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To investigate the prevalence and genotype-phenotype correlations of parkin RBR E3 ubiquitin protein ligase (PRKN) variants in Parkinson's disease (PD), we first included 2,527 patients with PD. Through the defined selection, we enrolled 2,322 patients, including 1,204 with familial and 1,118 with sporadic PD. We identified 242 patients harboring PRKN variants, which were thought to be susceptibility factors, comprising 137 patients with familial and 105 with sporadic PD; among the 26 identified variants, 13 were novel. We divided our cohort into 2 groups: heterozygote (hereafter called one-allele) and homozygote or compound heterozygote (hereafter called two-allele). The patients with two-allele were significantly younger at onset than those with one-allele. Six families harbored the complex forms of one- and two-allele in different individuals of the same family. The presence of two-allele reflected more frequent normal values of [

Background Oxidative stress is involved in the progression of Parkinson’s disease (PD). Recent studies have confirmed that molecular hydrogen (H2) functions as a highly effective antioxidant in animal models of PD. A placebo-controlled, randomized, double-blind, parallel-group clinical pilot study was conducted to assess the efficacy of hydrogen gas inhalation in Japanese patients with PD on treatment with levodopa. Methods Twenty participants fulfilling the Movement Disorder Society criteria were enrolled. Participants inhaled 6.5 (0.1) vol% hydrogen gas in 2 L/min of mixed air or placebo air for 16 weeks, twice a day for 1 h. Results Five participants were excluded due to deviation from the protocol of the total duration of inhalation th week between the group that inhaled hydrogen gas and the group that inhaled placebo air (Mann–Whitney U test, p > 0.05). No adverse events were seen. The compliance to the protocol-based duration of inhalation time in all participants decreased with the elderly participants, the higher daily dose of levodopa, and the higher PDQ-39 items on emotions (n = 20, p Conclusion This pilot study revealed that the inhalation of molecular hydrogen gas was safe, but did not show any beneficial effects in patients with PD. Trial registration: UMIN ID: 000,039,217 (October 6, 2018)

Background Levodopa remains the most effective symptomatic treatment for Parkinson’s disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. Methods This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30–84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300–400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. Discussion This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. Trial registration Japan Registry of Clinical Trials, jRCTs031180248; registered 12 March 2019.

Parkin (encoded by PRKN) is a ubiquitin ligase that plays an important role in cellular mitochondrial quality control. Mutations in PRKN cause selective dopaminergic cell loss in the substantia nigra and are presumed to induce a decrease in mitochondrial function caused by the defective clearance of mitochondria. Several studies have demonstrated that parkin dysfunction causes mitochondrial injury and astrocytic dysfunction. Using immunohistochemical methods, we analyzed astrocytic changes in human brains from individuals with PRKN mutations. Few glial fibrillary acidic protein- and vimentin-positive astrocytes were observed in the substantia nigra in PRKN-mutated subjects compared with subjects with idiopathic Parkinson’s disease. We also differentiated patient-specific induced pluripotent stem cells into midbrain organoids and confirmed decreased numbers of glial fibrillary acidic protein-positive astrocytes in PRKN-mutated organoids compared with age- and sex-matched controls. Our study reveals PRKN-mutation-induced astrocytic alteration and suggests the possibility of an astrocyte-related non-autonomous cell death mechanism for dopaminergic neurons in brains of PRKN-mutated patients.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Hyposmia is one of the earliest and the most common symptoms in Parkinson’s disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2′-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either ~1.2–1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082).

Background: Istradefylline is a selective adenosine A2A receptor antagonist approved for Parkinson’s disease (PD) patients with wearing-off symptoms. The Japanese phase III trial showed that 20 mg of orally administrated istradefylline decreased the Off-time. However, istradefylline showed prominent effects in some patients and no benefits in others. We examined the differences in characteristics between responders and non-responders who received 8 weeks of 20 mg/day istradefylline. Methods: Thirty-one patients were enrolled (age, 65.4 [SD 10.4] years; disease duration, 10.4 [SD 6.1] years; daily levodopa dosage, 553.2 [SD 228.7] mg; frequency of levodopa consumption, 4.7 [SD 1.5] times; levodopa equivalent dose, 811.2 [SD 307.5] mg). Results: There were significant differences (p < 0.05) in sex (male/female: 5/16, 6/4), age (62.9 (SD 10.4), 70.6 (SD 8.0) years), age at onset (51.9 (SD 12.3), 61.5 (SD 10.5) years old), age at dyskinesia onset (57.9 (SD 8.8), 67.6 (SD 7.2), and Epworth sleepiness scale scores (4.5 (SD 2.7), 11.2 (SD 6.7), p < 0.01) for the responders and non-responders, respectively. There were no differences in disease duration, On-time, Off-time, Unified Parkinson’s disease Rating scale scores, daily levodopa dose, levodopa equivalent dose, cumulative levodopa dose, or coffee intake. Conclusions: Younger or female patients who are not excessively sleepy during daytime are better candidates for the istradefylline therapy.

Objective Parkinson's disease (PD) is a common, progressive, neurodegenerative disorder. With progression of PD, the wearing-off phenomenon occurs more frequently as a motor complication, decreasing the patient's quality of life. The aim of this study was to investigate the risk factors for the wearing-off phenomenon in Japanese PD patients. Methods All of the study participants were clinically diagnosed as having PD. Each patient was assessed for the wearing-off phenomenon based on the findings of clinical assessments and interviews that were conducted during a single visit. The risk factors for wearing-off were analyzed by univariate and multivariate logistic regression analyses. Results Wearing-off was observed in 101 of the 180 (56.1%) patients who were enrolled in this study. The multivariate logistic regression analysis revealed that the onset of PD at ≥69 years of age (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.05-0.88; p=0.032), female sex (OR, 6.49; 95% CI, 2.34-17.99; p

Objective Many studies on the cost of Parkinson disease (PD) have been published; however, there are limited studies pertaining to this issue in Asia. This study looks to assess the direct medical costs of patients with PD at a university hospital in Japan by calculating the average monthly direct medical costs of PD patients from July to December 2008. Methods We enrolled 724 consecutive patients (411 women and 313 men) with PD who were registered in Japan's "Specified Disease Treatment Research Program" and obtained data on the total direct medical costs of all patients. Results Values are reported as the mean (standard deviation). The major finding of the direct medical cost analysis was that the outpatient clinic cost per subject (n=715) was USD 485.74 (376.31) per month. A multivariate analysis revealed that a younger age, the presence of wearing-off, hallucination, and longer disease duration increased the direct medical cost significantly. Disease severity had no influence on the direct medical costs. A longer disease duration was significantly correlated with higher hospitalization costs. Conclusion The direct medical cost of PD in Japan was found to be similar to that in Western countries. Costs due to productivity loss exceeded the direct costs, and they may be reduced through the better integration of PD patients in the work environment.

Background: Camptocormia in Parkinson's disease (PD) is unresponsive to various therapies and induced difficulties in their day-to-day life. Objective: This study, an open trial, was aimed at assessing the efficacy of selegiline in the treatment of mild camptocormia in PD patients. Methods: Participants were administered 5 mg of selegiline for the first 8 weeks and 7.5 mg for the second 8 weeks. Results: As primary endpoints, the degree of thoracolumbar anteflexion decreased from 23.2° (mean) (11.8° (SD)) at baseline to 18.3° (7.1°) at 16 weeks, and the area of postural sway measured using a Gravicorder increased. However, the differences were not significant. Thoracolumbar anteflexion improved in 60% of the participants. Conclusions: In this study, 60% of the participants showed an improvement in anteflexion of the thoracolumbar spine with selegiline, but the change in the degree of anteflexion was 5°, which was not statistically significant. Participants with significant improvement in thoracolumbar anteflexion had an increased postural sway. This change was induced by a decrease in truncal muscle tonus or change in the center of gravity. This study combined the study of anteflexion and stability, and provides information on the treatment of short-term or mild camptocormia.

Background Our previous randomized double-blind study showed that drinking hydrogen (H 2 ) water for 48 weeks significantly improved the total Unified Parkinson’s Disease Rating Scale (UPDRS) score of Parkinson’s disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. Methods Changes in the total UPDRS scores from baseline to the 8 th , 24 th , 48 th , and 72 nd weeks, and after the 8 th week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72 nd week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H 2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (89 women, 89 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. Discussion This study will confirm whether H 2 water can improve PD symptoms. Trial registration UMIN000010014 (February, 13, 2013)

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.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).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 (p0.05) 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).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.