Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Impact of D-dimer for pathologic differentiation on transesophageal echocardiography in embolic stroke of undetermined source: a single-center experience.

BACKGROUND: Embolic stroke of undetermined source (ESUS) encompasses diverse embologenic mechanisms, which transesophageal echocardiography (TEE) is critical to detect. Specific markers related to each embolic source in ESUS is not fully studied. We focused on D-dimer levels, and explored the association of D-dimer with potential embolic sources (PES) identified on TEE in ESUS. METHODS: Consecutive patients with ESUS were included in this study. Clinical characteristics including D-dimer levels were compared between ESUS patients with and without TEE, and among none of, one, and at least two PES in ESUS patients undergoing TEE. Factors related to elevation of D-dimer were analyzed. RESULTS: A total of 211 patients (age, 69.3 ± 13.2 years; 149 males) with ESUS were enrolled. Of these, 115 received TEE, displaying significantly younger age and lower D-dimer levels than patients without TEE (P < 0.05), and 20 (17%), 61 (53%), and 34 (30%) patients were classified into none of, one, and ≥ two PES, respectively. On multiple logistic regression analysis, D-dimer levels were related to one PES (odds ratio [OR]: 9.01; 95% confidence interval [CI]: 1.00-81.51; P = 0.050) and PES ≥ two (OR: 9.76; 95% CI: 1.07-88.97; P = 0.043). Right-to-left shunt (RLS) with deep venous thrombosis (DVT)(OR: 13.94; 95% CI: 1.77-109.99; P = 0.012) and without DVT (OR: 3.90; 95% CI: 1.20-12.70; P = 0.024) were associated with elevation of D-dimer. CONCLUSIONS: D-dimer levels were higher in patients with PES. Among PES, RLS, with and without DVT, were associated with increase of D-dimer in ESUS.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

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.

Mucosal-Associated Invariant T Cells Are Involved in Acute Ischemic Stroke by Regulating Neuroinflammation.

Background Mucosal-associated invariant T (MAIT) cells have been associated with inflammation in several autoimmune diseases. However, their relation to ischemic stroke remains unclear. This study attempted to elucidate the role of MAIT cells in acute ischemic stroke in mice. Methods and Results We used MR1 knockout C57BL/6 (MR1-/-) mice and wild-type littermates (MR1+/+). After performing a transient middle cerebral artery occlusion (tMCAO), we evaluated the association with inflammation and prognosis in the acute cerebral ischemia. Furthermore, we analyzed the tMCAO C57BL/6 mice administered with the suppressive MR1 ligand and the vehicle control. We also evaluated the infiltration of MAIT cells into the ischemic brain by flow cytometry. Results showed a reduction of infarct volume and an improvement of neurological impairment in MR1-/- mice (n=8). There was a reduction in the number of infiltrating microglia/macrophages (n=3-5) and in their activation (n=5) in the peri-infarct area of MR1-/- mice. The cytokine levels of interleukin-6 and interleukin-17 at 24 hours after tMCAO (n=3-5), and for interleukin-17 at 72 hours after tMCAO (n=5), were lower in the MR1-/- mice. The administration of the suppressive MR1 ligand reduced the infarct volume and improved functional impairment (n=5). Flow cytometric analysis demonstrated there was a reduction of MAIT cells infiltrating into the ischemic brain at 24 hours after tMCAO (n=17). Conclusions Our results showed that MAIT cells play an important role in neuroinflammation after focal cerebral ischemia and the use of MAIT cell regulation has a potential role as a novel neuroprotectant for the treatment of acute ischemic stroke.

Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.

BACKGROUND: Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders. METHODS: This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale. RESULTS: After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration. CONCLUSION: Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function. TRIAL REGISTRATION: UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.

Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia.

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes (db/db) and phenotypically normal littermates (db/+). Compared to db/+ mice, db/db mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, db/db mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes in db/db mice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes.

Analysis of Clinical Symptoms and Brain MRI of Heat Stroke: 2 Case Reports and a Literature Review.

INTRODUCTION: Heat stroke is defined as high body temperature causing multiple organ failure, psychological change, seizure, and consciousness disturbance, which lead to its high mortality rate. However, the involvement of brain injury is rare, and heat-stroke has only been reported in a few case reports or case series. The purpose of this case study was to evaluate the clinical symptoms and radiological features of heat stroke. METHODS: We reviewed our hospital records and previously published reports to find cases of heat stroke. We excluded those with unknown clinical features or radiological findings. RESULTS: We retrieved 2 cases of heat stroke from our hospital, which presented as extensive lesions on brain imaging that led to disseminated intravascular coagulation and death within a few days. In 21 previously reported cases of heat stroke, similar brain lesions were noted. These were classified as infarction/posterior reversible encephalopathy syndrome (PRES)-like lesions. The patients who developed PRES-like lesions and survived often developed cerebellar sequelae. CONCLUSION: The mechanism of heat stroke is presumed to be multifactorial. Ischemic-like lesions result from hypovolemia and unusual coagulation, whereas PRES-like lesions are caused by direct heat and vasogenic edema due to hypercytokinemia. We need to consider the above mentioned conditions when evaluating heat stroke.

New Alzheimer's disease model mouse specialized for analyzing the function and toxicity of intraneuronal Amyloid ß oligomers.

Oligomers of intracellular amyloid ß protein (Aß) are strongly cytotoxic and play crucial roles in synaptic transmission and cognitive function in Alzheimer's disease (AD). However, there is currently no AD model mouse in which to specifically analyze the function of Aß oligomers only. We have now developed a novel AD model mouse, an Aß-GFP transgenic mouse (Aß-GFP Tg), that expresses the GFP-fused human Aß1-42 protein, which forms only Aß oligomers within neurons throughout their life. The fusion proteins are expressed mainly in the hippocampal CA1-CA2 region and cerebral cortex, and are not secreted extracellularly. The Aß-GFP Tg mice exhibit increased tau phosphorylation, altered spine morphology, decreased expressions of the GluN2B receptor and neuroligin in synaptic regions, attenuated hippocampal long-term potentiation, and impaired object recognition memory compared with non-Tg littermates. Interestingly, these dysfunctions have already appeared in 2-3-months-old animals. The Aß-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated Aß oligomer derived from postmortem AD patient brains and synthetic Aß oligomers. Thus, Aß-GFP Tg mouse is a new tool specialized to analyze the function of Aß oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.

Multiple cerebral infarction diagnosed as Eosinophilic Granulomatosis with Polyangiitis by autopsy.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of unknown cause involving the brain and accompanied by prominent eosinophilia. Intracardiac thrombosis is a major cardiac complication of EGPA that may cause thromboembolism. CASE PRESENTATION: A 53-year-old man presenting with abulia (consciousness disturbance) and left upper limb paralysis was admitted to our hospital. His case was complicated by penetrating branches, small vessel infarcts, and endocardial thrombosis in the right and left ventricle. Cardiomyopathy was also observed. Sixteen days after admission, the patient died from intracranial hemorrhage. Brain autopsy revealed two major findings: 1) large hemorrhagic infarction caused by cardiac embolism; and 2) granuloma and eosinophil infiltration. Vasculitis was accompanied by eosinophil infiltration in the cortical blood vessels and granuloma. CONCLUSIONS: In this case study, we report autopsy findings of brain infarction in a patient with EGPA and endocardial thrombosis. The brain infarction was caused by the cardiac embolisms and vasculitis.

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson's disease: A single-arm, open-label, prospective, multicenter study.

Background: Gait disorders are common in Parkinson's disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A2A receptor antagonist with benefits for motor complications associated with Parkinson's disease. Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson's disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed. Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4-12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients. Conclusions: Istradefylline improved gait disorders in Parkinson's disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified. Trial registration: UMIN-CTR (UMIN000020288).

Phosphorylated recombinant HSP27 protects the brain and attenuates blood-brain barrier disruption following stroke in mice receiving intravenous tissue-plasminogen activator.

Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections.

Widespread enlarged perivascular spaces associated with dementia and focal brain dysfunction: case report.

BACKGROUND: Enlarged perivascular spaces (PVS) are common magnetic resonance imaging (MRI) findings, whereas widespread enlarged PVS are extremely rare. Although most patients with widespread enlarged PVS remain asymptomatic, some develop neurological dysfunctions; however, it remains unclear whether these are the consequence of widespread enlarged PVS. CASE PRESENTATION: A 64-year-old female patient developed consciousness disturbance, cognitive dysfunctions, fluent aphasia, agraphia, acalculia, and left-right disorientation after suffering from bronchopneumonia. Brain MRI revealed unusually widespread enlarged PVS predominantly in the left cerebral hemisphere. Following bronchopneumonia treatment, her cognitive dysfunction, fluent aphasia, agraphia, acalculia, and left-right disorientation persisted despite improvement of her general condition. Furthermore, the hypoperfusion area on single photon emission computed tomography and slow wave sites on electroencephalography were consistent with the location of enlarged PVS, indicating that severe enlarged PVS impaired focal brain functions. CONCLUSIONS: This case suggested that widespread enlarged PVS could be a potential cause of neurological deficits. We propose that impaired perivascular circulation due to enlarged PVS might lead to focal brain dysfunction.

Glycyl-alanyl-histidine protects PC12 cells against hydrogen peroxide toxicity.

BACKGROUND: Peptides with cytoprotective functions, including antioxidants and anti-infectives, could be useful therapeutics. Carnosine, ß-alanine-histidine, is a dipeptide with anti-oxidant properties. Tripeptides of Ala-His-Lys, Pro-His-His, or Tyr-His-Tyr are also of interest in this respect. RESULTS: We synthesized several histidine-containing peptides including glycine or alanine, and tested their cytoprotective effects on hydrogen peroxide toxicity for PC12 cells. Of all these peptides (Gly-His-His, Ala-His-His, Ala-His-Ala, Ala-Ala-His, Ala-Gly-His, Gly-Ala-His (GAH), Ala-His-Gly, His-Ala-Gly, His-His-His, Gly-His-Ala, and Gly-Gly-His), GAH was found to have the strongest cytoprotective activity. GAH decreased lactate dehydrogenase (LDH) leakage, apoptosis, morphological changes, and nuclear membrane permeability changes against hydrogen peroxide toxicity in PC12 cells. The cytoprotective activity of GAH was superior to that of carnosine against hydrogen peroxide toxicity in PC12 cells. GAH also protected PC12 cells against damage caused by actinomycin D and staurosporine. Additionally, it was found that GAH also protected SH-SY5Y and Jurkat cells from damage caused by hydrogen peroxide, as assessed by LDH leakage. CONCLUSION: Thus, a novel tripeptide, GAH, has been identified as having broad cytoprotective effects against hydrogen peroxide-induced cell damage.

White matter lesions and cognitive impairment may be related to recovery from unilateral spatial neglect after stroke.

BACKGROUND: Unilateral spatial neglect (USN) is frequently found in ischemic stroke patients. Because USN is related to poor functional outcomes, evaluating recovery from USN after stroke is critical. METHODS: Patients with acute ischemic stroke with lesions in the right cerebral hemisphere on MRI and exhibiting left USN were administered the Behavior Inattention Test (BIT) at 1 and 3weeks after admission. BIT improvement was defined as a ≥1-point increase in ≥4 of the 6 BIT subtests from 1 to 3weeks, or a total BIT score ≥131 at 3weeks. Factors associated with improvement of left USN were analyzed. RESULTS: Eighteen patients (8 men; mean age, 70±12years) were enrolled in this study. BIT was performed at 5.3±0.7 and 18.2±0.7days after admission. Twelve patients were classified to the improvement (I) group, and 6 to the non-improvement (NI) group. BIT scores increased substantially from 76.6±40.5 in the acute phase to 109.2±43.3 in the subacute phase. The I group displayed higher BIT scores than the NI group in both acute and subacute phases (P<0.01 each). The degree of white matter lesions on the Fazekas scale was lower in the I group (0.6±0.7) than in the NI group (1.7±1.2, P=0.028). Increased BIT scores correlated significantly with increased Mini Mental State Examination scores (r=0.487, P=0.040). CONCLUSIONS: Amelioration of left USN might be related to white matter lesions and cognitive impairment. Sample size in the current study was small, limiting the generalizability of results, and larger studies are warranted in the future.

[Disease-Modifying Therapy for Parkinson's Disease].

Currently, treatment of Parkinson's disease aims at alleviating its symptoms. However development of disease-modifying drugs has been a remarkable advancement in recent years. Furthermore, clinical trials of immunotherapy against α-synuclein, a protein involved in the pathogenesis of and lesion expansion in Parkinson's disease, have been initiated. Here, the disease-modifying treatment for patients with Parkinson's disease including the current α-synuclein immunotherapy, gene therapy, protein injection therapy, and cell transplantation therapy, has been reviewed.

Anhedonia and its correlation with clinical aspects in Parkinson's disease.

Anhedonia is one of the non-motor symptoms observed in the Parkinson's disease (PD). However, there is no clear relationship between anhedonia and its correlation with other symptoms of PD. The aim of this study is to evaluate the characteristics of anhedonia and its correlation with clinical aspects of PD in a relatively large cohort. We enrolled 318 patients with PD and 62 control subjects for this study. Patients and subjects were tested using the Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition for the assessment of anhedonia and depression. We also investigated the correlation among clinical aspects of PD, anhedonia, and depression in patients with PD. The Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition scores were significantly higher in patients with PD than in control subjects (p=0.03 and p=0.0006, respectively). All PD patients with anhedonia had a significantly higher score on the unified Parkinson's disease rating scale (UPDRS) parts I and II compared to PD patients without anhedonia. Additionally, all PD patients with depression scored significantly higher on UPDRS part I-IV than PD patients without depression. The patients with anhedonia and without depression had mild motor severity and their treatment was relatively low dosage. These results suggest that anhedonia and depression are slightly linked, but not the same. PD patients with only anhedonia may be closely linked apathy found in untreated early stages of PD.

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) 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 H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 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 H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

A Japanese multicenter survey characterizing pain in Parkinson's disease.

BACKGROUND: Pain is a frequent, troublesome symptom of PD but is under-recognized and poorly understood. AIM: We characterized pain prevalence, severity, and location in PD, to better understand its pathophysiology and improve diagnosis and treatment. SUBJECTS AND METHODS: A cross-sectional controlled study was conducted at 19 centers across Japan. A total of 632 subjects with Mini-Mental State Examination scores ≥24 were enrolled, including 324 PD patients and 308 controls. Sex and mean age did not differ between the two groups. Demographic and clinical data were collected. Pain was assessed using questionnaires, the SF-36v2 bodily pain scale, and a body illustration for patients to indicate the location of pain in 45 anatomical areas. RESULTS: Pain prevalence in the PD group was 78.6%, significantly higher than in controls (49.0%), as was its severity. There was no correlation between SF-36v2 score and motor scores, such as Unified Parkinson's Disease Rating Scale III or Hoehn & Yahr scores. Pain distribution was similar between groups, predominantly in the lower back, followed by the gluteal region, lower legs, thighs, posterior neck, and shoulders. CONCLUSION: Pain is a significant problem in the Japanese PD population and we discuss its pathophysiology.