Unified Parkinson's Disease Rating Scale Motor Examination Research Articles

Neurostimulation for Advanced Parkinson Disease and Quality of Life at 5 Years

Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life (QOL) in patients with advanced Parkinson disease (PD). However, controlled studies with more than 3 years of follow-up are lacking. To investigate the long-term effects of STN-DBS on QOL compared with standard-of-care medication (MED). In this prospective, observational, quasi-experimental, longitudinal nonrandomized controlled trial, 183 patients were screened for eligibility and 167 were enrolled from March 1, 2011, to May 31, 2017, at 3 European university centers. Propensity score matching for demographic and clinical characteristics was applied to 108 patients with PD (62 in the STN-DBS group and 46 in the MED group), resulting in a well-balanced, matched subcohort of 25 patients per group. Data analysis was performed from September 2022 to January 2023. Treatment for PD of STN-DBS or MED. Assessments included Parkinson's Disease Questionnaire 8 (PDQ-8), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-activities of daily living (ADL) and motor complications, and levodopa-equivalent daily dose. Within-group longitudinal outcome changes, between-group differences, and correlations of change scores were analyzed. The study population in the analysis included 108 patients (mean [SD] age, 63.7 [8.3] years; 66 [61.1%] male). At 5-year follow-up, PDQ-8 and ADL worsened only in the MED group (PDQ-8 change, -10.9; 95% CI, -19.0 to -2.7; P = .01; ADL change: -2.0; 95% CI, -3.1 to -0.8; P = .002), whereas both outcomes remained stable in the STN-DBS group (PDQ-8 change, -4.3; 95% CI, -13.2 to 4.7; P = .34; ADL change, -0.8; 95% CI, -2.5 to 1.0; P = .38). Changes in PDQ-8 and ADL correlated moderately (rs = .40, P = .008). Furthermore, STN-DBS outcomes were favorable for motor complications (median difference in change scores between STN-DBS and MED, -2.0; 95% CI, -4.0 to -1.0; P = .003), mobility (-1.0; 95% CI, -2.0 to 0; P = .03), and levodopa-equivalent daily dose reduction (-821.4; 95% CI, -1111.9 to -530.8; P < .001). This study provides evidence of differences in QOL outcomes at 5-year follow-up between STN-DBS (stable) and MED (worsened), mainly driven by the favorable effect of STN-DBS on mobility (class IIb evidence). The association between changes in QOL and ADL, but not motor impairment or complications, highlights the relative importance of ADL outcomes for long-term DBS assessments. German ClinicalTrials Registry: DRKS00006735.

Non-motor effects of deep brain stimulation in Parkinson's disease motor subtypes

IntroductionDeep brain stimulation (DBS) is a well-established treatment for patients with Parkinson's disease (PD) improving quality of life, motor, and non-motor symptoms. However, non-motor effects in PD subtypes are understudied. We hypothesized that patients with ‘postural instability and gait difficulty’ (PIGD) experience more beneficial non-motor effects than ‘tremor-dominant’ patients undergoing DBS for PD. MethodsIn this prospective, observational, international multicentre study with a 6-month follow-up, we assessed the Non-Motor Symptom Scale (NMSS) as primary and the following secondary outcomes: Unified PD Rating Scale-motor examination (UPDRS-III), Scales for Outcomes in PD (SCOPA)-activities of daily living (ADL) and -motor complications, PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose (LEDD). We analysed within-group longitudinal changes with Wilcoxon signed-rank test and Benjamini-Hochberg correction for multiple comparisons. Additionally, we explored outcome between-group differences of motor subtypes with Mann-Whitney U-tests. ResultsIn 82 PIGD and 33 tremor-dominant patients included in this study, baseline NMSS total scores were worse in PIGD patients, both groups experienced postoperative improvements of the NMSS sleep/fatigue domain, and between-group differences in postoperative outcomes were favourable in the PIGD group for the NMSS total and miscellaneous domain scores. ConclusionsThis study provides evidence of a favourable outcome of total non-motor burden in PIGD compared to tremor-dominant patients undergoing DBS for PD. These differences of clinical efficacy on non-motor aspects should be considered when advising and monitoring patients with PD undergoing DBS.

Normalized Mutual Information of phonetic sound to distinguish the speech of Parkinson's disease.

This study has investigated the use of inter-personnel mutual information computed from the phonetic sound recordings to differentiate between Parkinson's disease (PD) and control subjects. The normalized mutual information (NMI) denotes the amount of information shared between the voice recordings of people within the same group: PD and Control. The hypothesis of this study was that within group NMI will be significantly different when compared with inter- group NMI. For each phonetic sound, the NMI was computed for every pairing of recordings for both the PD and control groups. Pearson correlation coefficient analysis was used to determine the association of NMI with clinical parameters including Unified Parkinson's Disease Rating Scale (UPDRS), Montreal cognitive assessment (MoCA) and disease duration. ANOVA test for the three phonetic sounds of control and PD subjects showed that there is significant difference between the intra-group mean NMI for the two groups (p <; 0.003) and also showed significant association with the UPDRS motor examination score, MoCA and disease duration.

Beneficial effects of bilateral subthalamic stimulation on alexithymia in Parkinson's disease.

Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL) and motor and non-motor symptoms in advanced Parkinson's disease (PD). However, its effect on alexithymia and its relationship to other neuropsychiatric symptoms and QoL in PD is unclear. In this prospective, observational study of 39 patients with PD undergoing STN-DBS, we examined the Parkinson's Disease Questionnaire-8 (PDQ-8), 20-item Toronto Alexithymia Scale (TAS-20), Hospital Anxiety and Depression Scale (HADS), Self-Report Manic Inventory (SRMI), Apathy Evaluation Scale (AES), Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living, UPDRS motor examination and UPDRS complications (UPDRS-II/-III/-IV) and levodopa-equivalent daily dose (LEDD) pre-operatively and at 5-month follow-up. Outcome changes were tested with Wilcoxon signed-rank or paired t-test when parametric tests were applicable and corrected for multiple comparisons. The relationship between outcome changes was explored with bivariate correlations. Additionally, partial correlations between PDQ-8 and TAS-20 were computed controlling for HADS, SRMI and AES change scores. Predictor analyses for PDQ-8 improvement were calculated for all baseline parameters. The baseline prevalence of alexithymia was 17.9%. We observed significant beneficial effects of STN-DBS on PDQ-8, TAS-20, HADS, UPDRS-II, -III and -IV scores and significant LEDD reduction. The correlation between TAS-20 and PDQ-8 improvements remained significant after controlling for all other aforementioned outcomes. Predictor analyses for PDQ-8 improvement were significant for PDQ-8 and TAS-20. This is the first report of beneficial effects of STN-DBS on alexithymia. Alexithymia was significantly associated with QoL outcome independent of anxiety, depression, mania and apathy. Our study highlights the importance of alexithymia for holistic assessments of DBS outcomes.

TNF-α − 308 G/A and − 238 G/A promoter polymorphisms and sporadic Parkinson's disease in an Italian cohort

The etiology of sporadic Parkinson's disease is (PD) still not understood but it is believed that a complex interplay between environmental and genetic factors could trigger the pathology. Pro-inflammatory TNF-α is released by activated microglia and is up-regulated in the brain and cerebrospinal fluid of PD patients; TNF-α modulates neuroinflammation and can activate the molecular mechanisms that lead to neurotoxicity and neuronal death. We analyzed two functional SNPs within the TNF-α gene promoter (rs361525 and rs1800629) in 354 Italian PD patients and 443 healthy controls (HC). In our cohort of patients, no significant associations could be observed between rs361525 and rs1800629 SNPs and either PD onset risk or PD-associated clinical parameters including age at onset of fluctuations, UPDRS-ME (Unified Parkinson Disease Rating Scale-Motor Examination), Schwab & England, Hohen & Yahr stage scale, and MMSE (Mini-Mental State Examination) score. Conflicting results on the role played by TNF-α rs1800629 SNP on PD onset risk are present in the literature. We could not find any association between TNF-α rs361525 and rs1800629 and PD.

Switching L-dopa Therapy from Pulsatile to Pulse Administration Reduces Motor Complications in Parkinson's Disease.

To evaluate the severity of wearing-off and dyskinesia in patients with complicated Parkinson disease (PD) after switching L-dopa oral therapy from a "pulsatile" administration, consisting in intermittent multiple daily small doses of the drug, to a "pulse" administration, consisting in standard oral doses given at specific interdose intervals. Thirty-four PD patients with motor complications were monitored twice with standardized waking day motor status evaluations using the Unified Parkinson Disease Rating Scale-Motor Examination (UPDRS-ME) and the Abnormal Involuntary Movement Scale (AIMS) after switching L-dopa administration modality from "pulsatile" to "pulse." To quantify predictable motor fluctuations, a Wearing Off Index was computed based on changes in treatment response magnitude. On the whole, after switching from "pulsatile" to "pulse" administration, there was a reduction in number of L-dopa daily doses and an increase in the amount of the dosage of the single doses, AIMS maximum score decreased without increasing motor disability. More specifically, in predominant fluctuating patients, there was a significant reduction in UPDRS-ME average score as well as in Wearing Off Index. In predominant dyskinetic patients, there was a significant reduction in average and maximum AIMS scores with no changes in average and maximum UPDRS-ME scores. Switching L-dopa therapy from "pulsatile" to "pulse" modality may reduce the severity of wearing-off and dyskinesia in complicated PD.

A randomized controlled trial of patient-reported outcomes with tai chi exercise in Parkinson's disease.

A previous randomized, controlled trial of tai chi showed improvements in objectively measured balance and other motor-related outcomes in patients with Parkinson's disease. This study evaluated whether patient-reported outcomes could be improved through exercise interventions and whether improvements were associated with clinical outcomes and exercise adherence. In a secondary analysis of the tai chi trial, patient-reported and clinical outcomes and exercise adherence measures were compared between tai chi and resistance training and between tai chi and stretching exercise. Patient-reported outcome measures were perceptions of health-related benefits resulting from participation, assessed by the Parkinson's Disease Questionnaire (PDQ-8) and Vitality Plus Scale (VPS). Clinical outcome measures included motor symptoms, assessed by a modified Unified Parkinson's Disease Rating Scale–Motor Examination (UPDRS-ME) and a 50-foot speed walk. Information on continuing exercise after the structured interventions were terminated was obtained at a 3-month postintervention follow-up. Tai chi participants reported significantly better improvement in the PDQ-8 (−5.77 points, P = 0.014) than did resistance training participants and in PDQ-8 (−9.56 points, P < 0.001) and VPS (2.80 points, P = 0.003) than did stretching participants. For tai chi, patient-reported improvement in the PDQ-8 and VPS was significantly correlated with their clinical outcomes of UPDRS-ME and a 50-foot walk, but these correlations were not statistically different from those shown for resistance training or stretching. However, patient-reported outcomes from tai chi training were associated with greater probability of continued exercise behavior than were either clinical outcomes or patient-reported outcomes from resistance training or stretching. Tai chi improved patient-reported perceptions of health-related benefits, which were found to be associated with a greater probability of exercise adherence. The findings indicate the potential of patient perceptions to drive exercise behavior after structured exercise programs are completed and the value of strengthening such perceptions in any behavioral intervention.

Withdrawing amantadine in dyskinetic patients with Parkinson disease

The AMANDYSK trial was designed to assess long-term efficacy of chronic treatment with amantadine in patients with Parkinson disease (PD) and levodopa-induced dyskinesia (LID). This was a 3-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group, wash-out study conducted in 57 amantadine-treated (≥200 mg/d for ≥6 months) dyskinetic patients with PD. The primary outcome measure was the change from baseline in a Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia subscore (items 32 [duration] + 33 [severity]). Secondary outcomes included other LID measurements ("responders" analysis, premature dropout for LID, Abnormal Involuntary Movement Scale). Exploratory outcomes included time with troublesome dyskinesia as measured by diaries, UPDRS Motor Examination (part III) for motor symptoms of PD, and fatigue and apathy scores for nonmotor symptoms. UPDRS items 32 + 33 deteriorated more in patients switched to placebo ("discontinuing" group) (+1.7 ± 2.0 units; 95% confidence interval 0.9, 2.4) as compared with those maintained on amantadine ("continuing" group) (+0.2 ± 1.5 units; 95% confidence interval -0.4, 0.8; p = 0.003). Secondary outcomes confirmed this difference because there were significantly more responders, more dropouts for LID, greater increase in "ON" time with troublesome dyskinesia, and greater worsening of Abnormal Involuntary Movement Scale score in the discontinuing group. There were no between-group differences in the UPDRS Motor Examination, whereas apathy (as measured by caregivers) and fatigue scores tended to worsen more in patients randomized to placebo. Wash-out of amantadine in dyskinetic patients with PD significantly worsened LID. No significant effect was observed on motor parkinsonian symptoms, while exploratory outcomes suggested that amantadine might improve apathy and fatigue in such patients. This article provides Class II evidence that in patients with PD, withdrawing amantadine significantly aggravates LID in a median time of 7 days.

Examination of the UPDRS Bradykinesia Subscale: Equivalence, Reliability and Validity

Administering items or subscales separately from the measure for which they were designed to be a part may have unintended consequences for research and practice in Parkinson's disease (PD). The current study tested the equivalence of the bradykinesia subscale when administered alone versus as a component of the full 14-item Unified Parkinson's Disease Rating Scale (UPDRS) motor examination, as well as examined the reliability and validity of the bradykinesia subscale. The study sample consisted of 112 patients with PD. Patients were randomly assigned to either the bradykinesia subscale alone group (n = 56), who were administered the bradykinesia subscale separately from the rest of the UPDRS motor examination, or the full scale group (n = 56), who were administered the UPDRS motor examination in its standard format. The two one-sided t-test (TOST) procedure was used to test for mean equivalency between the two administration groups. Additionally, reliability and validity analyses were performed. The bradykinesia subscale mean scores from the full scale group and the subscale alone group were not statistically equivalent. However, in both groups, the bradykinesia subscale had exceptional reliability and was strongly and similarly related to age, activities of daily living, disability, and other assessments of motor symptom severity. The bradykinesia subscale is a valid and reliable assessment when administered separately from the rest of the UPDRS motor examination; however, caution should be taken when comparing mean scores across studies or occasions when different administrations are used.

Single‐Dose Administration of MK‐0657, an NR2B‐Selective NMDA Antagonist, Does Not Result in Clinically Meaningful Improvement in Motor Function in Patients With Moderate Parkinson's Disease

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Metric attributes of the unified Parkinson's disease rating scale 3.0 battery: Part II, construct and content validity

This article is the second of a two-part series concerning the metric properties of the following three Parkinson's disease (PD) scales: modified Hoehn and Yahr staging (H&Y), Schwab and England (S&E), and Unified Parkinson's Disease Rating Scale (UPDRS) 3.0. Part II focuses on construct and content validity. To assess construct validity, a sample of 1,136 PD patients completed the above-mentioned PD scales. Correlation coefficients between measures of disability and dysfunction [S&E, UPDRS Activities of Daily Living (ADL), and UPDRS Motor Examination] were |r| = 0.69-0.77, indicating good convergent validity. Results showed that the S&E (F(5,945) = 193.47; P < 0.0001) and UPDRS subscales discriminated between modified H&Y stages (F(20,2784) = 25.28; P < 0.001). A panel of 12 to 13 international experts rated the relevance of the scales and items. This enabled the scales' content validity index to be calculated, which ranged from 41.7% (UPDRS Mentation) to 83.3% (UPDRS Motor Examination). In conclusion, while the modified H&Y, S&E, and UPDRS displayed satisfactory construct validity, the content validity of all scales except UPDRS Motor Examination failed to attain adequate standards.

Unified Parkinson's disease rating scale motor examination: Are ratings of nurses, residents in neurology, and movement disorders specialists interchangeable?

The Unified Parkinson's Disease Rating Scale (UPDRS) is widely used for the clinical evaluation of Parkinson's disease (PD). We assessed the rater variability of the UPDRS Motor examination (UPDRS-ME) of nurse practitioners, residents in neurology, and a movement disorders specialist (MDS) compared to a senior MDS. We assessed the videotaped UPDRS-ME of 50 PD patients. Inter-rater and intra-rater variability were estimated using weighted kappa (kappa(w)) and intraclass correlation coefficients (ICC). Additionally, inter-rater agreement was quantified by calculation of the mean difference between 2 raters and its 95% limits of agreement. Intra-rater agreement was also estimated by calculation of a 95% repeatability limits. The kappa(w) and ICC statistics indicated good to very good inter-rater and intra-rater reliability for the majority of individual UPDRS items and the sum score of the UPDRS-ME in all raters. However, for inter-rater agreement, it appeared that both nurses, residents, and the MDS consistently assigned higher scores than the senior MDS. Mean differences ranged between 1.7 and 5.4 (all differences P < 0.05), with rather wide 95% limits of agreement. The intra-rater 95% repeatability limits were rather wide. We found considerable rater difference for the whole range of UPDRS-ME scores between a senior MDS and nurse practitioners, residents in neurology, and the MDS. This finding suggests that the amount by which raters may disagree should be quantified before starting longitudinal studies of disease progression or clinical trials. Finally, evaluation of rater agreement should always include the assessment of the extent of bias between different raters.

Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses

The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa. Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P< or = 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo. No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone.

Teaching tape for the motor section of the unified Parkinson's disease rating scale.

We developed a teaching tape of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) to provide investigators with a visual document of three raters' interpretations of the scoring system for each item except rigidity. The rate of agreement for the selected samples was always significant, with Kendall's coefficient of concordance W ranging between 0.97 and 0.62. We also provided full UPDRS ratings on sample patients that may be used for training and for multicenter studies to assure uniformity of rating. The study identified several items of the UPDRS motor examination for which written instructions were vague, including speech, action tremor, finger taps, rapid alternating movements, and postural stability. Future versions of the scale should address these problems and correct ambiguities. This project offers the first attempt to provide a visual analog for the UPDRS.

Interrater reliability of the Unified Parkinson's Disease Rating Scale motor examination.

Interrater reliability of the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination was assessed by three neurologists experienced in the administration of this scale. Intraclass correlation coefficients indicated good-to-excellent agreement for speeded repeated movements, resting tremor, arising from a chair, and gait; moderate agreement for action tremor, rigidity, posture, postural stability, and bradykinesia; and poor agreement for speech disorder and facial immobility. Overall, these results indicate that satisfactory interrater reliability is attainable with the UPDRS motor examination.