Mitsutoshi Yamamoto

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.

To identify susceptibility variants for Parkinsons disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 × 10−12) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 × 10−9). We also detected strong associations at SNCA on 4q22 (P = 7.35 × 10−17) and LRRK2 on 12q12 (P = 2.72 × 10−8), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

BACKGROUND Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease

BACKGROUND Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD). OBJECTIVES To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD. DESIGN Case-control study. SETTING Multicenter university-based study. PARTICIPANTS Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects. MAIN OUTCOME MEASURES Disease status and GBA variations. RESULTS Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD. CONCLUSION Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.

A reassessment of risks and benefits of dopamine agonists in Parkinson's disease

Neurologists have several choices of drugs that have been shown to be effective for the treatment of the symptoms of Parkinsons disease. Among the first options are the dopamine agonists, which are commonly used both as an early monotherapy and as an adjunct therapy to levodopa. However, before starting any treatment, the overall benefit-to-risk ratio to individual patients must be considered. For the dopamine agonists, the available evidence on their symptomatic efficacy, effect on long-term levodopa-related motor complications, putative effect on progression of disease, and adverse event profile must be taken into account. Recently, the occurrence of adverse events such as leg oedema, daytime somnolence, impulse control disorders, and fibrosis have increasingly been recognised. The risks of these potentially serious adverse events must therefore be taken into account and treatment decisions should be based on considerations of risks versus benefits for individual patients.

DOPAMINE AGONISTS AND CARDIAC VALVULOPATHY IN PARKINSON DISEASE: A CASE-CONTROL STUDY

VALVULOPATHY IN PARKINSON DISEASE: A CASE-CONTROL STUDY To the Editor: We read the article by Yamamoto et al., who address the issue of the management of Parkinson disease (PD).1 The large number of subjects and the conclusions are impressive. We have a few concerns with the design of the study. The number of subjects was not equal or similar among the treatment groups (cabergoline 16, pramipexole 16, pergolide 66, past treated 27). In addition, the female/male ratio in the cabergoline and control groups was high in comparison to the other groups and the illness duration of the patients who received pramipexole was not significantly different from the control group, while it was longer for the other groups. The duration of illness is significantly higher in the pergolide and cabergoline treated groups than the control group and the other two treatment groups. The patients in these have had the disease for a significantly longer time than the patients in the other two treatment groups. The Hoehn & Yahr score (HYS) is high in the pergolide (2.6) and cabergoline-treated (2.63) groups compared to the control group, while it is similar to the control group in the other treatment groups and the duration of illness is lower in the pramipexole group than the other groups. The cumulative dose is low for the pramipexole group, although the daily dose is in the therapeutic range. This is because the duration of treatment is longer in the other groups. In the study by Murakami et al.,2 the low dose of pergolide is reported to be 1.5 mg. In the present study, the reported mean pergolide dose is 1.4 mg. The 85 patients in the control group were not treated for an average of 5 years, while the HYS is relatively high ( 2). We would like clarification about the follow-up in this study. In reviewing the authors’ references, we note that the study by Van Camp et al. is a study solely on pergolide,3 and the study by Horvath et al.4 reports complications with the use of pergolide and cabergoline together. There is no study on monotherapy with cabergoline or pramipexole in their references 8 through 11 or 13. The cited study by Dhawan et al.5 reports results on patients with previous histories of congestive heart disease and hypertension and they did transthoracic echocardiography only on patients with complaints. Since this study is not prospective, there is no information on the baseline ECG, telecardiography, or trans-thoracic echocardiography of the subjects. There is no information whether the patients had previous cardiac disease. Similar and more carefully designed studies are needed to address these concerns.

Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson's disease

Toxicologists have thought that the paraoxonase (PON) enzyme polymorphism might contribute to effects of pollutants and other environmental chemicals on susceptibility to cancer, birth defects and Parkinsons disease (PD). We studied a biallelic PON1 polymorphism at codon 192 (A and B alleles) in 166 patients with sporadic idiopathic PD. The frequency of the B (Arg) allele of PON1 was significantly increased in patients with PD than in healthy controls (chi2=8.75, df=1, P<0.005). The relative risk of PD in homozygotes for the B allele was 1.60 fold higher than individuals with the A (Gln) allele (chi2=7.38, df=1, P<0.01). Our data suggest that environmental neurotoxins metabolized by PON1 might be responsible for neurodegeneration with aging and that the B (Arg) allele form might have genetic susceptibility to PD.

Amantadine for Dyskinesias in Parkinson's Disease: A Randomized Controlled Trial

Background Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinsons disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinsons disease patients suffering from dyskinesias. Methods In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinsons disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg /day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinsons Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function). Results RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores. Conclusions Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60–70% of patients. Trial Registration UMIN Clinical Trial Registry UMIN000000780

Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy

Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P<0.001) and those in CTL (P<0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P<0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P<0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P=0.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.

Depression in Parkinson's disease: its prevalence, diagnosis, and neurochemical background.

Abstract There are several problems related to the diagnosis and the biochemical background of depression in patients with Parkinsons disease (PD). The most important problem is how do we understand depression in PD. According to surveys using the diagnostic procedures specified in the Diagnostic Statistic Manual-III or IV, the prevalence of depression is 20–40 % in PD. However, the reported rate varies according to the composition of the subject group and whether or not a control group is used, so it is still controversial whether a figure of 20–40 % reflects the actual prevalence of depression. Latest studies showed about 2–8 % of PD patients are diagnosed with major depression by DSM-III-R. These recent studies suggest that major depression and PD may coexist and dysthimic disorder may be an essential feature in PD. With regard to the neurochemical background, the level of 5-hydroxyindoleacetic acid (a major metabolite of serotonin) is reduced in the cerebrospinal fluid suggesting that serotonergic dysfunction exists in the brain of PD patients. However, there is no high quality evidence to indicate the effectiveness of selective serotonin reuptake inhibitors for depression in PD. Autopsy studies have revealed that not only serotonin, but also dopamine, noradrenaline and other neurotransmitters are reduced in the brains of patients with PD. Accordingly, treatment may become difficult in many cases due to these changes of multiple neurotransmitters. Development of a better treatment strategy based on improved understanding of the neurochemical background is needed.

Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease

LRRK2 G2019S is the most common known cause of Parkinson disease (PD) in patients of European origin, but little is known about its distribution in other populations. The authors identified two of 586 Japanese patients with PD heterozygous for the mutation who shared a haplotype distinct from that observed in Europeans. This suggests that G2019S originated from separate founders in Europe and Japan and is more widely dispersed than previously recognized.