Parkinsons Abstracts 3


Special low-protein foods ameliorate postprandial off in patients with advanced Parkinson's disease.
            (Barichella et al., 2006)  Download
Protein intake interferes with levodopa therapy. Patients with advanced Parkinson's disease (PD) should restrict daily protein intake and shift protein intake to the evening. For further reduction of protein intake in the first part of the day, special low-protein products (LPP) should be used instead of normal food products at breakfast and lunch. We studied the efficacy of LPP on postprandial off periods, in PD patients on levodopa therapy. The methods included a randomized, cross-over, single-blind, pilot clinical trial comparing a 2-month balanced diet with a 2-month LPP diet in 18 PD patients with motor fluctuations. The off phases were significantly shorter after LPP diet than after balanced diet (postprandial off, 49 +/- 73 min vs. 79 +/- 72 min and total off, 164 +/- 148 min vs. 271 +/- 174 min, both P < 0.0001). Moreover, a reduction in total off time during LPP diet (3.3 +/- 2.7 hr vs. 4.7 +/- 3.3 hr, P < 0.0001), occurred also in the 9 patients who did not experience subjective benefit. No significant changes in hematological and biochemical variables or body composition were recorded; a slight reduction in body weight (mean, -1.8%) was observed. Consumption of LPP in the first part of the day ameliorates off periods in PD patients, but additional studies including pharmacokinetics are needed.

Controlled-protein dietary regimens for Parkinson's disease.
            (Cereda et al., 2010a)  Download
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.

Low-protein and protein-redistribution diets for Parkinson's disease patients with motor fluctuations: a systematic review.
            (Cereda et al., 2010b)  Download
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).

The discrediting of the monoamine hypothesis.
            (Hinz et al., 2012)  Download
BACKGROUND:  The monoamine hypothesis has been recognized for over half a century as a reference point to understanding electrical dysfunction associated with disease states, and/or regulatory dysfunction related to synaptic, centrally acting monoamine concentrations (serotonin, dopamine, norepinephrine, and epinephrine). METHODS:  Organic cation transporters (OCT) are a primary force controlling intracellular and extracellular (including synaptic) concentrations of centrally acting monoamines and their amino acid precursors. A new type of research was analyzed in this paper (previously published by the authors) relating to determining the functional status of the nutritionally driven organic cation transporters. It was correlated with the claims of the monoamine hypothesis. RESULTS:  Results of laboratory assays from subjects not suffering from a hyperexcreting tumor show that centrally acting monoamine concentrations are indistinguishable in subjects with and without disease symptoms and/or regulatory dysfunction. Analysis of centrally acting monoamine concentrations in the endogenous state reveals a significant difference in day-to-day assays performed on the same subject with and without monoamine-related disease symptoms and/or regulatory dysfunction. The day-to-day difference renders baseline testing in the endogenous state non-reproducible in the same subject. CONCLUSION:  It is asserted that the monoamine hypothesis, which claims that low synaptic levels of monoamines are a primary etiology of disease, is not a valid primary reference point for understanding chronic electrical dysfunction related to the centrally acting monoamines. Furthermore, the "bundle damage theory" is a more accurate primary model for understanding chronic dysfunction. The "bundle damage theory" advocates that synaptic monoamine levels are normal but not adequate in states associated with chronic electrical dysfunction and that levels need to be increased to compensate for the chronic postsynaptic electrical dysfunction due to existing damage. The monoamine hypothesis, in failing to accurately explain the etiology of chronic neuronal electrical flow dysfunction in the endogenous state, is reduced to no more than a historical footnote.

Gastric acidity and levodopa in Parkinsonism
            (Jenkins et al., 1973)  Download
To the Editor.—  About 20% of patients with Parkinson's disease have a poor therapeutic response to levodopa taken by mouth. It has been suggested that the pH of gastric juice modifies absorption. Rivera-Calimlin and co-workers showed that parkinsonian patients with alkaline gastric juice achieve a peak serum level of levodopa more rapidly,1 and they reported such a patient whose failure to improve when given levodopa was corrected by alkalinization of the stomach contents.2 Conversely, Cotzias has shown that the action of levodopa in mice is enhanced when it is delivered intragastrically with molar concentrations of hydrochloric acid.3We used the azuresin (Diagnex Blue) diagnostic test to test the secretion of gastric hydrochloric acid in 93 consecutive, unselected, parkinsonian patients. Levodopa was given in therapeutic doses and postural stability, bradykinesia, finger dexterity, tremor, and rigidity were each scored at intervals on a 0- to 4-point scale.4

Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study.
            (Katzenschlager et al., 2004)  Download
BACKGROUND:  The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). METHODS:  Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. RESULTS:  Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. CONCLUSIONS:  The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.

Coenzyme Q10 for Parkinson's disease
            (Liu et al., 2011)  Download
BACKGROUND: A number of preclinical studies in both in vitro and in vivo models of Parkinson's disease have demonstrated that coenzyme Q10 can protect the nigrostriatal dopaminergic system. Some clinical trials have looked at the neuroprotective effects of coenzyme Q10 in patients with early and midstage Parkinson's disease. OBJECTIVES: To assess the evidence from randomized controlled trials on the efficacy and safety of treatment with coenzyme Q10 compared to placebo in patients with early and midstage Parkinson's disease. SEARCH METHODS: We searched the Cochrane Movment Disorders Group Trials Register, CENTRAL (The Cochrane Library 2009, Issue 4), MEDLINE (January 1966 to March 2011), and EMBASE (January 1985 to March 2011). We handsearched the references quoted in the identified trials, congress reports from the most important neurological association and movement disorder societies in Europe and America (March 2011), checked reference lists of relevant studies and contacted other researchers. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared coenzyme Q10 to placebo for patients who suffered early and midstage primary Parkinson's disease. Studies in which the method of randomization or concealment were unknown were included. Cross-over studies were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. All disagreements were resolved by consensus between authors and were explained. We attempted to contact the authors of studies for further details if any data were missing and to establish the characteristics of unpublished trials through correspondence with the trial coordinator or principal investigator. Adverse effects information was collected from the trials. MAIN RESULTS: Four randomized, double-blind, placebo-controlled trials with a total of 452 patients met the inclusion criteria and were included in the review. In overall, there were improvements in activities of daily living (ADL) UPDRS (WMD -3.12, 95% CI -5.88 to -0.36) and Schwab and England (WMD 4.43, 95% CI 0.05 to 8.81) for coenzyme Q10 at 1200 mg/d for 16 months versus placebo.In safety outcomes, only the risk ratios (RR) of pharyngitis (RR 1.04, 95% CI 0.18 to 5.89) and diarrhea (RR 1.39, 95% CI 0.62 to 3.16) are mild elevated between coenzyme Q10 therapy and placebo and there were no differences in the number of withdrawals due to adverse effects (RR 0.61, 95% CI 0.23 to 1.62). AUTHORS' CONCLUSIONS: Coenzyme Q10 therapy with 1200 mg/d for 16 months was well tolerated by patients with Parkinson's disease. The improvements in ADL UPDRS and Schwab and England were positive, but it need to be further confirmed by larger sample. For total and other subscores of UPDRS, the effects of coenzyme Q10 seemed to be less clear.

A clinical trial of folic acid in Parkinson's disease
            (McGeer et al., 1972)  Download
Eighten patients were each given 15mg per day of folic acid oraly for a period of 14 to 182 days (average45 days). No therapeutic benefit was noted in six patients, a slight subjective benefit (without apreciable objective change) was reported by 11 patients and one showed a worsening of gait.

Homotaurine in Parkinson's disease.
            (Ricciardi et al., 2015)  Download
Homotaurine is a natural compound of red algae, which has been demonstrated to have a neuroprotective effect and has been evaluated as a possible therapeutic agent for Alzheimer's disease. This was a single blind, randomized, controlled study to evaluate the safety and efficacy of homotaurine in patients with Parkinson's disease (PD) and cognitive impairment. Patients were evaluated at baseline and 6 months later. Assessments included, the evaluation of: motor and non-motor conditions and complications (Unified Parkinson's Disease Rating Scale, UPDRS); disability and quality of life; depression; excessive daytime sleepiness and fatigue. An extensive neuropsychological tests battery was administered evaluating specific cognitive domains: memory, phonemic verbal fluency, executive functions and selective visual attention. After baseline testing, patients were allocated to one of the two groups: (A) treatment group: patients treated with homotaurine 100 mg; (B) control group: patients not treated with homotaurine. Forty-seven patients were evaluated at baseline, 24 (51 %) completed the study (PD-homotaurine: n = 11; 44 % and PD-controls: n = 13; 59 %); discontinuation rate was similar across subjects (p = 1.0). Intention to treat analyses to evaluate homotaurine safety showed mild side effects (gastrointestinal upsetting) in 3 patients. Per protocol analyses of homotaurine efficacy showed no difference between groups. Within group analyses showed that PD-homotaurine patients had better score at UPDRS-I at the end of the study compared to baseline (p = 0.017) and at Epworth Sleepiness Scale (p = 0.01). No other differences were found. No significant difference arose for the PD-ctrl group. Homotaurine is a safe drug. Our data suggest a beneficial effect of homotaurine on excessive sleepiness. Future studies are encouraged to confirm this promising role of homotaurine in promoting the sleep/awake cycle in patients with PD.

Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease.
            (Suzuki et al., 2013)  Download
BACKGROUND:  In our previous study, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations and the vitamin D receptor (VDR) FokI CC genotype were associated with milder Parkinson disease (PD). OBJECTIVE:  We evaluated whether vitamin D3 supplementation inhibits the progression of PD on the basis of patient VDR subgroups. DESIGN:  Patients with PD (n = 114) were randomly assigned to receive vitamin D3 supplements (n = 56; 1200 IU/d) or a placebo (n = 58) for 12 mo in a double-blind setting. Outcomes were clinical changes from baseline and the percentage of patients who showed no worsening of the modified Hoehn and Yahr (HY) stage and Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS:  Compared with the placebo, vitamin D3 significantly prevented the deterioration of the HY stage in patients [difference between groups: P = 0.005; mean ± SD change within vitamin D3 group: +0.02 ± 0.62 (P = 0.79); change within placebo group: +0.33 ± 0.70 (P = 0.0006)]. Interaction analyses showed that VDR FokI genotypes modified the effect of vitamin D3 on changes in the HY stage (P-interaction = 0.045), UPDRS total (P-interaction = 0.039), and UPDRS part II (P-interaction = 0.021). Compared with the placebo, vitamin D3 significantly prevented deterioration of the HY stage in patients with FokI TT [difference between groups: P = 0.009; change within vitamin D3 group: -0.38 ± 0.48 (P = 0.91); change within placebo group, +0.63 ± 0.77 (P = 0.009)] and FokI CT [difference between groups: P = 0.020; change within vitamin D3 group: ±0.00 ± 0.60 (P = 0.78); change within placebo group: +0.37 ± 0.74 (P = 0.014)] but not FokI CC. Similar trends were observed in UPDRS total and part II. CONCLUSION:  Vitamin D3 supplementation may stabilize PD for a short period in patients with FokI TT or CT genotypes without triggering hypercalcemia, although this effect may be nonspecific for PD. This trial was registered at UMIN Clinical Trials Registry as UMIN000001841.


Biochemical and clinical effects of Whey protein supplementation in Parkinson's disease: A pilot study.
            (Tosukhowong et al., 2016)  Download
BACKGROUND:  Parkinson's disease (PD) is an oxidative stress-mediated degenerative disorder. Elevated plasma homocysteine (Hcy) is frequently found in the levodopa-treated PD patients, is associated with disease progression and is a marker of oxidative stress. Whey protein is a rich source of cysteine, and branched-chain amino acids (BCAA). It has been shown that supplementation with Whey protein increases glutathione synthesis and muscle strength. OBJECTIVES AND METHODS:  In this study, we conducted a placebo-controlled, double-blind study (NCT01662414) to investigate the effects of undenatured Whey protein isolate supplementation for 6months on plasma glutathione, plasma amino acids, and plasma Hcy in PD patients. Clinical outcome assessments included the unified Parkinson's disease rating scale (UPDRS) and striatal L-3,4-dihydroxy-6-(18)F-fluorophenylalanine (FDOPA) uptake were determined before and after supplementation. 15 patients received Whey protein, and 17 received Soy protein, served as a control group. RESULTS:  Significant increases in plasma concentration of reduced glutathione and the ratio of reduced to oxidized glutathione were found in the Whey-supplemented patients but not in a control group. This was associated with a significant decrease of plasma levels of Hcy. The plasma levels of total glutathione were not significantly changed in either group. Plasma BCAA and essential amino acids (EAA) were significantly increased in the Whey-supplemented group only. The UPDRS and striatal FDOPA uptake in PD patients were not significantly ameliorated in either group. However, significant negative correlation was observed between the UPDRS and plasma BCAA and EAA in the pre-supplemented PD patients. CONCLUSION:  This study is the first to report that Whey protein supplementation significantly increases plasma reduced glutathione, the reduced to oxidized glutathione ratio, BCAAs and EAAs in patients with PD, together with a concomitant significant reduction of plasma Hcy. However, there were no significant changes in clinical outcomes. Long-term, large randomized clinical studies are needed to explore the benefits of Whey protein supplementation in the management of PD patients.

Both stimulatory and inhibitory effects of dietary 5-hydroxytryptophan and tyrosine are found on urinary excretion of serotonin and dopamine in a large human population.
            (Trachte et al., 2009)  Download
Amino acid precursors of dopamine and serotonin have been administered for decades to treat a variety of clinical conditions including depression, anxiety, insomnia, obesity, and a host of other illnesses. Dietary administration of these amino acids is designed to increase dopamine and serotonin levels within the body, particularly the brain. Convincing evidence exists that these precursors normally elevate dopamine and serotonin levels within critical brain tissues and other organs. However, their effects on urinary excretion of neurotransmitters are described in few studies and the results appear equivocal. The purpose of this study was to define, as precisely as possible, the influence of both 5-hydroxytryptophan (5-HTP) and tyrosine on urinary excretion of serotonin and dopamine in a large human population consuming both 5-HTP and tyrosine. Curiously, only 5-HTP exhibited a marginal stimulatory influence on urinary serotonin excretion when 5-HTP doses were compared to urinary serotonin excretion; however, a robust relationship was observed when alterations in 5-HTP dose were compared to alterations in urinary serotonin excretion in individual patients. The data indicate three statistically discernible components to 5-HTP responses, including inverse, direct, and no relationships between urinary serotonin excretion and 5-HTP doses. The response to tyrosine was more consistent but primarily yielded an unexpected reduction in urinary dopamine excretion. These data indicate that the urinary excretion pattern of neurotransmitters after consumption of their precursors is far more complex than previously appreciated. These data on urinary neurotransmitter excretion might be relevant to understanding the effects of the precursors in other organs.

The Treatment Of Chronic Encephalitic Parkinsonism With Dried Preparations Of Stramonium.
            (Worster-Drought and Hill, 1930)  Download
IN the investigation of different forms of treatment likely to benefit chronic encephalitic parkinsonism, it soon becomes apparent that no actual curative effect is possible. The symptoms and signs presented result almost entirely from neuronal destruction, and although it is possible that in some cases the severity of the condition may be increased by toxic depression of neurones owing to the presence of an active infection in the brain, there is little doubt that the progressive changes exhibited by most chronic cases are due to the …

Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's disease.
            (Yoritaka et al., 2015)  Download
INTRODUCTION:  Mitochondrial complex I deficiencies have been found in post-mortem brains of patients with Parkinson's disease (PD). Coenzyme Q10 (CoQ10) is the electron acceptor found in complexes I and II, and is a potent antioxidant. A recent trial of the oxidized form of CoQ10 for PD failed to show benefits; however, the reduced form of CoQ10 (ubiquinol-10) has shown better neuroprotective effects in animal models. METHODS:  Randomized, double-blind, placebo-controlled, parallel-group pilot trials were conducted to assess the efficacy of ubiquinol-10 in Japanese patients with PD. Participants were divided into two groups: PD experiencing wearing off (Group A), and early PD, without levodopa (with or without a dopamine agonist) (Group B). Participants took 300 mg of ubiquinol-10 or placebo per day for 48 weeks (Group A) or 96 weeks (Group B). RESULTS:  In Group A, total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the ubiquinol-10 group (n = 14; mean ± SD [-4.2 ± 8.2]), indicating improvement in symptoms. There was a statistically significant difference (p < 0.05) compared with the placebo group (n = 12; 2.9 ± 8.9). In Group B, UPDRS increased in the ubiquinol-10 group (n = 14; 3.9 ± 8.0), as well as in the placebo group (n = 8; 5.1 ± 10.3). CONCLUSIONS:  This is the first report showing that ubiquinol-10 may significantly improve PD with wearing off, as judged by total UPDRS scores, and that ubiquinol-10 is safe and well tolerated.



Barichella, M, et al. (2006), ‘Special low-protein foods ameliorate postprandial off in patients with advanced Parkinson’s disease.’, Mov Disord, 21 (10), 1682-87. PubMed: 16773618
Cereda, E, M Barichella, and G Pezzoli (2010a), ‘Controlled-protein dietary regimens for Parkinson’s disease.’, Nutr Neurosci, 13 (1), 29-32. PubMed: 20132652
Cereda, E, et al. (2010b), ‘Low-protein and protein-redistribution diets for Parkinson’s disease patients with motor fluctuations: a systematic review.’, Mov Disord, 25 (13), 2021-34. PubMed: 20669318
Hinz, M, A Stein, and T Uncini (2012), ‘The discrediting of the monoamine hypothesis.’, Int J Gen Med, 5 135-42. PubMed: 22371656
Jenkins, R., S. Lamid, and H. Klawans (1973), ‘Gastric acidity and levodopa in Parkinsonism’, JAMA, 223 (1), 81. PubMed: 4739103
Katzenschlager, R, et al. (2004), ‘Mucuna pruriens in Parkinson’s disease: a double blind clinical and pharmacological study.’, J Neurol Neurosurg Psychiatry, 75 (12), 1672-77. PubMed: 15548480
Liu, J., et al. (2011), ‘Coenzyme Q10 for Parkinson’s disease’, Cochrane Database Syst Rev, (12), CD008150. PubMed: 22161420
McGeer, P. L., L. Zeldowicz, and E. G. McGeer (1972), ‘A clinical trial of folic acid in Parkinson’s disease’, Can Med Assoc J, 106 (2), 145-6 passim. PubMed: 4400558
Ricciardi, L, et al. (2015), ‘Homotaurine in Parkinson’s disease.’, Neurol Sci, 36 (9), 1581-87. PubMed: 25894843
Suzuki, M, et al. (2013), ‘Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease.’, Am J Clin Nutr, 97 (5), 1004-13. PubMed: 23485413
Tosukhowong, P, et al. (2016), ‘Biochemical and clinical effects of Whey protein supplementation in Parkinson’s disease: A pilot study.’, J Neurol Sci, 367 162-70. PubMed: 27423583
Trachte, GJ, T Uncini, and M Hinz (2009), ‘Both stimulatory and inhibitory effects of dietary 5-hydroxytryptophan and tyrosine are found on urinary excretion of serotonin and dopamine in a large human population.’, Neuropsychiatr Dis Treat, 5 227-35. PubMed: 19557117
Worster-Drought, C and TR Hill (1930), ‘The Treatment Of Chronic Encephalitic Parkinsonism With Dried Preparations Of Stramonium.’, The Lancet, PubMed:
Yoritaka, A, et al. (2015), ‘Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease.’, Parkinsonism Relat Disord, 21 (8), 911-16. PubMed: 26054881