ABSTRACT
Dopamine (DA) is a neurotransmitter in the brain, playing a central role in several disease conditions, including tetrahydrobiopterin (BH4) metabolism disorders and Parkinson's disease (PD). BH4 metabolism disorders present a variety of clinical manifestations including motor disturbance via altered DA metabolism, since BH4 is a cofactor for tyrosine hydroxylase (TH), a rate-limiting enzyme for DA synthesis. Genetically, BH4 metabolism disorders are, in an autosomal recessive pattern, caused by a variant in genes encoding enzymes for BH4 synthesis or recycling, including 6-pyruvoyltetrahydropterin synthase (PTPS) or dihydropteridine reductase (DHPR), respectively. Although BH4 metabolism disorders and its metabolisms have been studied, it is unclear how gene variants cause aberrant DA synthesis in patient neurons. Here, we generated induced pluripotent stem cells (iPSCs) from BH4 metabolism disorder patients with PTPS or DHPR variants, corrected the gene variant in the iPSCs using the CRISPR/Cas9 system, and differentiated the BH4 metabolism disorder patient- and isogenic control iPSCs into midbrain DA neurons. We found that by the gene correction, the BH4 amount, TH protein level and extracellular DA level were restored in DA neuronal culture using PTPS deficiency iPSCs. Furthermore, the pharmacological correction by BH4 precursor sepiapterin treatment also improved the phenotypes of PTPS deficiency. These results suggest that patient iPSCs with BH4 metabolism disorders provide an opportunity for screening substances for treating aberrant DA synthesis-related disorders.
Subject(s)
Biopterins/analogs & derivatives , Dopamine/genetics , Induced Pluripotent Stem Cells/metabolism , Metabolic Diseases/genetics , Parkinson Disease/genetics , Biopterins/metabolism , Cell Differentiation/genetics , Dopamine/biosynthesis , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Genotype , Humans , Karyotype , Metabolic Diseases/metabolism , Metabolic Diseases/pathology , Parkinson Disease/metabolism , Parkinson Disease/pathology , Pterins/metabolism , Tyrosine 3-Monooxygenase/geneticsABSTRACT
OBJECTIVES: Brain acetylcholine is decreased even in patients with cognitively preserved Parkinson's disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients. METHODS: A double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson's Psychosis Questionnaire (PPQ) B score ≥2 or C score ≥2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein ε4 genotyping. RESULTS: Kaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11-0.86) against psychosis in 48 weeks for apolipoprotein ε4 non-carriers. CONCLUSIONS: Although donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein ε4 may suppress the antipsychotic effect of donepezil. TRIAL REGISTRATION NUMBER: UMIN000005403.
Subject(s)
Cognitive Dysfunction/drug therapy , Donepezil/therapeutic use , Parkinson Disease/drug therapy , Psychotic Disorders/prevention & control , Aged , Aged, 80 and over , Apolipoprotein E4/genetics , Cholinesterase Inhibitors/therapeutic use , Cognitive Dysfunction/complications , Double-Blind Method , Female , Genotype , Humans , Male , Mental Status and Dementia Tests/statistics & numerical data , Middle Aged , Neuropsychological Tests/statistics & numerical data , Parkinson Disease/complications , Parkinson Disease/genetics , Psychotic Disorders/complications , Treatment OutcomeSubject(s)
Anesthetics, Local/therapeutic use , Apraxias , Eyelids/drug effects , Parkinson Disease/complications , Procaine/analogs & derivatives , Apraxias/drug therapy , Apraxias/etiology , Apraxias/pathology , Eyelids/physiopathology , Female , Humans , Male , Pilot Projects , Procaine/therapeutic use , Single-Blind MethodABSTRACT
BACKGROUND: Psychoses such as hallucinations are a frequent non-motor problem in patients with Parkinson disease (PD) and serious psychosis requires anti-psychotic medications that worsen Parkinsonism. Although psychosis could be associated with patient-related or biological factors such as cognition, age, and severity of PD, it can also be associated with medications.Therefore we aimed to investigate patient-related and medication-related risks of psychosis requiring anti-psychotic medications (serious psychosis). METHODS: A retrospective cohort of 331 PD patients was followed for 2 years. Patient-related factors associated with risk of psychosis were identified by a survival time analysis. In patients who developed psychosis, medications during the hazard period (1-14 days before psychosis) were contrasted with those during the control periods (1 and 3 months before psychosis) using a case-crossover analysis to identify medication-related risks of psychosis. RESULTS: Serious psychosis was detected in 52 patients and the incidence was estimated to be 116 (95% confidence interval [CI], 85-148) per 1,000 person-years. Analyses of baseline characteristics revealed the risk to be higher in patients with a modified Hoehn-Yahr stage of ≥4 (hazard ratio [HR], 2.22; 95% CI, 1.11-4.40), those with a longer duration of PD (HR, 1.25; 95% CI, 1.00-1.55, per 5 years) and those with Mini-Mental State Examination scores of ≤24 (HR, 2.66; 95% CI, 1.37-5.16). The case-crossover analysis revealed that anti-cholinergics use (HR, 19.7; 95% CI, 2.39-162) elevated the risk, while donepezil use reduced it (HR, 0.48; 95% CI, 0.27-0.85). CONCLUSIONS: Risk of psychosis was elevated by increasing severity of PD, cognitive dysfunction and duration of the disease. It was elevated by use of anti-cholinergic drugs and reduced by use of donepezil. The medication-related risk was higher in patients aged ≥ 70 years. In contrast, there was no significant medication-related risk in younger patients, suggesting different pathomechanisms between young and old patients.
Subject(s)
Parkinson Disease/complications , Parkinson Disease/psychology , Psychotic Disorders/complications , Psychotic Disorders/drug therapy , Adult , Aged , Antipsychotic Agents/therapeutic use , Cognition Disorders/epidemiology , Cognition Disorders/etiology , Cohort Studies , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Parkinson Disease/epidemiology , Proportional Hazards Models , Psychiatric Status Rating Scales , Psychotic Disorders/mortality , Time FactorsABSTRACT
BACKGROUND: A recent meta-analysis on the UCHL1 S18Y variant and Parkinson's disease (PD) showed a significant inverse association between the Y allele and PD; the individual studies included in that meta-analysis, however, have produced conflicting results. We examined the relationship between UCHL1 S18Y single nucleotide polymorphism (SNP) and sporadic PD in Japan. METHODS: Included were 229 cases within 6 years of onset of PD, defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, smoking, and caffeine intake. RESULTS: Compared with subjects with the CC or CA genotype of UCHL1 S18Y SNP, those with the AA genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95 % CI: 1.06 - 2.31). Compared with subjects with the CC or CA genotype of UCHL1 S18Y and the CC or CT genotype of SNCA SNP rs356220, those with the AA genotype of UCHL1 S18Y and the TT genotype of SNP rs356220 had a significantly increased risk of sporadic PD; the interaction, however, was not significant. Our previous investigation found significant inverse relationships between smoking and caffeine intake and PD in this population. There were no significant interactions between UCHL1 S18Y and smoking or caffeine intake affecting sporadic PD. CONCLUSIONS: This study reveals that the UCHL1 S18Y variant is a risk factor for sporadic PD. We could not find evidence for interactions affecting sporadic PD between UCHL1 S18Y and SNCA SNP rs356220, smoking, or caffeine intake.
Subject(s)
Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Parkinson Disease/epidemiology , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , Ubiquitin Thiolesterase/genetics , Aged , Female , Genetic Variation/genetics , Humans , Japan/epidemiology , Male , Prevalence , Risk FactorsABSTRACT
OBJECTIVE: The aim of the RIN-2 study was a compassionate use of rituximab (RTX) for patients who completed the RIN-1 study, a multicentre, randomised, double-blind, placebo-controlled trial of RTX. We also investigated the long-term safety and efficacy of RTX. METHODS: A study design was a prospective open-label extension study following the RIN-1 study. RTX was infused repeatedly under monthly monitoring of CD19-positive and CD 20-positive B cell lymphocyte subsets from 24 weeks after an infusion. RESULTS: Thirty-three (87%) of 38 patients of the RIN-1 study were enrolled from February 2016 to March 2019 at six sites in Japan. In RIN-2, RTX was administered three times (median, range 1-5 times), and the interval of RTX administrations were 9.5 [2.5] months (mean [SD]). The observation period was 20.5 [10.1] months. During the trial, three patients dropped out due to two withdrawals and one adverse event. During the study, 28 (90%) of 31 patients were treated with RTX monotherapy. Neuromyelitis optica (NMO) relapses were observed in two patients. The annualized relapse rate (ARR) was 0.035 counts per person-years, â¼1/10th compared with 0.321 in the placebo arm of the RIN-1 study. We observed 14 severe adverse events in six (18%) and 156 adverse events, of which 135 were grade 1, 11 were grade 2 and 10 were grade 3. CONCLUSIONS: Under B cell monitoring, the interval of RTX re-infusion was elongated to nine months, and NMO relapses were suppressed with 0.035 of ARR.
Subject(s)
Neuromyelitis Optica , Compassionate Use Trials , Humans , Immunologic Factors/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neuromyelitis Optica/chemically induced , Neuromyelitis Optica/drug therapy , Prospective Studies , Rituximab/adverse effects , Treatment OutcomeABSTRACT
Apolipoprotein E (APOE) is associated with increased oxidative stress, which is caused by reactive oxygen species (ROS). Enhanced cytochrome P450 2E1 (CYP2E1) activity may also increase formation of neurotoxins such as ROS. As Parkinson's disease (PD) is a neurodegenerative disorder, both the APOE and CYP2E1 genes that are involved in neurodegeneration by oxidative stress may be associated with PD risk. We investigated the relationship of the APOE and CYP2E1 rs2864987 polymorphisms and PD risk with special attention to the interaction with alcohol consumption among 238 patients with PD and 296 controls in a Japanese population. The frequencies of the É2, É3, and É4 alleles of the APOE polymorphism among controls were 3.72, 86.7, and 9.63%, respectively. As compared with the APOE ε3/ε3 genotype, the 2/ε4 genotype was associated with an increased risk of PD (adjusted odds ratio (OR) = 9.50, 95% (confidence interval) CI = 1.12-80.6). The presence of the ε3 allele was associated with a decreased risk of PD. Meanwhile, CYP2E1 rs2864987 was not associated with PD risk. Although CYP2E1 is involved in the metabolism of alcohol, there was no evidence of interaction between alcohol consumption and CYP2E1 rs2864987. Our results suggested that the APOE polymorphism might play an important role in PD susceptibility in our Japanese population. Future studies involving larger control and case populations and better alcohol consumption histories will undoubtedly lead to a more thorough understanding of the role of polymorphisms of genes related to the generation of ROS in PD development.
Subject(s)
Alcohol Drinking/ethnology , Alcohol Drinking/genetics , Apolipoprotein E2/genetics , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Cytochrome P-450 CYP2E1/genetics , Parkinson Disease/ethnology , Parkinson Disease/genetics , Aged , Asian People/genetics , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Japan/epidemiology , Male , Middle Aged , Parkinson Disease/enzymology , Polymorphism, Genetic/genetics , Risk FactorsABSTRACT
BACKGROUND: Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. METHODS: We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. RESULTS: Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. CONCLUSIONS: The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
Subject(s)
Asian People/genetics , Catechol O-Methyltransferase/genetics , Genetic Predisposition to Disease , Monoamine Oxidase/genetics , Parkinson Disease/genetics , Receptors, Dopamine D2/genetics , Receptors, Dopamine D4/genetics , Female , Humans , Male , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Risk Factors , SmokingABSTRACT
BACKGROUND: The evidence for associations between occupational factors and the risk of Parkinson's disease (PD) is inconsistent. We assessed the risk of PD associated with various occupational factors in Japan. METHODS: We examined 249 cases within 6 years of onset of PD. Control subjects were 369 inpatients and outpatients without neurodegenerative disease. Information on occupational factors was obtained from a self-administered questionnaire. Relative risks of PD were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) based on logistic regression. Adjustments were made for gender, age, region of residence, educational level, and pack-years of smoking. RESULTS: Working in a professional or technical occupation tended to be inversely related to the risk of PD: adjusted OR was 0.59 (95% CI: 0.32-1.06, P = 0.08). According to a stratified analysis by gender, the decreased risk of PD for persons in professional or technical occupations was statistically significant only for men. Adjusted ORs for a professional or technical occupation among men and women were 0.22 (95% CI: 0.06-0.67) and 0.99 (0.47-2.07), respectively, and significant interaction was observed (P = 0.048 for homogeneity of OR). In contrast, risk estimates for protective service occupations and transport or communications were increased, although the results were not statistically significant: adjusted ORs were 2.73 (95% CI: 0.56-14.86) and 1.74 (95% CI: 0.65-4.74), respectively. No statistical significance was seen in data concerning exposure to occupational agents and the risk of PD, although roughly a 2-fold increase in OR was observed for workers exposed to stone or sand. CONCLUSION: The results of our study suggest that occupational factors do not play a substantial etiologic role in this population. However, among men, professional or technical occupations may decrease the risk of PD.
Subject(s)
Occupational Exposure/adverse effects , Parkinson Disease/epidemiology , Parkinson Disease/etiology , Animals , Case-Control Studies , Female , Humans , Japan/epidemiology , Male , Odds Ratio , Risk FactorsABSTRACT
BACKGROUND: Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS: The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS: A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × Îµ4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS: Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Parkinson Disease , Cholinesterase Inhibitors/therapeutic use , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , Donepezil , Double-Blind Method , Humans , Indans , Parkinson Disease/drug therapy , Piperidines/therapeutic use , Treatment OutcomeABSTRACT
Increased homocysteine levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects; thus, increasing intake of B vitamins involved in the regulation of homocysteine metabolism might decrease the risk of PD through decreasing plasma homocysteine. However, epidemiological evidence for the association of dietary B vitamins with PD is sparse, particularly in non-Western populations. We conducted a hospital-based case-control study in Japan to examine associations between dietary intake of folate, vitamin B6, vitamin B12 and riboflavin and the risk of PD. Patients with PD diagnosed using the UK PD Society Brain Bank criteria (n 249) and controls without neurodegenerative diseases (n 368) were recruited. Dietary intake during the preceding month was assessed at the time of study recruitment using a validated, self-administered, semi-quantitative, comprehensive diet history questionnaire. After adjustment for potential dietary and non-dietary confounding factors, intake of folate, vitamin B12 and riboflavin was not associated with the risk of PD (P for trend = 0.87, 0.70 and 0.11, respectively). However, low intake of vitamin B6 was associated with an increased risk of PD, independent of potential dietary and non-dietary confounders. Multivariate OR (95 % CI) for PD in the first, second, third and fourth quartiles of vitamin B6 were 1 (reference), 0.56 (0.33, 0.94), 0.69 (0.38, 1.25) and 0.48 (0.23, 0.99), respectively (P for trend = 0.10). In conclusion, in the present case-control study in Japan, low intake of vitamin B6, but not of folate, vitamin B12 or riboflavin, was independently associated with an increased risk of PD.
Subject(s)
Diet , Folic Acid/administration & dosage , Parkinson Disease/etiology , Riboflavin/administration & dosage , Vitamin B 12/administration & dosage , Vitamin B 6/administration & dosage , Vitamin B Complex/administration & dosage , Aged , Case-Control Studies , Diet Surveys , Female , Humans , Japan , Male , Middle Aged , Odds Ratio , Risk Factors , Surveys and QuestionnairesABSTRACT
BACKGROUND: Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study. METHODS: From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors. RESULTS: Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk. CONCLUSIONS: We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.
Subject(s)
Alcohol Drinking , Flushing , Parkinson Disease/etiology , Risk , Aged , Case-Control Studies , Female , Humans , Japan , Male , Middle Aged , Odds Ratio , Surveys and QuestionnairesABSTRACT
BACKGROUND: Pharmacological prevention against relapses in patients with neuromyelitis optica spectrum disorder (NMOSD) is developing rapidly. We aimed to investigate the safety and efficacy of rituximab, an anti-CD20 monoclonal antibody, against relapses in patients with NMOSD. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled clinical trial at eight hospitals in Japan. Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4 (AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an Expanded Disability Status Scale (EDSS) score of 7·0 or less were eligible for the study. Individuals taking any other immunosuppressants were excluded. Participants were randomly allocated (1:1) either rituximab or placebo by a computer-aided dynamic random allocation system. The doses of concomitant steroid (converted to equivalent doses of prednisolone) and relapses in previous 2 years were set as stratification factors. Participants and those assessing outcomes were unaware of group assignments. Rituximab (375 mg/m2) was administered intravenously every week for 4 weeks, then 6-month interval dosing was done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation). A matching placebo was administered intravenously. Concomitant oral prednisolone was gradually reduced to 2-5 mg/day, according to the protocol. The primary outcome was time to first relapse within 72 weeks. Relapses were defined as patient-reported symptoms or any new signs consistent with CNS lesions and attributable objective changes in MRI or visual evoked potential. The primary analysis was done in the full analysis set (all randomly assigned patients) and safety analyses were done in the safety analysis set (all patients who received at least one infusion of assigned treatment). The primary analysis was by intention-to-treat principles. This trial is registered with the UMIN clinical trial registry, UMIN000013453. FINDINGS: Between May 10, 2014, and Aug 15, 2017, 38 participants were recruited and randomly allocated either rituximab (n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinued the study and were analysed as censored cases. Seven (37%) relapses occurred in patients allocated placebo and none were recorded in patients assigned rituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). Eight serious adverse events were recorded, four events in three (16%) patients assigned rituximab (lumbar compression fracture and infection around nail of right foot [n=1], diplopia [n=1], and uterine cancer [n=1]) and four events in two (11%) people allocated to placebo (exacerbation of glaucoma and bleeding in the right eye chamber after surgery [n=1], and visual impairment and asymptomatic white matter brain lesion on MRI [n=1]); all patients recovered. No deaths were reported. INTERPRETATION: Rituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive. FUNDING: Japanese Ministry of Health, Labour and Welfare, Japan Agency for Medical Research and Development, and Zenyaku Kogyo.
Subject(s)
Aquaporin 4/genetics , Immunologic Factors/therapeutic use , Neuromyelitis Optica/drug therapy , Rituximab/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Disability Evaluation , Double-Blind Method , Drug Therapy, Combination , Evoked Potentials, Visual , Female , Humans , Immunologic Factors/adverse effects , Infusions, Intravenous , Japan , Magnetic Resonance Imaging , Male , Middle Aged , Neuromyelitis Optica/diagnostic imaging , Neuromyelitis Optica/genetics , Prednisolone/therapeutic use , Recurrence , Rituximab/adverse effects , Steroids/therapeutic use , Treatment Outcome , White Matter/diagnostic imaging , Young AdultABSTRACT
INTRODUCTION: Patients with Parkinson's disease (PD) frequently lose weight, even in the early stages of the disease. Our objective was to clarify the association between low body mass index (BMI) and life prognosis in PD. METHODS: We conducted a retrospective cohort study of 651 PD patients (380 females), with a primary endpoint of survival. Because of sex differences in BMI, male and female data were separated. We compared survival times between underweight (BMIâ¯<â¯18.5) and non-underweight (BMIâ¯≥â¯18.5) patients and calculated hazard ratios (HRs) adjusted for other relevant factors. To investigate the semi-quantitative relationship between relative risk of death and BMI, we divided patients into lower, middle, and upper thirds of BMI and calculated the HRs of the lower and upper thirds, with reference to the middle third. RESULTS: Seventy-nine patients (41 females) died over a mean (standard deviation) observation period of 39 (26) months. Underweight patients had poorer life prognosis than non-underweight patients and the difference was larger in males than in females (adjusted HR 3.8 (95% confidence interval 1.9-7.9) in males and 1.8 (0.9-3.5) in females). In males, the relationship between survival and BMI was much poorer in the bottom third and slightly poorer in the top third compared with the middle third. In females, the higher the BMI, the better the survival prognosis; however, the difference was not statistically significant. CONCLUSION: Low BMI had a significant impact on the life prognosis of PD patients, especially males.
Subject(s)
Body Mass Index , Parkinson Disease , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Parkinson Disease/diagnosis , Parkinson Disease/physiopathology , Parkinson Disease/psychology , Prognosis , Statistics, Nonparametric , Survival RateABSTRACT
INTRODUCTION: Anxiety disorders are a common non-motor symptom of Parkinson's disease (PD) with a reported prevalence ranging from 20% to 50%. Although anxiety is associated with Parkinson's disease, anxiety disorders can begin before the onset of motor symptoms, and have been linked to a possible abnormality of dopaminergic, serotonergic, and adrenergic neurons that precedes motor disturbance. AREAS COVERED: Several studies have reported the pharmacological treatment of depression in PD, but none have been randomized clinical trials with a primary outcome measure of anxiety. Two trials showed that pharmacological intervention with tricyclic antidepressants or selective serotonin reuptake inhibitors proved beneficial in treating anxiety in PD. However, the effect size was modest. Anxiety is associated with off-periods and improved by L-Dopa, especially in patients with high levels of anxiety. EXPERT OPINION: Decreasing off-periods is important for managing anxiety in patients with motor fluctuations. Minor suggestive data indicate that tricyclic antidepressants and selective serotonin reuptake inhibitors can be helpful with modest effect sizes, but the former can cause additional side effects. Only one study has examined the use of benzodiazepines to treat anxiety in PD, and benzodiazepines cannot be recommended because they increase the risk of falling. Further clinical studies for pharmacological intervention against anxiety are required.
Subject(s)
Anxiety Disorders/drug therapy , Dopamine/therapeutic use , Parkinson Disease/pathology , Selective Serotonin Reuptake Inhibitors/therapeutic use , Antidepressive Agents, Tricyclic/therapeutic use , Anxiety Disorders/complications , Anxiety Disorders/epidemiology , Dopamine Agonists/therapeutic use , Humans , Nortriptyline/therapeutic use , Parkinson Disease/complications , Parkinson Disease/drug therapyABSTRACT
INTRODUCTION: A number of video-fluoroscopic swallowing study (VFSS) abnormalities have been reported in patients with Parkinson's disease (PD). However, the most crucial finding of subsequent aspiration pneumonia has not been validated fully. We conducted a retrospective and case-control study to determine the clinically significant VFSS findings in this population, and to propose a practical scale for predicting aspiration pneumonia in patients with PD. METHODS: We enrolled 184 PD patients who underwent VFSS because of suspected dysphagia. The patients who developed aspiration pneumonia within six months of the VFSS were assigned as cases and the patients without aspiration pneumonia at six months were designated as controls. Logistic regression analysis was performed to determine the prognostic VFSS features based on the data of swallowing 3 mL of jelly, which were used to make a PD VFSS scale (PDVFS). The validity of the new PDVFS was evaluated by ROC analysis. Additionally, we used the survival time analysis to compare time to death between groups, stratified by the PDVFS score. RESULTS: Twenty-five patients developed aspiration pneumonia. Among the previously-proposed VFSS features, mastication, lingual motility prior to transfer, aspiration, and total swallow time were identified as significant prognostic factors. We combined these factors to form the PDVFS. The PDVFS score ranges from 0 to 12, with 12 being the worst. ROC analysis revealed 92% sensitivity and 82% specificity at a cutoff point of 3. The higher PDVFS group showed shorter time-to-death than the lower PDVFS group (log rank P = 0.001). CONCLUSION: Our newly developed VFSS severity scale (based on jelly swallowing) for patients with PD was easy to rate and could predict subsequent aspiration pneumonia and poor prognosis in patients with PD.
Subject(s)
Fluoroscopy , Parkinson Disease/diagnostic imaging , Pneumonia, Aspiration/diagnostic imaging , Video Recording , Aged , Case-Control Studies , Cineradiography , Female , Humans , Male , Middle Aged , Parkinson Disease/complications , Parkinson Disease/physiopathology , Pneumonia, Aspiration/complications , Pneumonia, Aspiration/diagnosis , Pneumonia, Aspiration/physiopathology , Respiratory Aspiration/complications , Respiratory Aspiration/diagnostic imaging , Respiratory Aspiration/physiopathology , Retrospective StudiesABSTRACT
OBJECTIVES: Levodopa-carbidopa intestinal gel (LCIG) was developed to reduce motor complications in Parkinson's disease (PD) caused by pulsatile levodopa plasma concentrations following oral levodopa administration. Dyskinesia and 'wearing off' symptoms can vary between Asian and Caucasian patients with PD, thus highlighting the importance of assessing the effectiveness of LCIG in an Asian population. Efficacy and safety of LCIG were previously assessed in a 12-week open-label study; we report the efficacy and safety of at least 52 weeks of LCIG treatment in Japanese, Taiwanese, and Korean patients with advanced PD in the ongoing extension study. METHODS: In this interim analysis of a phase III, open-label, multicenter extension study in Japan, South Korea, and Taiwan [ClinicalTrials.gov identifier: NCT02082249/JapiCTI-142482], the mean change from baseline to final visit in 'off' time, as reported in the PD symptom diary, was normalized to a 16-h waking day. Changes in Parkinson's Disease Questionnaire-39 (PDQ-39) summary index and domains scores were also analyzed. Adverse events (AEs) were recorded. RESULTS: Of the 28 patients enrolled (21 Japanese, 3 Taiwanese, 4 Korean), 27 completed at least 52 total weeks of treatment, and 25 patients were continuing in the study at data cutoff. The mean [standard deviation (SD)] 'off' time was significantly reduced by 4.6 (3.1) h/day (p < 0.001, n = 28). Patients experienced significant improvements in quality of life, as recorded by the mean change from baseline in PDQ-39 summary index (p < 0.001). All patients had at least one AE; three patients (11%) discontinued due to an AE. There were two deaths (sepsis and drowning), both of which the investigator considered unrelated to LCIG treatment. CONCLUSIONS: These data suggest that LCIG treatment is efficacious, safe, and well tolerated in Japanese, Taiwanese, and Korean patients with advanced PD, thus confirming the consistency of LCIG treatment in patients with advanced PD.
ABSTRACT
A 77-year-old man visited our hospital with unstable gait following 2 months of anorexia. Brain MRI showed multiple infarcts; cardiac echocardiography revealed mitral-valve vegetation; and blood culture revealed methicillin-resistant coagulase-negative staphylococci. The patient was diagnosed with infective endocarditis (IE). Subarachnoid hemorrhage (SAH) developed ten days after antibiotic treatment. Intracranial aneurysm was not found. We speculated that chronic inflammation of the cerebral arterial walls by bacteria of low virulence was associated with SAH complication. The vegetation disappeared following additional gentamicin administration and the patient recovered to walk.
Subject(s)
Endocarditis/complications , Endocarditis/microbiology , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Subarachnoid Hemorrhage/etiology , Aged , Anti-Bacterial Agents/administration & dosage , Ceftriaxone/administration & dosage , Echocardiography, Transesophageal , Endocarditis/diagnostic imaging , Endocarditis/drug therapy , Gentamicins/administration & dosage , Humans , Magnetic Resonance Imaging , Male , Subarachnoid Hemorrhage/diagnostic imaging , Tomography, X-Ray Computed , Treatment Outcome , Vancomycin/administration & dosageABSTRACT
Epidemiological evidence on the relationships between the vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), and rs2228570 (FokI) and Parkinson's disease (PD) is inconsistent. We investigated these relationships in 229 sporadic PD patients within six years of onset in Japan. Controls were 357 patients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. A significant inverse association was found between SNP rs2228570 and the risk of sporadic PD under the additive but not the co-dominant or dominant model (P=0.048); however, this fell below significance after adjustment for multiple comparisons (adjusted P=0.46). No significant relationships were found between SNPs rs731236, rs7975232, or rs1544410 and the risk of sporadic PD in any genetic model. VDR haplotypes inferred in the current study were not associated with sporadic PD. Compared with subjects with the GA or AA genotype of SNP rs2228570 who had ever smoked, those with the GG genotype who had never smoked had a 3.78-fold increased risk of sporadic PD; however, no significant interaction was observed. VDR SNP rs2228570 may be associated with sporadic PD in Japan. Smoking did not significantly modify the relationship between SNP rs2228570 and sporadic PD.
Subject(s)
Genetic Predisposition to Disease , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Calcitriol/genetics , Smoking/adverse effects , Aged , Aged, 80 and over , Female , Genetic Association Studies , Genotype , Humans , Japan , Male , Middle Aged , Risk Factors , Smoking/geneticsABSTRACT
In a previous multinational, randomized, double-blind, double-dummy study, levodopa-carbidopa intestinal gel (LCIG) was tolerable and significantly improved 'off' time in advanced Parkinson's disease (PD) patients. However, efficacy and safety in the Asian population has not yet been demonstrated. In this open-label study, efficacy and safety of LCIG were assessed in Japanese, Korean, and Taiwanese advanced PD patients with motor complications not adequately controlled by available PD medication. The patients were treated with LCIG monotherapy for 12 weeks. The primary end point was the mean change from baseline to week 12 in 'off' time, as reported in the PD Symptom Diary, normalized to a 16 h waking day and analyzed by a mixed-model repeated-measures analysis. Adverse events (AEs) were recorded. Thirty-one patients were enrolled (23 Japanese, 4 Taiwanese, 4 Korean) and 28 (90%) completed the study. For those who completed the study, the mean (s.d.) total daily levodopa dose from LCIG was 1,206.3 (493.6) mg/day at final visit (n=28); last observation carried forward (n=30) was 1,227.6 (482.8) mg/day. There was a significant mean change (s.d.) of -4.6 (3.0) hours of 'off' time from baseline (mean (s.d.)=7.4 (2.3)) to week 12 (n=29), P<0.001. All the patients had an AE, with the most frequently reported being incision site pain (42%); 1 (3.2%) discontinued treatment because of an AE and later died because of sepsis, which the investigator considered unrelated to LCIG treatment. These results suggest that LCIG is efficacious and tolerable in Japanese, Taiwanese, and Korean advanced PD patients.