they were markedly heterogeneous. There was not enough evidence to support the use of LPD. Response to PRD seemed very good. Acceptability appeared high upon introduction, but it seemed to progressively decrease over time. On average, PRD resulted in improved motor function, but also complications occurred. At the beginning, drop-outs were due to levodopa side effects rather than unsatisfactory benefits. Long-term adherence was more affected by changes in dietary habits than by diet-related side effects. Efficacy and benefits appeared to be higher when the intervention was proposed to subjects in the early stages of PD. PRD can be safely advised to fluctuating patients with PD, but those in whom benefits override the possible inconveniences still need to be identified. The long-term effects of PRD on nutritional status should be evaluated and true effectiveness in clinical practice should be reassessed, given the changes in levodopa formulations and the introduction of several adjuvants (levodopa degradation inhibitors and/or dopamine agonists).

Controlled-protein dietary regimens for Parkinson's disease.

Continuous levodopa replacement still is the most efficacious treatment for patients with Parkinson's disease. Unfortunately, the neutral aromatic amino acids contained in dietary proteins may compete with this drug for intestinal absorption and transport across the blood-brain barrier, thus limiting its efficacy and being responsible for the occurrence of motor fluctuations. Current guidelines recommend low-protein dietary regimens with protein redistribution, as shifting protein intake to the evening has proved to ameliorate the response to levodopa. However, adherence to this dietary regimen does not seem to be satisfactory and response is variable. Recent studies have shown that low-protein products designed for chronic renal failure patients are safe, tasty, well-tolerated and useful in improving both adherence to low-protein dietary regimens and levodopa-related motor fluctuations. However, there still is the need to define the selection criteria for the patients who may benefit the most from adherence to this regimen.

Major nutritional issues in the management of Parkinson's disease.

As with other neurodegenerative diseases, neurologic and nutritional elements may interact affecting each other in Parkinson's disease (PD). However, the long-term effects of such interactions on prognosis and outcome have not been given much attention and are poorly addressed by current research. Factors contributing to the clinical conditions of patients with PD are not only the basic features of PD, progression of disease, and the therapeutic approach but also fiber and nutrient intakes (in terms of both energy and protein content), fluid and micronutrient balance, and pharmaconutrient interactions (protein and levodopa). During the course of PD nutritional requirements frequently change. Accordingly, both body weight gain and loss may occur and, despite controversy, it seems that both changes in energy expenditure and food intake contribute. Nonmotor symptoms play a significant role and dysphagia may be responsible for the impairment of nutritional status and fluid balance. Constipation, gastroparesis, and gastro-oesophageal reflux significantly affect quality of life. Finally, any micronutrient deficiencies should be taken into account. Nutritional assessments should be performed routinely. Optimization of pharmacologic treatment for both motor and nonmotor symptoms is essential, but nutritional interventions and counseling could and should also be planned with regard to nutritional balance designed to prevent weight loss or gain; optimization of levodopa pharmacokinetics and avoidance of interaction with proteins; improvement in gastrointestinal dysfunction (e.g., dysphagia and constipation); prevention and treatment of nutritional deficiencies (micronutrients or vitamins). A balanced Mediterranean-like dietary regimen should be recommended before the introduction of levodopa; afterward, patients with advanced disease may benefit considerably from protein redistribution and low-protein regimens.