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Sawada H.,National Hospital of Utano | Oeda T.,National Hospital of Utano | Umemura A.,National Hospital of Utano | Tomita S.,National Hospital of Utano | And 4 more authors.
PLoS ONE | Year: 2015

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. Copyright: © 2015 Sawada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Sawada H.,National Hospital of Utano | Oeda T.,National Hospital of Utano
BMJ Open | Year: 2013

Introduction: Psychosis, including hallucinations and delusions, is one of the important non-motor problems in patients with Parkinson's disease (PD) and is possibly associated with cholinergic neuronal degeneration. The EDAP (Efficacy of Donepezil against Psychosis in PD) study will evaluate the efficacy of donepezil, a brain acetylcholine esterase inhibitor, for prevention of psychosis in PD. Methods and analysis: Psychosis is assessed every 4 weeks using the Parkinson Psychosis Questionnaire (PPQ) and patients with PD whose PPQ-B score (hallucinations) and PPQ-C score (delusions) have been zero for 8 weeks before enrolment are randomised to two arms: patients receiving donepezil hydrochloride or patients receiving placebo. The patients are then followed for 96 weeks. The primary outcome measure is the time to the event, defined as getting 2 points or more on the PPQ-B score or PPQ-C score, which is assessed using a survival time analysis. The hypothesis being tested is that donepezil prevents psychosis in patients with PD. Efficacy will be tested statistically using the intention-to-treat analysis including a log-rank test or Cox proportional hazard models. Secondary outcomes, such as changes of PPQ scores and Unified Parkinson's Disease Rating Scale scores from baseline will be assessed. Ethics and dissemination: Ethics approval was received from the Central Review Board of the National Hospital Organization, Tokyo, Japan. The trial was declared and registered to the Pharmaceuticals and Medical Devices Agency(PMDA), Japan (No. 22-4018). All participants will receive a written informed consent that was approved by the Central Review. A completed written informed consent is required to enrol in the study. Severe adverse events will be monitored by investigators and in cases where a severe adverse event was previously unreported, it will be reported to the PMDA.


Umemura A.,National Hospital of Utano | Oeda T.,National Hospital of Utano | Tomita S.,National Hospital of Utano | Hayashi R.,National Hospital of Utano | And 4 more authors.
PLoS ONE | Year: 2014

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. © 2014 Umemura et al.


Sawada H.,National Hospital of Utano | Oeda T.,National Hospital of Utano | Umemura A.,National Hospital of Utano | Tomita S.,National Hospital of Utano | And 5 more authors.
PLoS ONE | Year: 2014

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. © 2014 Sawada et al.


Oeda T.,National Hospital of Utano | Umemura A.,National Hospital of Utano | Tomita S.,National Hospital of Utano | Hayashi R.,National Hospital of Utano | And 2 more authors.
PLoS ONE | Year: 2013

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. © 2013 Oeda et al.


Umemura A.,National Hospital of Utano | Oeda T.,National Hospital of Utano | Hayashi R.,National Hospital of Utano | Tomita S.,National Hospital of Utano | And 3 more authors.
PLoS ONE | Year: 2013

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 123I-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. © 2013 Umemura et al.


PubMed | National Hospital of Utano
Type: Journal Article | Journal: PloS one | Year: 2015

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.To determine the role of baseline CRP levels in the prognosis of patients with Parkinson disease (PD).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.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).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.


PubMed | National Hospital of Utano
Type: Comparative Study | Journal: PloS one | Year: 2015

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.To investigate the longitudinal effects of baseline CRP concentrations on motor prognosis in PD.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 Parkinsons 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).Change of UPDRS-III scores from baseline to each of the five follow-up periods.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.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.


PubMed | National Hospital of Utano
Type: Journal Article | Journal: PloS one | Year: 2013

Abnormal posture (AP) is often seen in Parkinsons 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.To clarify factors associated with neck and thoracolumbar AP.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 NFA and TLA, respectively. The association of NFA or TLA and predictable factors such as age, sex, duration of PD, Hoehn Yahr (H-Y) stage, Unified Parkinsons 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 NFA or TLA. The association between predictable factors and NFA or TLA was estimated as odds ratio (OR), comparing with the lowest quartile as the reference by multivariate regression analysis.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 NFA, 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 TLA 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].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.


PubMed | National Hospital of Utano
Type: Journal Article | Journal: PloS one | Year: 2014

Though infections are associated with psychotic symptoms, whether or not subclinical inflammation is associated with hallucinations is not known in Parkinsons disease (PD).To investigate the association of illusions/hallucinations and plasma CRP levels in PD patients without symptomatic infections.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 Parkinsons 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.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).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.

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