Search

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 × ε4 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.

We studied whether 123 I-FP-CIT uptake in the striatum correlates with cognitive performance in patients with Parkinson's disease (PD). Sixty-nine patients with PD (24 men and 45 women, average age = 71.3 years, disease duration = 5.2 years) underwent 123 I-FP-CIT SPECT and neuropsychiatric measurements. Cognitive performance was assessed using the MMSE (Mini-mental state examination), TMT (Trail making test), MoCA-J (Japanese version of Montreal cognitive assessment), FAB (Frontal assessment battery), ACE-R (Addenbrooke's cognitive examination revised), BDI-II (Beck depression inventory-II), and RBMT (Rivermead behavioural memory test) in the ON state. The average specific binding ratio (SBR) and AI (Asymmetry index) of striatal 123 I-FP-CIT uptake were semi-quantitatively measured using DaTView software. Clinical data and SBR were compared. In addition, participants were divided into four groups according to the visibility of the striatum on 123 I-FP-CIT SPECT images, and results of the Eagle Wing (EW) group and the Egg shape (ES) group were compared. SBR was negatively correlated with age (P < 0.001), disease duration (P < 0.001), H-Y stage (P < 0.001), levodopa equivalent dose (P = 0.004), TMT-A (P = 0.001), and TMT-B (P < 0.001), and positively correlated with MMSE (P = 0.021) and FAB (P = 0.029), MoCA-J (P = 0.012)，RBMT (P = 0.021). Multiple regression analysis confirmed that age (P = 0.016) and FAB (P = 0.035) were independent predictors for SBR. Furthermore, in the ES group, Movement Disorder Society - Unified Parkinson's disease rating scale part III scores were significantly higher (P = 0.013) and the AI was lower (P < 0.001) than those in the EW group. Conversely, there were no differences in the findings of neuropsychiatric measures between the two groups. Our study results demonstrate that imaging with 123 I-FP-CIT SPECT is sensitive for detecting dopaminergic deficits associated with frontal lobe functions in patients with PD.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 (BMI < 18.5) and non-underweight (BMI ≥ 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

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., Competing Interests: The authors have declared that no competing interests exist.

Homozygous mutations of the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), and heterozygous mutations of GBA are a major risk factor for Parkinson's disease (PD). This study examined the impact of GBA mutations on the longitudinal clinical course of PD patients by retrospective cohort design. GBA-coding regions were fully sequenced in 215 PD patients and GD-associated GBA mutations were identified in 19 (8.8%) PD patients. In a retrospective cohort study, time to develop dementia, psychosis, wearing-off, and dyskinesia were examined. Survival time analysis followed a maximum 12-year observation (median 6.0 years), revealing that PD patients with GD-associated mutations developed dementia and psychosis significantly earlier than those without mutations (p < 0.001 and p = 0.017, respectively). Adjusted hazard ratios of GBA mutations were 8.3 for dementia (p < 0.001) and 3.1 for psychosis (p = 0.002). No statistically significant differences were observed for wearing-off and dyskinesia between the groups. N-isopropyl-p[(123)I] iodoamphetamine single-photon emission tomography pixel-by-pixel analysis revealed that regional cerebral blood flow was reduced in the bilateral parietal cortex, including the precuneus of GD-associated mutant PD patients, compared with matched PD controls without mutations., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: C-reactive protein (CRP), a blood inflammatory biomarker, is associated with the development of Alzheimer disease. In animal models of Parkinson disease (PD), systemic inflammatory stimuli can promote neuroinflammation and accelerate dopaminergic neurodegeneration. However, the association between long-term systemic inflammations and neurodegeneration has not been assessed in PD patients., Objective: To investigate the longitudinal effects of baseline CRP concentrations on motor prognosis in PD., Design, Setting, and Participants: Retrospective analysis of 375 patients (mean age, 69.3 years; mean PD duration, 6.6 years). Plasma concentrations of high-sensitivity CRP were measured in the absence of infections, and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores were measured at five follow-up intervals (Days 1-90, 91-270, 271-450, 451-630, and 631-900)., Main Outcome Measure: Change of UPDRS-III scores from baseline to each of the five follow-up periods., Results: Change in UPDRS-III scores was significantly greater in PD patients with CRP concentrations ≥0.7 mg/L than in those with CRP concentrations <0.7 mg/L, as determined by a generalized estimation equation model (P = 0.021) for the entire follow-up period and by a generalized regression model (P = 0.030) for the last follow-up interval (Days 631-900). The regression coefficients of baseline CRP for the two periods were 1.41 (95% confidence interval [CI] 0.21-2.61) and 2.62 (95% CI 0.25-4.98), respectively, after adjusting for sex, age, baseline UPDRS-III score, dementia, and incremental L-dopa equivalent dose., Conclusion: Baseline plasma CRP levels were associated with motor deterioration and predicted motor prognosis in patients with PD. These associations were independent of sex, age, PD severity, dementia, and anti-Parkinsonian agents, suggesting that subclinical systemic inflammations could accelerate neurodegeneration in PD.

Background: C-reactive protein (CRP) is a biomarker of inflammation, and high levels of CRP correlate with vascular death. Chronic inflammation is considered to be involved in neurodegeneration, although there is no evidence linking it with the process of neurodegenerative diseases., Objective: To determine the role of baseline CRP levels in the prognosis of patients with Parkinson disease (PD)., Methods: A cohort of 313 patients with a mean age of 69.1 and mean PD duration of 7.9 years was retrospectively followed for a mean observation time of 1,753 days. CRP was measured when patients were not diagnosed with any infections, and levels were repetitively measured to investigate a tendency of "regression to mean." The primary outcome measure was a survival time from study enrollment to death., Results: During the observation period 56 patients died. Baseline CRP was log-linearly associated with a risk of death in PD. Mean survival time was 3,149 (95% confidence interval; 3,009-3,289) days in patients with CRP ≤ 0.8mg/L (lower two thirds) and 2,620 (2,343-2,897) days in those with CRP > 0.8 mg/L (top third, p < 0.001, log-rank test). The adjusted hazard ratio (HR) per two-fold higher CRP concentration for all deaths was 1.29 (1.10-1.52), and after excluding PD-unrelated deaths, such as cancer or stroke, HR was 1.23 (1.01-1.49) (adjusted for age, sex, PD duration, modified Hohen-Yahr stages, MMSE scores, and serum albumin)., Conclusions: Baseline CRP concentrations were associated with the risk of death and predicted life prognosis of patients with PD. The associations were independent from PD duration, PD severity, cognitive function, ages, and nutritional conditions, suggesting the possibility that subclinical chronic inflammation is associated with a neurodegenerative process in PD.

Background: In Parkinson disease (PD), systemic inflammation caused by respiratory infections such as pneumonia frequently occurs, often resulting in delirium in the advanced stages of this disease. Delirium can lead to cognitive and functional decline, institutionalization, and mortality, especially in the elderly. Inflammation causes rapid worsening of PD motor symptoms and signs, sometimes irreversibly in some, but not all, patients., Purpose: To identify factors associated with subacute motor deterioration in PD patients with systemic inflammation., Methods: The association of clinical factors with subacute motor deterioration was analyzed by a case-control study. Subacute motor deterioration was defined as sustained worsening by one or more modified Hoehn and Yahr (H-Y) stages. Using multivariable logistic regression incorporating baseline characteristics (age, sex, PD duration, modified H-Y stage, dementia, and psychosis history) and statistically selected possible predictors (peak body temperature, duration of leukocytosis, and presence of delirium), the odds ratios for these factors were estimated as relative risks., Results: Of 80 PD patients with systemic inflammation, 26 with associated subacute motor deterioration were designated as cases and the remainder as controls. In the 26 cases, 6 months after its onset the motor deterioration had persisted in 19 patients and resolved in four (three were lost for follow-up). Multivariable logistic regression analysis showed that delirium and body temperature are significantly associated with motor deterioration after systemic inflammation (P = 0.001 for delirium and P = 0.026 for body temperature), the adjusted odds ratios being 15.89 (95% confidence interval [CI]: 3.23-78.14) and 2.78 (95% CI: 1.13-6.83), respectively., Conclusions: In patients with PD and systemic inflammation, delirium and high body temperature are strong risk factors for subsequent subacute motor deterioration and such deterioration can persist for over 6 months.

Background: Though infections are associated with psychotic symptoms, whether or not subclinical inflammation is associated with hallucinations is not known in Parkinson's disease (PD)., Purpose: To investigate the association of illusions/hallucinations and plasma CRP levels in PD patients without symptomatic infections., Methods: PD patients not diagnosed as having infections were assessed for illusions and hallucinations using the Parkinson Psychosis Questionnaire (PPQ). It comprises four-domain questions: PPQ-A for sleep problems, PPQ-B for hallucinations/illusions, PPQ-C for delusions, and PPQ-D for disorientation. Assigning patients with ≥1 points in the PPQ-B score to be cases and others as controls, the association of hallucinations/illusions and clinical features (age, sex, duration of PD, Unified Parkinson's Disease Rating Scale part 3 (UPDRS-3), Mini-Mental State Examination (MMSE) score, sleep disturbance (PPQ-A score) as well as daily doses of L-Dopa, dopamine agonists, amantadine, and selegiline) were analyzed using a case-control design., Results: A total of 111 patients were examined and plasma CRP levels were <0.1-6.0 mg/L. Hallucinations or illusions were detected in 28 (25.2%). There were significant differences in age, UPDRS-3 score, MMSE score, PPQ-A, daily doses of L-Dopa and dopamine agonists and plasma CRP levels between cases and controls. A multivariate logistic regression model revealed that UPDRS-3 scores and plasma CRP levels were significantly associated with hallucinations/illusions with an adjusted odds ratio of 1.96 (95% confidence interval (CI) 1.20-3.20) per 10 points and 1.57 (95% confidence interval 1.13-2.16) per two-fold, respectively. Dividing patients into thirds by CRP levels (≤0.2, 0.3-0.6, ≥0.7 mg/L), the prevalence of hallucinations/illusions was 13.2%, 21.6%, and 41.7%, in the bottom-, middle-, and top-thirds, respectively (for trend p = 0.012)., Conclusions: Subclinical elevation of plasma CRP levels was associated with hallucinations or illusions after adjustment for motor disability, suggesting that subclinical elevations of CRP levels might be an independent risk for hallucinations/illusions.

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.

Background: Abnormal posture (AP) is often seen in Parkinson's disease (PD), and marked forms known as dropped head syndrome and camptocormia encumber daily living activities. Unlike other motor disabilities such as bradykinesia or muscular rigidity, AP is not always improved but rather deteriorated by PD medication., Purpose: To clarify factors associated with neck and thoracolumbar AP., Methods: Neck flexion (NF) and thoracolumbar (TL) angles were measured in 216 consecutive PD patients and 175 elderly healthy controls. The differences in NF and TL angles between PD patients and controls were designated as ΔNFA and ΔTLA, respectively. The association of ΔNFA or ΔTLA and predictable factors such as age, sex, duration of PD, Hoehn Yahr (H-Y) stage, Unified Parkinson's Disease Rating Scale Part 3 (UPDRS-3), daily dose of dopamine agonists, and comorbid orthopedic spinal lesions was investigated in PD patients. Patients were divided into quartiles according to ΔNFA or ΔTLA. The association between predictable factors and ΔNFA or ΔTLA was estimated as odds ratio (OR), comparing with the lowest quartile as the reference by multivariate regression analysis., Results: Compared with controls, distributions of all three posture angles were significantly shifted rightward in PD patients. Although there were no difference in UPDRS-3 scores in the quartiles of ΔNFA, the highest quartile was associated with H-Y stage ≥3 [OR 2.99, 95% confidence interval (CI) 1.33-6.70, p = 0.008] after adjustment for age, sex and comorbid orthopedic spinal lesions. The highest quartile of ΔTLA was associated with comorbid orthopedic spinal lesions [OR 5.83 (1.42-23.8), p = 0.014], and UPDRS-3 score [OR 3.04 (1.80-5.15)/10 points, p<0.0001]., Conclusion: Thoraco-lumbar AP was associated with UPDRS-3 scores and orthopedic spinal lesions, and in contrast, neck AP was not associated with these factors, suggesting that they had different pathomechanisms.

Background: It is often hard to differentiate Parkinson's disease (PD) and parkinsonian variant of multiple system atrophy (MSA-P), especially in the early stages. Cardiac sympathetic denervation and putaminal rarefaction are specific findings for PD and MSA-P, respectively., Purpose: We investigated diagnostic accuracy of putaminal apparent diffusion coefficient (ADC) test for MSA-P and (123)I-metaiodobenzylguanidine (MIBG) scintigram for PD, especially in early-stage patients., Methods: The referral standard diagnosis of PD and MSA-P were the diagnostic criteria of the United Kingdom Parkinson's Disease Society Brain Bank Criteria and the second consensus criteria, respectively. Based on the referral standard criteria, diagnostic accuracy [area under the receiver-operator characteristic curve (AUC), sensitivity and specificity] of the ADC and MIBG tests was estimated retrospectively. Diagnostic accuracy of these tests performed within 3 years of symptom onset was also investigated., Results: ADC and MIBG tests were performed on 138 patients (20 MSA and 118 PD). AUC was 0.95 and 0.83 for the ADC and MIBG tests, respectively. Sensitivity and specificity were 85.0% and 89.0% for MSA-P diagnosis by ADC test and 67.0% and 80.0% for PD diagnosis by MIBG test. When these tests were restricted to patients with disease duration ≤ 3 years, the sensitivity and specificity were 75.0% and 91.4% for the ADC test (MSA-P diagnosis) and 47.7% and 92.3% for the MIBG test (PD diagnosis)., Conclusions: Both tests were useful in differentiating between PD and MSA-P, even in the early stages. In early-stage patients, elevated putaminal ADC was a diagnostic marker for MSA-P. Despite high specificity of the MIBG test, careful neurological history and examinations were required for PD diagnosis because of possible false-negative results.

Background: Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias., Methods: In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's 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 Parkinson's 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.

Parkinson's disease is characterized by selective loss of dopaminergic neurons in the substantia nigra and by the appearance of Lewy bodies. Fibrillar alpha-synuclein is the main component of Lewy bodies. Previous studies have suggested that dopamine promotes alpha-synuclein oligomerization and that partially aggregated or oligomeric alpha-synuclein could be cytotoxic. To confirm this hypothesis using cell cultures, we performed size exclusion chromatography as a pretreatment method prior to Western blotting to more clearly detect a small amount of alpha-synuclein oligomers in wild-type alpha-synuclein-overexpressing SH-SY5Y cells. Using this method, we confirmed that stable overexpression of alpha-synuclein in SH-SY5Y cells indeed increased the amounts of alpha-synuclein oligomers in these cells and exposure of the cells to dopamine for 6h facilitated alpha-synuclein oligomerization. These dopamine-induced alpha-synuclein oligomers continued to exist for the following 24h. However, the dopamine-treated cells did not undergo cell death or apoptosis in spite of the presence of increased oligomeric alpha-synuclein. Our data may contribute to the understanding of the mechanisms underlying alpha-synuclein oligomer formation and its suspected cytotoxicity toward dopaminergic neurons., (Copyright 2009 Elsevier Inc. All rights reserved.)

An association between ergot-derived dopamine agonists and asymptomatic valvular heart disease in Parkinson's disease has been established. For safe use of these agonists, it is important to specify those at high risk for valvular heart disease among patients with Parkinson's disease. We performed a nested case-control study of 223 patients with Parkinson's disease. In results of multivariable logistic analyses, use of pergolide, use of cabergoline, age, male sex, and hypertension were independent significant risk factors for left-sided valvular regurgitation. In patients receiving cabergoline or pergolide, elderly (>or=70 years) hypertensive patients had a markedly high risk for valvular regurgitation (odds ratio 94.5) as compared to non-elderly (<70 years) patients without hypertension. The risk of valvular regurgitation caused by pergolide or cabergoline was found to be highly enhanced by comorbid hypertension or aging, suggesting that special attention should be paid when prescribing cabergoline or pergolide for those patients.

Background and Purpose: To estimate the diagnostic accuracy of cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigram for detection of Parkinson disease., Methods: A cross-sectional study with index test of MIBG scintigram and reference standard of U.K. Parkinson's Disease Brain Bank Criteria was performed in 403 patients. Ratio of cardiac-to-mediastinum MIBG accumulation was determined at 20 min (early H/M) and 4 h (late H/M). Area under the receiver-operator characteristic (ROC) curve, sensitivity and specificity in detecting Parkinson disease were analyzed. Accuracy was analyzed in a subgroup of patients with disease duration of 3 years or less., Results: Area under the ROC curve was 0.89 using either early or late H/M as a diagnostic marker (95% CI 0.85-0.92 for early H/M and 0.86-0.93 for late H/M). Sensitivity and specificity were 81.3% (76.1-85.8%) and 85.0% (77.7-90.6%) for early H/M and 84.3% (79.3-88.4%) and 89.5% (83.01-94.1%) for late H/M. In the subgroup with duration of 3 years or less, the ROC curve area, sensitivity, and specificity were 0.86 (0.79-0.92), 76.0% (64.8-85.1%), and 83.9% (71.7-92.4%) for early H/M and 0.85 (0.78-0.92), 73.3% (61.9-82.9%), and 87.5% (75.9-94.8%) for late H/M., Conclusion: Although diagnostic accuracy of cardiac MIBG scintigram is high, it is limited because of insufficient sensitivity in patients with short duration.

Parkinson disease is characterized by selective degeneration of mesencephalic dopaminergic neurons, and endogenous dopamine may play a pivotal role in the degenerative processes. Using primary cultured mesencephalic neurons, we found that glutamate, an excitotoxin, caused selective dopaminergic neuronal death depending on endogenous dopamine content. Pramipexole, a dopamine D2/D3 receptor agonist used clinically in the treatment of Parkinson disease, did not affect glutamate-induced calcium influx but blocked dopaminergic neuronal death induced by glutamate. Pramipexole reduced dopamine content but did not change the levels of total or phosphorylated tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis. The neuroprotective effect of pramipexole was independent of dopamine receptor stimulation because it was not abrogated by domperidone, a dopamine D2-type receptor antagonist. Moreover, both active S(-)- and inactive R(+)-enantiomers of pramipexole as a dopamine D2-like receptor agonist equally suppressed dopaminergic neuronal death. These results suggest that pramipexole protects dopaminergic neurons from glutamate neurotoxicity by the reduction of intracellular dopamine content, independently of dopamine D2-like receptor activation.

The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. In this report, we investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. Treatment with proteasome inhibitors provided significant protection against toxicity by 6-hydroxydopamine and H(2)O(2) in a concentration-dependent manner. The measurement of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate demonstrated that lactacystin, a proteasome inhibitor, significantly reduced 6-hydroxydopamineand H(2)O(2)-induced reactive oxygen species production. Proteasome inhibitors elevated the amount of glutathione and phosphorylated p38 mitogen-activated protein kinase (MAPK) prior to glutathione elevation. The treatment with lactacystin induced the nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased the level of mRNA for gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione synthesis. Furthermore, SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin. These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation.

Interventional paired associative stimulation (IPAS) to the contralateral peripheral nerve and cerebral cortex can enhance the primary motor cortex (M1) excitability with two synchronously arriving inputs. This study investigated whether dopamine contributed to the associative long-term potentiation-like effect in the M1 in Parkinson's disease (PD) patients. Eighteen right-handed PD patients and 11 right-handed age-matched healthy volunteers were studied. All patients were studied after 12 hours off medication with levodopa replacement (PD-off). Ten patients were also evaluated after medication (PD-on). The IPAS comprised a single electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 milliseconds (240 paired stimuli every 5 seconds for 20 minutes). The motor-evoked potential amplitude in the right abductor pollicis brevis muscle was increased by IPAS in healthy volunteers, but not in PD patients. IPAS did not affect the motor-evoked potential amplitude in the left abductor pollicis brevis. The ratio of the motor-evoked potential amplitude before and after IPAS in PD-off patients increased after dopamine replacement. Thus, dopamine might modulate cortical plasticity in the human M1, which could be related to higher order motor control, including motor learning.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. The pathology of PD is typified by the presence of cytoplasmic inclusions (Lewy bodies) containing alpha-synuclein and ubiquitin. The pathogenesis of PD is not completely understood but environmental and genetic factors are thought to play important roles. To understand the pathophysiology of PD, and to develop novel therapies for improved symptomatic management, it is important to have relevant disease models. In this review, we summarize the available in vivo and in vitro models of PD and discuss their value.

Epidemiologic studies revealed that the prevalence of Parkinson disease is higher in males than in females and that the progression of the disease might be rapid in males compared with females. The reason for the gender difference is unknown; however, estrogens may be involved. Many studies have revealed that estrogens provide neuroprotective effects and that the protective mechanisms include antioxidant property and upregulation of Bcl-2, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor (GDNF). Upregulation of Bcl-2 or GDNF is mediated by nonnuclear estrogen receptor (ER) in addition to transcription regulation by ER. To avoid undesirable effect of estrogens, several selective ER modulators, raloxifene and genistein are considered.

We report a 62-year-old Japanese man with familial frontotemporal dementia and a novel missense mutation (N296H) in exon 10 of the tau gene. The patient presented with frontal signs followed by temporal signs and parkinsonism. The brain showed localized frontotemporal lobe atrophy including the precentral gyrus and discoloration of the substantia nigra, and revealed severe neuronal loss with proliferation of tau-positive protoplasmic astroglia in the affected cerebral cortex, tau-positive coiled bodies and threads in the subcortical white matter, and tau-positive pretangle neurons in the subcortical and brain stem nuclei. There were no tau-positive neurofibrillary tangles, Pick bodies, tuft-shaped astrocytes or astrocytic plaques in the cerebral cortex. Immunoelectron microscopically, phosphorylated tau accumulated in both neurons and glial cells in different modalities, such as glial filaments in protoplasmic astroglia, straight tubules in coiled bodies, and free ribosomes in pretangle neurons. These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17. Immunoblotting of sarkosyl-insoluble tau exhibited accumulation of four-repeat tau isoforms in the brain. The N296H mutation may interfere with the ability of mutated tau to bind with microtubules and lead to tau aggregation. Further study is necessary to determine whether this mutation can account for the characteristic tau pathology of this case.

Oxidative stress is important in the process of dopaminergic neuronal degeneration in Parkinson's disease. Recent studies suggest that estrogens have neuroprotective effects in neurodegenerative disorders, including Alzheimer's disease. In the present study, we investigated neuroprotection against oxidative stress afforded by estradiol using primary neuronal culture of the rat ventral mesencephalon. Oxidative stress induced by glutamate, superoxide anions, and hydrogen peroxide caused significant neuronal death. Although simultaneous administration of 17beta-estradiol and glutamate did not show any significant effects, preincubation with 17beta-estradiol provided significant neuroprotection against glutamate-induced neurotoxicity (ED50 was 50 microM for dopaminergic and 15 microM for nondopaminergic neurons). Neuroprotection occurred even after a brief preincubation with 17beta-estradiol and was not significantly blocked by either an estrogen receptor antagonist or a protein synthesis inhibitor. These findings indicate that the neuroprotection against glutamate neurotoxicity is mediated by neither estrogen receptors nor activation of genome transcription. Other steroids (corticosterone, testosterone, and cholesterol) did not provide significant neuroprotection against glutamate-induced neurotoxicity. Furthermore, preincubation with 17beta-estradiol provided neuroprotection against neuronal death induced by both superoxide anions and hydrogen peroxide. Dichlorofluorescin diacetate, a marker of oxygen radicals, revealed that preincubation with 17beta-estradiol suppressed intracellular oxygen radicals induced by hydrogen peroxide. The biologically inactive stereoisomer of estradiol, 17alpha-estradiol, provided neuroprotection against glutamate-induced toxicity in dopaminergic neurons, as well as the 17beta isoform. 17Alpha-estradiol may be a potential therapeutic agent used to prevent dopaminergic neuronal death induced by oxidative stress in Parkinson's disease.

Parkinson's disease is characterized by chronic progression of dopaminergic neuronal death, the mechanism of which is still unknown. Although methyl-4-phenylpyridium ion (MPP+) or MPP(+)-like substance, that can reduce mitochondrial complex I activity, is supposed to be a causative agent for Parkinson's disease, it is difficult to explain the chronic neuronal degeneration for years. It is important to identify other putative agents capable of causing chronic cell death besides MPP+. We hypothesized that treatment with small doses of MPP+, not causing severe damage to dopaminergic neurons but merely reducing the activity of mitochondrial complex I, can be a model of Parkinson's disease, and that glutamate can be a putative agent causing chronic neuronal degeneration. Using primary culture of the rat mesencephalon, we investigated glutamate-induced cytotoxicity against dopaminergic and non-dopaminergic neurons with or without the pretreatment with MPP+. Brief exposure to glutamate showed similar cytotoxicity against both dopaminergic and non-dopaminergic neurons. An N-methyl-D-aspartate receptor antagonist completely blocked the glutamate-induced cytotoxicity against both dopaminergic and non-dopaminergic neurons. In the dopaminergic neurons, MPP+ caused cytotoxicity that was not blocked by co-administration of MK-801. After pretreatment with small doses of MPP+, sub-lethal doses of glutamate caused severe cell damage restricted to dopaminergic neurons, suggesting that MPP+ potentiates the glutamate-induced cytotoxicity only against dopaminergic neurons. As glutamate is putatively capable of causing cytotoxicity against dopaminergic neurons, the present findings might be important in considering the pathogenesis of dopaminergic neuronal degeneration and a possible therapeutic application of glutamate receptor antagonists in Parkinson's disease.

Dementia in Parkinson's disease is thought to be attributable not only to subcortical lesions but also to cortical alterations, especially frontal lobe dysfunction. To evaluate cortical function, the regional cerebral blood flow (rCBF) was estimated of 13 demented and 13 non-demented age matched patients with Parkinson's disease compared with that of 10 age matched controls using I-123 iodoamphetamine single photon emission tomography (IMP-SPECT). The rCBF of the nondemented Parkinson's patients showed no significant differences from that of the control subjects. In the demented patients, the bilateral frontal and parietal and left temporal regional blood flow was significantly less than in the controls. Four demented patients showed isolated frontal hypoperfusion, 8 showed fronto-parietal hypoperfusion, and 1 showed isolated parietal hypoperfusion. Frontal hypoperfusion was therefore present in 12 of the 13 demented patients, and this finding agrees with the frontal lobe dysfunction hypothesis. Parietal rCBF had a significant positive correlation with cortical functions such as calculation and language ability in the MMSE scores. The parietal and temporal reduction in rCBF probably reflects the presence of Alzheimer pathology, cortical Lewy body disease, or both.

A response by H. Sawada and colleagues to a letter to the editor about their article on diabetes mellitus and neurology is presented.