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Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers
Parkinsonism and Related Disorders xxx (2017) 1e7
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Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers Tetsuya Maeda, MD, PhD a, b, *, Yasushi Shimo, MD, PhD c, Shih-Wei Chiu, MS d, Takuhiro Yamaguchi, PhD d, Kenichi Kashihara, MD, PhD e, Yoshio Tsuboi, MD, PhD f, Masahiro Nomoto, MD, PhD g, Nobutaka Hattori, MD, PhD c, Hirohisa Watanabe, MD, PhD h, Hidemoto Saiki, MD, PhD i, on behalf of the J-FIRST group a
Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan b Department of Neurology and Movement Disorder Research, Research Institute for Brain and Blood Vessels-Akita, 6-10 Senshukubotamachi, Akita 0100874, Japan c Department of Neurology, Juntendo University School of Medicine 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan d Division of Biostatistics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan e Department of Neurology, Okayama Kyokuto Hospital, 567-1 Kurata, Okayama, 703-8265, Japan f Department of Neurology, Faculty of Medicine, Fukuoka University, 3-1-1, Maidashi, Higashi-ku, Fukuoka City, 812-8582, Japan g Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, 454 Shizukawa, Tohon, Ehime 791-0295, Japan h Brain and Mind Research Center, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan i Department of Neurology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 October 2016 Received in revised form 27 December 2016 Accepted 19 February 2017
Introduction: We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD). Methods: A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDSUPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study. Results: The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (72.0%). Fatigue was an NMS that affected 79.6% of females but only 72.6% of males, whereas features of dopamine dysregulation syndrome affected only 5.6% of females and 10.8% of males. Positive correlations were found between the MDS-UPDRS part I and the PDQ-8 (p < 0.0001, r ¼ 0.56) and between the number of NMSs and the PDQ-8 score (p < 0.0001, r ¼ 0.47). Conclusions: This study revealed distinctive patterns of NMSs in Japanese patients with PD and suggested that the prevalence and severity of NMSs vary between sexes, and that the NMSs are important factors affecting the long-term quality of life of PD patients. © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Parkinson's disease Nonmotor symptoms Japan Quality of life
* Corresponding author. Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan. E-mail addresses: [email protected] (T. Maeda), [email protected] (Y. Shimo), [email protected] (S.-W. Chiu), [email protected] (T. Yamaguchi), [email protected] (K. Kashihara), [email protected] (Y. Tsuboi), [email protected] (M. Nomoto), [email protected] (N. Hattori), [email protected] (H. Watanabe), [email protected] (H. Saiki). http://dx.doi.org/10.1016/j.parkreldis.2017.02.024 1353-8020/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
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T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
1. Introduction
2.3. Evaluation schedule
Parkinson's disease (PD) is characterized by some cardinal motor features, including resting tremor, muscle rigidity, akinesia and postural instability. Alleviation of motor symptoms directly improves clinical prognosis and health-related quality of life (HrQOL). In addition to motor symptoms, PD can cause nonmotor symptoms (NMSs), such as autonomic failure, sensory problems, mood disorders and sleep disorders [1], which can have a significant impact on patients' HrQOL [2e4], especially in the advanced stage in clinical practice. Because dopamine replacement therapy is generally ineffective against NMSs [5,6], physicians must carefully assess patients on a case-by-case basis and determine the appropriate treatment based on their NMSs. In practice, there is relatively little evidence regarding clinical management of NMSs compared with motor symptoms. Because PD patients typically have multiple NMSs, the number of NMSs may have a subclinical importance. Therefore, this observational study was planned to gain a better understanding of the NMSs affecting Japanese patients with PD, taking into consideration other factors that may affect patients' NMSs and/or HrQOL, including clinical backgrounds and antiparkinsonian medical interventions. In this paper, we describe the clinical manifestations of NMSs and their effects on HrQOL.
A baseline structured interview and a neurological examination were performed to obtain baseline clinical characteristics of patients. The presence and severity of NMSs were evaluated using the MDS-UPDRS part I. Motor complications were also evaluated using the MDS-UPDRS part IV. Overall motor disability was evaluated in on and off states using the modified Hoehn and Yahr scale (mH&Y). Because it was impractical to assess both on and off states directly in office visits for each patient, patients reported their worst state to the attending physician (a neurologist well-versed in the treatment of movement disorders), who then judged the level of H&Y based on the patients' recollections. The HrQOL was evaluated with the PDQ-8. Anti-parkinsonian medical interventions were recorded, including daily dose of LDs, dopamine agonists, dopamine economizers, non-dopaminergic agents and method of functional neurosurgery (if applicable). Patients continue to be evaluated at every subsequent visit during the 52-week study period.
2. Methods 2.1. Study design This is the first-in-Japan large-scale observational study for NMSs and treatment in patients with PD (J-FIRST). A target sample size of 1000 advanced-stage PD patients was planned in light of the feasibility of the study and the number of patients required for identification of the factors related to NMSs. This prospective study is currently being conducted in 35 sites between February 2014 and December 2016 (see Supplementary Information for list of sites and investigators). Patients were enrolled between March 2014 and January 2015 in participating medical centers throughout Japan and are being prospectively examined for 52 weeks. The primary measurements include the interval changes over 52 weeks for the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) part I [7,8] and the eight-item PD questionnaire (PDQ-8) [9,10] both of which were translated into Japanese. The cross-sectional analysis is designed to investigate the prevalence, severity and number of NMSs and the relationship with HrQOL at baseline of the J-FIRST. Ethics review committees of each study site approved this study. All patients provided written informed consent. The study is registered at clinicaltrials.gov (NCT02073981) and umin. ac.jp/ctr/ index-j.htm (UMIN000013161).
2.2. Eligibility criteria Patients with advanced-stage PD, as diagnosed according to the United Kingdom PD Society Brain Bank clinical diagnostic criteria [11], were eligible for this study if they met the following inclusion criteria: wearing-off of treatment with levodopa-containing drugs (LDs), 1 NMS assessed by MDS-UPDRS part I, 20 years old at the time of consent, gave written consent and were receiving outpatient care. Patients were excluded if they met the following criteria: dementia or a Mini-Mental State Examination score (MMSE) 23, or conditions impairing the proper assessment of the MDS-UPDRS or the PDQ-8, as determined by the investigator.
2.4. Statistical analysis The prevalence is summarized using frequency and percentage, and the MDS-UPDRS part I scores and the PDQ-8 scores are summarized by sample size and mean ± standard deviation. Comparisons between demographic variables and the MDS-UPDRS part I score were performed by t-test, analysis of covariance for mean values, Fisher exact test for prevalence, or ManteleHaenszel test for ordered categorized data. Age, onset age, duration of illness, mH&Y, smoking history and LD dosage were each divided into three or four subcategories and results were compared among them. To determine the relationship between total score for the MDS-UPDRS part I and the PDQ-8, a multivariate linear regression model was used. Associations between the MDS-UPDRS part I score and the PDQ-8, and between total number of NMSs and the PDQ-8 were evaluated using Pearson correlation coefficients. A two-sided p-value with a significance level of 5% was applied. Statistical analysis was performed using SAS software (ver.9.4; SAS Institute Inc., Cary, NC, USA).
3. Results 3.1. Baseline clinical backgrounds In total, 1021 patients were enrolled. Of these patients, three did not meet the eligibility criteria, five withdrew consent, five satisfied the study criteria but were ineligible to continue because of hospitalization, death or difficulty in evaluation, and 12 had no wearing-off under treatment with LDs, as determined by MDSUPDRS part IV screening at baseline. Therefore, 996 patients entered the observational period (Supplementary Fig. 1). Baseline clinical characteristics are shown in Table 1. Briefly, 624 females and 372 males had a mean age of 68.1 years and median duration of illness of 10 years; mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively, and the mean number of NMSs was 6.6. The mean levodopa equivalent dose was 769.5 ± 339.0 mg/day [12]. All patients had previously been treated with LDs; dopamine agonists were used in ~80% of patients. Non-ergot agonists were predominantly used rather than ergot agonists. Selegiline and entacapone were commonly used as adjunctive therapy with LDs. Some non-dopaminergic agents are also used in Japan, such as droxidopa, zonisamide and istradefylline. Functional brain surgery was performed in 3.4% of patients and deep brain stimulation in 3.2% of patients.
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
3.2. Nonmotor severity and clinical backgrounds Table 2 shows the comparison between the nonmotor scores and clinical backgrounds. No significant differences were found in the nonmotor scores based on sex, onset age, smoking history or comorbidity. However, the nonmotor scores significantly increased with age. The clinical severity of motor symptoms, as determined by the on and off state mH&Y, dyskinesia and duration of illness, was associated with higher nonmotor scores. Patients living with a caregiver also had significantly higher nonmotor scores. Elevated nonmotor scores were also found in patients taking the following anti-parkinsonian medications: apomorphine (13.50 ± 6.26 vs. 10.85 ± 5.33; p ¼ 0.0099), rotigotine (12.07 ± 5.29 vs. 10.69 ± 5.36; p ¼ 0.0023), entacapone (11.63 ± 5.59 vs. 10.45 ± 5.17; p ¼ 0.0007) and istradefylline (11.80 ± 5.73 vs. 10.72 ± 5.27; p ¼ 0.0146). Nonmotor scores were higher in patients taking higher doses of LDs: 9.59 ± 4.97 (<400 mg), 11.30 ± 5.30 (400e599 mg), and 12.30 ± 5.66 (600 mg) (p < 0.0001). The nonmotor scores were also significantly higher in patients who had functional surgery (13.43 ± 5.09 vs. 10.83 ± 5.36; p ¼ 0.0049). Patients treated with selegiline had significantly lower nonmotor scores (10.45 ± 5.17 vs. 11.63 ± 5.59; p ¼ 0.0051). Less than 10% of patients were treated with ergot agonists, talipexole, apomorphine, droxidopa or functional surgery.
3.3. Prevalence and severity of each NMS between sexes The most frequent NMSs included constipation, sleep problems, pain and other sensations, daytime sleepiness, fatigue, urinary problems and anxious mood. Severe NMSs included constipation, daytime sleepiness, sleep problems, pain and other sensations, fatigue, and urinary problems. The distribution of NMSs was different between sexes, with features of dopamine dysregulation syndrome (DDS) and urinary problems significantly more common in males, and fatigue being more common in females (Table 3). Cognitive impairment, features of DDS, daytime sleepiness, urinary problems and constipation problems were more severe in males, and depressed moods were more severe in females.
Table 1 Clinical characteristics at baseline. Total number (n ¼ 996) Sex, n, female:male (%) Age (y), mean ± SD Duration of illness (y), median ± IQR Levodopa equivalent dose (mg/day), mean ± SD On state mH&Ya, n (%) mild moderate severe unrated Off state mH&Ya, n (%) mild moderate severe unrated Score of NMSb, mean ± SD Number of NMSc, n, mean ± SD PDQ-8, mean ± SD
624:372 (62.7:37.4) 68.1 ± 8.8 10 ± 7 769.5 ± 339.0 452 (45.4) 483 (48.5) 59 (5.9) 2 (0.2) 89 (8.9) 547 (54.9) 357 (35.8) 3 (0.3) 10.9 ± 5.4 6.6 ± 2.5 7.3 ± 5.2
SD: standard deviation, IQR: interquartile range, mH&Y: modified Hoehn and Yahr stage, MDS-UPDRS: Movement Disorder Society version unified Parkinson's disease rating scale, PDQ-8: 8 items of Parkinson's Disease questionnaire. a Modified H&Y stages divided as mild, moderate and severe were stage 0e2, stage 2.5 and 3, stage 4 and 5. b MDS-UPDRS part I score. c Number of sub-items with MDS-UPDRS part I scoring 1 to 4.
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3.4. Multivariate linear regression analysis in clinical severity of NMSs and HrQOL Multivariate linear regression analysis was performed for the nonmotor scores against all clinical parameters under adjustment with sex (male), age (less than 60 years), onset age (less than 50 years), smoking history (none), on state mH&Y (stage 0), off state mH&Y (stage 0), LD dosage (less than 400 mg/day), all antiparkinsonian drugs (none), dopamine agonists (none) and functional surgery (none). The nonmotor score was higher in patients with a higher HrQOL score (p < 0.0001), moderate off-state mH&Y (p ¼ 0.0075), severe off-state mH&Y (p ¼ 0.0458), LD treatment from 400 to 599 mg per day (p ¼ 0.0071) and LD treatment of 600 mg or more per day (p ¼ 0.0442), whereas it was lower in patients treated with amantadine (p ¼ 0.0011). 3.5. NMSs and HrQOL There was a significant correlation between the nonmotor score and the HrQOL score (p < 0.0001; regression coefficient, 0.6108) as shown in Fig. 1. The HrQOL score also showed a significant correlation to all MDS-UPDRS part I sub-items. Multivariate linear regression analysis showed that a high nonmotor score was associated with a significantly lower HrQOL for patients with PD (p < 0.0001; regression coefficient, 0.60; 95% confidence interval: 0.54e0.65). This correlation remained after an adjustment for sex, age, smoking history, onset age, mH&Y (either on state or off state), medications, surgery, dyskinesia, duration of illness, caregiver burden, and the presence of a comorbidity (p < 0.0001; regression coefficient, 0.57). NMSs, regardless of severity, were investigated as one of the deteriorating factors of HrQOL. The total number of NMSs was significantly correlated with the HrQOL score (p < 0.0001; regression coefficient, 0.47). The HrQOL score also showed a significant correlation with all of the MDS-UPDRS part I sub-items. 4. Discussion The J-FIRST is the first and largest prospective clinical study to investigate the nonmotor aspects of patients with advanced-stage PD in Japan. The aim of the study was to gain a better understanding of NMSs and the various factors that affect them. From the baseline results of this cross-sectional study, it is clear that the HrQOL of patients is significantly affected by NMSs. Once available, the full results obtained from this 52-week study with 1021 patients will provide information relevant to clinicians worldwide. The primary measurements in this study were the MDS-UPDRS part I score and the PDQ-8 score, which enable analysis of NMSs and HrQOL over 52 weeks. The MDS-UPDRS part I was reported as a revised version of the UPDRS in 2007 [7], which was revised based on an increasing understanding of the impact of NMSs on the lives of patients. The Japanese version of the MDS-UPDRS was validated in 2014 [8] and is widely used in clinical trials in Japan. Part I of the MDS-UPDRS is comprehensively constructed to determine NMSs. Therefore, we adopted the MDS-UPDRS part I to detect NMSs in patients. Compared with other large-scale studies, the prevalence rates of NMSs in the J-FIRST at baseline were generally high [13e16]. The PRIAMO study was a multi-center study in Italy with 1325 PD patients. In the PRIAMO study, a structured interview was performed to evaluate the NMSs by experienced neurologists. Fatigue (58.1%), anxiety (55.8%) and leg pain (37.9%) were the most frequent NMSs. The distributions of frequent NMSs in these studies were similar to those in the J-FIRST; however, the prevalence rates were markedly different among studies. The reasons for this are unclear but
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
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T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Table 2 Severity of nonmotor symptoms and clinical backgrounds.
Sex Age, y
Onset age, y
Smoking history
On state mH&Y
Off state mH&Y
Dyskinesia Duration of illness, y
Caregiver Comorbidity
male female <60 60e69 70e79 80þ <50 50e59 60e69 70þ none >1 year (current nonsmoker) <1 year (current nonsmoker) current smoker mild moderate severe mild moderate severe negative positive 1e5 6e10 11e15 16þ negative positive negative positive
n
MDS-UPDRS part I (mean ± SD)
p value
372 624 154 369 402 71 188 343 343 120 736 205 4 51 452 483 59 89 547 357 546 450 141 381 307 165 465 531 268 728
11.27 ± 5.53 10.71 ± 5.27 11.37 ± 5.94 10.26 ± 4.96 11.11 ± 5.45 12.28 ± 5.36 11.54 ± 5.29 10.92 ± 5.66 10.64 ± 5.17 10.83 ± 5.19 10.83 ± 5.33 11.18 ± 5.51 13.25 ± 9.84 11.04 ± 5.11 10.20 ± 5.38 11.25 ± 5.18 13.56 ± 5.76 7.98 ± 4.72 10.59 ± 5.20 12.15 ± 5.45 10.36 ± 5.15 11.60 ± 5.56 9.46 ± 4.94 10.59 ± 5.34 11.38 ± 5.44 12.15 ± 5.34 10.26 ± 5.25 11.50 ± 5.41 10.44 ± 5.34 11.10 ± 5.38
0.1079 0.0463
0.0684
0.1929
<0.0001
<0.0001
0.0003 <0.0001
0.0003 0.0875
MDS-UPDRS: Movement Disorder Society version unified Parkinson's disease rating scale, mH&Y: modified Hoehn and Yahr stage, SD: standard deviation.
Table 3 Frequency and severity of each nonmotor symptom between sexes. Sub-item of MDS-UPDRS part I Total (n ¼ 996)
Female (n ¼ 624)
Male (n ¼ 372)
p value*
Prevalence n (%) Score (mean ± SD) Prevalence n (%) Score (mean ± SD) Prevalence n (%) Score (mean ± SD) Prevalence Score Cognitive impairment Hallucinations and psychosis Depressed mood Anxious mood Apathy Features of DDS Sleep problems Daytime sleepiness Pain and other sensations Urinary problems Constipation problems Light-headedness on standing Fatigue
196 (19.7) 206 (20.7) 491 (49.3) 501 (50.3) 233 (23.4) 75 (7.5) 735 (73.8) 789 (79.2) 752 (75.5) 656 (65.9) 793 (79.6) 439 (44.1) 767 (77.0)
0.23 0.29 0.63 0.66 0.32 0.10 1.32 1.44 1.30 1.16 1.53 0.69 1.25
± ± ± ± ± ± ± ± ± ± ± ± ±
0.52 0.63 0.76 0.77 0.66 0.38 1.07 0.97 1.06 1.11 1.19 0.92 0.98
114 (18.3) 127 (20.4) 318 (51.0) 325 (52.1) 142 (22.8) 35 (5.6) 456 (73.1) 487 (78.0) 475 (76.1) 387 (62.0) 486 (77.9) 264 (42.3) 497 (79.6)
0.20 0.29 0.67 0.69 0.33 0.07 1.30 1.37 1.29 1.09 1.46 0.67 1.28
± ± ± ± ± ± ± ± ± ± ± ± ±
0.45 0.65 0.79 0.79 0.68 0.31 1.06 0.96 1.05 1.12 1.16 0.92 0.96
82 (22.0) 79 (21.2) 173 (46.5) 176 (47.3) 91 (24.5) 40 (10.8) 279 (75.0) 302 (81.2) 277 (74.5) 269 (72.3) 307 (82.5) 175 (47.0) 270 (72.6)
0.29 0.28 0.57 0.61 0.32 0.15 1.36 1.55 1.30 1.27 1.65 0.73 1.20
± ± ± ± ± ± ± ± ± ± ± ± ±
0.62 0.60 0.70 0.75 0.63 0.46 1.07 0.99 1.08 1.09 1.24 0.91 1.01
0.1614 0.7468 0.1901 0.1500 0.5371 0.0041 0.5514 0.2587 0.5941 0.0009 0.0877 0.1474 0.0126
0.0099 0.7405 0.0466 0.1274 0.9004 0.0030 0.4074 0.0046 0.8618 0.0111 0.0144 0.3391 0.1894
MDS-UPDRS: Movement Disorder Society version unified Parkinson's disease rating scale, SD: standard deviation. *p value between sexes.
possible ones include different methods of surveillance or evaluation, or cultural/ethnic differences. Using the MDS-UPDRS part I may have had a strong influence on the data obtained in this study. Constipation is one of the most common NMSs and it was the most frequent NMS in the J-FIRST. The overall prevalence of constipation varies from around 30%e80% in previous reports; our results showed a relatively high prevalence [4,16,17]. A recent study found constipation to be the second most common NMS in PD (50%) following hyposmia [18]. Because there is no sub-item that directly assesses smelling function in the MDS-UPDRS, we could not determine the prevalence of hyposmia. Notably, fatigue was a common NMS in both the PRIAMO study and this study; the prevalence was reported to be between 30% and 60% [19e21]. In another study [22] of Japanese patients with PD, fatigue was identified in 41.8% of patients using a 16-item Parkinson fatigue
scale [23]. Although inclusion criteria and patient background are different among each study, our results may suggest that the MDSUPDRS part I can result in higher frequency scores. Our finding of sex-related differences in the frequency and severity of NMSs is supported by previous studies [24e27]. In the study reported by Martinez-Martin et al. [27], the prevalence and severity of the NMSs were evaluated by sex in an international sample of 951 patients with PD using the NMS scale. Fatigue, weight changes, constipation, feelings of sadness, feelings of nervousness, abnormalities in sense of taste or smell, pain, and restless legs were significantly more prevalent and severe in women than in men. Daytime sleepiness, dribbling saliva, problems having sex and reduced or increased interest in sex were significantly more frequent and severe in men. Fatigue was also a frequent NMS in females and males in the J-FIRST, whereas the prevalence of
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Fig. 1. Correlation between MDS-UPDRS part I total score and PDQ-8. The size of the circle represents the number of patients.
weight loss was unclear because the MDS-UPDRS part I does not include a sub-item associated with appetite or body weight. In the J-FIRST, fatigue was significantly more frequent in females, and features of DDS and urinary problems were more frequent in males. DDS is a well-known NMS associated with impulse control disorder. Weintraub et al. [28] identified some risk factors including male sex; our result may also suggest that impulse control disorder is a frequent NMS in males. Significant differences were also found in the severity of NMSs between sexes and this was consistent with the previous study. These data suggest that the NMSs experienced by males and females differ significantly. Therefore, the greatest improvement to quality of life is most likely to be gained when females and males are assessed and treated differently. From the recent advances in clinical studies focused on NMSs, together with this study, it appears that NMSs can be divided into two categories: long-lasting NMSs that occur throughout the course of PD, from prior PD with evident motor symptoms to death; and NMSs developed during the course of PD during modification with medical interventions. In fact, there is an association between anti-parkinsonian medications and significant changes in the prevalence and severity of almost all NMSs listed in the MDSUPDRS part I; however, determining if the change in NMSs is caused by a specific agent is difficult because of the high proportion of patients receiving multiple treatments. Exceptionally, the prevalence and severity of some NMSs were lower in patients treated with selegiline, but the mechanism could not be clarified in this study. Recent clinical concerns about NMSs typically relate to the prodromal phase or very early motor phase. Although recognition and appropriate treatment of NMSs in the early stages of PD is important, patients in the advanced stages of PD face many more difficulties related to NMSs because they may also experience wearing-off and/or dyskinesia. Therefore, J-FIRST focused on NMSs emerging in the advanced phase and their relation to HrQOL. There was a strong association between the motor severity of PD and the severity of NMSs, which has been previously reported [14,16]. In addition, the prevalence and severity of NMSs were higher during the off state than during the on state of mH&Y. This finding suggests that dopamine replacement therapy may provide some clinical benefits regarding NMSs. Because NMSs are difficult to treat and affect HrQOL, any potential treatments require further research.
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Non-dopaminergic anti-parkinsonian agents, which have a different mechanism of action than dopamine replacement therapy, are also expected to reduce the burden of NMSs, and these alternate therapies are an active area of research worldwide. One of these, an adenosine A2A receptor antagonist, has already been approved in Japan. Understanding the actual burden of NMSs in patients with advanced-stage PD is important from a clinical perspective and can also provide valuable insights for research of prodromal PD. Multivariate linear regression analysis showed the PDQ-8 score, off state mH&Y and 400 mg/day LD treatment were associated with an elevated MDS-UPDRS part I score, and treatment with amantadine was associated with a reduced MDS-UPDRS part I score. Conversely, a significant association was identified between the MDS-UPDRS part I score and the PDQ-8 score. This effect remained after adjusting for multiple clinical parameters. Both the off state for the mH&Y and 400 mg/day LD treatment were associated with increased motor dysfunction. Therefore, it is likely that the severity of PD motor dysfunction increases the risk of developing NMSs. For amantadine, there are conflicting reports on its therapeutic effects for impulse control disorder [29,30]; however, because the frequency of NMSs was low in patients treated with amantadine, we speculate that the drug may potentially have a positive effect on NMSs associated with PD. As suggested by many previous studies, the HrQOL was also strongly related to the NMS severity in patients with PD in this study. The mean number of NMSs was 6.6 (range, 1e13); this showed no significant relationship to the deterioration of the PDQ8 score in multivariate linear regression analysis. However, scores of all sub-items in the MDS-UPDRS part I correlated with a reduced PDQ-8 score, which suggests that any NMSs can lead to deterioration in HrQOL. These data and those of previous studies indicate that reducing 1 NMS will improve the HrQOL of patients with PD. Limitations of the study include that the results obtained using the MDS-UPDRS part I differ significantly from other methods, making it difficult to compare data between studies. The study was also conducted in Japan only and the results are not applicable worldwide. Finally, patients with an MMSE score 23 were excluded from the study, meaning that cognitive impairment may have been underestimated. 5. Conclusion This is the first large-scale, multicenter, observational clinical study in Japan designed to investigate the prevalence and severity of NMSs in association with clinical backgrounds and treatments of patients with PD. The prevalence and severity of some NMSs were found to be associated with sex, age, age at disease onset, duration of disease, and type of anti-parkinsonian treatments administered. There is a significant association between the severity of NMSs and HrQOL in Japanese patients. Study funding This study was supported by a grant from Kyowa Hakko Kirin, Japan. Author contributions NH and MN designed the study, coordinated its execution and data analysis and contributed to data collection. TM wrote the manuscript, contributed to data interpretation and revised the manuscript. YS contributed to data collection and revised the manuscript. KK, YT, HW and HS contributed to data collection. Statistical analysis was conducted by SC and TY.
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
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T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Conflict of interest Masahiro Nomoto received consulting fees from Hisamitsu Pharmaceutical Co. and Dainippon Sumitomo Pharma Co. Ltd.; grants from the Japanese Ministry of Health, Labour and Welfare; and honoraria from Dainippon Sumitomo Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Novartis Pharma K$K. and Ono Pharmaceutical Co. Ltd. Nobutaka Hattori received consulting fees from GlaxoSmithKline K$K. AbbVie., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Hisamitsu Pharmaceutical Co. Inc., Meiji Seika Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd. and FP Pharmaceutical Corporation; lecture fees from MSD K$K., Eli Lilly Japan K$K., Eisai Co. Ltd., FP Pharmaceutical Corporation, Otsuka Pharmaceutical Co. Ltd., Tsumura & Co., Kyowa Hakko Kirin Co. Ltd., GlaxoSmithKline K$K., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Nihon Medi-Physics Co. Ltd., Novartis Pharma K$K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd. and Daiichi Sankyo Company, Limited; honoraria from FP Pharmaceutical Corporation, Novartis Pharma K$K., Kyowa Hakko Kirin Co. Ltd. and AbbVie; research support from Otsuka Pharmaceutical Co. Ltd. and grants from Astellas Pharma Inc., Eisai Co. Ltd., GlaxoSmithKline K$K, Dainippon Sumitomo Pharma Co. Ltd., Takeda Pharmaceutical Company Limited, Novartis Pharma K$K, Pfizer Japan Inc., Kyowa Hakko Kirin Co. Ltd., Medtronic, Inc., Nippon Boehringer Ingelheim Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd. Tetsuya Maeda received lecture fees from Kyowa Hakko Kirin Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd. and Novartis Pharma K$K. Yoshio Tsuboi received lecture fees from Japan Blood Products Organization, Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Meiji Seika Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd., Nihon Medi-Physics Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Novartis Pharma K$K., Otsuka Pharmaceutical Co. Ltd. and Kyowa Hakko Kirin Co. Ltd.; and research support from Otsuka Pharmaceutical Co. Ltd. Kaketsuken, Eisai Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Daiichi Sankyo Company, Limited, Japan Blood Products Organization, Kyowa Hakko Kirin Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd. and Tsumura & Co. Kenichi Kashihara received lecture fees from Boehringer Ingelheim, Kyowa Hakko Kirin Co., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Dainippon Sumitomo Pharm Co., FP Pharmaceutical Co., Nihon Medi-Physics Co. Ltd. and Eisai Co. Ltd; and honoraria from Dainippon Sumitomo Pharm Co. Shih-Wei Chiu received lecture fees from Kyowa Hakko Kirin Co. Ltd. and honoraria from Kyowa Hakko Kirin Co. Ltd. Takuhiro Yamaguchi owns stock in Statcom Company Limited, received lecture fees from Kowa Company, Ltd., Nippon Zoki Pharmaceutical Co. Ltd., Japan Tobacco Inc., Taiho Pharmaceutical Co. Ltd. and EPS Corporation; honoraria from Ono Pharmaceutical Co. Ltd.; research support from Kyowa Hakko Kirin Co. Ltd.; and grants from EPS Corporation, Nifix, Kowa Pharmaceutical Company Ltd., MSD K$K., Pharma Consulting Group, Statcom Company Limited, Dainippon Sumitomo Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd., AC Medical Inc., A2 Healthcare Corp., FMD K & L Japan K$K., CAC Croit Corporation, Japan Tobacco Inc., Japan Media Corporation, Medidata Solutions, Inc. and Luminary Medical K$K. Hidemoto Saiki received lecture fees from Dainippon Sumitomo Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Medtronic, Inc., Takeda Pharmaceutical Company Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K$K., M3,
Inc., Eisai Co. Ltd., GlaxoSmithKline K$K. and Nihon Medi-Physics Co. Ltd.; honoraria from Elsevier Japan K.K. and Japan Medical Journal; research support from Kyowa Hakko Kirin Co. Ltd.; and grants from Otsuka Pharmaceutical Co. Ltd. and Nippon Boehringer Ingelheim Co. Ltd. Hirohisa Watanabe received lecture fees from Nippon Boehringer Ingelheim Co. Ltd., GlaxoSmithKline K$K., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., FP Pharmaceutical Corporation, Eisai Co. Ltd., Daiichi Sankyo Company, Limited, Bayer Yakuhin, Ltd. and Novartis Pharma K.K. and grants from Otsuka Pharmaceutical Co. Ltd. and FUJIFILM RI Pharma Co. Ltd. Yasushi Shimo received lecture fees from Medtronic, Inc., Dainippon Sumitomo Pharma Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Novartis Pharma K$K., Boston Scientific Corporation and Nihon Medi-Physics Co. Ltd.; research support from Kyowa Hakko Kirin Co. Ltd.; and grants from Medtronic, Inc., Kyowa Hakko Kirin Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Boston Scientific Corporation and Kissei Pharmaceutical Co. Ltd. Role of the sponsor Kyowa Hakko Kirin was involved in the process of study design and protocol development. Acknowledgments Data management was independently operated by A2 Healthcare, Japan. We are grateful to Elsevier Japan for assistance in writing the manuscript. The authors would like to thank John Gibbins, PhD, Edanz Group, for his editorial assistance. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2017.02.024. References [1] K.R. Chaudhuri, D.G. Healy, A.H.V. Schapira, Non motor symptoms of Parkinson's disease: diagnosis and management, Lancet. Neurol. 5 (2006) 235e245. [2] Z. Qin, L. Zhang, F. Sun, X. Fang, C. Meng, C. Tanner, P. Chan, Chinese Parkinson Study Group, Health related quality of life in early Parkinson's disease: impact of motor and non-motor symptoms, results from Chinese levodopa exposed cohort, Park. Relat. Disord. 15 (2009) 767e771. [3] D.A. Gallagher, A.J. Lees, A. Schrag, What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them? Mov. Disord. 25 (2010) 2493e2500. [4] P. Martinez-Martin, C. Rodriguez-Blazquez, M.M. Kurtis, K.R. Chaudhuri NMSS Validation Group, The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease, Mov. Disord. 26 (2011) 399e406. [5] B.S. Connolly, A.E. Lang, Pharmacological treatment of Parkinson disease: a review, JAMA 311 (2014) 1670e1683. [6] K. Seppi, D. Weintraub, M. Coelho, S. Perez-Lloret, S.H. Fox, R. Katzenschlager, E.M. Hametner, W. Poewe, O. Rascol, C.G. Goetz, C. Sampaio, The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease, Mov. Disord. 26 (Suppl 3) (2011) S42eS80. [7] C.G. Goetz, S. Fahn, P. Martinez-Martin, W. Poewe, C. Sampaio, G.T. Stebbins, M.B. Stern, B.C. Tilley, R. Dodel, B. Dubois, R. Holloway, J. Jankovic, J. Kulisecsky, A.E. Lang, A. Lees, S. Leurgans, P.A. LeWitt, D. Nyenhuis, C.W. Olanow, O. Rascol, A. Schrag, J.A. Teresi, J.J. Van Hilten, N. LaPelle, Movement Disorder Society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): process, format, and clinimetric testing plan, Mov. Disord. 22 (2007) 41e47. [8] K. Kashihara, T. Kondo, Y. Mizuno, S. Kikuchi, S. Kuno, K. Hasegawa, N. Hattori, H. Mochizuki, H. Mori, M. Murata, M. Nomoto, R. Takahashi, A. Takeda, Y. Tsuboi, Y. Ugawa, M. Yamanmoto, F. Yokochi, F. Yoshii, G.T. Stebins, B.C. Tilley, S. Luo, L. Wang, N.R. LaPelle, C.G. Goetz, MDS-UPDRS Japanese validation study group, official Japanese version of the International Parkinson
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
and Movement Disorder Societyeunified Parkinson's disease rating scale: validation against the original english version, Mov. Disord. Clin. Pract. 1 (2014) 200e212. V. Peto, C. Jenkinson, R. Fitzpatrick, R. Greenhall, The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease, Qual. Life. Res. 4 (1995) 241e248. C. Jenkinson, R. Fitzpatrick, V. Peto, R. Greenhall, N. Hyman, The PDQ-8: development and validation of a short-form Parkinson's disease questionnaire, Psychol. Health 12 (1997) 805e814. W.R. Gibb, A.J. Lees, The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 511 (1988) 745e752. C.L. Tomlinson, R. Stowe, S. Patel, C. Rick, R. Gray, C.E. Clarke, Systematic review of levodopa dose equivalency reporting in Parkinson's disease, Mov. Disord. 25 (2010) 2649e2685. K.R. Chaudhuri, P. Martinez-Martin, A.H. Schapira, F. Stocchi, K. Sethi, P. Odin, P.G. Brown, W. Koller, P. Barone, G. MacPhee, L. Kelly, M. Rabey, D. MacMahon, S. Thomas, W. Ondo, D. Rye, A. Forbes, S. Tluk, V. Dhawan, A. Bowron, A.J. Wilians, C.W. Olanow, International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study, Mov. Disord. 21 (2006) 916e923. P. Martinez-Martin, A.H. Schapira, F. Stocchi, K. Sethi, P. Odin, G. MacPhee, R.G. Brown, Y. Naidu, L. Clayton, K. Abe, Y. Tsuboi, D. MacMahon, P. Barone, M. Rabey, U. Bonuccelli, A. Forbes, K. Breen, S. Tluk, C.W. Olanow, S. Thomas, D. Rye, A. Hand, A.J. Williams, W. Ondo, K.R. Chaudhuri, Prevalence of nonmotor symptoms in Parkinson's disease in an international setting; study using nonmotor symptoms questionnaire in 545 patients, Mov. Disord. 22 (2007) 1623e1629. A. Antonini, C. Colosimo, R. Marconi, L. Morgante, P. Barone, PRIAMO Study Group, The PRIAMO study: background, methods and recruitment, Neurol. Sci. 29 (2008) 61e65. P. Barone, A. Antonini, C. Colosimo, R. Marconi, L. Morgante, T.P. Avarello, E. Bottacchi, A. Cannas, G. Ceravolo, R. Ceravolo, G. Cicarelli, R.M. Gaglio, R.M. Giglia, F. Iemolo, M. Manfredi, G. Meco, A. Nicoletti, M. Pederzoli, A. Petrone, A. Pisani, F.E. Pontieri, R. Quatrale, S. Ramat, R. Scala, G. Volpe, S. Zappulla, A.R. Bentivoglio, F. Stocchi, G. Trianni, P.D. Dotto, PRIAMO study group, The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease, Mov. Disord. 24 (2009) 1641e1649. C. Pont-Sunyer, A. Hotter, C. Gaig, K. Seppi, Y. Compta, R. Katzenschlager, s, K. Wenzel, J. Infante, H. Zach, N. Mas, D. Hofeneder, T. Brücke, A. Baye n, L. Ispierto, O. De F abregues, A. Calle W. Pirker, I.J. Posada, R. Alvarez, A. Palasí, M. Aguilar, M.J. Martí, F. Valldeoriola, M. Salamero, W. Poewe,
[18]
[19]
[20]
[21] [22]
[23] [24] [25] [26]
[27]
[28]
[29]
[30]
7
E. Tolosa, The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study), Mov. Disord. 30 (2015) 229e237. H. Chen, E.J. Zhao, W. Zhang, Y. Lu, R. Liu, X. Huang, A.J. Ciesielski-Jones, M.A. Justice, D.S. Cousins, S. Peddada, Meta-analyses on prevalence of selected Parkinson's nonmotor symptoms before and after diagnosis, Transl. Neurodegener. 4 (2015) 1. J.J. van Hilten, G. Hoogland, E.A. van der Veld, H.A. Middelkoop, G.A. Kerkhof, R.A. Roos, Diurnal effects of motor activity and fatigue in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 56 (1993) 874e877. L.M. Shulman, R.L. Taback, A.A. Rabinstein, W.J. Weiner, Non-recognition of depression and other non-motor symptoms in Parkinson's disease, Park. Relat. Disord. 8 (2002) 193e197. K. Karlsen, J.P. Larsen, E. Tandberg, K. Jorgensen, Fatigue in patients with Parkinson's disease, Mov. Disord. 14 (1999) 237e241. Y. Okuma, S. Kamei, A. Morita, F. Yoshii, T. Yamamoto, S. Hashimoto, H. Utsumi, T. Hatano, N. Hattori, M. Matsumura, K. Takahashi, S. Nogawa, Y. Watanabe, T. Miyamoto, M. Miyamoto, K. Hirata, Fatigue in Japanese patients with Parkinson's disease: a study using Parkinson fatigue scale, Mov. Disord. 24 (2009) 1977e1983. R.G. Brown, A. Dittner, L. Findley, S.C. Wessely, The Parkinson fatigue scale, Park. Relat. Disord. 11 (2005) 49e55. S. Solimeo, S. Sex and gender in older adults' experience of Parkinson's disease, J. Gerontol. B. Psychol. Sci. Soc. Sci. 63 (2008) S42eS48. I.N. Miller, A. Cronin-Golomb, Gender differences in Parkinson's disease: clinical characteristics and cognition, Mov. Disord. 25 (2010) 2695e2703. S. Krishnan, G. Sarma, S. Sarma, A. Kishore, Do nonmotor symptoms in Parkinson's disease differ from normal aging? Mov. Disord. 26 (2011) 2110e2113. P. Martinez-Martin, C. Falup Pecurariu, P. Odin, J.J. van Hilten, A. Antonini, J.M. Rojo-Abuin, V. Borges, C. Trenkwalder, D. Aarsland, D.J. Brooks, K. Ray Chaudhuri, Gender-related differences in the burden of non-motor symptoms in Parkinson's disease, J. Neurol. 259 (2012) 1639e1647. D. Weintraub, A.S. David, A.H. Evans, J.E. Grant, M. Stacy, Clinical spectrum of impulse control disorders in Parkinson's disease, Mov. Disord. 30 (2015) 121e127. A. Thomas, L. Bonanni, F. Gambi, A. Di Lorio, M. Onofrj, Pathological gambling in Parkinson disease is reduced by amantadine, Ann. Neurol. 68 (2010) 400e404. D. Weintraub, M. Sohr, M.N. Potenza, A.D. Siderowf, M. Stacy, V. Voon, J. Whetteckey, G.R. Wunderlich, A.E. Lang, Amantadine use associated with impulse control disorders in Parkinson disease in cross-sectional study, Ann. Neurol. 68 (2010) 963e968.
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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers Tetsuya Maeda, MD, PhD a, b, *, Yasushi Shimo, MD, PhD c, Shih-Wei Chiu, MS d, Takuhiro Yamaguchi, PhD d, Kenichi Kashihara, MD, PhD e, Yoshio Tsuboi, MD, PhD f, Masahiro Nomoto, MD, PhD g, Nobutaka Hattori, MD, PhD c, Hirohisa Watanabe, MD, PhD h, Hidemoto Saiki, MD, PhD i, on behalf of the J-FIRST group a
Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan b Department of Neurology and Movement Disorder Research, Research Institute for Brain and Blood Vessels-Akita, 6-10 Senshukubotamachi, Akita 0100874, Japan c Department of Neurology, Juntendo University School of Medicine 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan d Division of Biostatistics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan e Department of Neurology, Okayama Kyokuto Hospital, 567-1 Kurata, Okayama, 703-8265, Japan f Department of Neurology, Faculty of Medicine, Fukuoka University, 3-1-1, Maidashi, Higashi-ku, Fukuoka City, 812-8582, Japan g Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, 454 Shizukawa, Tohon, Ehime 791-0295, Japan h Brain and Mind Research Center, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan i Department of Neurology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 October 2016 Received in revised form 27 December 2016 Accepted 19 February 2017
Introduction: We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD). Methods: A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDSUPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study. Results: The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (72.0%). Fatigue was an NMS that affected 79.6% of females but only 72.6% of males, whereas features of dopamine dysregulation syndrome affected only 5.6% of females and 10.8% of males. Positive correlations were found between the MDS-UPDRS part I and the PDQ-8 (p < 0.0001, r ¼ 0.56) and between the number of NMSs and the PDQ-8 score (p < 0.0001, r ¼ 0.47). Conclusions: This study revealed distinctive patterns of NMSs in Japanese patients with PD and suggested that the prevalence and severity of NMSs vary between sexes, and that the NMSs are important factors affecting the long-term quality of life of PD patients. © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Parkinson's disease Nonmotor symptoms Japan Quality of life
* Corresponding author. Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan. E-mail addresses: [email protected] (T. Maeda), [email protected] (Y. Shimo), [email protected] (S.-W. Chiu), [email protected] (T. Yamaguchi), [email protected] (K. Kashihara), [email protected] (Y. Tsuboi), [email protected] (M. Nomoto), [email protected] (N. Hattori), [email protected] (H. Watanabe), [email protected] (H. Saiki). http://dx.doi.org/10.1016/j.parkreldis.2017.02.024 1353-8020/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
2
T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
1. Introduction
2.3. Evaluation schedule
Parkinson's disease (PD) is characterized by some cardinal motor features, including resting tremor, muscle rigidity, akinesia and postural instability. Alleviation of motor symptoms directly improves clinical prognosis and health-related quality of life (HrQOL). In addition to motor symptoms, PD can cause nonmotor symptoms (NMSs), such as autonomic failure, sensory problems, mood disorders and sleep disorders [1], which can have a significant impact on patients' HrQOL [2e4], especially in the advanced stage in clinical practice. Because dopamine replacement therapy is generally ineffective against NMSs [5,6], physicians must carefully assess patients on a case-by-case basis and determine the appropriate treatment based on their NMSs. In practice, there is relatively little evidence regarding clinical management of NMSs compared with motor symptoms. Because PD patients typically have multiple NMSs, the number of NMSs may have a subclinical importance. Therefore, this observational study was planned to gain a better understanding of the NMSs affecting Japanese patients with PD, taking into consideration other factors that may affect patients' NMSs and/or HrQOL, including clinical backgrounds and antiparkinsonian medical interventions. In this paper, we describe the clinical manifestations of NMSs and their effects on HrQOL.
A baseline structured interview and a neurological examination were performed to obtain baseline clinical characteristics of patients. The presence and severity of NMSs were evaluated using the MDS-UPDRS part I. Motor complications were also evaluated using the MDS-UPDRS part IV. Overall motor disability was evaluated in on and off states using the modified Hoehn and Yahr scale (mH&Y). Because it was impractical to assess both on and off states directly in office visits for each patient, patients reported their worst state to the attending physician (a neurologist well-versed in the treatment of movement disorders), who then judged the level of H&Y based on the patients' recollections. The HrQOL was evaluated with the PDQ-8. Anti-parkinsonian medical interventions were recorded, including daily dose of LDs, dopamine agonists, dopamine economizers, non-dopaminergic agents and method of functional neurosurgery (if applicable). Patients continue to be evaluated at every subsequent visit during the 52-week study period.
2. Methods 2.1. Study design This is the first-in-Japan large-scale observational study for NMSs and treatment in patients with PD (J-FIRST). A target sample size of 1000 advanced-stage PD patients was planned in light of the feasibility of the study and the number of patients required for identification of the factors related to NMSs. This prospective study is currently being conducted in 35 sites between February 2014 and December 2016 (see Supplementary Information for list of sites and investigators). Patients were enrolled between March 2014 and January 2015 in participating medical centers throughout Japan and are being prospectively examined for 52 weeks. The primary measurements include the interval changes over 52 weeks for the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) part I [7,8] and the eight-item PD questionnaire (PDQ-8) [9,10] both of which were translated into Japanese. The cross-sectional analysis is designed to investigate the prevalence, severity and number of NMSs and the relationship with HrQOL at baseline of the J-FIRST. Ethics review committees of each study site approved this study. All patients provided written informed consent. The study is registered at clinicaltrials.gov (NCT02073981) and umin. ac.jp/ctr/ index-j.htm (UMIN000013161).
2.2. Eligibility criteria Patients with advanced-stage PD, as diagnosed according to the United Kingdom PD Society Brain Bank clinical diagnostic criteria [11], were eligible for this study if they met the following inclusion criteria: wearing-off of treatment with levodopa-containing drugs (LDs), 1 NMS assessed by MDS-UPDRS part I, 20 years old at the time of consent, gave written consent and were receiving outpatient care. Patients were excluded if they met the following criteria: dementia or a Mini-Mental State Examination score (MMSE) 23, or conditions impairing the proper assessment of the MDS-UPDRS or the PDQ-8, as determined by the investigator.
2.4. Statistical analysis The prevalence is summarized using frequency and percentage, and the MDS-UPDRS part I scores and the PDQ-8 scores are summarized by sample size and mean ± standard deviation. Comparisons between demographic variables and the MDS-UPDRS part I score were performed by t-test, analysis of covariance for mean values, Fisher exact test for prevalence, or ManteleHaenszel test for ordered categorized data. Age, onset age, duration of illness, mH&Y, smoking history and LD dosage were each divided into three or four subcategories and results were compared among them. To determine the relationship between total score for the MDS-UPDRS part I and the PDQ-8, a multivariate linear regression model was used. Associations between the MDS-UPDRS part I score and the PDQ-8, and between total number of NMSs and the PDQ-8 were evaluated using Pearson correlation coefficients. A two-sided p-value with a significance level of 5% was applied. Statistical analysis was performed using SAS software (ver.9.4; SAS Institute Inc., Cary, NC, USA).
3. Results 3.1. Baseline clinical backgrounds In total, 1021 patients were enrolled. Of these patients, three did not meet the eligibility criteria, five withdrew consent, five satisfied the study criteria but were ineligible to continue because of hospitalization, death or difficulty in evaluation, and 12 had no wearing-off under treatment with LDs, as determined by MDSUPDRS part IV screening at baseline. Therefore, 996 patients entered the observational period (Supplementary Fig. 1). Baseline clinical characteristics are shown in Table 1. Briefly, 624 females and 372 males had a mean age of 68.1 years and median duration of illness of 10 years; mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively, and the mean number of NMSs was 6.6. The mean levodopa equivalent dose was 769.5 ± 339.0 mg/day [12]. All patients had previously been treated with LDs; dopamine agonists were used in ~80% of patients. Non-ergot agonists were predominantly used rather than ergot agonists. Selegiline and entacapone were commonly used as adjunctive therapy with LDs. Some non-dopaminergic agents are also used in Japan, such as droxidopa, zonisamide and istradefylline. Functional brain surgery was performed in 3.4% of patients and deep brain stimulation in 3.2% of patients.
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
3.2. Nonmotor severity and clinical backgrounds Table 2 shows the comparison between the nonmotor scores and clinical backgrounds. No significant differences were found in the nonmotor scores based on sex, onset age, smoking history or comorbidity. However, the nonmotor scores significantly increased with age. The clinical severity of motor symptoms, as determined by the on and off state mH&Y, dyskinesia and duration of illness, was associated with higher nonmotor scores. Patients living with a caregiver also had significantly higher nonmotor scores. Elevated nonmotor scores were also found in patients taking the following anti-parkinsonian medications: apomorphine (13.50 ± 6.26 vs. 10.85 ± 5.33; p ¼ 0.0099), rotigotine (12.07 ± 5.29 vs. 10.69 ± 5.36; p ¼ 0.0023), entacapone (11.63 ± 5.59 vs. 10.45 ± 5.17; p ¼ 0.0007) and istradefylline (11.80 ± 5.73 vs. 10.72 ± 5.27; p ¼ 0.0146). Nonmotor scores were higher in patients taking higher doses of LDs: 9.59 ± 4.97 (<400 mg), 11.30 ± 5.30 (400e599 mg), and 12.30 ± 5.66 (600 mg) (p < 0.0001). The nonmotor scores were also significantly higher in patients who had functional surgery (13.43 ± 5.09 vs. 10.83 ± 5.36; p ¼ 0.0049). Patients treated with selegiline had significantly lower nonmotor scores (10.45 ± 5.17 vs. 11.63 ± 5.59; p ¼ 0.0051). Less than 10% of patients were treated with ergot agonists, talipexole, apomorphine, droxidopa or functional surgery.
3.3. Prevalence and severity of each NMS between sexes The most frequent NMSs included constipation, sleep problems, pain and other sensations, daytime sleepiness, fatigue, urinary problems and anxious mood. Severe NMSs included constipation, daytime sleepiness, sleep problems, pain and other sensations, fatigue, and urinary problems. The distribution of NMSs was different between sexes, with features of dopamine dysregulation syndrome (DDS) and urinary problems significantly more common in males, and fatigue being more common in females (Table 3). Cognitive impairment, features of DDS, daytime sleepiness, urinary problems and constipation problems were more severe in males, and depressed moods were more severe in females.
Table 1 Clinical characteristics at baseline. Total number (n ¼ 996) Sex, n, female:male (%) Age (y), mean ± SD Duration of illness (y), median ± IQR Levodopa equivalent dose (mg/day), mean ± SD On state mH&Ya, n (%) mild moderate severe unrated Off state mH&Ya, n (%) mild moderate severe unrated Score of NMSb, mean ± SD Number of NMSc, n, mean ± SD PDQ-8, mean ± SD
624:372 (62.7:37.4) 68.1 ± 8.8 10 ± 7 769.5 ± 339.0 452 (45.4) 483 (48.5) 59 (5.9) 2 (0.2) 89 (8.9) 547 (54.9) 357 (35.8) 3 (0.3) 10.9 ± 5.4 6.6 ± 2.5 7.3 ± 5.2
SD: standard deviation, IQR: interquartile range, mH&Y: modified Hoehn and Yahr stage, MDS-UPDRS: Movement Disorder Society version unified Parkinson's disease rating scale, PDQ-8: 8 items of Parkinson's Disease questionnaire. a Modified H&Y stages divided as mild, moderate and severe were stage 0e2, stage 2.5 and 3, stage 4 and 5. b MDS-UPDRS part I score. c Number of sub-items with MDS-UPDRS part I scoring 1 to 4.
3
3.4. Multivariate linear regression analysis in clinical severity of NMSs and HrQOL Multivariate linear regression analysis was performed for the nonmotor scores against all clinical parameters under adjustment with sex (male), age (less than 60 years), onset age (less than 50 years), smoking history (none), on state mH&Y (stage 0), off state mH&Y (stage 0), LD dosage (less than 400 mg/day), all antiparkinsonian drugs (none), dopamine agonists (none) and functional surgery (none). The nonmotor score was higher in patients with a higher HrQOL score (p < 0.0001), moderate off-state mH&Y (p ¼ 0.0075), severe off-state mH&Y (p ¼ 0.0458), LD treatment from 400 to 599 mg per day (p ¼ 0.0071) and LD treatment of 600 mg or more per day (p ¼ 0.0442), whereas it was lower in patients treated with amantadine (p ¼ 0.0011). 3.5. NMSs and HrQOL There was a significant correlation between the nonmotor score and the HrQOL score (p < 0.0001; regression coefficient, 0.6108) as shown in Fig. 1. The HrQOL score also showed a significant correlation to all MDS-UPDRS part I sub-items. Multivariate linear regression analysis showed that a high nonmotor score was associated with a significantly lower HrQOL for patients with PD (p < 0.0001; regression coefficient, 0.60; 95% confidence interval: 0.54e0.65). This correlation remained after an adjustment for sex, age, smoking history, onset age, mH&Y (either on state or off state), medications, surgery, dyskinesia, duration of illness, caregiver burden, and the presence of a comorbidity (p < 0.0001; regression coefficient, 0.57). NMSs, regardless of severity, were investigated as one of the deteriorating factors of HrQOL. The total number of NMSs was significantly correlated with the HrQOL score (p < 0.0001; regression coefficient, 0.47). The HrQOL score also showed a significant correlation with all of the MDS-UPDRS part I sub-items. 4. Discussion The J-FIRST is the first and largest prospective clinical study to investigate the nonmotor aspects of patients with advanced-stage PD in Japan. The aim of the study was to gain a better understanding of NMSs and the various factors that affect them. From the baseline results of this cross-sectional study, it is clear that the HrQOL of patients is significantly affected by NMSs. Once available, the full results obtained from this 52-week study with 1021 patients will provide information relevant to clinicians worldwide. The primary measurements in this study were the MDS-UPDRS part I score and the PDQ-8 score, which enable analysis of NMSs and HrQOL over 52 weeks. The MDS-UPDRS part I was reported as a revised version of the UPDRS in 2007 [7], which was revised based on an increasing understanding of the impact of NMSs on the lives of patients. The Japanese version of the MDS-UPDRS was validated in 2014 [8] and is widely used in clinical trials in Japan. Part I of the MDS-UPDRS is comprehensively constructed to determine NMSs. Therefore, we adopted the MDS-UPDRS part I to detect NMSs in patients. Compared with other large-scale studies, the prevalence rates of NMSs in the J-FIRST at baseline were generally high [13e16]. The PRIAMO study was a multi-center study in Italy with 1325 PD patients. In the PRIAMO study, a structured interview was performed to evaluate the NMSs by experienced neurologists. Fatigue (58.1%), anxiety (55.8%) and leg pain (37.9%) were the most frequent NMSs. The distributions of frequent NMSs in these studies were similar to those in the J-FIRST; however, the prevalence rates were markedly different among studies. The reasons for this are unclear but
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
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T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Table 2 Severity of nonmotor symptoms and clinical backgrounds.
Sex Age, y
Onset age, y
Smoking history
On state mH&Y
Off state mH&Y
Dyskinesia Duration of illness, y
Caregiver Comorbidity
male female <60 60e69 70e79 80þ <50 50e59 60e69 70þ none >1 year (current nonsmoker) <1 year (current nonsmoker) current smoker mild moderate severe mild moderate severe negative positive 1e5 6e10 11e15 16þ negative positive negative positive
n
MDS-UPDRS part I (mean ± SD)
p value
372 624 154 369 402 71 188 343 343 120 736 205 4 51 452 483 59 89 547 357 546 450 141 381 307 165 465 531 268 728
11.27 ± 5.53 10.71 ± 5.27 11.37 ± 5.94 10.26 ± 4.96 11.11 ± 5.45 12.28 ± 5.36 11.54 ± 5.29 10.92 ± 5.66 10.64 ± 5.17 10.83 ± 5.19 10.83 ± 5.33 11.18 ± 5.51 13.25 ± 9.84 11.04 ± 5.11 10.20 ± 5.38 11.25 ± 5.18 13.56 ± 5.76 7.98 ± 4.72 10.59 ± 5.20 12.15 ± 5.45 10.36 ± 5.15 11.60 ± 5.56 9.46 ± 4.94 10.59 ± 5.34 11.38 ± 5.44 12.15 ± 5.34 10.26 ± 5.25 11.50 ± 5.41 10.44 ± 5.34 11.10 ± 5.38
0.1079 0.0463
0.0684
0.1929
<0.0001
<0.0001
0.0003 <0.0001
0.0003 0.0875
MDS-UPDRS: Movement Disorder Society version unified Parkinson's disease rating scale, mH&Y: modified Hoehn and Yahr stage, SD: standard deviation.
Table 3 Frequency and severity of each nonmotor symptom between sexes. Sub-item of MDS-UPDRS part I Total (n ¼ 996)
Female (n ¼ 624)
Male (n ¼ 372)
p value*
Prevalence n (%) Score (mean ± SD) Prevalence n (%) Score (mean ± SD) Prevalence n (%) Score (mean ± SD) Prevalence Score Cognitive impairment Hallucinations and psychosis Depressed mood Anxious mood Apathy Features of DDS Sleep problems Daytime sleepiness Pain and other sensations Urinary problems Constipation problems Light-headedness on standing Fatigue
196 (19.7) 206 (20.7) 491 (49.3) 501 (50.3) 233 (23.4) 75 (7.5) 735 (73.8) 789 (79.2) 752 (75.5) 656 (65.9) 793 (79.6) 439 (44.1) 767 (77.0)
0.23 0.29 0.63 0.66 0.32 0.10 1.32 1.44 1.30 1.16 1.53 0.69 1.25
± ± ± ± ± ± ± ± ± ± ± ± ±
0.52 0.63 0.76 0.77 0.66 0.38 1.07 0.97 1.06 1.11 1.19 0.92 0.98
114 (18.3) 127 (20.4) 318 (51.0) 325 (52.1) 142 (22.8) 35 (5.6) 456 (73.1) 487 (78.0) 475 (76.1) 387 (62.0) 486 (77.9) 264 (42.3) 497 (79.6)
0.20 0.29 0.67 0.69 0.33 0.07 1.30 1.37 1.29 1.09 1.46 0.67 1.28
± ± ± ± ± ± ± ± ± ± ± ± ±
0.45 0.65 0.79 0.79 0.68 0.31 1.06 0.96 1.05 1.12 1.16 0.92 0.96
82 (22.0) 79 (21.2) 173 (46.5) 176 (47.3) 91 (24.5) 40 (10.8) 279 (75.0) 302 (81.2) 277 (74.5) 269 (72.3) 307 (82.5) 175 (47.0) 270 (72.6)
0.29 0.28 0.57 0.61 0.32 0.15 1.36 1.55 1.30 1.27 1.65 0.73 1.20
± ± ± ± ± ± ± ± ± ± ± ± ±
0.62 0.60 0.70 0.75 0.63 0.46 1.07 0.99 1.08 1.09 1.24 0.91 1.01
0.1614 0.7468 0.1901 0.1500 0.5371 0.0041 0.5514 0.2587 0.5941 0.0009 0.0877 0.1474 0.0126
0.0099 0.7405 0.0466 0.1274 0.9004 0.0030 0.4074 0.0046 0.8618 0.0111 0.0144 0.3391 0.1894
MDS-UPDRS: Movement Disorder Society version unified Parkinson's disease rating scale, SD: standard deviation. *p value between sexes.
possible ones include different methods of surveillance or evaluation, or cultural/ethnic differences. Using the MDS-UPDRS part I may have had a strong influence on the data obtained in this study. Constipation is one of the most common NMSs and it was the most frequent NMS in the J-FIRST. The overall prevalence of constipation varies from around 30%e80% in previous reports; our results showed a relatively high prevalence [4,16,17]. A recent study found constipation to be the second most common NMS in PD (50%) following hyposmia [18]. Because there is no sub-item that directly assesses smelling function in the MDS-UPDRS, we could not determine the prevalence of hyposmia. Notably, fatigue was a common NMS in both the PRIAMO study and this study; the prevalence was reported to be between 30% and 60% [19e21]. In another study [22] of Japanese patients with PD, fatigue was identified in 41.8% of patients using a 16-item Parkinson fatigue
scale [23]. Although inclusion criteria and patient background are different among each study, our results may suggest that the MDSUPDRS part I can result in higher frequency scores. Our finding of sex-related differences in the frequency and severity of NMSs is supported by previous studies [24e27]. In the study reported by Martinez-Martin et al. [27], the prevalence and severity of the NMSs were evaluated by sex in an international sample of 951 patients with PD using the NMS scale. Fatigue, weight changes, constipation, feelings of sadness, feelings of nervousness, abnormalities in sense of taste or smell, pain, and restless legs were significantly more prevalent and severe in women than in men. Daytime sleepiness, dribbling saliva, problems having sex and reduced or increased interest in sex were significantly more frequent and severe in men. Fatigue was also a frequent NMS in females and males in the J-FIRST, whereas the prevalence of
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Fig. 1. Correlation between MDS-UPDRS part I total score and PDQ-8. The size of the circle represents the number of patients.
weight loss was unclear because the MDS-UPDRS part I does not include a sub-item associated with appetite or body weight. In the J-FIRST, fatigue was significantly more frequent in females, and features of DDS and urinary problems were more frequent in males. DDS is a well-known NMS associated with impulse control disorder. Weintraub et al. [28] identified some risk factors including male sex; our result may also suggest that impulse control disorder is a frequent NMS in males. Significant differences were also found in the severity of NMSs between sexes and this was consistent with the previous study. These data suggest that the NMSs experienced by males and females differ significantly. Therefore, the greatest improvement to quality of life is most likely to be gained when females and males are assessed and treated differently. From the recent advances in clinical studies focused on NMSs, together with this study, it appears that NMSs can be divided into two categories: long-lasting NMSs that occur throughout the course of PD, from prior PD with evident motor symptoms to death; and NMSs developed during the course of PD during modification with medical interventions. In fact, there is an association between anti-parkinsonian medications and significant changes in the prevalence and severity of almost all NMSs listed in the MDSUPDRS part I; however, determining if the change in NMSs is caused by a specific agent is difficult because of the high proportion of patients receiving multiple treatments. Exceptionally, the prevalence and severity of some NMSs were lower in patients treated with selegiline, but the mechanism could not be clarified in this study. Recent clinical concerns about NMSs typically relate to the prodromal phase or very early motor phase. Although recognition and appropriate treatment of NMSs in the early stages of PD is important, patients in the advanced stages of PD face many more difficulties related to NMSs because they may also experience wearing-off and/or dyskinesia. Therefore, J-FIRST focused on NMSs emerging in the advanced phase and their relation to HrQOL. There was a strong association between the motor severity of PD and the severity of NMSs, which has been previously reported [14,16]. In addition, the prevalence and severity of NMSs were higher during the off state than during the on state of mH&Y. This finding suggests that dopamine replacement therapy may provide some clinical benefits regarding NMSs. Because NMSs are difficult to treat and affect HrQOL, any potential treatments require further research.
5
Non-dopaminergic anti-parkinsonian agents, which have a different mechanism of action than dopamine replacement therapy, are also expected to reduce the burden of NMSs, and these alternate therapies are an active area of research worldwide. One of these, an adenosine A2A receptor antagonist, has already been approved in Japan. Understanding the actual burden of NMSs in patients with advanced-stage PD is important from a clinical perspective and can also provide valuable insights for research of prodromal PD. Multivariate linear regression analysis showed the PDQ-8 score, off state mH&Y and 400 mg/day LD treatment were associated with an elevated MDS-UPDRS part I score, and treatment with amantadine was associated with a reduced MDS-UPDRS part I score. Conversely, a significant association was identified between the MDS-UPDRS part I score and the PDQ-8 score. This effect remained after adjusting for multiple clinical parameters. Both the off state for the mH&Y and 400 mg/day LD treatment were associated with increased motor dysfunction. Therefore, it is likely that the severity of PD motor dysfunction increases the risk of developing NMSs. For amantadine, there are conflicting reports on its therapeutic effects for impulse control disorder [29,30]; however, because the frequency of NMSs was low in patients treated with amantadine, we speculate that the drug may potentially have a positive effect on NMSs associated with PD. As suggested by many previous studies, the HrQOL was also strongly related to the NMS severity in patients with PD in this study. The mean number of NMSs was 6.6 (range, 1e13); this showed no significant relationship to the deterioration of the PDQ8 score in multivariate linear regression analysis. However, scores of all sub-items in the MDS-UPDRS part I correlated with a reduced PDQ-8 score, which suggests that any NMSs can lead to deterioration in HrQOL. These data and those of previous studies indicate that reducing 1 NMS will improve the HrQOL of patients with PD. Limitations of the study include that the results obtained using the MDS-UPDRS part I differ significantly from other methods, making it difficult to compare data between studies. The study was also conducted in Japan only and the results are not applicable worldwide. Finally, patients with an MMSE score 23 were excluded from the study, meaning that cognitive impairment may have been underestimated. 5. Conclusion This is the first large-scale, multicenter, observational clinical study in Japan designed to investigate the prevalence and severity of NMSs in association with clinical backgrounds and treatments of patients with PD. The prevalence and severity of some NMSs were found to be associated with sex, age, age at disease onset, duration of disease, and type of anti-parkinsonian treatments administered. There is a significant association between the severity of NMSs and HrQOL in Japanese patients. Study funding This study was supported by a grant from Kyowa Hakko Kirin, Japan. Author contributions NH and MN designed the study, coordinated its execution and data analysis and contributed to data collection. TM wrote the manuscript, contributed to data interpretation and revised the manuscript. YS contributed to data collection and revised the manuscript. KK, YT, HW and HS contributed to data collection. Statistical analysis was conducted by SC and TY.
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024
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T. Maeda et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Conflict of interest Masahiro Nomoto received consulting fees from Hisamitsu Pharmaceutical Co. and Dainippon Sumitomo Pharma Co. Ltd.; grants from the Japanese Ministry of Health, Labour and Welfare; and honoraria from Dainippon Sumitomo Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Novartis Pharma K$K. and Ono Pharmaceutical Co. Ltd. Nobutaka Hattori received consulting fees from GlaxoSmithKline K$K. AbbVie., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Hisamitsu Pharmaceutical Co. Inc., Meiji Seika Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd. and FP Pharmaceutical Corporation; lecture fees from MSD K$K., Eli Lilly Japan K$K., Eisai Co. Ltd., FP Pharmaceutical Corporation, Otsuka Pharmaceutical Co. Ltd., Tsumura & Co., Kyowa Hakko Kirin Co. Ltd., GlaxoSmithKline K$K., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Nihon Medi-Physics Co. Ltd., Novartis Pharma K$K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd. and Daiichi Sankyo Company, Limited; honoraria from FP Pharmaceutical Corporation, Novartis Pharma K$K., Kyowa Hakko Kirin Co. Ltd. and AbbVie; research support from Otsuka Pharmaceutical Co. Ltd. and grants from Astellas Pharma Inc., Eisai Co. Ltd., GlaxoSmithKline K$K, Dainippon Sumitomo Pharma Co. Ltd., Takeda Pharmaceutical Company Limited, Novartis Pharma K$K, Pfizer Japan Inc., Kyowa Hakko Kirin Co. Ltd., Medtronic, Inc., Nippon Boehringer Ingelheim Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd. Tetsuya Maeda received lecture fees from Kyowa Hakko Kirin Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd. and Novartis Pharma K$K. Yoshio Tsuboi received lecture fees from Japan Blood Products Organization, Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Meiji Seika Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd., Nihon Medi-Physics Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Novartis Pharma K$K., Otsuka Pharmaceutical Co. Ltd. and Kyowa Hakko Kirin Co. Ltd.; and research support from Otsuka Pharmaceutical Co. Ltd. Kaketsuken, Eisai Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Daiichi Sankyo Company, Limited, Japan Blood Products Organization, Kyowa Hakko Kirin Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd. and Tsumura & Co. Kenichi Kashihara received lecture fees from Boehringer Ingelheim, Kyowa Hakko Kirin Co., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Dainippon Sumitomo Pharm Co., FP Pharmaceutical Co., Nihon Medi-Physics Co. Ltd. and Eisai Co. Ltd; and honoraria from Dainippon Sumitomo Pharm Co. Shih-Wei Chiu received lecture fees from Kyowa Hakko Kirin Co. Ltd. and honoraria from Kyowa Hakko Kirin Co. Ltd. Takuhiro Yamaguchi owns stock in Statcom Company Limited, received lecture fees from Kowa Company, Ltd., Nippon Zoki Pharmaceutical Co. Ltd., Japan Tobacco Inc., Taiho Pharmaceutical Co. Ltd. and EPS Corporation; honoraria from Ono Pharmaceutical Co. Ltd.; research support from Kyowa Hakko Kirin Co. Ltd.; and grants from EPS Corporation, Nifix, Kowa Pharmaceutical Company Ltd., MSD K$K., Pharma Consulting Group, Statcom Company Limited, Dainippon Sumitomo Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd., AC Medical Inc., A2 Healthcare Corp., FMD K & L Japan K$K., CAC Croit Corporation, Japan Tobacco Inc., Japan Media Corporation, Medidata Solutions, Inc. and Luminary Medical K$K. Hidemoto Saiki received lecture fees from Dainippon Sumitomo Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Medtronic, Inc., Takeda Pharmaceutical Company Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K$K., M3,
Inc., Eisai Co. Ltd., GlaxoSmithKline K$K. and Nihon Medi-Physics Co. Ltd.; honoraria from Elsevier Japan K.K. and Japan Medical Journal; research support from Kyowa Hakko Kirin Co. Ltd.; and grants from Otsuka Pharmaceutical Co. Ltd. and Nippon Boehringer Ingelheim Co. Ltd. Hirohisa Watanabe received lecture fees from Nippon Boehringer Ingelheim Co. Ltd., GlaxoSmithKline K$K., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., FP Pharmaceutical Corporation, Eisai Co. Ltd., Daiichi Sankyo Company, Limited, Bayer Yakuhin, Ltd. and Novartis Pharma K.K. and grants from Otsuka Pharmaceutical Co. Ltd. and FUJIFILM RI Pharma Co. Ltd. Yasushi Shimo received lecture fees from Medtronic, Inc., Dainippon Sumitomo Pharma Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Novartis Pharma K$K., Boston Scientific Corporation and Nihon Medi-Physics Co. Ltd.; research support from Kyowa Hakko Kirin Co. Ltd.; and grants from Medtronic, Inc., Kyowa Hakko Kirin Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Boston Scientific Corporation and Kissei Pharmaceutical Co. Ltd. Role of the sponsor Kyowa Hakko Kirin was involved in the process of study design and protocol development. Acknowledgments Data management was independently operated by A2 Healthcare, Japan. We are grateful to Elsevier Japan for assistance in writing the manuscript. The authors would like to thank John Gibbins, PhD, Edanz Group, for his editorial assistance. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2017.02.024. References [1] K.R. Chaudhuri, D.G. Healy, A.H.V. Schapira, Non motor symptoms of Parkinson's disease: diagnosis and management, Lancet. Neurol. 5 (2006) 235e245. [2] Z. Qin, L. Zhang, F. Sun, X. Fang, C. Meng, C. Tanner, P. Chan, Chinese Parkinson Study Group, Health related quality of life in early Parkinson's disease: impact of motor and non-motor symptoms, results from Chinese levodopa exposed cohort, Park. Relat. Disord. 15 (2009) 767e771. [3] D.A. Gallagher, A.J. Lees, A. Schrag, What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them? Mov. Disord. 25 (2010) 2493e2500. [4] P. Martinez-Martin, C. Rodriguez-Blazquez, M.M. Kurtis, K.R. Chaudhuri NMSS Validation Group, The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease, Mov. Disord. 26 (2011) 399e406. [5] B.S. Connolly, A.E. Lang, Pharmacological treatment of Parkinson disease: a review, JAMA 311 (2014) 1670e1683. [6] K. Seppi, D. Weintraub, M. Coelho, S. Perez-Lloret, S.H. Fox, R. Katzenschlager, E.M. Hametner, W. Poewe, O. Rascol, C.G. Goetz, C. Sampaio, The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease, Mov. Disord. 26 (Suppl 3) (2011) S42eS80. [7] C.G. Goetz, S. Fahn, P. Martinez-Martin, W. Poewe, C. Sampaio, G.T. Stebbins, M.B. Stern, B.C. Tilley, R. Dodel, B. Dubois, R. Holloway, J. Jankovic, J. Kulisecsky, A.E. Lang, A. Lees, S. Leurgans, P.A. LeWitt, D. Nyenhuis, C.W. Olanow, O. Rascol, A. Schrag, J.A. Teresi, J.J. Van Hilten, N. LaPelle, Movement Disorder Society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): process, format, and clinimetric testing plan, Mov. Disord. 22 (2007) 41e47. [8] K. Kashihara, T. Kondo, Y. Mizuno, S. Kikuchi, S. Kuno, K. Hasegawa, N. Hattori, H. Mochizuki, H. Mori, M. Murata, M. Nomoto, R. Takahashi, A. Takeda, Y. Tsuboi, Y. Ugawa, M. Yamanmoto, F. Yokochi, F. Yoshii, G.T. Stebins, B.C. Tilley, S. Luo, L. Wang, N.R. LaPelle, C.G. Goetz, MDS-UPDRS Japanese validation study group, official Japanese version of the International Parkinson
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[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
and Movement Disorder Societyeunified Parkinson's disease rating scale: validation against the original english version, Mov. Disord. Clin. Pract. 1 (2014) 200e212. V. Peto, C. Jenkinson, R. Fitzpatrick, R. Greenhall, The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease, Qual. Life. Res. 4 (1995) 241e248. C. Jenkinson, R. Fitzpatrick, V. Peto, R. Greenhall, N. Hyman, The PDQ-8: development and validation of a short-form Parkinson's disease questionnaire, Psychol. Health 12 (1997) 805e814. W.R. Gibb, A.J. Lees, The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 511 (1988) 745e752. C.L. Tomlinson, R. Stowe, S. Patel, C. Rick, R. Gray, C.E. Clarke, Systematic review of levodopa dose equivalency reporting in Parkinson's disease, Mov. Disord. 25 (2010) 2649e2685. K.R. Chaudhuri, P. Martinez-Martin, A.H. Schapira, F. Stocchi, K. Sethi, P. Odin, P.G. Brown, W. Koller, P. Barone, G. MacPhee, L. Kelly, M. Rabey, D. MacMahon, S. Thomas, W. Ondo, D. Rye, A. Forbes, S. Tluk, V. Dhawan, A. Bowron, A.J. Wilians, C.W. Olanow, International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study, Mov. Disord. 21 (2006) 916e923. P. Martinez-Martin, A.H. Schapira, F. Stocchi, K. Sethi, P. Odin, G. MacPhee, R.G. Brown, Y. Naidu, L. Clayton, K. Abe, Y. Tsuboi, D. MacMahon, P. Barone, M. Rabey, U. Bonuccelli, A. Forbes, K. Breen, S. Tluk, C.W. Olanow, S. Thomas, D. Rye, A. Hand, A.J. Williams, W. Ondo, K.R. Chaudhuri, Prevalence of nonmotor symptoms in Parkinson's disease in an international setting; study using nonmotor symptoms questionnaire in 545 patients, Mov. Disord. 22 (2007) 1623e1629. A. Antonini, C. Colosimo, R. Marconi, L. Morgante, P. Barone, PRIAMO Study Group, The PRIAMO study: background, methods and recruitment, Neurol. Sci. 29 (2008) 61e65. P. Barone, A. Antonini, C. Colosimo, R. Marconi, L. Morgante, T.P. Avarello, E. Bottacchi, A. Cannas, G. Ceravolo, R. Ceravolo, G. Cicarelli, R.M. Gaglio, R.M. Giglia, F. Iemolo, M. Manfredi, G. Meco, A. Nicoletti, M. Pederzoli, A. Petrone, A. Pisani, F.E. Pontieri, R. Quatrale, S. Ramat, R. Scala, G. Volpe, S. Zappulla, A.R. Bentivoglio, F. Stocchi, G. Trianni, P.D. Dotto, PRIAMO study group, The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease, Mov. Disord. 24 (2009) 1641e1649. C. Pont-Sunyer, A. Hotter, C. Gaig, K. Seppi, Y. Compta, R. Katzenschlager, s, K. Wenzel, J. Infante, H. Zach, N. Mas, D. Hofeneder, T. Brücke, A. Baye n, L. Ispierto, O. De F abregues, A. Calle W. Pirker, I.J. Posada, R. Alvarez, A. Palasí, M. Aguilar, M.J. Martí, F. Valldeoriola, M. Salamero, W. Poewe,
[18]
[19]
[20]
[21] [22]
[23] [24] [25] [26]
[27]
[28]
[29]
[30]
7
E. Tolosa, The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study), Mov. Disord. 30 (2015) 229e237. H. Chen, E.J. Zhao, W. Zhang, Y. Lu, R. Liu, X. Huang, A.J. Ciesielski-Jones, M.A. Justice, D.S. Cousins, S. Peddada, Meta-analyses on prevalence of selected Parkinson's nonmotor symptoms before and after diagnosis, Transl. Neurodegener. 4 (2015) 1. J.J. van Hilten, G. Hoogland, E.A. van der Veld, H.A. Middelkoop, G.A. Kerkhof, R.A. Roos, Diurnal effects of motor activity and fatigue in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 56 (1993) 874e877. L.M. Shulman, R.L. Taback, A.A. Rabinstein, W.J. Weiner, Non-recognition of depression and other non-motor symptoms in Parkinson's disease, Park. Relat. Disord. 8 (2002) 193e197. K. Karlsen, J.P. Larsen, E. Tandberg, K. Jorgensen, Fatigue in patients with Parkinson's disease, Mov. Disord. 14 (1999) 237e241. Y. Okuma, S. Kamei, A. Morita, F. Yoshii, T. Yamamoto, S. Hashimoto, H. Utsumi, T. Hatano, N. Hattori, M. Matsumura, K. Takahashi, S. Nogawa, Y. Watanabe, T. Miyamoto, M. Miyamoto, K. Hirata, Fatigue in Japanese patients with Parkinson's disease: a study using Parkinson fatigue scale, Mov. Disord. 24 (2009) 1977e1983. R.G. Brown, A. Dittner, L. Findley, S.C. Wessely, The Parkinson fatigue scale, Park. Relat. Disord. 11 (2005) 49e55. S. Solimeo, S. Sex and gender in older adults' experience of Parkinson's disease, J. Gerontol. B. Psychol. Sci. Soc. Sci. 63 (2008) S42eS48. I.N. Miller, A. Cronin-Golomb, Gender differences in Parkinson's disease: clinical characteristics and cognition, Mov. Disord. 25 (2010) 2695e2703. S. Krishnan, G. Sarma, S. Sarma, A. Kishore, Do nonmotor symptoms in Parkinson's disease differ from normal aging? Mov. Disord. 26 (2011) 2110e2113. P. Martinez-Martin, C. Falup Pecurariu, P. Odin, J.J. van Hilten, A. Antonini, J.M. Rojo-Abuin, V. Borges, C. Trenkwalder, D. Aarsland, D.J. Brooks, K. Ray Chaudhuri, Gender-related differences in the burden of non-motor symptoms in Parkinson's disease, J. Neurol. 259 (2012) 1639e1647. D. Weintraub, A.S. David, A.H. Evans, J.E. Grant, M. Stacy, Clinical spectrum of impulse control disorders in Parkinson's disease, Mov. Disord. 30 (2015) 121e127. A. Thomas, L. Bonanni, F. Gambi, A. Di Lorio, M. Onofrj, Pathological gambling in Parkinson disease is reduced by amantadine, Ann. Neurol. 68 (2010) 400e404. D. Weintraub, M. Sohr, M.N. Potenza, A.D. Siderowf, M. Stacy, V. Voon, J. Whetteckey, G.R. Wunderlich, A.E. Lang, Amantadine use associated with impulse control disorders in Parkinson disease in cross-sectional study, Ann. Neurol. 68 (2010) 963e968.
Please cite this article in press as: T. Maeda, et al., Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.02.024