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1.  Subjective poor sleep quality in Chinese patients with Parkinson's disease without dementia 
Journal of Biomedical Research  2013;27(4):291-295.
Parkinson's disease (PD) is a common progressive neurological disorder and is composed of motor and non-motor symptoms. Sleep disturbances are frequent problems for patients with PD. The relationship between sleep disturbances with Hoehn and Yahr (H&Y) staging have been demonstrated. However, the relationship between sleep disorders and H&Y is still unclear in patients with PD without dementia in Chinese PD patients. In this study, we interviewed 487 non-demented PD patients of Chinese Han descents by H&Y classification. We found that night sleep quality was significantly associated with the severity of PD (P = 0.008). Panic disorder severity scale (PDSS) total scores were correlated with PD non-motor symptoms scale (PDNMS) scores (r = -0.528, P < 0.001), the Hamilton depression scale (HAMD) scores (r = -0.545, P < 0.001) and the Hamilton anxiety scale (HAMA) scores (r = -0.498, P < 0.001). Our results indicated that sleep quality deteriorated with the advancing of PD in Chinese non-demented patients with PD. Depression and anxiety may partly explain sleep disturbances in non-demented patients with PD.
PMCID: PMC3721037  PMID: 23885268
sleep quality; depression; anxiety; Parkinson disease; non-demented
2.  Parkinson’s disease sleep scale, sleep logs, and actigraphy in the evaluation of sleep in parkinsonian patients 
Journal of Neurology  2009;256(9):1480-1484.
The aim of this study was to compare the results of the day-to-day self-evaluation of sleep quality by sleep logs with Parkinson’s disease sleep scale (PDSS) in Parkinson’s disease (PD) patients. Actigraphy was used as an independent analysis of nighttime activity interfering with sleep. A total of 71 idiopathic PD patients and 21 age- and sex-matched normal individuals lacking any type of sleep disturbance were recruited. Sleep was evaluated by PDSS, 7-d sleep log and actigraphy. Sleep logs and PDSS showed reduced sleep quality and daytime somnolence scores in moderate/severe PD patients as compared to healthy controls. Significant correlations were found between sleep quality in sleep logs and all domains of PDSS sleep quality, except for the presence of nocturia, which correlated with nocturnal activity. PD severity and depression were the only predictors of reduced sleep quality. The retrospective and day-to-day sleep self-evaluations were coincident. Reduced sleep quality was related to increased PD severity and depression scores.
PMCID: PMC3085768  PMID: 19404716
Sleep logs; Parkinson’s disease; Actigraphy; Sleep disorders; Sleep evaluation
3.  Therapeutic effect of Yang-Xue-Qing-Nao granules on sleep dysfunction in Parkinson’s disease 
Chinese Medicine  2013;8:14.
This study aimed to evaluate the effects of add-on Yang-Xue-Qing-Nao granules (YXQN) on sleep dysfunction in patients with Parkinson’s disease (PD).
PD participants fitted with an actigraph took either YXQN or placebo granules in a randomized manner for 12 weeks while maintaining other anti-parkinsonism medications (e.g., dopaminergic agent, dopamine agonist) unchanged. Additional participants without sleep disturbance or PD served as controls. The changes in detrended fluctuation analysis (DFA) of physical activity with respect to diurnal activity (DA), evening activity (EA), nocturnal activity (NA), Parkinson’s disease sleep scale (PDSS) score and unified Parkinson’s disease rating scale (UPDRS) score were evaluated every 4 weeks during the 12-week YXQN intervention period and again at week 16.
A total of 61 (placebo group, n = 30; YXQN group, n = 31) idiopathic PD participants with sleep dysfunction (mean age ± standard deviation, 63.4 ± 8.6 years; mean duration of illness, 5.8 ± 6.6 years) completed the study. Significant improvements in EA (p = 0.033, 0.037 and 0.029), DA (p = 0.041, 0.038 and 0.027) and PDSS score (p = 0.034, 0.028 and 0.029) were observed in the YXQN group at weeks 8 and 12, and maintained until week 16, respectively.
YXQN improved the DFA parameters, and PDSS and UPDRS scores in PD participants.
PMCID: PMC3733743  PMID: 23890176
4.  The Parkinson's disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson's disease 
Background: No formal instruments are available for quantifying sleep problems in Parkinson's disease.
Objective: To develop a new sleep scale to quantify the various aspects of nocturnal sleep problems in Parkinson's disease, which may occur in up to 96% of affected individuals.
Methods: Employing a multidisciplinary team approach, a visual analogue scale was devised addressing 15 commonly reported symptoms associated with sleep disturbance in Parkinson's disease—the Parkinson's disease sleep scale (PDSS). In all, 143 patients with Parkinson's disease completed the PDSS, covering the entire spectrum of disease from newly diagnosed to advanced stage. As controls, 137 age healthy matched subjects also completed the scale. Test–retest reliability was assessed in a subgroup of subjects. The Epworth sleepiness scale was also satisfactorily completed by 103 of the patients with Parkinson's disease.
Results: PDSS scores in the Parkinson group were significantly different from the healthy controls. Patients with advanced Parkinson's disease had impaired scores compared with early/moderate disease. Individual items of the scale showed good discriminatory power between Parkinson's disease and healthy controls. Relevant items of the PDSS correlated with excessive daytime sleepiness. The scale showed robust test–retest reliability.
Conclusions: This appears to be the first description of a simple bedside screening instrument for evaluation of sleep disturbances in Parkinson's disease. A combination of subitems may help identify specific aspects of sleep disturbance, which in turn may help target treatment.
PMCID: PMC1757333  PMID: 12438461
5.  Quality of Sleep in Patients with Parkinson's Disease 
International Journal of Preventive Medicine  2013;4(Suppl 2):S229-S233.
Parkinson's disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms. The latter are common and include autonomic dysfunction, cognitive impairment, and sleep difficulties. Many of the non-motor aspects of PD such as sleep disturbance are more common and significantly affect the day-to-day activities of patients and their quality of life. The most important aim of this study was to evaluate the sleep quality in patients with PD.
This case-control study was performed on patients with PD referred to the Neurology Clinic of our teaching hospital in 2011. Thirty-four patients with PD and 34 healthy people as control group were enrolled in this study. Sleep quality of patients and control was evaluated by Parkinson's disease sleep scale (PDSS) questionnaire. PDSS is a reliable and valid tool to measure sleep disorders in PD.
The mean total PDSS score in patient group was 55.29 (SD = 26.92) indicating moderate to severe sleep disturbances whereas, the mean total score in control group was 20.34 (SD = 10.65). Difference between the two groups’ mean scores was significant (P < 0.05).
Our study demonstrated that patients with PD experienced poorer nocturnal sleep quality than the control group.
PMCID: PMC3678223  PMID: 23776729
Parkinson's disease; Parkinson's disease sleep scale; sleep disturbances; sleep quality
6.  Nonmotor Symptoms Groups in Parkinson's Disease Patients: Results of a Pilot, Exploratory Study 
Parkinson's Disease  2011;2011:473579.
Nonmotor symptoms (NMS) like neuropsychiatric symptoms, sleep disturbances or autonomic symptoms are a common feature of Parkinson's disease (PD). To explore the existence of groups of NMS and to relate them to PD characteristics, 71 idiopathic non-demented PD out-patients were recruited. Sleep was evaluated by the PD Sleep Scale (PDSS). Several neuropsychiatric, gastrointestinal and urogenital symptoms were obtained from the NMSQuest. Sialorrhea or dysphagia severity was obtained from the Unified PD Rating Scale activities of daily living section. MADRS depression scale was also administered. Exploratory factor analysis revealed the presence of 5 factors, explaining 70% of variance. The first factor included PDSS measurement of sleep quality, nocturnal restlessness, off-related problems and daytime somnolence; the second factor included nocturia (PDSS) and nocturnal activity; the third one included gastrointestinal and genitourinary symptoms; the forth one included nocturnal psychosis (PDSS), sialorrhea and dysphagia (UPDRS); and the last one included the MADRS score as well as neuropsychiatric symptoms. Sleep disorders correlated with presence of wearing-off, nocturia with age >69 years, and nocturnal psychosis with levodopa equivalent dose or UPDRS II score. Neuropsychiatric symptoms correlated with UPDRS II+III score and non-tricyclic antidepressants. These results support the occurrence of significant NMS grouping in PD patients.
PMCID: PMC3109353  PMID: 21687754
7.  Sleep Disorders in Parkinson’s Disease: Clinical Features, Iron Metabolism and Related Mechanism 
PLoS ONE  2013;8(12):e82924.
To investigate clinical features, iron metabolism and neuroinflammation in Parkinson’s disease (PD) patients with sleep disorders (SD).
211 PD patients were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a body of scales for motor symptoms and non-motor symptoms. 94 blood and 38 cerebral spinal fluid (CSF) samples were collected and iron and its metabolism-relating proteins, neuroinflammatory factors were detected and analyzed.
136 cases (64.5%) of PD patients were accompanied by SD. Factor with the highest score in PSQI was daytime dysfunction. Depression, restless leg syndrome, autonomic symptoms and fatigue contributed 68.6% of the variance of PSQI score. Transferrin level in serum and tumor necrosis factor–α level in CSF decreased, and the levels of iron, transferrin, lactoferrin and prostaglandin E2 in CSF increased in PD patients with SD compared with those without SD. In CSF, prostaglandin E2 level was positively correlated with the levels of transferrin and lactoferrin, and tumor necrosis factor–α level was negatively correlated with the levels of iron, transferrin and lactoferrin in CSF.
Depression, restless leg syndrome, autonomic disorders and fatigue are the important contributors for the poor sleep in PD patients. Abnormal iron metabolism may cause excessive iron deposition in brain and be related to SD in PD patients through dual potential mechanisms, including neuroinflammation by activating microglia and neurotoxicity by targeting neurons. Hence, inhibition of iron deposition-related neuroinflammation and neurotoxicity may cast a new light for drug development for SD in PD patients.
PMCID: PMC3871565  PMID: 24376607
8.  Reliability and Validity of the Persian Version of the Fatigue Severity Scale in Idiopathic Parkinson's Disease Patients 
Parkinson's Disease  2013;2013:935429.
As one of the most frequent symptoms, measurement of fatigue is an issue of interest in Parkinson's disease (PD). The fatigue severity scale (FSS) is one of the recommended questionnaires for this purpose. The aim of our study was to evaluate psychometric properties of the Persian version of the FSS (FSS-Per) to assess fatigue in PD patients. Ninety nondemented idiopathic Parkinson's disease (IPD) patients were consecutively recruited from an outpatient referral movement disorder clinic. In addition to the disease severity scales, the FSS-Per was used for fatigue measurement. The internal consistency coefficient was larger than 0.8 for all of the items with a total Cronbach's alpha of 0.96 (95% CI: 0.95–0.97). The FSS-Per score correlated with the UPDRS score (r = 0.55, P < 0.001) and the “Hoehn and Yahr” (HY) stage (r = 0.48, P < 0.001). The total score of the FSS-Per significantly discriminated IPD patients with more severe disability (HY stage > 2) versus those with less severe disease (HY stage ≤2) (AUC = 0.81 (95% CI: 0.72–0.90)). The FSS-Per fulfilled a high internal consistency and construct validity to measure the severity of fatigue in Iranian IPD patients. These acceptable psychometric properties were reproducible in subgroups of IPD patients regarding different levels of education, disease severity, sex and age groups.
PMCID: PMC3780699  PMID: 24089644
9.  Diurnal and nocturnal drooling in Parkinson’s disease 
Journal of Neurology  2011;259(1):119-123.
Drooling as symptom of Parkinson’s disease (PD) has thus far been poorly defined. This uncertainty is reflected by high variations in published prevalence rates. The aim of this study was to investigate the prevalence of saliva loss versus accumulation of saliva as a possible preliminary stage, and diurnal drooling versus nocturnal drooling. In addition, we evaluated the association between drooling severity and the severity of facial and oral motor disorders. We collected age, disease duration, UPDRS III and Hoehn & Yahr stage from 104 consecutive outpatients with PD. Diurnal and nocturnal drooling was evaluated with a validated questionnaire (ROMP-saliva). A speech pathologist, blinded for drooling severity, rated facial expression, involuntary mouth opening and difficulty with nose breathing and also interviewed patients about sleeping position and nose-breathing during the night. Thirty patients (29%) had no complaints with saliva control (‘non-droolers’), 45 patients (43%) experienced accumulation of saliva or only nocturnal drooling (‘pre-droolers’), and 29 (28%) had diurnal drooling (24 of which also drooled during the night; ‘droolers’). The droolers had longer disease duration (10 vs. 7 years, p = 0.01) and drooling was independently associated with involuntary mouth opening (OR = 2.0; 95% CI 1.02–3.99) and swallowing complaints (OR = 1.2; 95% CI 1.03–1.31). Diurnal drooling—defined as dribbling of saliva while awake—is present in about 28% of PD patients. This is less than usually reported. Diurnal drooling typically appeared later in the disease course. The association with oral motor behavior should encourage the development of behavioral treatment approaches.
PMCID: PMC3251785  PMID: 21698387
Parkinson’s disease; Diurnal drooling; Nocturnal drooling
10.  Unbiased and Mobile Gait Analysis Detects Motor Impairment in Parkinson's Disease 
PLoS ONE  2013;8(2):e56956.
Motor impairments are the prerequisite for the diagnosis in Parkinson's disease (PD). The cardinal symptoms (bradykinesia, rigor, tremor, and postural instability) are used for disease staging and assessment of progression. They serve as primary outcome measures for clinical studies aiming at symptomatic and disease modifying interventions. One major caveat of clinical scores such as the Unified Parkinson Disease Rating Scale (UPDRS) or Hoehn&Yahr (H&Y) staging is its rater and time-of-assessment dependency. Thus, we aimed to objectively and automatically classify specific stages and motor signs in PD using a mobile, biosensor based Embedded Gait Analysis using Intelligent Technology (eGaIT). eGaIT consist of accelerometers and gyroscopes attached to shoes that record motion signals during standardized gait and leg function. From sensor signals 694 features were calculated and pattern recognition algorithms were applied to classify PD, H&Y stages, and motor signs correlating to the UPDRS-III motor score in a training cohort of 50 PD patients and 42 age matched controls. Classification results were confirmed in a second independent validation cohort (42 patients, 39 controls). eGaIT was able to successfully distinguish PD patients from controls with an overall classification rate of 81%. Classification accuracy increased with higher levels of motor impairment (91% for more severely affected patients) or more advanced stages of PD (91% for H&Y III patients compared to controls), supporting the PD-specific type of analysis by eGaIT. In addition, eGaIT was able to classify different H&Y stages, or different levels of motor impairment (UPDRS-III). In conclusion, eGaIT as an unbiased, mobile, and automated assessment tool is able to identify PD patients and characterize their motor impairment. It may serve as a complementary mean for the daily clinical workup and support therapeutic decisions throughout the course of the disease.
PMCID: PMC3576377  PMID: 23431395
11.  Daytime Sleepiness in Parkinson's Disease: Perception, Influence of Drugs, and Mood Disorder 
Sleep Disorders  2014;2014:939713.
Parkinson's disease (PD) is associated with sleep complaints as excessive daytime sleepiness (EDS) and several factors have been implicated in the genesis of these complaints. Objective. To correlate the subjective perception of EDS with variables as the severity of the motor symptoms, medications, and the presence of depressive symptoms. Materials and Methods. A cross-sectional study, using specific scales as Epworth sleepiness scale (ESS), Beck depression inventory (iBeck) and Hoehn and Yahr (HY), in 42 patients with PD. Results. The patients had a mean age of 61.2 ± 11.3 years and mean disease duration of 4.96 ± 3.3 years. The mean ESS was 7.5 ± 4.7 and 28.6% of patients reached a score of abnormally high value (>10). There was no association with gender, disease duration, and dopamine agonists. Patients with EDS used larger amounts of levodopa (366.7 ± 228.0 versus 460.4 ± 332.25 mg, P = 0.038), but those who had an iBeck >20 reached lower values of ESS than the others (5.9 ± 4.1 versus 9.3 ± 4.8, P = 0.03). Conclusions. EDS was common in PD patients, being related to levodopa intake. Presence of depressed mood may influence the final results of self-assessment scales for sleep disorders.
PMCID: PMC3920819  PMID: 24587912
12.  Loss of ability to work and ability to live independently in Parkinson’s Disease 
Parkinsonism & related disorders  2011;18(2):130-135.
Ability to work and independent living capacity are of particular concern for patients with Parkinson’s disease (PD). We utilized a series of PD patients able to work or live independently at baseline, and evaluated potential risk factors for the two separate outcomes of loss of ability to work and loss of ability to live independently.
The series was comprised of 495 PD patients followed prospectively. Ability to work and ability to live independently were based on clinical interview and examination. Cox regression models adjusted for age and disease duration were used to evaluate associations of baseline characteristics with loss of ability to work and loss of ability to live independently.
Higher UPDRS dyskinesia score, UPDRS instability score, UPDRS total score, Hoehn and Yahr stage, and presence of intellectual impairment at baseline were all associated with increased risk of future loss of ability to work and loss of ability to live independently (P≤0.0033). Five years after initial visit, for patients ≤70 years of age with a disease duration ≤4 years at initial visit, 88% were still able to work and 90% to live independently. These estimates worsened as age and disease duration at initial visit increased; for patients >70 years of age with a disease duration >4 years, estimates at 5 years were 43% and 57%, respectively.
The information provided in this study can offer useful information for PD patients in preparing for future loss of ability to perform activities of daily living.
PMCID: PMC3977346  PMID: 21975262
Parkinson disease; work ability; independence
13.  Clinical heterogeneity in patients with early-stage Parkinson’s disease: a cluster analysis*  
The aim of this study was to investigate the clinical heterogeneity of Parkinson’s disease (PD) among a cohort of Chinese patients in early stages. Clinical data on demographics, motor variables, motor phenotypes, disease progression, global cognitive function, depression, apathy, sleep quality, constipation, fatigue, and L-dopa complications were collected from 138 Chinese PD subjects in early stages (Hoehn and Yahr stages 1–3). The PD subject subtypes were classified using k-means cluster analysis according to the clinical data from five to three-cluster consecutively. Kappa statistical analysis was performed to evaluate the consistency among different subtype solutions. The cluster analysis indicated four main subtypes: the non-tremor dominant subtype (NTD, n=28, 20.3%), rapid disease progression subtype (RDP, n=7, 5.1%), young-onset subtype (YO, n=50, 36.2%), and tremor dominant subtype (TD, n=53, 38.4%). Overall, 78.3% (108/138) of subjects were always classified between the same three groups (52 always in TD, 7 in RDP, and 49 in NTD), and 98.6% (136/138) between five- and four-cluster solutions. However, subjects classified as NTD in the four-cluster analysis were dispersed into different subtypes in the three-cluster analysis, with low concordance between four- and three-cluster solutions (kappa value=−0.139, P=0.001). This study defines clinical heterogeneity of PD patients in early stages using a data-driven approach. The subtypes generated by the four-cluster solution appear to exhibit ideal internal cohesion and external isolation.
PMCID: PMC3167902  PMID: 21887844
Parkinson’s disease; Heterogeneity; Subtype; Cluster analysis
14.  What contributes to quality of life in patients with Parkinson's disease? 
OBJECTIVE—To identify the factors that determine quality of life (QoL) in patients with idiopathic Parkinson's disease in a population based sample. Quality of life (QoL) is increasingly recognised as a critical measure in health care as it incorporates the patients' own perspective of their health.
METHODS—All patients with Parkinson's disease seen in a population based study on the prevalence of parkinsonism were asked to complete a disease-specific QoL questionnaire (PDQ-39) and the Beck depression inventory. A structured questionnaire interview and a complete neurological examination, including the Hoehn and Yahr scale, the Schwab and England disability scale, the motor part of the unified Parkinson's disease rating scale (UPDRS part III), and the mini mental state examination were performed by a neurologist on the same day.
RESULTS—The response rate was 78%. The factor most closely associated with QoL was the presence of depression, but disability, as measured by the Schwab and England scale, postural instability, and cognitive impairment additionally contributed to poor QoL. Although the UPDRS part III correlated significantly with QoL scores, it did not contribute substantially to predicting their variance once depression, disability, and postural instability had been taken into account. In addition, patients with akinetic rigid Parkinson's disease had worse QoL scores than those with tremor dominant disease, mainly due to impairment of axial features.
CONCLUSION—Depression, disability, postural instability, and cognitive impairment have the greatest influence on QoL in Parkinson's disease. The improvement of these features should therefore become an important target in the treatment of the disease.

PMCID: PMC1737100  PMID: 10945804
15.  Postural Abnormality as a Risk Marker for Leg Deep Venous Thrombosis in Parkinson’s Disease 
PLoS ONE  2013;8(7):e66984.
Pulmonary thromboembolism is a common cause of death in patients with autopsy-confirmed Parkinsonism. This study investigated the incidence of leg deep vein thrombosis in Parkinson’s disease and relationships between deep vein thrombosis and clinical/laboratory findings, including postural abnormalities as assessed by photographic measurements.
This cross-sectional study assessed the presence of deep vein thrombosis using bilateral leg Doppler ultrasonography in 114 asymptomatic outpatients with Parkinson’s disease.
Deep vein thrombosis was detected in 23 patients (20%) with Parkinson’s disease. Deep vein thrombosis was located in the distal portion in 18 patients and in the proximal portion in 5 patients. No significant differences in age, sex, body mass index, disease duration, Hoehn-Yahr stage, anti-Parkinson’s drugs, or daily levodopa-equivalent dose were seen between deep vein thrombosis-positive and -negative groups. Univariate analysis for developing deep vein thrombosis in patients with Parkinson’s disease identified the following markers: long-term wheelchair use, bent knee, bent spine, and D-dimer elevation. Bending angles were significantly greater in the deep vein thrombosis-positive group at the knee and spine than in the deep vein thrombosis-negative group. Half of Parkinson’s disease patients with camptocormia had deep vein thrombosis. Among diabetes mellitus cases, long-term wheelchair use, bent knee over 15°, camptocormia, D-dimer elevation, the more risk markers were associated with a higher incidence of DVT. The presence of risk markers contributed to the development of deep vein thrombosis. On multivariate logistic regression analysis, a bent knee posture was strongly associated with an increased risk of deep vein thrombosis.
Presence of leg deep vein thrombosis correlated with postural abnormalities in Parkinson’s disease. We recommend non-invasive ultrasonographic screening for leg deep vein thrombosis in these high-risk patients with Parkinson’s disease.
PMCID: PMC3699565  PMID: 23843975
16.  Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression 
Clinics  2011;66(4):623-627.
To compare verbal fluency among Alzheimer's disease, Parkinson's disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity.
Patients from an outpatient university center with a clinical diagnosis of Alzheimer's disease, Parkinson's disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson's disease, major depression, and Alzheimer's disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals).
We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model.
The mean digit span and verbal fluency scores were lower in patients with Alzheimer's disease (n = 34) than in patients with major depression (n = 52) or Parkinson's disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer's disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson's disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson's disease groups listed 44% (ROM = 1.44) and 48% (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer's disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26% (ROM = 0.74) reduction in the number of words listed when compared to mild cases.
Verbal fluency provides a better characterization of Alzheimer's disease, major depression, and Parkinson's disease, even at later stages.
PMCID: PMC3093793  PMID: 21655757
Verbal fluency; cognition; diagnosis; neuropsychology
17.  Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease: A Double-Blind, Randomized, pLacebo-Controlled Study (RECOVER) 
Movement Disorders  2010;26(1):90-99.
In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS-2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society
PMCID: PMC3072524  PMID: 21322021
dopamine agonist; rotigotine; transdermal; motor function; sleep; quality of life
18.  Fatigue in levodopa-naïve subjects with Parkinson disease 
Neurology  2008;71(7):481-485.
Fatigue is a common complaint in Parkinson disease (PD). We investigated fatigue in a cohort of previously untreated patients with early PD enrolled in the Earlier vs Later Levodopa (ELLDOPA) clinical trial.
A total of 361 patients were enrolled in the randomized, double-blind, placebo-controlled ELLDOPA trial and assigned to receive placebo or carbidopa-levodopa 37.5/150 mg, 75/300 mg, or 150/600 mg daily for 40 weeks, followed by a 2-week medication washout period. Subjects who scored >4 on the Fatigue Severity Scale were classified as fatigued. PD severity was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and Schwab-England Activities of Daily Living Scale. A subgroup of subjects underwent [123I]-β-CIT SPECT to measure striatal dopamine transporter density.
Of the 349 ELLDOPA subjects who completed fatigue measures, 128 were classified as fatigued at baseline. The fatigued group was significantly more impaired neurologically (UPDRS, all subscales and Hoehn and Yahr staging) and functionally (Schwab-England Scale) but no significant differences were observed in β-CIT measurements between the two groups. Analysis of covariance showed a greater increase in fatigue score from baseline to the end of the 2-week washout in the placebo group (0.75 points) than in the three groups receiving levodopa (increases of 0.30 [150 mg/day], 0.36 [300 mg/day], and 0.33 [600 mg/day]; p = 0.03 for heterogeneity).
Fatigue is a frequent symptom in early, untreated, non-depressed patients with Parkinson disease (PD), affecting over 1/3 of the patients in this cohort at baseline and 50% by week 42. Fatigue was associated with the severity of PD, and progressed less in patients treated with levodopa.
= Earlier vs Later Levodopa;
= Fatigue Severity Scale;
= Hamilton Depression Scale;
= Parkinson disease;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2937041  PMID: 18695158
19.  Subthalamic nucleus stimulation in advanced Parkinson's disease: blinded assessments at one year follow up 
Objective: To measure the effect of deep brain stimulation (DBS) of the subthalamic nucleus in patients with advanced Parkinson's disease.
Design: Open label follow up using blinded ratings of videotaped neurological examinations.
Patients: 30 patients with advanced Parkinson's disease (19 male, 11 female; mean age 58.8 years; mean disease duration 12.8 years), complicated by intractable wearing off motor fluctuations and dopaminergic dyskinesias.
Main outcome measures: Unified Parkinson's disease rating scale (UPDRS), part III (motor), score at one year, from blinded reviews of videotaped neurological examinations. Secondary outcomes included the other UPDRS subscales, Hoehn and Yahr scale, activities of daily living (ADL) scale, mini-mental state examination (MMSE), estimates of motor fluctuations and dyskinesia severity, drug intake, and patient satisfaction questionnaire.
Results: Subthalamic nucleus stimulation was associated with a 29.5% reduction in motor scores at one year (p<0.0001). The only important predictors of improvement in UPDRS part III motor scores were the baseline response to dopaminergic drugs (p = 0.015) and the presence of tremor (p = 0.027). Hoehn and Yahr scores and ADL scores in the "on" and "off" states did not change, nor did the mean MMSE score. Weight gain occurred in the year after surgery, from (mean) 75.8 kg to 78.5 kg (p = 0.028). Duration of daily wearing off episodes was reduced by 69%. Dyskinesia severity was reduced by 60%. Drug requirements (in levodopa equivalents) declined by 30%.
Conclusions: The 30% improvement in UPDRS motor scores was a more modest result than previously reported. DBS did not improve functional capacity independent of drug use. Its chief benefits were reduction in wearing off duration and dyskinesia severity.
PMCID: PMC1739226  PMID: 15314110
20.  An Eight-Year Clinic Experience with Clozapine Use in a Parkinson’s Disease Clinic Setting 
PLoS ONE  2014;9(3):e91545.
To examine our eight year clinic-based experience in a Parkinson’s disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinson's disease (PD).
The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy.
There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45–87 years (mean 68.3±10.15), disease duration of 17–240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = −0.36, p<0.01) and H&Y score (r = −0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05).
This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.
PMCID: PMC3960134  PMID: 24646688
21.  Relation between Voice Handicap Index (VHI) and disease severity in Iranian patients with Parkinson's disease 
One third of patients with Parkinson's disease (PD) have mentioned “dysphonia” as their most debilitating communication deficit. Patient-based measurements, such as Voice Handicap Index (VHI) add necessary supplementary information to clinical and physiological assessment. There are a few studies about relation between VHI and disease severity in PD, although none of them showed any significant correlation. The goal of this study was to find correlation between these variables in Iranian PD patients.
This cross-sectional, analytical and non-interventional study was done on 23 PD patients who reported a voice disorder related to their disease. They were selected from attendants of movement disorders clinic of Hazrat Rasool Akram Hospital. The relationship between disease severity (according to Hoehn and Yahr/H&Y and Unified Parkinson's Disease Rating Scale-part3 /UPDRS-III) and VHI questionnaire (and its 3 domains) was investigated based on patients’ sex, UPDRS-III score H&Y and VHI.
Total VHI and its 3 domains had no relationship with disease severity (H&Y) in all patients and by sex separation. However, there was a positive correlation between VHI and disease severity (UPDRS-III) (r = 0.485). There was also a relation between physical and functional domains of VHI and UPDRS (rP=0.530, rF=0.479) while no relationship observed regarding sex differences. 9 out of 18 UPDRS-III items had strong relationship with VHI (total and 3subscales).
Iranian PD patients feel handicap according to voice disorder caused by PD. Patient satisfaction of voice decreases with the disease severity and progression. A larger sample size is necessary to find relationship in genders. VHI is an important issue could be offered to be used in PD beside other assessments
PMCID: PMC3562535  PMID: 23482344
Parkinson's disease; Disease severity; Voice; VHI; Quality of life
22.  Probable RBD is Increased in Parkinson’s Disease But Not in Essential Tremor or Restless Legs Syndrome 
Parkinsonism & related disorders  2011;17(6):456-458.
Compare the frequency of REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) in Parkinson’s disease (PD), restless legs syndrome (RLS), essential tremor (ET), and control subjects.
Subjects enrolled in a longitudinal clinicopathologic study, and when available an informant, completed the Mayo Sleep Questionnaire, which asks “Have you ever been told that you act out your dreams?”, and the Epworth Sleepiness Scale (ESS).
Probable RBD (based on informant response to the questionnaire) was much more frequent in PD (34/49, 69%, p<0.001) than in RLS (6/30, 20%), ET (7/53, 13%), or control subjects (23/175, 13%), with an odds ratio of 11 for PD compared to controls. The mean ESS and the number of subjects with an ESS ≥ 10 was higher in PD (29/60, 48%, p<0.001) and RLS (12/39, 31%, p<0.001) compared with ET (12/93, 13%) and Controls (34/296, 11%).
Probable RBD is much more frequent in PD with no evidence to suggest an increase in either RLS or ET. Given the evidence that RBD is a synucleinopathy, the lack of an increased frequency of RBD in subjects with ET or RLS suggests the majority of ET and RLS subjects are unlikely to be at increased risk for developing PD.
PMCID: PMC3119772  PMID: 21482171
Parkinson’s disease; REM sleep behavior disorder; essential tremor; restless legs syndrome; excessive daytime sleepiness
23.  Static posturography in aging and Parkinson's disease 
Introduction: In clinical practice, evaluation of postural control is based on the neurological examination, including Romberg's test, examination of gait and performance of pull test as part of the Unified Parkinson's Disease Rating Scale (UPDRS). The goal of our study was to identify posturographic parameters since quantitative technical methods for the measurement of postural control are not established in clinical routine yet. Methods: In this cross-sectional study design we examined patients with Parkinson's disease (PD) (Hoehn and Yahr < 3; PD n = 12) on a static posturographic platform (eyes open and eyes closed), performing a standard Romberg's test during neurological examination and compared the results with an age-matched healthy adult control (HAC n = 10) and a healthy young control (HYC n = 21). Results: In the platform Romberg's test with open eyes, the patients with PD showed a significantly greater mean sway [PD: 14.98 vs. HAC: 8.77 (mm), p < 0.003 vs. HYC 7.80 (mm)], greater mean radius [PD: 28.31 vs. HAC: 16.36 (mm), p < 0.008 vs. HYC: 14.19 (mm)] and greater marked area [PD: 2.38 vs. HAC: 0.88 (cm2), p < 0.016 vs. HYC: 0.78 (cm2)] compared to the HAC. The Romberg's test with closed eyes revealed a significantly greater mean sway [PD: 13.83 vs. HAC: 10.12 (mm), p < 0.033 vs. HYC: 5.82 (mm)] and greater mean radius [PD: 25.03 vs. HAC: 18.15 (mm), p < 0.045 vs. HYC: 9.11 (mm)] compared to both groups. Conclusions: The platform Romberg-test with closed eyes detected significant differences in elderly people and patients with Parkinson's disease, which could be objectively quantified with static posturography testing. Age alone showed significant changes, only detectable with closed eyes. Therefore, balance testing with a new computerized approach could help to identify balance problems in a geriatric assessment in clinical routine, especially with the parameters marked area and mean sway.
PMCID: PMC3412413  PMID: 22888319
Parkinson's disease; aging; posturography; balance testing; Romberg-test
24.  PINK1 mutations and parkinsonism 
Neurology  2008;71(12):896-902.
PINK1 loss-of-function causes recessive, early-onset parkinsonism. In Tunisia there is a high rate of consanguineous marriage but PINK1 carrier frequency and disease prevalence have yet to be assessed.
The frequency of PINK1 mutations in familial parkinsonism, community-based patients with idiopathic Parkinson disease (PD) (non-familial PD), and control subjects was determined. Demographic and clinical characteristics of individuals with PINK1 homozygous or heterozygous variants, or without PINK1 mutations, were compared.
A total of 92 kindreds (with 208 affected and 340 unaffected subjects), 240 nonfamilial PD, and 368 control participants were recruited from the Institut National de Neurologie, Tunis. Clinical examinations included Hoehn &Yahr, UPDRS, and Epworth scales. PINK1 sequencing and dosage analysis was performed in familial index patients, the variants identified screened in all subjects. Parkin and LRRK2 genes were also examined.
Four PINK1 homozygous mutations, three novel (Q129X, Q129fsX157, G440E, and one previously reported; Q456X), segregate with parkinsonism in 46 individuals in 14 of 92 families (15%). Six of 240 patients with nonfamilial PD were found with either homozygous Q456X or Q129X (2.5%) substitutions. In patients with familial disease, PINK1 homozygotes were younger at disease onset (36 ± 12 years) than noncarriers (57 ± 15 years) and more often had an akinetic-rigid presentation at examination and slow progression.
Segregation of PINK1 mutations with parkinsonism within families, and frequency estimates within population controls, suggested only four PINK1 mutations were pathogenic. Several PINK1 sequence variants are potentially benign and there was no evidence that PINK1 heterozygosity increases susceptibility to idiopathic Parkinson disease.
= age at onset;
= case report forms;
= essential tremor;
= Parkinson disease;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2676945  PMID: 18685134
25.  Sleep disorders in Parkinson’s disease 
Sleep disorders occur commonly in Parkinson’s disease (PD), and reduce quality of life. Sleep-related problems in PD include insomnia, restless legs syndrome, rapid eye movement sleep behavior disorder, sleep apnea, parasomnias, excessive daytime sleepiness, and sleep attacks. This article reviews sleep disorders and their treatment in PD.
PMCID: PMC2773284  PMID: 19898667
insomnia; restless legs syndrome; sleep apnea

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