Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part Research Articles

Long-Term Dementia Risk in Parkinson Disease.

It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point. For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years. Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.

Associations between non-motor symptoms and patient characteristics in Parkinson's disease: a multicenter cross-sectional study.

Parkinson's disease (PD) is characterized by various non-motor symptoms (NMS), such as constipation, olfactory disturbance, sleep disturbance, mental disorders, and motor symptoms. This study aimed to investigate factors associated with NMS in patients with PD. Symptoms of PD were evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parts I-IV. NMS was assessed using the MDS-UPDRS Part I (self-assessment of NMS) and rapid eye movement sleep behavior disorder (RBD) questionnaires. Patients were categorized by age into <70 years and ≥ 70 years (older adults) groups, according to disease duration into early-stage and advanced-stage groups with a cut-off value of 5 years for motor symptoms, and by sex into male and female groups. A total of 431 patients with PD (202 males and 229 females) with a mean age of 67.7 years, a mean disease duration of 6.4 years, and a mean Part I total score of 9.9 participated in this study. The Part I total score was significantly positively correlated (p < 0.01) with disease duration and Part II, III, and IV scores. For Part I sub-item scores, the older group had significantly higher scores for cognitive impairment, hallucinations, sleep problems, urinary problems, and constipation than the <70 years group, whereas the advanced-stage group had significantly higher scores for hallucinations, sleep problems, daytime sleepiness, pain, urinary problems, and constipation (p < 0.05) than the early-stage group. Anxiety was higher in female patients than in male patients, whereas daytime sleepiness, urinary problems, and RBD were higher in male patients than in female patients (p < 0.05). Factors affecting Part I included disease duration, Part II total scores, Part IV total scores, and RBD. According to the self-questionnaire assessment, NMS was highly severe in older adult patients, those with longer illness duration, subjective and objective motor function impairments, and RBD. Sex-based differences were also observed.

Risk factors for developing dyskinesia among Parkinson's disease patients with wearing-off: J-FIRST

BackgroundDyskinesia frequently occurs during long-term treatment with levodopa in patients with Parkinson's disease (PD) and impacts quality of life. Few studies have examined risk factors for developing dyskinesia in PD patients exhibiting wearing-off. Therefore, we investigated the risk factors and impact of dyskinesia in PD patients exhibiting wearing-off. MethodsWe investigated the risk factors and impact of dyskinesia in a 1-year observational study of Japanese PD patients exhibiting wearing-off (J-FIRST). Risk factors were assessed by logistic regression analyses in patients without dyskinesia at study entry. Mixed-effect models were used to evaluate the impact of dyskinesia on changes in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Part I and PD Questionnaire (PDQ)-8 scores from one timepoint before dyskinesia was observed. ResultsOf 996 patients analyzed, 450 had dyskinesia at baseline, 133 developed dyskinesia within 1 year, and 413 did not develop dyskinesia. Female sex (odds ratio [95% confidence interval]: 2.636 [1.645–4.223]) and administration of a dopamine agonist (1.840 [1.083–3.126]), a catechol-O-methyltransferase inhibitor (2.044 [1.285–3.250]), or zonisamide (1.869 [1.184–2.950]) were independent risk factors for dyskinesia onset. MDS-UPDRS Part I and PDQ-8 scores increased significantly after the onset of dyskinesia (least-squares mean change [standard error] at 52 weeks: 1.11 [0.52], P = 0.0336; 1.53 [0.48], P = 0.0014; respectively). ConclusionFemale sex and administration of a dopamine agonist, a catechol-O-methyltransferase inhibitor, or zonisamide were risk factors for dyskinesia onset within 1 year in PD patients exhibiting wearing-off. Nonmotor symptoms and quality of life deteriorated after dyskinesia onset.

Influence of istradefylline on non-motor symptoms of Parkinson's disease: A subanalysis of a 1-year observational study in Japan (J-FIRST)

IntroductionThe non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD. MethodsPatients with PD and ≥1 NMS and ‘wearing-off’ with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model. ResultsOverall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score. ConclusionNMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs.

Determinants of self-efficacy in patients with Parkinson's disease.

Self-efficacy is the individual's assessment of his or hers ability to complete a specific task successfully and has been closely related to self-management and quality of life in several diseases. To investigate self-efficacy in a population of Parkinson's disease (PD) patients in Mexico and study the factors that are associated with this measure. We carried out a cross-sectional observational study involving patients with PD in an outpatient neurology clinic in Mexico, using the following instruments: Spanish version of the Chronic Disease Self-Efficacy Scale (CDSES), Quality of Life Questionnaire PDQ-8, Movement Disorders Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), and Non-Motor Symptom Scale (NMSS). Clinical and demographic variables were also recorded. We included 73 patients with a mean age of 65 years and most patients were male. Patients with lower CDSES scores (<7.75) had worse scores in MDS-UPDRS, NMSS, and PDQ-8 scales. CDSES scores were significantly correlated with MDS-UPDRS Part I (r=-0.497, p=<0.001), Part II (r= -0.271, p=0.020), Part III (r=-0.304, p=<0.001), PDQ-8 (r=-0.472, p=<0.001), and NMSS (r=-0.504, p=<0.001). Furthermore, when assessing the simultaneous effect of covariates associated with CDSES score, only Mood/Apathy domain of NMSS was significant (beta= -0.446, t= -3.807, p= 0.012). PD patients with lower self-efficacy scores had worse motor and non-motor symptomatology and quality of life. Mood/Apathy disorders were negatively associated with self-efficacy and contributed significantly to this measure.

Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study

Parkinson's disease (PD) is characterized by both motor and nonmotor deficits. Among cardinal symptoms of this disorder, tremor is the least responsive to dopamine replacement therapy and is often undertreated. Zuranolone (SAGE-217) is an investigational oral neuroactive steroid (NAS) gamma-aminobutyric acid A (GABAA) receptor–positive allosteric modulator (PAM) that has been investigated for its safety and efficacy in patients with PD. In the current open-label study, zuranolone capsules (20 to 30 mg) were administered for 7 days in 14 patients (mean age, 65.1 years; mean time since PD diagnosis, 9 years). The primary efficacy endpoint was reduction in tremor symptoms, as assessed by change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II/III Tremor Scores on Day 8. Additional endpoints included improvements in overall motor symptoms, and motor and nonmotor aspects of daily living. Adverse events (AEs) were also monitored. The MDS-UPDRS Part II/III Tremor Score improved by 40% (P < 0.0001) from baseline on Day 8. The motor score, and nonmotor experiences of daily living (nM-EDL), and motor experiences of daily living (m-EDL) scores (MDS-UPDRS Parts I and II, respectively), also improved on Day 8. No serious AEs were reported, and no patients discontinued treatment. The most common AEs were dizziness, sedation, and somnolence. Zuranolone was generally well tolerated and improved tremor symptoms in patients with PD who were on stable doses of concurrent dopaminergic agents. These data support the further investigation of NAS GABAA receptor PAMs as adjunctive treatments for tremor in patients with PD.

Changes in Motor, Cognitive, and Behavioral Symptoms in Parkinson's Disease and Mild Cognitive Impairment During the COVID-19 Lockdown.

Objective: The effects of the COVID-19 lockdown on subjects with prodromal phases of dementia are unknown. The aim of this study was to evaluate the motor, cognitive, and behavioral changes during the COVID-19 lockdown in Italy in patients with Parkinson's disease (PD) with and without mild cognitive impairment (PD-MCI and PD-NC) and in patients with MCI not associated with PD (MCInoPD).Methods: A total of 34 patients with PD-NC, 31 PD-MCI, and 31 MCInoPD and their caregivers were interviewed 10 weeks after the COVID-19 lockdown in Italy, and changes in cognitive, behavioral, and motor symptoms were examined. Modified standardized scales, including the Neuropsychiatric Inventory (NPI) and the Movement Disorder Society, Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I and II, were administered. Multivariate logistic regression was used to evaluate associated covariates by comparing PD-NC vs. PD-MCI and MCInoPD vs. PD-MCI.Results: All groups showed a worsening of cognitive (39.6%), pre-existing (37.5%), and new (26%) behavioral symptoms, and motor symptoms (35.4%) during the COVID-19 lockdown, resulting in an increased caregiver burden in 26% of cases. After multivariate analysis, PD-MCI was significantly and positively associated with the IADL lost during quarantine (OR 3.9, CI 1.61–9.58), when compared to PD-NC. In the analysis of MCInoPD vs. PD-MCI, the latter showed a statistically significant worsening of motor symptoms than MCInoPD (OR 7.4, CI 1.09–45.44). Regarding NPI items, nighttime behaviors statistically differed in MCInoPD vs. PD-MCI (16.1% vs. 48.4%, p = 0.007). MDS-UPDRS parts I and II revealed that PD-MCI showed a significantly higher frequency of cognitive impairment (p = 0.034), fatigue (p = 0.036), and speech (p = 0.013) than PD-NC. On the contrary, PD-MCI showed significantly higher frequencies in several MDS-UPDRS items compared to MCInoPD, particularly regarding pain (p = 0.001), turning in bed (p = 0.006), getting out of bed (p = 0.001), and walking and balance (p = 0.003).Conclusion: The COVID-19 quarantine is associated with the worsening of cognitive, behavioral, and motor symptoms in subjects with PD and MCI, particularly in PD-MCI. There is a need to implement specific strategies to contain the effects of quarantine in patients with PD and cognitive impairment and their caregivers.

Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

IntroductionThe efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of “OFF” episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. MethodsAdult patients with levodopa-responsive PD and “OFF” episodes were enrolled. In practically defined “OFF,” patients were observed for a FULL “ON” after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10–35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. ResultsAmong 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL “ON” (66.1% at 10–20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). ConclusionAmong eligible patients with PD and “OFF” episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of “OFF” episodes.

Neuroimaging and neurophysiological evaluation of severity of Parkinson’s disease

ObjectivesParkinson’s disease (PD) is a neurodegenerative disease presenting characteristic motor features. Severity is usually assessed by clinical symptoms; however, few objective indicators are available. In this study, we evaluated the utility of dopamine transporter (DAT) imaging and subthalamic nucleus (STN) activities as indicators of PD severity. Materials and methodsTwelve hemispheres of ten patients with PD who underwent deep brain stimulation (DBS) were included in this study. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 scores were used to evaluate clinical severity. The relationship between specific binding ratio (SBR) of DAT imaging and the root mean square (RMS) of STN micro-electrode recording (MER) was evaluated. ResultsA negative correlation was detected between the MDS-UPDRS part 3 scores and SBR (N = 20, R2 = 0.418; P = 0.002). With respect to subscores, rigidity (R2 = 0.582; P < 0.001) and bradykinesia (R2 = 0.378; P = 0.004) showed negative correlation with SBR, whereas tremor showed no correlation (R2 = 0.054; P = 0.324) (N = 20). On the other hand, no correlation was found between MER and the MDS-UPDRS part 3 scores in ten hemispheres of six patients. ConclusionDAT findings may be useful in evaluating PD severity, especially rigidity and bradykinesia.

Relationship of Movement Disorders Society-Unified Parkinson's Disease Rating Scale Nonmotor Symptoms to Cognitive Functioning in Patients with Parkinson's Disease.

Few studies assess the relationships between nonmotor aspects of experiences of daily living and cognitive functioning in Parkinson's disease (PD). To evaluate the relationships among the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I items and neuropsychological tests in PD.Methods: We assessed 151 PD patients with the MDS-UPDRS part I and a battery of cognitive tests focused on the following 5 cognitive domains: attention/working memory, executive functioning, recent memory, language, visuoperception. Raw scores for individual cognitive tests were transformed to z scores, and cognitive domain scores were calculated by averaging z scores within each domain. Individual items from the MDS-UPDRS part I were entered in a stepwise linear regression analysis assessing item contribution to cognitive domain scores. The MDS-UPDRS part I item scores for hallucinations and psychosis and light headedness on standing predicted attention/working memory domain scores (P = 0.004). These same item scores, along with apathy, depressed mood, and dopamine dysregulation syndrome, predicted executive functioning (P = 0.044). The apathy and dopamine dysregulation syndrome items predicted language (P = 0.006). In addition, the cognitive impairment and sleep items were predictors of recent memory (P = 0.031). None of the items were predictors of visuoperception (P = 0.006). Other part I items were not significantly related to cognitive domain scores. Specific nonmotor MDS-UPDRS part I items, particularly mood, behavior, and autonomic-related items, exhibited significant relationships with cognitive domains. The highest number of items were predictive of the executive functioning domain, which is the hallmark cognitive dysfunction in PD.

Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 study

Many patients with Parkinson's disease have potentially disabling off episodes that are not predictably responsive to levodopa. In this study, we assessed the safety and efficacy of apomorphine sublingual film as an on-demand therapy for off episodes in patients with Parkinson's disease. This randomised, double-blind, placebo-controlled study was done by movement disorder specialists at 32 sites in the USA and one in Canada. Patients with Parkinson's disease who had 2 h or more of off time per day with predictable morning off periods, were responsive to levodopa, and were on stable doses of anti-parkinsonian medication were eligible. In an open-label titration phase, increasing doses of apomorphine sublingual film (10-35 mg) were administered until a tolerable full on response was achieved. Patients were then randomly assigned (1:1) with an interactive web-response system to receive the effective dose of apomorphine sublingual film or matching placebo in a 12-week, double-blind maintenance phase. Randomisation was not stratified, and the block size was four. All patients and study personnel were masked to treatment assignments. The primary endpoint was the in-clinic change from predose to 30 min post-dose in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 (motor) score at week 12, analysed on a modified intention-to-treat population by use of a mixed-effect model for repeated measures. Safety analyses were done on all enrolled patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT02469090. Between June 18, 2015, and Dec 11, 2017, 109 patients were enrolled and randomly assigned to receive apomorphine sublingual film (n=54) or placebo (n=55). All patients received the assigned study treatment, and 34 (63%) of 54 patients receiving apomorphine sublingual film and 46 (84%) of 55 receiving placebo completed the study. Least squares mean (SE) change from predose to 30 min post-dose in MDS-UPDRS part 3 score at week 12 was -11·1 (SE 1·46, 95% CI -14·0 to -8·2) with apomorphine sublingual film and -3·5 (1·29, -6·1 to -0·9) with placebo (difference -7·6, SE 1·96, 95% CI -11·5 to -3·7; p=0·0002). Mild-to-moderate oropharyngeal events were the most common side-effect, reported in 17 (31%) of 54 patients receiving apomorphine sublingual film and in four (7%) of 55 patients receiving placebo, leading to treatment discontinuation in nine (17%) patients treated with apomorphine and in one (2%) patient treated with placebo. Other treatment-emergent adverse events were transient nausea (in 15 [28%] patients receiving apomorphine sublingual film), somnolence (seven [13%]), and dizziness (five [9%]). Orthostatic hypotension, syncope, dyskinesia, hallucinations, prolongation of the QT interval, and impulse control disorders were infrequent (prevalence ≤2% of all patients) or did not occur. One patient treated with apomorphine sublingual film (with known cardiac risk factors) had a fatal cardiac arrest. Although nearly a third of patients discontinued treatment primarily because of oropharyngeal side-effects, apomorphine sublingual film provided an efficacious, on-demand treatment for off episodes for most patients with Parkinson's disease in this trial. The long-term safety and efficacy of apomorphine sublingual film are currently being investigated. Cynapsus Therapeutics and Sunovion.

Falls in persons with Parkinson's disease: Do non-motor symptoms matter as much as motor symptoms?

Falls are common among persons with Parkinson's disease (PD). On the other hand, predicting falls is complex as there are both generic and PD-specific contributors. In particular, the role of non-motor symptoms has been less studied. The objective of this study was to identify the role of non-motor predictors of falling in persons with PD (PwP). A cross-sectional study was carried out in PwP recruited from a movement disorders clinic. Clinical and demographical data were collected. All PwP were assessed using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Non-Motor Symptoms Scale (NMSS). Variables were assessed at the bivariate level. Significant variables were put into a logistic regression model. A total of 179 PwP were included. Overall, 16.8% of PwP had fallen in the past 12 months, with 53.3% of them being recurrent fallers. The mean number of monthly falls was 2.5 ± 3.3. Factors associated with falling in the bivariate analysis included the disease duration, Hoehn and Yahr stage, MDS-UPDRS part I and II, postural instability/gait disturbance (PIGD) subtype, NMSS urinary domain, NMSS miscellaneous domain, and non-motor severity burden (all p-values < 0.05). After multivariate analysis, only the disease duration (p = 0.03) and PIGD (p = 0.03) remained as independent risk factors. Disease duration and the PIGD subtype were identified as relevant risk factors for falls in PwP Non-motor symptoms appear to have a less important role as risk factors for falls.