Motor and Non-motor Symptoms Associated With Exercise Behavior in Parkinson's Disease Patients: Factors Differ Between Patients With and Without Postural Instability

Background: Exercise is an important treatment for Parkinson's disease (PD). Therefore, recognizing determinants of exercise behavior for PD based on disease stage is essential. We sought to find whether the determinants differ based on presence of postural instability (PI), which is indicative of disease stage in PD.Methods: We enrolled patients at Samsung Medical Center from September 2019 to November 2020, who had the ability to perform exercise [modified Hoehn and Yahr (HY) stage ≤ 3]. All the motor and non-motor symptoms were investigated. The exercise of the PD patients was evaluated using the Physical Activity Scale of the Elderly (PASE)-leisure score. We classified patients into PD without PI (HY stage 1 – 2) and PD with PI (HY stage 2.5 – 3) groups. Multivariate linear regression was performed using backward elimination in each group to determine factors associated with PASE-leisure score.Results: A total of 233 patients were enrolled. In the PD without PI group (n = 177), the positive determinant of exercise was Activities-Specific Balance Confidence (ABC) score (β = 0.142, p = 0.032), and the negative determinants were fatigue score (β = −0.228, p = 0.018), female (β = −6.900, p = 0.016) and currently employed status (β = −6.072, p = 0.046). In the PD with PI group (n = 56), the positive determinant was non-motor symptom scale (NMSS) score (β = 0.221, p = 0.017) and disease duration (β = 1.001, p = 0.036), while the negative determinants were UPDRS part 3 score (β = −0.974, p < 0.001), UPDRS part 4 score (β = −2.192, p = 0.002), and age (β = −1.052, p < 0.001).Conclusion: Different motor and non-motor symptoms were associated with the exercise in PD patients with and without PI. When encouraging PD patients to exercise, personalized and different strategies should be applied based on the presence of PI.

Clinical Efficacy and Dosing of Vibrotactile Coordinated Reset Stimulation in Motor and Non-motor Symptoms of Parkinson's Disease: A Study Protocol

Enhanced neuronal synchronization of the subthalamic nucleus (STN) is commonly found in PD patients and corresponds to decreased motor ability. Coordinated reset (CR) was developed to decouple synchronized states causing long lasting desynchronization of neural networks. Vibrotactile CR stimulation (vCR) was developed as non-invasive therapeutic that delivers gentle vibrations to the fingertips. A previous study has shown that vCR can desynchronize abnormal brain rhythms within the sensorimotor cortex of PD patients, corresponding to sustained motor relief after 3 months of daily treatment. To further develop vCR, we created a protocol that has two phases. Study 1, a double blinded randomized sham-controlled study, is designed to address motor and non-motor symptoms, sensorimotor integration, and potential calibration methods. Study 2 examines dosing effects of vCR using a remote study design. In Study 1, we will perform a 7-month double-blind sham-controlled study including 30 PD patients randomly placed into an active vCR or inactive (sham) vCR condition. Patients will receive stimulation for 4 h a day in 2-h blocks for 6 months followed by a 1-month pause in stimulation to assess long lasting effects. Our primary outcome measure is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off medication after 6 months of treatment. Secondary measures include a freezing of gait (FOG) questionnaire, objective motor evaluations, sensorimotor electroencephalography (EEG) results, a vibratory temporal discrimination task (VTDT), non-motor symptom evaluations/tests such as sleep, smell, speech, quality of life measurements and Levodopa Equivalent Daily Dose (LEDD). Patients will be evaluated at baseline, 3, 6, and 7 months. In the second, unblinded study phase (Study 2), all patients will be given the option to receive active vCR stimulation at a reduced dose for an additional 6 months remotely. The remote MDS-UPDRS part III off medication will be our primary outcome measure. Secondary measures include sleep, quality of life, objective motor evaluations, FOG and LEDD. Patients will be evaluated in the same time periods as the first study. Results from this study will provide clinical efficacy of vCR and help validate our investigational vibrotactile device for the purpose of obtaining FDA clearance.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT04877015.

Sex-Related Longitudinal Change of Motor, Non-Motor, and Biological Features in Early Parkinson’s Disease

Background: Investigation of sex-related motor and non-motor differences and biological markers in Parkinson’s disease (PD) may improve precision medicine approach. Objective: To examine sex-related longitudinal changes in motor and non-motor features and biologic biomarkers in early PD. Methods: We compared 5-year longitudinal changes in de novo, untreated PD men and women (at baseline N = 423; 65.5%male) of the Parkinson’s Progression Markers Initiative (PPMI), assessing motor and non-motor manifestations of disease; and biologic measures in cerebrospinal fluid (CSF) and dopamine transporter deficit on DaTscanTM uptake. Results: Men experienced greater longitudinal decline in self-reported motor (p < 0.001) and non-motor (p = 0.009) aspects of experiences of daily living, such that men had a yearly increase in MDS-UPDRS part II by a multiplicative factor of 1.27 compared to women at 0.7, while men had a yearly increase in MDS-UPDRS part I by a multiplicative factor of 0.98, compared to women at 0.67. Compared to women, men had more longitudinal progression in clinician-assessed motor features in the ON medication state (p = 0.010) and required higher dopaminergic medication dosages over time (p = 0.014). Time to reach specific disease milestones and longitudinal changes in CSF biomarkers and DaTscanTM uptake were not different by sex. Conclusion: Men showed higher self-assessed motor and non-motor burden of disease, with possible contributions from suboptimal dopaminergic therapeutic response in men. However, motor features of disease evaluated with clinician-based scales in the OFF medication state, as well as biological biomarkers do not show specific sex-related progression patterns.

Eight-hours conventional versus adaptive deep brain stimulation of the subthalamic nucleus in Parkinson’s disease

This study compares the effects on motor symptoms between conventional deep brain stimulation (cDBS) and closed-loop adaptive deep brain stimulation (aDBS) in patients with Parkinson’s Disease. The aDBS stimulation is controlled by the power in the beta band (12–35 Hz) of local field potentials recorded directly by subthalamic nucleus electrodes. Eight subjects were assessed in two 8-h stimulation sessions (first day, cDBS; second day, aDBS) with regular levodopa intake and during normal daily activities. The Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores, the Rush scale for dyskinesias, and the total electrical energy delivered to the tissues per second (TEEDs) were significantly lower in the aDBS session (relative UPDRS mean, cDBS: 0.46 ± 0.05, aDBS: 0.33 ± 0.04, p = 0.015; UPDRS part III rigidity subset mean, cDBS: 2.9143 ± 0.6551 and aDBS: 2.1429 ± 0.5010, p = 0.034; UPDRS part III standard deviation cDBS: 2.95, aDBS: 2.68; p = 0.047; Rush scale, cDBS 2.79 ± 0.39 versus aDBS 1.57 ± 0.23, p = 0.037; cDBS TEEDs mean: 28.75 ± 3.36 µj s−1, aDBS TEEDs mean: 16.47 ± 3.33, p = 0.032 Wilcoxon’s sign rank test). This work further supports the safety and effectiveness of aDBS stimulation compared to cDBS in a daily session, both in terms of motor performance and TEED to the patient.

Focused Ultrasound Thalamotomy in Tremor Dominant Parkinson’s Disease: Long-Term Results

Background: MRI-guided focused ultrasound (FUS) has established short-term efficacy in tremor relief. Objective: We report our long-term experience of treating tremor with unilateral FUS unilateral VIM-thalamotomy in tremor dominant Parkinson’s disease (TDPD) patients. Methods: We report outcome of FUS thalamotomy in TDPD patients with 1–5 years of follow-up. Outcomes: tremor reduction assessed with Clinical Rating Scale for Tremor (CRST) and Unified Parkinson’s Disease Rating Scale (UPDRS part III) overall and in the treated hemibody and safety. Results: Twenty-six TDPD patients completed 1–5 years of follow-up (median follow-up 36 months, range 12–60 months). Median age was 60 years (range 46–79), with median disease duration of 6 years (range 2–16). Immediately, treatment resulted in 100%improvement in tremor in the treated arm in 23 patients and 90%improvement in 3 patients. In 15 patients with leg tremor, 2 patients with chin tremor and 1 patient with head tremor, tremor was significantly improved. Up to 5 years, median CRST score, median UPDRS score, overall and in treated hemibody, decreased significantly as compared with baseline (p < 0.0001). In 2 patients tremor returned completely and in 8 patients there was partial return of tremor. Adverse events were mild and resolved within 3 months. At baseline 4 patients were not receiving any medication vs. 3 at last follow-up and 15 were not taking levodopa vs.9 at last follow-up. Conclusion: Unilateral FUS VIM-thalamotomy in TDPD patients was effective and safe and provided long-term tremor relief in most patients. FUS thalamotomy for tremor may delay initiation of levodopa treatment.

Different Catechol-O-Methyl Transferase Inhibitors in Parkinson's Disease: A Bayesian Network Meta-Analysis

Parkinson's disease (PD) is a common, chronic, progressive, debilitating neurodegenerative disease. The current levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced PD. Therefore, a theoretical reference for treatment is urgently needed. In this study, an appropriate search strategy was used to screen eligible studies on different drugs to treat patients with PD from the Embase, PubMed, and Cochrane Library. The publication dates were from January 1990 to June 2021. We integrated eligible randomized controlled trials, and statistical analysis was performed on three kinds of effectiveness outcomes and two types of safety outcomes. We assessed the average difference or odds ratio between each drug and placebo and summarized them as the average and 95% confidence interval (CI), respectively. In terms of efficacy, entacapone (mean difference [MD], 0.64 h; 95% CI, 0.29–1.0), opicapone (MD, 0.92 h; 95% CI, 0.35–1.5), and tolcapone (MD, 3.2 h; 95% CI, 2.1–4.2) increased patients' total ON-time compared to placebo. Tolcapone (MD, −100 mg; 95% CI −160 to −45) reduced the total daily dose of levodopa therapy. None of these three drugs was found to have statistical significance in mean change from baseline in UPDRS part III scores when compared with others. In terms of safety, tolcapone (MD, 3.8; 95% CI, 2.1–6.8), opicapone (MD, 3.7; 95% CI, 2–7.2), and entacapone (MD, 2.2; 95% CI, 1.5–3.3) increased the number of cases of dyskinesia compared to placebo. Entacapone (MD, 1.7; 95% CI, 1.3–2.2) and tolcapone (MD, 4.3; 95% CI, 1.3–15) were more likely to cause adverse events than placebo. In conclusion, opicapone showed higher efficiency and fewer safety problems in five indicators we selected when compared with the other two drugs.

Lateralization of Motor Signs Affects Symptom Progression in Parkinson Disease

Background: Asymmetry of motor signs is a cardinal feature of Parkinson disease which may impact phenotypic expression.Objective: To investigate the relationship between lateralization of motor signs and symptom progression and severity during longitudinal observation for up to 4 years in a naturalistic study.Methods: We analyzed data prospectively collected during the NINDS Parkinson Disease Biomarker Project (PDBP). We defined the Movement Disorder Society Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II as the primary measure of symptom progression. Left side predominant subjects were those whose lateralized motor scores on the MDS-UPDRS part III were ≥2 points higher on the left side than on the right side of the body. Multiple regression models (controlled for age, gender, education years, ethnicity, levodopa equivalent daily dose (LEDD) at baseline, and years with PD) were used to estimate the rate of symptom progression comparing left predominant (LPD) with non-left predominant (NLPD) subjects. A sensitivity analysis was performed using the same multiple regression models in the subgroups of low (0–26) or high (&gt;27) MDS-UPDRS II score at baseline to determine if PD severity influenced the results.Results: We included 390 participants, 177 LPD and 213 NLPD. We found that MDS-UPDRS part II progression from baseline to 48 months was faster in LPD compared to NLPD (0.6 points per year faster in LPD, p = 0.05). Additionally, the LPD group was statistically significantly worse at baseline and at 48 months in several subparts of the MDS-UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) mobility score. Significantly slower progression (difference of −0.8, p = 0.01) and lower score at 48 months (difference of −3.8, p = 0.003) was seen for NLPD vs. LPD in the group with lower baseline MDS-UPDRS part II score.Conclusion: Left side lateralization was associated with faster symptom progression and worse outcomes in multiple clinical domains in our cohort. Clinicians should consider using motor predominance in their counseling regarding prognosis.

Lockdown effects on Parkinson’s disease during COVID-19 pandemic: a pilot study

The coronavirus-disease 2019 (COVID-19) outbreak precipitated prolonged lock-down measures. The subsequent social distancing, isolation, and reduction in mobility increased psychological stress, which may worsen Parkinson’s disease (PD). Therefore, telemedicine has been proposed to provide care to PD patients. To evaluate the effects of lock-down on motor and nonmotor symptoms in PD patients during the COVID-19 pandemic and the feasibility of telemedicine. Motor and nonmotor aspects were longitudinally assessed using structured questionnaires at baseline (in-person, February 2020) and at follow-up (remote web-based video, lock-down) evaluation. Of the seventeen PD patients evaluated at baseline, fourteen agreed to participate in, and completed follow-up evaluations. There was an impairment of nonmotor aspects measured with the MDS-UPDRS part I (p < 0.001) during lock-down. Nine patients participated independently in the telemedicine evaluation while five needed help from relatives. Our preliminary findings suggest an impairment of nonmotor symptoms in PD patients and support the feasibility and need for telemedicine in monitoring PD patients during the COVID-19 pandemic, to guarantee optimal assistance with reducing the burden of infection. Our findings also suggest that movement disorder clinics should be carefully considering socio-demographics and clinical features when developing telemedicine programs.

Voice of the patient: Emergence of new motor and non-motor symptoms in early Parkinsons Disease?

Objective: To explore the utility of using patient reported emergence of new symptoms (ES) as an outcome measure during the early phase of the disease. Methods: We analyzed data from MDS-UPDRS Part IB and Part II from the Safety, Tolerability, and Efficacy Assessment of Isradipine for PD (STEADY-PD3) study, with at least one annual follow-up over two years. We divided the sample into categories of follow-up visit (between 0 and 12-months, and 13 and 24-months) and the number of ES for each part of the scale between participants who started symptomatic treatment and those who did not (STx-yes/no). We assessed ES differences between participants STx in each follow-up visit using Mann-Whitney U test, and the Kaplan-Meier analyses. Results: Of 331 participants observed for months 0 to 12, 288 (87%) developed ES, and 182 (55%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.86, p = 0.39), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.38, p=0.02). Of 148 participants who continued to be observed for months 13 to 24, 114 (77%) developed ES, and 62 (42%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.33, p = 0.74), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.25, p=0.02). Conclusions: Assessing ES among patient-reported experiences of daily living may provide a useful marker for tracking PD progression.

Short-term retention of effects of lee silverman voice treatment® BIG on quality of life improvement: A 1-year follow-up in a patient with Parkinson’s disease

BACKGROUND: There are no reports regarding the long-term retention of effects of Lee Silverman Voice Treatment® BIG (LSVT® BIG) on improvements in quality of life (QOL) among patients with Parkinson’s disease (PD). OBJECTIVE: This study aimed to evaluate the short-term effect of LSVT® BIG on QOL improvement and its retention in a patient with PD. Motor symptoms, walking ability, and walking speed were evaluated as factors associated with QOL. METHODS: A 63-year-old woman who was diagnosed with PD received a 4-week LSVT® BIG program under the supervision of certified LSVT® BIG physical therapists. The participant’s disease severity was classified as Hoehn and Yahr stage 2. The Parkinson’s Disease Questionnaire-39 (PDQ-39), Movement Disorder Society-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3, timed up-and-go test (TUG), and 10 m walk test (10 MWT) were evaluated before, after, and 1-year after the intervention. RESULTS: The results indicated short-term improvements in the PDQ-39, MDS-UPDRS part 3, TUG, and 10 MWT which were retained for up to 1 year. CONCLUSIONS: This case report suggests the possibility of 1-year retention of improvements in QOL, motor symptoms, walking ability, and walking speed resulting from LSVT® BIG intervention in a patient with mild PD.