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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 Serum uric acid (UA) concentration is linked to the risk of progression of Parkinson's disease (PD). Objectives The aim of this study was to examine the association between serum UA concentration and the occurrence of wearing-off fluctuation (WOF) in Japanese PD patients. Methods A total of 123 Japanese patients with PD were enrolled in this study. We collected data on demographics, clinical features, medications, and laboratory findings including serum UA concentration, and examined the presence of WOF. The association between serum UA concentration and WOF was assessed using multivariate logistic regression analysis. Results After adjusting for possible confounders, it was found that the odds ratio (OR) for WOF decreased with increasing quartile of UA (highest quartile vs. lowest quartile, adjusted OR 0.218, 95% confidence interval [CI] 0.053-0.891). This association was significant only in male PD patients, regardless of the use of sex-specific quartiles of UA. Additionally, disease duration (OR 7.80, 95% CI 2.62-23.17) and daily levodopa dosage (OR 4.06, 95% CI 1.45-11.38) were associated with the occurrence of WOF. Conclusions Our results showed that serum UA concentration was associated with the occurrence of WOF. Serum UA concentration may be a predictive factor for WOF.

PurposeWe examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinson's disease (PD) (n = 1453; 650 males).MethodsEvents were analyzed using Kaplan–Meier survival curves, logistic regression, and Cox proportional-hazards models.ResultsThe mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females (p

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 cultured cells and animal models. Drinking H₂-dissolved water (H₂-water) reduced oxidative stress and improved Parkinson's features in model animals. Methods In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H₂ -water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H₂-water or pseudo water for 48 weeks. Results Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H₂-water group (n=9) improved (median, -1.0; mean ± standard deviation, -5.7 ± 8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean ± standard deviation, 4.1 ± 9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant (P Conclusions The results indicated that drinking H₂-water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H₂-water group was demonstrated.

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)

Objective To evaluate the efficacy and safety of Yokukansan, a traditional Chinese herbal medicine, for treating behavioral and psychological symptoms of dementia (BPSD) in patients with Parkinson disease (PD; n = 7) and those with PD with dementia (PDD; n = 7). Background BPSD are often seen in patients with senile dementia and have serious deleterious effects on the lives of patients and caregivers. Recent studies indicate that the traditional Chinese herbal medicine Yokukansan may be safe and beneficial for the treatment of BPSD patients. Methods We treated 7 PD and 7 PDD patients for 4 weeks with Yokukansan and observed them without Yokukansan for 4 weeks. Changes in behavioral and psychological symptoms were evaluated every 4 weeks according to the Neuropsychiatric Inventory (NPI) scale. Results Significant improvements in behavioral and psychological symptoms, particularly in the incidence and duration of hallucinations, were observed in most PD and PDD patients after 4 weeks of Yokukansan treatment. No significant changes were observed in the laboratory tests, cognitive function, activities of daily living, or parkinsonism. Conclusion Our results suggest that Yokukansan improves BPSD in both PD and PDD patients without worsening their cognitive function, ability to perform activities of daily living, or parkinsonism.

A 49-year-old male presented with hemisensory disturbance and gait unsteadiness following a previous episode of meningitis. He had no contributory medical or head injury history. Magnetic resonance imaging revealed innumerable medullary vessels in the white matter of the left cerebral hemisphere, which had not been recognized in the previous imaging study. Cerebral angiography showed variant superior sagittal sinus (SSS) arteriovenous fistula (AVF) fed by the bilateral middle meningeal and superficial temporal arteries, and drained directly to the cortical veins with marked venous engorgement in the affected hemisphere. The fistulas were located on the cortical veins, apart from the SSS. Initial percutaneous transarterial embolization failed, so the AVF was completely obliterated with a combination of surgical and endovascular techniques. The symptoms ameliorated postoperatively. Meningitis may be an underlying pathology of dural AVF. Variant SSS AVF can be treated with a combination of surgical and endovascular techniques.

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.

Background and purpose The 9-item Wearing-off Questionnaire (WOQ-9) is a useful tool for screening of wearing-off. We performed a validation study of the Japanese version of the WOQ-9 (JWOQ-9) using a cross-sectional design in Japanese Parkinson's disease (PD) patients diagnosed with sporadic PD and treated with levodopa. Methods Subjects with severe dementia, uncontrolled psychiatric comorbidities, and previous PD neurosurgery were excluded. The wearing-off phenomenon was detected according to the JWOQ-9, and the results were compared with independent evaluations of wearing-off conducted by PD specialists blinded to the JWOQ-9 results. To validate the JWOQ-9, a sample size of at least 70 patients with wearing-off and 70 patients without wearing-off was required. Therefore, a total of 180 patients (101 patients with wearing-off and 79 patients without wearing-off) were enrolled. Results The sensitivity, specificity, positive predictive value, and negative predictive value of the JWOQ-9 were 94.1%, 39.2%, 66.4%, and 83.8%, respectively. Motor symptom questions demonstrated both moderate sensitivity (58.1–87.3%) and specificity (60.4–87.5%). In contrast, non-motor symptom questions demonstrated fair to moderate sensitivity (51.5–64.6%), with high specificity (80.0–94.1%). Like the original WOQ-9, the JWOQ-9 exhibits significant value for detecting possible wearing-off. Conclusions The JWOQ-9 is a useful screening tool for detecting wearing-off of both motor and non-motor symptoms.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young-onset parkinsonism with remarkable response to levodopa. Recently, we mapped the gene locus for AR-JP to chromosome 6q25.2-q27 by linkage analysis and we identified a novel large gene, Parkin, consisting of 12 exons from this region; mutations of this gene were found to be the cause of AR-JP in two families. Now we report results of extensive molecular analysis on 34 affected individuals from 18 unrelated families with AR-JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exon 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one-base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one-base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR-JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. To date, we found two different deletional mutations including single and multiple exonic deletions. In the present study, we identified two types of point mutations (Thr240Arg and Gln311Stop) involving exons 6 and 8 in the parkin gene of the AR-JP patients from two Turkish families. This is the first report on point mutations for the parkin gene. Furthermore, the Thr240Arg mutation was located on a consensus sequence for the site of phosphorylation by casein kinase II. Identification of its mutation provides an important clue as to the role of the Parkin protein in degeneration of the substantia nigra in the brain of AR-JP patients.

We report −108Met/Val polymorphism of the COMT gene in Japanese patients with Parkinson's disease (PD). The allele frequency for −108Val was higher in PD patients compared with controls, although the differences did not reach the statistical significance. However, the frequency of -108Val homozygotes was significantly higher in PD patients (56.8%) than in control subjects (44.2%), and heterozygotes of −108Met/Val were less in PD. COMT gene polymorphism may constitute a genetic risk factor for PD among Japanese.

We report Mn superoxide dismutase (SOD) protein and activity in a patient with familial autosomal recessive Lewy body-negative parkinsonism in comparison with patients with sporadic Parkinson's disease (PD) and controls. We recently proved linkage of this family with markers of chromosome 6 at 6q25.2-27, which included the Mn SOD gene. We used a novel polymorphic mutation at -9 position of the signal peptide of the Mn SOD precursor protein, which caused valine to alanine substitution. All the affected members of this family showed homozygosity for alanine, whereas nonaffected members, sporadic PD patients, and the control subjects studied showed either heterozygosity of alanine and valine or homozygosity of valine. The Mn SOD activity of this familial patient was the highest among the PD patients and the control subjects studied, and an abundant expression of Mn SOD was found in the substantia nigra. The molecular weight of Mn SOD protein by Western blotting of this patient was essentially similar to that of PD patients and the control subjects. High Mn SOD activity may constitute a genetic risk factor in this familial patient. The difference in the signal peptide sequence may affect the expression of Mn SOD within mitochondria; however, it is unlikely that loss of function type Mn SOD mutation is the cause of this familial parkinsonism. Mn SOD in sporadic PD patients was similar to that in controls.

A 19-year-old woman had right occipital infarction 3 months after she had injected methamphetamine. No other possible causes of stroke could be found in this case. Magnetic resonance angiography revealed beading of the right posterior cerebral artery, which suggested vasculitis. Her symptoms were right-sided headache, left superior quadrant hemianopia, and left hypesthesia, which gradually improved without any treatment. Methamphetamine has been known to cause hemorrhagic and ischemic stroke relatively soon after administration. We report here that methamphetamine may also cause chronic cerebral vasculitis and delayed ischemic stroke.

There is growing evidence that oxidative stress and mitochondrial respiratory failure with attendant decrease in energy output are implicated in nigral neuronal death in Parkinson disease (PD). It is not known, however, which cellular elements (neurons or glial cells) are major targets of oxygen-mediated damage. 4-Hydroxy-2-nonenal (HNE) was shown earlier to react with proteins to form stable adducts that can be used as markers of oxidative stress-induced cellular damage. We report here results of immunochemical studies using polyclonal antibodies directed against HNE-protein conjugates to label the site of oxidative damage in control subjects (ages 18-99 years) and seven patients that died of PD (ages 57-78 years). All the nigral melanized neurons in one of the midbrain sections were counted and classified into three groups according to the intensity of immunostaining for HNE-modified proteins--i.e., no staining, weak staining, and intensely positive staining. On average, 58% of nigral neurons were positively stained for HNE-modified proteins in PD; in contrast only 9% of nigral neurons were positive in the control subjects; the difference was statistically significant (Mann-Whitney U test; P < 0.01). In contrast to the substantia nigra, the oculomotor neurons in the same midbrain sections showed no or only weak staining for HNE-modified proteins in both PD and control subjects; young control subjects did not show any immunostaining; however, aged control subjects showed weak staining in the oculomotor nucleus, suggesting age-related accumulation of HNE-modified proteins in the neuron. Our results indicate the presence of oxidative stress within nigral neurons in PD, and this oxidative stress may contribute to nigral cell death.

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 cultured cells and animal models. Drinking H₂-dissolved water (H₂-water) reduced oxidative stress and improved Parkinson's features in model animals.In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H₂ -water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H₂-water or pseudo water for 48 weeks.Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H₂-water group (n=9) improved (median, -1.0; mean ± standard deviation, -5.7 ± 8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean ± standard deviation, 4.1 ± 9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant (P0.05).The results indicated that drinking H₂-water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H₂-water group was demonstrated.

The present study reports a young woman with acute ataxia, areflexia and ophthalmoplegia, accompanied by psychosis and involuntary movements (IVMs) from disease onset. Anti-GQ1b and anti-GT1a antibodies were detected allowing for a diagnosis of Miller Fisher syndrome (MFS). However, psychosis and IVMs are atypical MFS symptoms and often mimic symptoms of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Interestingly, the autoantibodies against full-length glutamate receptor-e2 (GluRe2) and glutamate NR2B- and NR2A-containing heteromers (NR1/NR2) of NMDAR were also detected in the patient serum and cerebrospinal fluid. It was concluded that psychosis and IVMs in this patient were associated with autoantibodies against various GluRs.

Anabolic androgenic steroid (AAS) abuse has increased among athletes in recent years. However, AAS abuse can increase hypercoagulopathy and cause cerebrovascular disease. We report a case of a 27-year-old man who had right hemiparalysis, hemianopia, dysarthria, and double vision in the middle of muscle training. He suspected acute disseminated encephalomyelitis at first, because of a preceding respiratory infection. However, extensive work-up was performed, including brain magnetic resonance imaging, transcranial Doppler and transesophageal echocardiography, confirming the final diagnosis of cardioembolic stroke. Physicians should be aware that cerebrovascular disease may be a side effect of AAS, even in younger populations.

Decreased123I-meta-iodobenzylguanidine (MIBG) uptake in MIBG myocardial scintigraphy, olfactory dysfunction, and rapid eye movement (REM) sleep behavior disorder (RBD) are considered useful early indicators of Parkinson disease. We investigated whether patients withPARK2mutations exhibited myocardial sympathetic abnormalities using MIBG scintigraphy, olfactory dysfunction using the Sniffin’ Sticks olfactory test, and RBD using polysomnography. None of the examined patients had RBD, and all except 1 patient exhibited an increase in the olfactory threshold. Moreover, one of the oldest patients exhibited impairment in identification and discrimination. Of 12 patients withPARK2mutations, 4 patients, who were older than patients without abnormal uptake, exhibited decreased MIBG uptake. The results obtained in this study suggest that some patients withPARK2mutations have increased thresholds of olfactory function and myocardial sympathetic dysfunction as nonmotor symptoms.

We report on a patient with transient facial myokymia. He had an isolated lesion of the right facial nucleus in the pontine tegmentum. Facial myokymia is a rare symptom and its pathogenesis is not known. Our case had a very localized lesion and we attempted to determine the case of the facial myokymia.

Levodopa is the most effective medication for Parkinson's disease (PD). In contrast, there is evidence that levodopa and its metabolites such as dopa/dopamine quinone are toxic for nigral neurons based on in vitro studies. Moreover, there is growing evidence that oxidative stress and mitochondrial dysfunction contribute the pathogenesis of PD. Thus, studies for oxidative stress give us good information for elucidating the pathogenesis of PD. In this regard, it is mandatory to develop markers such as 4-hydroxy-nonenal (HNE). HNE is a product of lipid peroxidation. Indeed, immunohistochemical studies have revealed that HNE-modified proteins accumulate within ragged red fibers (RRFs). This finding indicated that mitochondrial impairment may be linked to oxidative stress. Moreover, HNE-modified proteins accumulate in nigral neurons. In PD, mitochondrial dysfunction such as complex I deficiency has also been reported. In addition, HNE can modify alpha-synuclein (SNCA). Subsequently, this modification may trigger the aggregation of this protein. At a minimum, this modification could be associated with oligomer formation or fibrillation of SNCA.

A rare case of de novo formation of dural and osteodural arteriovenous fistulas after encephalitis is presented. We review and discuss the etiological angiogenetic factors and processes in intracranial dural arteriovenous fistulas formation. Local tissue hypoxia may have played a role in the initial step causing sprouting angiogenesis as the main pathogenesis of DAVFs formation.

Rapid eye movement sleep behaviour disorder (RBD) may serve as a useful indicator to approach Parkinson’s disease (PD); however, PD patients do not always exhibit RBD. We wondered whether the presence of RBD would be reflected in the expansion of PD lesions and represent the same PD entity. We examined the clinical differences between PD with and without RBD and studied the frequency of RBD-like symptoms (RBD-s) and clinical differences in 150 PD patients, including 81 patients (54.0%) who satisfied the International Classification of Sleep Disorders, Revised, minimum clinical criteria for RBD. RBD-s preceding the appearance of parkinsonism were found in 44.4% of patients. Statistically, the presence of RBD-s was associated with ages above 65 years, male gender, constipation, dopa-induced dyskinesia and ‘sleep attack’, with odds ratios of 3.709, 2.469, 2.184, 5.046 and 6.562, respectively. No differences were found between the 2 groups with regard to symptoms at PD onset, disease duration, Hoehn-Yahr stage, hallucination, dementia, wearing-off, orthostatic hypotension, cerebral blood flow and antiparkinsonism drugs. In the early stage, RBD and autonomic system dysfunction are important factors in the progression of PD.

A 49-year-old male presented with hemisensory disturbance and gait unsteadiness following a previous episode of meningitis. He had no contributory medical or head injury history. Magnetic resonance imaging revealed innumerable medullary vessels in the white matter of the left cerebral hemisphere, which had not been recognized in the previous imaging study. Cerebral angiography showed variant superior sagittal sinus (SSS) arteriovenous fistula (AVF) fed by the bilateral middle meningeal and superficial temporal arteries, and drained directly to the cortical veins with marked venous engorgement in the affected hemisphere. The fistulas were located on the cortical veins, apart from the SSS. Initial percutaneous transarterial embolization failed, so the AVF was completely obliterated with a combination of surgical and endovascular techniques. The symptoms ameliorated postoperatively. Meningitis may be an underlying pathology of dural AVF. Variant SSS AVF can be treated with a combination of surgical and endovascular techniques.

We investigated trends in neurological complications of infection with human immunodeficiency virus (HIV) in Japan after the introduction of highly active antiretroviral therapy (HAART). Two questionnaire surveys were performed in hospitals treating acquired immunodeficiency syndrome (AIDS) to compare two periods: immediately after the introduction of HAART (1999-2001); and a few years later (2002-3). Neurological complications accompanied 15.9% in 1999-2001 and 9.8% in 2002-3. Neurological complications developed without HAART in about 80% of cases. Neurological complications developed as the first AIDS-defining disease for 8.3% of AIDS patients in 1999-2001 and for 5.4% in 2002-3. Prevalences of HIV encephalopathy and myelopathy decreased markedly over the study period, as reported in other developed nations. However, prevalences of cytomegalovirus encephalitis, PML and primary brain lymphoma did not decrease. PML and primary brain lymphoma occurred in patients who received HAART and whose CD4 counts were relatively high during the study period. This is probably related to the extended survival of HIV-infected individuals after the introduction of HAART as a worldwide therapy, and the reactivation of viremia or latent infection persisting within the central nervous system.

Parkinson’s disease (PD) is characterized by tremor, rigidity, bradykinesia, and loss of postural reflex clinically and degeneration of pigmented neurons in the substantia nigra and the locus coeruleus pathologically. It has been postulated that the nigral cell death is initiated by the interaction of genetic predisposition and environmental or endogenous nigral neurotoxins (Jenner et al., 1992). Although most of the patients with PD are sporadic cases, a small group of patients have affected members in their families. In these familial cases, a molecular genetic approach is very important to find a primary cause of nigral cell death in respective families. In addition, information obtained in the studies on familial PD will give us a clue to explore the etiology and pathogenesis of more common sporadic PD. Recently, the genes for two familial forms of parkinsonism have been mapped to the specific chromosome regions and in one of them, what appears to be the causative gene was identified. In this chapter, we will discuss recent progress in the genetics of PD.