Three-Year Follow-Up of High-Dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations.

We report a 3-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy (MSA) with compound heterozygous nonsense (R387X) and missense (V393A) mutations in COQ2. A high-dose ubiquinol supplementation substantially increased total coenzyme Q10 levels in cerebrospinal fluid as well as in plasma. The patient was at the advanced stage of MSA, and the various scores of clinical rating scales remained stable without changes during the 3 years. The cerebral metabolic ratio of oxygen measured by 15O2 PET, however, increased by approximately 30% after administration of ubiquinol, suggesting that ubiquinol can improve mitochondrial oxidative metabolism in the brain. It also suggests the therapeutic potential of ubiquinol for patients with MSA with COQ2 mutations. Further clinical trials of administration of high-dose ubiquinol to MSA patients are warranted.

Contrast enrichment of spinal cord MR imaging using a ratio of T1-weighted and T2-weighted signals.

PURPOSE: We aimed to assess if the T1-weighted (T1w)/T2-weighted (T2w) signal ratio could be used to improve image contrast in MR spinal cord imaging. MATERIALS AND METHODS: T1w and T2w cervical spinal cord MR images were acquired from 23 normal subjects using 3 Tesla (T) MR scanner. In addition, a multiple sclerosis patient, and a cervical spondylotic myelopathy patient were evaluated. White matter (WM) and gray matter (GM) signal intensities were measured for each image (T1w, T2w, and T1w/T2w) for seven cervical segments in each subject to calculate the contrast. Age-related changes in signal intensity were assessed at each location (lateral column, anterior column, dorsal column, and GM) for each image. Additionally, the imaging results of two subjects with spinal diseases and the controls were numerically compared. RESULTS: The contrast between the WM and GM in the T1w/T2w ratio image was approximately twice as much as that in the T1w and T2w images (mean ± SD = 1.8 ± 0.4). The signal intensity ratio was related to age. For both clinical patients, the signal intensities were significantly lower in the lesion areas in the ratio images. CONCLUSION: The T1w/T2w ratio images demonstrated increased image contrast compared with T1w and T2w images alone and, reduced inter-individual signal intensity differences.

Japanese Mucuna pruriens (Hasshou beans) Showed Fast-acting and Long-lasting Effects in Parkinson's Disease.

Objective Mucuna pruriens (MP) is a legume whose seeds contain levodopa (LD), which has potential therapeutic effects against Parkinson's disease (PD). However, further research is needed to thoroughly evaluate its efficacy and safety for treating this condition. In this study, we analyzed the pharmacokinetics of MP grown in Japan and investigated its mechanism of action in PD. Methods MP seeds ground after roasting (containing 4.02% LD per MP powder) were used as the reagent and compared with an equivalent LD/carbidopa (CD) preparation. This clinical trial was conducted using a crossover design among PD patients attending our institution. Each patient received a single dose of 100/10 mg LD/CD tablets and 11 g of MP reagent. Results Among the seven patients with PD, MP prolonged the ON time 2-fold compared to LD/CD. The LD concentrations after MP intake were higher than those after LD/CD intake, whereas dyskinesia did not increase. An analysis of the LD metabolites showed that the 3-O-methyl-dopa/LD metabolic ratio was significantly lower after MP ingestion than after LD/CD ingestion, indicating that MP has a catechol-O-methyl transferase inhibitory effect. Conclusions This is the first report of a pharmacokinetic analysis conducted on actual patients with PD showing that MP significantly prolongs the ON time. The advantages of MP as a treatment for PD have been confirmed: it is inexpensive, as effective as LD, works faster and longer than LD, and does not increase dyskinesia.

Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease.

BACKGROUND: We evaluated the efficacy and safety of istradefylline, a selective adenosine A2A receptor antagonist administered as adjunctive treatment to levodopa for 12 weeks in a double-blind manner in Parkinson's disease patients with motor complications in Japan. METHODS: A total of 373 subjects were randomized to receive placebo (n=126), istradefylline 20 mg/day (n=123), or istradefylline 40 mg/day (n=124). The primary efficacy variable was the change in daily OFF time. Other secondary variables were also evaluated. RESULTS: The change in daily OFF time was significantly reduced in the istradefylline 20 mg/day (-0.99 hours, P=.003) and istradefylline 40 mg/day (-0.96 hours, P=.003) groups compared with the placebo group (-0.23 hours). The most common adverse event was dyskinesia (placebo, 4.0%; istradefylline 20 mg/day, 13.0%; istradefylline 40 mg/day, 12.1%). CONCLUSIONS: Istradefylline reduced daily OFF time and was well tolerated in Japanese PD patients with motor complications on levodopa treatment.

Transdermal rotigotine in early stage Parkinson's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: We conducted a randomized, double-blind, placebo-controlled trial to determine the safety and efficacy of transdermal rotigotine at doses up to 16 mg/24 hours in patients with early stage Parkinson's disease (PD) in Japan. METHODS: Patients received once-daily rotigotine 2 to 16 mg/24 hours (mean dose, 12.8 mg/24 hours; n = 82) or placebo (n = 90) for 12 weeks. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part II (activities of daily living) and part III (motor function) scores from baseline to the end of treatment. RESULTS: The mean (± standard deviation) changes in UPDRS part II and III scores were -8.4 ± 9.7 in the rotigotine group and -4.1 ± 8.2 in the placebo group and were significantly different (P = 0.002). More patients in the rotigotine group than in the placebo group had a ≥ 20% score reduction. No serious drug-related adverse events were reported. CONCLUSIONS: Rotigotine at doses up to 16 mg/24 hours was well tolerated and improved function in patients with early stage PD.

Avoidance of swallowing saliva: a symptom related to aberrant basal ganglia functions?

We report two patients with avoidance of swallowing saliva despite intact swallowing functions. One, with mild, de novo Parkinson's disease, had a fear that his saliva was contaminated and would harm him. The other, with a history of CNS germinoma in remission for 3 years following chemotherapy, expectorated because his saliva was distasteful and disgusting. He had a lesion involving the left pallidum. Both appeared obsessed with the idea of saliva contamination and both expectorated compulsively, presenting obsessive-compulsive disorder (OCD) symptoms. OCD-like behavior may be induced in association with pathological conditions in which aberrant basal ganglia functions are present.

An increase in ALS incidence on the Kii Peninsula, 1960-2009: a possible link to change in drinking water source.

We investigated changes in the incidence of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto area (K. area) in the Kii Peninsula, Japan in 1960-2009. Probable and definite ALS cases diagnosed using El Escorial criteria were collected during a five-decade period: period I-V, 1960-2009. Forty-three ALS patients matched the selection criteria in the overall K. area, including three patients on Oshima, a small island opposite the mainland K. area. The age- and gender-adjusted incidence of ALS in the overall K. area (standardized for the 2005 Japanese population) decreased from 5.47/100,000 (95% CI 1.86-9.08) in period I to 0.61/100,000 (95% CI-0.28-1.50) in period III, and then increased to 4.39/100,000 (95% CI 1.70-7.07) in period V. On Oshima, the age- and gender-adjusted incidence of ALS was 9.45/100,000 (95% CI-7.39-26.29) in period V. The present research indicates an increase of ALS incidence in the K. area, especially on Oshima. A limitation of this study was the small population.

A dysphagia study in patients with sporadic inclusion body myositis (s-IBM).

The nature of the swallowing impairment in patients with sporadic inclusion body myositis (s-IBM) has not been well characterized. In this study, we examined ten consecutive s-IBM patients using videofluoroscopy (VF) and computed pharyngoesophageal manometry (CPM). The patients were divided into two groups: patients with complaint and without complaint of dysphagia. VF results indicated pharyngeal muscle propulsion (PP) at the hypopharyngeal and upper esophagus sphincter (UES) in all s-IBM patients. Patients without complaint of dysphagia showed a mild degree of PP, whereas a severe form of PP was observed in patients with complaint of dysphagia. CPM revealed that negative pressure during UES opening was not observed in the s-IBM patients with complaint of dysphagia. Incomplete opening and PP at the UES were observed in all s-IBM patients. These results indicate that the dysphagic processes occur subclinically in s-IBM patients who may not report swallowing impairments.

T-type calcium channel as a new therapeutic target for tremor.

Voltage-gated calcium channels play an important role in many physiological and pathological processes. Accumulating studies suggest that the T-type calcium channel is a potential target for the treatment of various neurological disorders, such as epilepsy, insomnia, and neuropathic pain. Here, we highlight recent advances in our understanding of T-type calcium channel regulation and their implications for tremor disorders. Several T-type calcium channel blockers effectively suppressed experimental tremors that have been suggested to originate from either the cerebellum or basal ganglia. Among T-type calcium channel blockers that have been used clinically, the anti-tremor efficacy of zonisamide garnered our attention. Based on both basic and clinical studies, the possibility is emerging that T-type calcium channel blockers that transit into the central nervous system may have therapeutic potentials for tremor disorders.

Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study.

The objectives of this study were to evaluate the efficacy of istradefylline at an oral dose of 20 mg or 40 mg once daily for 12 weeks in Parkinson's disease (PD) patients with motor complications on levodopa therapy based on the change in the daily OFF time compared with placebo and to assess the safety at these doses. A total of 363 subjects were randomly assigned to receive 20 mg/day istradefylline (n = 119), 40 mg/day istradefylline (n = 125), or placebo (n = 119). The primary outcome variable was the change from baseline at endpoint in daily OFF time based on patients' ON/OFF diaries. At endpoint, the daily OFF time reduced from baseline by 1.31 hours for 20 mg/day istradefylline (P = 0.013 as compared to the placebo), 1.58 hours for 40 mg/day istradefylline (P < 0.001), and 0.66 hours for placebo; istradefylline significantly reduced the daily OFF time compared with placebo. The UPDRS Part III subscale score (ON state) reduced by 5.7 at endpoint in both istradefylline groups and 3.7 in the placebo group (P = 0.006 for 20 mg/day and P = 0.006 for 40 mg/day group as compared with placebo). The most commonly reported drug-related treatment emergent adverse event (TEAE) was dyskinesia, which occurred in 2.5% (3/119) of subjects receiving placebo, 8.5% (10/118) receiving 20 mg/day istradefylline, and 6.4% (8/125) receiving 40 mg/day istradefylline. We conclude that istradefylline at 20 mg and 40 mg once daily is effective in relieving wearing-off fluctuations of PD patients. In addition, istradefylline was well tolerated at both doses.

Effects of zonisamide on c-Fos expression under conditions of tacrine-induced tremulous jaw movements in rats: a potential mechanism underlying its anti-parkinsonian tremor effect.

OBJECTIVES: To examine the mechanisms underlying the anti-tremor effect of zonisamide in rats under conditions of tacrine-induced tremulous jaw movements (TJMs). METHODS: Male adult rats received systemic administration of either zonisamide (5 or 50mg/kg) or vehicle at 20min prior to the administration of tacrine hydrochloride (5mg/kg). Animals were sacrificed 2h later, and the brains collected and immunostained for quantitative assessment of c-Fos expression. RESULTS: There was no effect of zonisamide on tacrine-induced c-Fos expression in the ventrolateral striatum, a primary site of the pharmacological action of tacrine. Zonisamide suppressed the tacrine-induced c-Fos expression in the cortex, the dorsal striatum, and the nucleus accumbens, which are involved in the architecture of the cortico-basal ganglia-thalamocortical circuits. CONCLUSION: The anti-TJM effect of zonisamide may not relate to suppression of neural activity specifically in primary tremor-generating sites, but may be due to a more broad inhibitory effect on tremor-related structures such as the cortex or the striatum. This effect of zonisamide may be a contributing mechanism underlying its therapeutic efficacy on parkinsonian tremor.

Immunohistochemical expression of IGF-I and GSK in the spinal cord of Kii and Guamanian ALS patients.

Insulin-like growth factor-I (IGF-I) is a potent survival factor for motor neurons in animals, and glycogen synthase kinase-3beta (GSK-3beta) is suspected to play roles in apoptosis and tau phosphorylation. Here we report the immunological expression of IGF-I, GSK-3beta, phosphorylated-GSK-3alpha/beta (p-GSK-3alpha/beta) and phosphorylated-tau in the spinal cord and hippocampus of Kii and Guam amyotrophic lateral sclerosis (ALS) patients. Sixteen ALS patients (10 Japanese sporadic, 3 Kii and 3 Guam ALS) and 14 neurological controls (10 Japanese and 4 Guamanian) were examined. The immunoreactivity for each antibody was rated by the percentages of positive neurons to total anterior horn neurons in each patient and was analyzed statistically. Many normal-looking neurons from Japanese sporadic ALS, Kii ALS and Guam ALS patients, as well as from Japanese and Guam controls, were positive for anti-IGF-I antibody. A positive correlation between IR scores for anti-IGF-I antibody and clinical durations of Japanese sporadic ALS patients was found in this study (P < 0.0001). This suggested that IGF-I might have a protective effect against ALS degeneration. In Japanese sporadic ALS patients, abnormal as well as normal-looking neurons showed significant high IR scores for anti-GSK-3beta antibody than those of controls. Anterior horn neurons from Guam and Kii ALS patients characteristically showed weak staining for anti-GSK-3beta antibody but were markedly positive for anti-pGSK-3alpha/beta antibody compared to those from both Japanese controls and Japanese sporadic ALS patients, and showed the co-localization of IGF-I and p-GSK-3alpha/beta. This suggested that the IGF-I signaling pathway in Guam and Kii ALS patients might function to phosphorylate GSK-3beta to protect neurons from ALS degeneration. Neurofibrillary tangles (NFTs) in the hippocampus and spinal cord from Kii and Guam ALS patients showed the co-localization of PHF-tau and p-GSK-3alpha/beta by a confocal laser scanning technique. The predominant expression of p-GSK-3alpha/beta compared to GSK-3beta in spinal motor neurons and the co-localization of p-GSK-3alpha/beta and PHF-tau in NFT-laden neurons in the hippocampus and spinal cord were characteristic findings of Kii and Guam ALS patients.

Long-Term Selegiline Monotherapy for the Treatment of Early Parkinson Disease.

OBJECTIVES: The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD). METHODS: We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated. RESULTS: Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, -2.62 ± 3.83; P < 0.0001) to week 56 (-3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (-5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration. CONCLUSIONS: Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.

The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. METHODS: The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as "definite" or "probable" sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. RESULTS: The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. CONCLUSIONS: We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

Dopamine dysregulation syndrome. Hypothetical application of reward system stimulation for the treatment of anhedonia in Parkinson's disease patients.

The management of motor symptoms in Parkinson's disease (PD), although imperfect, has already been standardized. However, patients often spend their time idly despite improvement in the elemental motor symptoms. The main cause of this may be anhedonia. Dopamine dysregulation syndrome (DDS) is a troublesome condition that can occur as a complication of dopamine replacement therapy in PD. As anhedonia and DDS may be converse syndromes in PD patients, it is very important to overcome anhedonia to improve patients' quality of life. In this article, the author proposes the possibility of stimulating patients' desire to participate in physical activity via the incentive of a reward system. Understanding the mechanism of DDS may help in the development of this type of approach.

Survival rate of patients with amyotrophic lateral sclerosis in Wakayama Prefecture, Japan, 1966 to 2005.

To investigate longitudinal changes in the survival rate of patients with amyotrophic lateral sclerosis in Wakayama Prefecture, Japan, we made a retrospective hospital-based study of 454 patients diagnosed with motor neuron disease (MND) at Wakayama Medical University (WMU) Hospital between 1966 and 2005. Of the 454 patients, 240 who were born and who lived in Wakayama Prefecture were diagnosed with definite or probable ALS during this period, according to the El Escorial criteria. The clinical data of the 240 patients, including sex, birth date, birthplace, address, age at onset, initial symptoms, date when respiratory support was applied (tracheostomy, noninvasive positive pressure ventilation, or mandatory artificial ventilation), and date of death were reviewed retrospectively. The age at onset of patients who developed initial symptoms before 1990 was 53.4+/-10.6 (mean+/-S.D.) and that in 1990 or thereafter was 64.8+/-10.3, respectively, showing a significant difference (p<0.0001). Clinical duration was determined from onset to either date of death or initiation of respiratory support in this study. Survival rate was compared using the Kaplan-Meier method according to age at onset, sex, initial symptoms and year of onset. Mean age at onset shifted towards older age according to a later year of onset, due to the overwhelming senility rate in Wakayama Prefecture. Older onset patients had a significantly poorer survival rate than younger onset patients when it was compared based on 10-year age groups (log rank, p<0.0001). Male patients had a poorer survival rate than female patients (p<0.0001). ALS patients with bulbar palsy onset showed shorter clinical durations than those with lower leg onset (p<0.0071, Breslow-Gehan-Wilcoxon test). Patients over 70 years old more frequently showed bulbar palsy onset compared to those younger than 69 (p=0.003). In a comparison of year of onset before and after 1990, ALS patients after 1990 had characteristics of older age onset and shorter clinical duration, and more frequently showed bulbar palsy onset compared with those before 1990. These findings indicated that younger onset patients with ALS decreased after 1990 in Wakayama Prefecture and this might partly explain the recent decline of ALS incidence in Wakayama Prefecture. The shift of the mean age at onset to older age might be due to exogenous factors, including changes in lifestyle, food, and drinking water in this area. Bulbar palsy onset and age at onset were expected as predictors of the survival rate.

Alteration of eating behaviors in patients with Parkinson's disease: possibly overlooked?

Patients with Parkinson's disease (PD) occasionally show food cravings and/or compulsive eating that result in significant, undesired weight gain. Dopamine replacement therapy may be the cause of this type of eating disorder. We evaluated 60 consecutive patients to see if they had any alteration of eating patterns after starting levodopa. Among them, five (8.3%) patients exhibited characteristic alterations of food preference following the start of dopamine replacement therapy. One patient showed an undesirable weight gain. Of the five patients exhibiting food preference alterations, all showed increased preference to consume sweet snacks, although this alteration was not always associated with hyperphagia (eating too much). This type of dietary alteration was not related to a specific antiparkinsonian drug, and could be observed in patients undergoing dopamine agonist monotherapy. Alteration of eating behavior may not be uncommon in PD patients, and is possibly overlooked. Since dopamine is closely involved in acquisition of food preferences, dietary changes with/without compulsive eating may be a manifestation of an alteration of appetitive behaviors due to excessive dopaminergic neurotransmission.

Effects of zonisamide on experimental tremors in rats.

OBJECTS: To study the effect of zonisamide on experimental tremors in rats. METHODS: Effect of zonisamide on harmaline- or oxotreorine-induced tremors, and tacrine-induced tremulous jaw movements (TJMs) was studied. RESULTS: Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion or dopaminergic blockade. CONCLUSION: The anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Since it effectively suppressed tremors that are based on different kinds of tremors, we propose a novel perspective of clinical potential of zonisamide as a non-specific, anti-tremor drug.

p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain.

We and other workers found markedly increased levels of proinflammatory cytokines and apoptosis-related proteins in parkinsonian brain. Although the pathogenesis of Parkinson's disease (PD) remains enigmatic, apoptosis might be involved in the degeneration of dopaminergic neurons in PD. To investigate the possible presence of other inflammatory cytokines and/or apoptosis-related protein, the levels of p53 protein, interferon-gamma, and NF-kappaB were measured for the first time in the brain (substantia nigra, caudate nucleus, putamen, cerebellum, and frontal cortex) from control and parkinsonian patients by a highly sensitive sandwich enzyme-linked immunosorbent assay. The p53 protein level in the caudate nucleus was significantly higher in parkinsonian patients than in controls (P<0.05), whereas this protein in the substantia nigra, putamen, and cerebral cortex showed no significant difference between parkinsonian and control subjects. The interferon-gamma level was significantly higher in the nigrostriatal dopaminergic regions (substantia nigra, caudate nucleus, and putamen) in parkinsonian patients than in the controls (P<0.05), but was not significantly different in the cerebellum or frontal cortex between the two groups. In accordance with previous immunohistochemical analysis, the NF-kappaB level in the nigrostriatal dopaminergic regions was significantly higher in parkinsonian patients than in the controls (P<0.05). These data suggest that the significant increase in the levels of p53 protein, interferon-gamma, and NF-kappaB reflect apoptosis and the inflammatory state in the parkinsonian brain and that their elevation is involved in the degeneration of the nigrostriatal dopaminergic neurons.