Society-Unified Parkinson's Disease Rating Research Articles

Patients with REM sleep behavior disorder have higher serum levels of allantoin

IntroductionRapid eye movement (REM) sleep behavior disorder (RBD) is associated with an increased risk of developing Parkinson's disease (PD). Low uric acid (UA) levels are associated with the risk of development and progression of PD. Allantoin is the major oxidation product of UA and is considered as a biomarker of oxidative stress. We aimed to compare serum levels of UA, allantoin, and allantoin/UA ratio in RBD patients with those in healthy controls, and to examine their associations with clinical severity. MethodsWe evaluated serum levels of UA, allantoin, and allantoin/UA ratio in 38 RBD patients (one female, mean age 66.8 (SD 6.3) years) and in 47 controls (four females, 66.8 (7.6) years). All RBD patients were assessed according to an examination protocol, which included structured interview, Montreal Cognitive Assessment (MoCA), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and dopamine transporter single-photon emission computed tomography (DAT-SPECT). The lower putaminal binding ratio from both hemispheres was used for analysis. ResultsMean serum allantoin concentration and allantoin/UA ratio were significantly increased in the RBD group compared to controls (2.6 (1.8) vs. 1.4 (0.7) μmol/l, p = 0.0004, and 0.008 (0.004) vs. 0.004 (0.002), p < 0.0001, respectively). There were no significant differences in UA levels between the two groups. No significant associations between any biochemical parameter and RBD duration, putaminal binding ratio on DAT-SPECT, MDS-UPDRS, or MoCA score were found. ConclusionSerum allantoin and allantoin/UA ratio are increased in RBD patients in comparison to controls, which may reflect increased systemic oxidative stress in prodromal synucleinopathy.

Efecto del entrenamiento resistido sobre el equilibrio y control postural en personas con párkinson: una revisión sistemática

BackgroundPhysical exercise has contributed significantly to the quality of life of the population. Therefore, countless specialists have established relationships between t people who perform physical exercise and success in the treatment of diseases, such as Parkinson's disease in older adults. ObjectiveThe aim of this research is to analyse the influence of resistance training in the correlation of balance and postural control in people with Parkinson's disease. MethodA systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews And Meta-Analyses (PRISMA), in consultation with the PubMed, Scielo, BVS (Lilacs), ScienceDirect and Cochrane databases, based on the influence of resistance training on postural balance and control in older adults with Parkinson's disease, highlighting as the main assessment tool the Movement Disorders Society - Unified Parkinson's Disease Rating Scale. ResultsAfter searching the selected databases and considering the inclusion and exclusion criteria of this study, 10 studies were selected to compose this review and a total of 556 participants were pooled. It was observed that most of the interventions (60%) had a duration of approximately 30-45minutes over 8to 12weeks, the most used measuring instruments were the BESTest (Balance Evaluation System Test), FOG-Q (Freezing of Gait Questionnaire) and the MDS-UPDRS (Movement Disorders Society-Unified Parkinson's Disease Rating Scale). ConclusionPhysical exercise plays a fundamental role in the intervention and prevention of Parkinson's disease symptoms with regard to balance, strength, and quality of life.

Putaminal y-Aminobutyric Acid Modulates Motor Response to Dopaminergic Therapy in Parkinson's Disease.

Motor response to dopaminergic therapy is a characteristic of patients with Parkinson's disease (PD). Whether nondopaminergic neurotransmitters contribute to treatment response is uncertain. The aim of this study is to determine whether putaminal y-aminobutyric acid (GABA) levels are associated with dopaminergic motor response. We assessed putaminal GABA levels in 19 PD patients and 13 healthy controls (HCs) utilizing ultra-high field proton magnetic resonance spectroscopy. Motor performance was evaluated using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III, in the ON and OFF states. Statistical analysis comprised group comparisons, correlation analysis, and multiple linear regression. In PD, GABA levels were significantly higher compared to HCs (1.50 ± 0.26 mM vs. 1.26 ± 0.31 mM, P= 0.022). Furthermore, GABA levels were independent predictors of absolute and relative dopaminergic treatment response. Our findings indicate that elevated putaminal GABA levels are associated with worse dopaminergic response in PD, emphasizing the essential role of nondopaminergic neurotransmitters in motor response. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Simple Smartphone-Based Assessment of Gait Characteristics in Parkinson Disease: Validation Study.

BackgroundParkinson disease (PD) is a common movement disorder. Patients with PD have multiple gait impairments that result in an increased risk of falls and diminished quality of life. Therefore, gait measurement is important for the management of PD.ObjectiveWe previously developed a smartphone-based dual-task gait assessment that was validated in healthy adults. The aim of this study was to test the validity of this gait assessment in people with PD, and to examine the association between app-derived gait metrics and the clinical and functional characteristics of PD.MethodsFifty-two participants with clinically diagnosed PD completed assessments of walking, Movement Disorder Society Unified Parkinson Disease Rating Scale III (UPDRS III), Montreal Cognitive Assessment (MoCA), Hamilton Anxiety (HAM-A), and Hamilton Depression (HAM-D) rating scale tests. Participants followed multimedia instructions provided by the app to complete two 20-meter trials each of walking normally (single task) and walking while performing a serial subtraction dual task (dual task). Gait data were simultaneously collected with the app and gold-standard wearable motion sensors. Stride times and stride time variability were derived from the acceleration and angular velocity signal acquired from the internal motion sensor of the phone and from the wearable sensor system.ResultsHigh correlations were observed between the stride time and stride time variability derived from the app and from the gold-standard system (r=0.98-0.99, P<.001), revealing excellent validity of the app-based gait assessment in PD. Compared with those from the single-task condition, the stride time (F1,103=14.1, P<.001) and stride time variability (F1,103=6.8, P=.008) in the dual-task condition were significantly greater. Participants who walked with greater stride time variability exhibited a greater UPDRS III total score (single task: β=.39, P<.001; dual task: β=.37, P=.01), HAM-A (single-task: β=.49, P=.007; dual-task: β=.48, P=.009), and HAM-D (single task: β=.44, P=.01; dual task: β=.49, P=.009). Moreover, those with greater dual-task stride time variability (β=.48, P=.001) or dual-task cost of stride time variability (β=.44, P=.004) exhibited lower MoCA scores.ConclusionsA smartphone-based gait assessment can be used to provide meaningful metrics of single- and dual-task gait that are associated with disease severity and functional outcomes in individuals with PD.

Revisiting the L-Dopa Response as a Predictor of Motor Outcomes After Deep Brain Stimulation in Parkinson's Disease.

Objective: To investigate the correlation between preoperative response to the L-dopa challenge test and efficacy of deep brain stimulation (DBS) on motor function in Parkinson’s disease (PD).Methods: We retrospectively reviewed the data of 38 patients with idiopathic PD who underwent DBS surgery with a median follow-up duration of 7 months. Twenty underwent bilateral globus pallidus interna (GPi) DBS, and 18 underwent bilateral subthalamic nucleus (STN) DBS. The Movement Disorder Society Unified Parkinson Disease Rating Scale-Motor Part (MDS UPDRS-III) was assessed before surgery and at the last follow-up in different medication and stimulation conditions, respectively.Results: Pearson’s correlation analysis revealed a positive correlation between preoperative L-dopa challenge responsiveness and GPi-DBS responsiveness on the total score (R2 = 0.283, p = 0.016) but not on the non-tremor total score (R2 = 0.158, p = 0.083) of MDS UPDRS-III. Such correlation remained significant (R2′ = 0.332, p = 0.010) after controlling for age at the time of surgery as confounding factor by partial correlation analysis. The preoperative L-dopa challenge responsiveness was significantly correlated with the tremor-controlling outcome of GPi-DBS (R2 = 0.390, p = 0.003). In contrast, we found a positive correlation between preoperative L-dopa challenge responsiveness and STN-DBS responsiveness on the non-tremor total score (R2 = 0.290, p = 0.021), but not on the total score (R2 = 0.130, p = 0.141) of MDS UPDRS-III. The partial correlation analysis further demonstrated that the predictive value of preoperative L-dopa challenge responsiveness on the non-tremor motor outcome of STN-DBS was eliminated (R2′ = 0.120, p = 0.174) after controlling for age at the time of surgery as confounding factor.Interpretation: The short-term predictive value of preoperative response to the L-dopa challenge test for the motor outcome of GPi-DBS in PD was systematically described. Our findings suggest: (1) a solid therapeutic effect of GPi-DBS in treating L-dopa-responsive tremors; (2) a negative effect of age at the time of surgery on motor outcomes of STN-DBS, (3) a possible preference of STN- to GPi-DBS in L-dopa-resistant tremor control, and (4) a possible preference of GPi- to STN-DBS in elderly PD patients who have a satisfactory dopamine response.

A Double-Blind, Randomized, Controlled Trial of Lovastatin in Early-Stage Parkinson's Disease.

Recent evidence indicates that lipophilic statins have a neuroprotective benefit in animal models of Parkinson's disease (PD). The objective of this study was to evaluate whether lovastatin has the potential to slow motor symptom progression in patients with early-stage PD. This double-blind, randomized, placebo-controlled trial enrolled 77 patients with early-stage PD between May 23, 2017, and July 12, 2018, with follow-up ending September 1, 2019. Lovastatin 80 mg/day or placebo with 1:1 randomization was administered for 48 weeks. Mean change in the parts I-III scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), changes in the striatal dopamine uptake ratio measured by 18 F-dopa PET scan, and changes in PD medications between baseline and the week 48 visit were measured. Of the 77 randomized patients, 70 (90.9%) completed the study. There was a slightly beneficial trend of the MDS-UPDRS motor score in the lovastatin group (-3.18± 5.50) compared with the placebo group (-0.50 ± 6.11); P=0.14 adjusted for age, sex, disease duration, and baseline LEDD. Mean percentage change in the striatal 18 F-dopa uptake ratio deteriorated less in the lovastatin group than in the placebo group on the dominant side of caudate (1.2% ± 7.3% vs -7.1% ± 8.2%, P < 0.01) and putamen (2.3% ± 7.1% vs -6.4% ± 8.1%, P < 0.01). We found no between-group differences in the change in part I or part II MDS-UPDRS scores. Lovastatin was generally well tolerated. Lovastatin treatment in patients with early-stage PD was associated with a trend of less motor symptom worsening and was well tolerated. A future larger long-term follow-up study is needed to confirm our findings. © 2021 International Parkinson and Movement Disorder Society.

Health-Related Quality of Life for Parkinson's Disease Patients and Their Caregivers.

Objective Motor and non-motor symptoms (NMS) negatively impact the health-related quality of life (HRQoL) for individuals with Parkinson’s disease (PD), as well as their caregivers. NMS can emerge decades prior to the manifestation of motor symptoms but often go unrecognized and therefore untreated. To guide clinical management, we surveyed differences and identified factors that influence HRQoL in a cohort of PD patients and family caregivers.Methods A total of 103 PD patients were compared with 81 caregivers. Outcome measures collected from validated questionnaires included generic and disease-specific HRQoL assessments, depression frequency and severity, constipation severity, upper and lower gastrointestinal symptoms, physical activity and motor symptom severity.Results PD patients reported significantly decreased physical and mental HRQoL compared to their caregivers (both p < 0.001). Unemployment, the need for social support services, rehabilitation use, REM sleep behavior disorder, impulse control disorders and features suggestive of increasing disease severity hallmarked by increasing PD duration, higher MDS UPDRS-III (Movement Disorder Society–Unified Parkinson’s Disease Rating Scale–Part III) scores, higher daily levodopa equivalence dose and motor fluctuations were consistent with a lower HRQoL in our PD cohort. Furthermore, decreased physical activity, chronic pain, depression, constipation and upper gastrointestinal dysfunction (particularly indigestion, excess fullness and bloating) suggested vulnerability to reduced HRQoL. Overall, PD patients perceived their health to decline by 12% more than their caregivers did over a 1-year period.Conclusion PD patients reported decreased HRQoL, with both motor symptoms and NMS negatively impacting HRQoL. Our findings support the routine clinical screening of HRQoL in PD patients to identify and address modifiable factors.

Validation and Reliability of the Japanese Version of the Modified Parkinson Activity Scale (M-PAS).

ABSTRACTObjective:The Modified Parkinson Activity Scale (M-PAS) is used to identify the most important activity limitations in patients with Parkinson’s disease. We developed a Japanese version of the M-PAS and evaluated its reliability and validity.Methods:Twenty-five patients with Parkinson’s disease (median age 71 years old, range 58–83) were enrolled, and two raters used the Japanese version of M-PAS to assess the subjects. The inter-rater reliability was evaluated using Cohen’s weighted kappa coefficient for the total score and three domain scores; systematic error was investigated using Bland-Altman analysis. Concurrent validity of the Japanese M-PAS was measured using Spearman’s rank correlation coefficients.Results:Cohen’s kappa coefficients for the total score and the three domain scores were in the range 0.81–0.98, and 95% confidence intervals included zero for each item, suggesting excellent agreement and no systematic errors. The scores of the Japanese version of M-PAS were significantly correlated with the scores of the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale Part II (Spearman’s rho=–0.56, P <0.01) and Part III (Spearman’s rho=–0.32, P <0.01). The percentage of patients with the highest and the lowest scores in the Japanese version of M-PAS suggested no ceiling or floor effects.Conclusion:The Japanese version of M-PAS showed excellent inter-rater reliability and good concurrent validity without ceiling or floor effects.

Teleneurorehabilitation Among Person with Parkinson's Disease in India: The Initial Experience and Barriers to Implementation.

Objective:We aimed to assess the feasibility of teleneurorehabilitation (TNR) among persons with Parkinson's disease (PD), considering difficulties imposed by the COVID-19 pandemic in access to healthcare, particularly in low-resource settings. The feasibility of TNR in India has not been formally assessed so far.Methods:We conducted a single-center, prospective cohort study at a tertiary center in India. Persons with PD with Hoehn & Yahr (H&Y) stages 1-2.5, who were not enrolled into any formal exercise program, were offered TNR as per a predesigned program for 12 weeks. Baseline and post-intervention assessment included Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part II and III, Parkinson's Disease Questionnaire (PDQ)-8 and Non-Motor Symptoms Scale (NMSS). We assessed adherence to TNR and problems expressed by patients/caregivers by means of open-ended surveys addressing barriers to rehabilitation.Results:We recruited 22 for TNR. Median age (interquartile range [IQR]) was 66.0 (44.0-71.0) years; 66.7% were H&Y stage 2.0. One patient died of COVID-19-related complications. Of the remaining 21, 14 (66.7%) had adherence of ≥75%; 16/21 (76.2%) patients had problems with attending TNR sessions as the family shared a single phone. Slow Internet speed was an issue among 13/21 (61.9%) of the patients. Other issues included lack of rapport, migration to distant hometowns and motor-hand impairment.Conclusion:Multiple challenges were faced in implementing a telerehabilitation program among persons with PD, exacerbated by the COVID-19 pandemic. These barriers were present at various levels: recruitment, adherence issues and maintenance. Future TNR programs must address these concerns.

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.

Striatal Dopamine Deficit and Motor Impairment in Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123 I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.

Comparing Objective and Subjective Measures of Parkinson's Disease Using the Parkinson's KinetiGraph.

Background: Parkinson's disease (PD) is a neurodegenerative disease that can lead to impaired motor function and execution of activities of daily living (ADL). Since clinicians typically can only observe patients' symptoms during visits, prescribed medication schedules may not reflect the full range of symptoms experienced throughout the day. Therefore, objective tools are needed to provide comprehensive symptom data to optimize treatment. One such tool is the Parkinson's KinetiGraph® (PKG), a wearable sensor that measures motor symptoms of Parkinson's disease.Objective: To build a mathematical model to determine if PKG data measuring Parkinson's patients' motor symptoms can predict patients' ADL impairment.Methods: Thirty-four patients with PD wore the PKG device for 6 days while performing their ADL. Patients' PKG scores for bradykinesia and dyskinesia, as well as their responses to a questionnaire asking if their ADL-level had been impacted by various motor symptoms, were used to build a multiple regression model predicting the patients' Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II scores.Results: Calculation of bradykinesia score response to medication showed that using a dosage response time of 30 min yielded a greater bradykinesia response than when the response time was set to 40, 50, 60, 70, 80, or 90 min. The overall multiple regression model predicting MDS-UPDRS part II score was significant (R2 = 0.546, p < 0.001).Conclusion: The PKG's ability to provide motor symptom data that correlates with clinical measures of ADL impairment suggests that it has strong potential as a tool for the assessment and management of Parkinson's disease motor symptoms.

Estimating the Effect of Early Treatment Initiation in Parkinson's Disease Using Observational Data.

ABSTRACTBackgroundBoth patients and physicians may choose to delay initiation of dopamine replacement therapy in Parkinson's disease (PD) for various reasons. We used observational data to estimate the effect of earlier treatment in PD. Observational data offer a valuable source of evidence, complementary to controlled trials.MethodWe studied the Parkinson's Progression Markers Initiative cohort of patients with de novo PD to estimate the effects of duration of PD treatment during the first 2 years of follow‐up, exploiting natural interindividual variation in the time to start first treatment. We estimated the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III (primary outcome) and several functionally relevant outcomes at 2, 3, and 4 years after baseline. To adjust for time‐varying confounding, we used marginal structural models with inverse probability of treatment weighting and the parametric g‐formula.ResultsWe included 302 patients from the Parkinson's Progression Markers Initiative cohort. There was a small improvement in MDS‐UPDRS Part III scores after 2 years of follow‐up for patients who started treatment earlier, and similar, but nonstatistically significant, differences in subsequent years. We found no statistically significant differences in most secondary outcomes, including the presence of motor fluctuations, nonmotor symptoms, MDS‐UPDRS Part II scores, and the Schwab and England Activities of Daily Living Scale.ConclusionEarlier treatment initiation does not lead to worse MDS‐UPDRS motor scores and may offer small improvements. These findings, based on observational data, are in line with earlier findings from clinical trials. Observational data, when combined with appropriate causal methods, are a valuable source of additional evidence to support real‐world clinical decisions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Rationale and Design of the PAIRED Trial: Partnered Dance Aerobic Exercise as a Neuroprotective, Motor, and Cognitive Intervention in Parkinson's Disease.

Parkinson's disease (PD), an intractable condition impairing motor and cognitive function, is imperfectly treated by drugs and surgery. Two priority issues for many people with PD are OFF-time and cognitive impairment. Even under best medical management, three-fourths of people with PD experience “OFF-time” related to medication-related motor fluctuations, which severely impacts both quality of life and cognition. Cognitive deficits are found even in newly diagnosed people with PD and are often intractable. Our data suggest that partnered dance aerobic exercise (PDAE) reduces OFF-time on the Movement Disorders Society Unified Parkinson Disease Rating Scale-IV (MDS-UPDRS-IV) and ameliorates other disease features, which motivate the PAIRED trial. PDAE provides AE during an improvisational, cognitively engaging rehabilitative physical activity. Although exercise benefits motor and cognitive symptoms and may be neuroprotective for PD, studies using robust biomarkers of neuroprotection in humans are rare. We propose to perform a randomized, controlled trial in individuals with diagnosed mild–moderate PD to compare the efficacy of PDAE vs. walking aerobic exercise (WALK) for OFF-time, cognition, and neuroprotection. We will assess neuroprotection with neuromelanin-sensitive MRI (NM-MRI) and iron-sensitive (R2*) MRI sequences to quantify neuromelanin loss and iron accumulation in substantia nigra pars compacta (SNc). We will use these biomarkers, neuromelanin loss, and iron accumulation, as tools to chart the course of neurodegeneration in patients with PD who have undergone long-term (16 months) intervention. We will randomly assign 102 individuals with mild–moderate PD to 16 months of PDAE or WALK. The 16-month intervention period will consist of Training (3 months of biweekly sessions) and Maintenance (13 months of weekly sessions) phases. We will assess participants at baseline, 3 months (immediately post-Training), and 16 months (immediately post-Maintenance) for OFF-time and behaviorally and physiologically measured cognition. We will acquire NM-MRI and R2* imaging data at baseline and 16 months to assess neuroprotection. We will (1) examine effects of Training and Maintenance phases of PDAE vs. WALK on OFF-time, (2) compare PDAE vs. WALK at 3 and 16 months on behavioral and functional MRI (fMRI) measures of spatial cognition, and (3) compare PDAE vs. WALK for effects on rates of neurodegeneration.

Longitudinal change in dopamine transporter availability in idiopathic REM sleep behavior disorder.

To elucidate longitudinal changes in the dopamine transporter (DAT) availability in association with the prodromal markers in idiopathic REM sleep behavior disorder (iRBD), we analyzed a longitudinal prospective iRBD cohort data. The study cohort consisted of patients with iRBD, individuals with Parkinson disease (PD), and healthy controls. All participants were evaluated for olfaction, neuropsychological tests, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale and underwent 18F-FP-CIT PET scans every 2 years. We calculated the DAT pattern by performing the principal component analysis of tracer uptakes in 6 striatal regions. DAT patterns in patients with iRBD with baseline hyposmia, constipation, and mild parkinsonian signs distributed toward the PD pattern and clearly distinguished from the healthy control pattern. The DAT pattern moved toward the PD pattern over time in some patients with iRBD during the follow-up, and baseline hyposmia was the only biomarker significantly associated with this change. Baseline PD pattern of DAT predicted 58% of disease converters (hazard ratio 4.95 [95% confidence interval 1.16-21.08]). The combination of hyposmia and baseline PD pattern of DAT predicted 67% of the conversion (hazard ratio 7.89 [confidence interval 1.85-33.69]). The estimated sample size required for a simulated neuroprotective clinical trial was 63 per group when the annual change of DAT pattern was used as an outcome in the subgroup with baseline DAT PD pattern and hyposmia, which is the smallest number reported so far. Baseline and longitudinal monitoring of the DAT pattern can be a useful biomarker in identifying individuals with a high risk of disease conversion and in selecting the potential population for clinical trials in iRBD.

Radiocirugía estereotáctica con Gamma Knife® como tratamiento del temblor esencial y parkinsoniano: experiencia a largo plazo

IntroductionUnilateral Gamma Knife™ stereotactic radiosurgery on the ventral-intermediate nucleus of the thalamus is a minimally invasive neurosurgical option for refractory tremor. We describe the experience of Gamma Knife™ thalamotomy (GKT) in patients with essential tremor (ET) and tremor-dominant Parkinson's disease (PD) at our specialised stereotactic neurosurgery unit. MethodsWe reviewed the cases of patients treated with GKT between January 2014 and February 2018 with a minimum of 12 months’ follow-up. We analysed clinical and demographic variables, indication, radiation dose, effectiveness (based on subscales of the Fahn-Tolosa-Marin [FTM] scale and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] motor score), and adverse events. ResultsThirteen patients were registered, 6 with a diagnosis of tremor-dominant PD, four with refractory ET, and three with ET and PD. Median age was 78 years (range, 62-83), with seven patients aged over 75 years. Four patients were receiving anticoagulants and two had history of stroke. The maximum radiation dose administered was 130 Gy. Mean (standard deviation) follow-up duration was 30.0 (14.5) months. Significant tremor improvement was observed on the FTM subscales: 63.6% at 12 months and 63.5% at the end of follow-up; MDS-UPDRS tremor items showed improvements of 71.3% at 12 months and 60.3% at the end of follow up. Eleven patients reported significant improvements in quality of life, and 3 reported mild and transient adverse effects. ConclusionsThis is the largest series of patients with essential and parkinsonian tremor treated with GKT and followed up in the long term in Spain. GKT can be safe and effective in the long term in patients with refractory tremor, including in elderly patients and those receiving anticoagulants.

Transcranial Magnetic Stimulation Promotes Gait Training in Parkinson Disease.

To determine whether priming with 1 or 25Hz repetitive transcranial magnetic stimulation (rTMS) will enhance the benefits from treadmill training up to 3 months postintervention in people with Parkinson disease (PD), and to evaluate the underlying changes in cortical excitability. This randomized double-blind, placebo-controlled trial was conducted between October 2016 and December 2018. Fifty-one participants with PD were randomized to receive 12 sessions of rTMS (25Hz, 1Hz, or sham) followed by treadmill training. All participants were assessed at baseline and 1 day, 1 month, and 3 months postintervention. Primary outcome was fastest walking speed, and secondary outcomes were timed up-and-go test (TUG), dual-task TUG (DT-TUG), motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III), and electrophysiological evaluation of cortical excitability by TMS. The 1 and 25Hz rTMS groups produced a greater improvement in fastest walking speed at 1 day and 3 months postintervention than the sham group. Only the 1 and 25Hz rTMS groups sustained the improvements in TUG, and had a significant improvement in DT-TUG and MDS-UPDRS-III for up to 3 months. Behavioral improvements correlated with increased cortical silent period and short-interval intracortical inhibition in both groups receiving real rTMS. Priming with 1 and 25Hz rTMS can augment the benefits of treadmill training and lead to long-term motor improvement up to 3 months postintervention. The motor improvement at follow-up was associated with a normalization of cortical excitability, which in turn suggests an alteration of the homeostatic plasticity range. Rebalancing cortical excitability by rTMS appears critical for plasticity induction. ANN NEUROL 2020;88:933-945.

Anticholinergics May Carry Significant Cognitive and Gait Burden in Parkinson's Disease

Anticholinergic drugs are associated with significant cognitive and other adverse events in older adults, including those with Parkinson's disease (PD). Anticholinergic effects are considered lesser in younger individuals and the burden and outcomes in younger patients with PD are unknown. To determine the cumulative anticholinergic burden in a cohort of younger of patients with PD and to correlate the same with cognitive impairment and freezing of gait (FOG). We conducted a cross-sectional study to identify the cumulative anticholinergic burden from medications prescribed to patients with PD. Two standard scales, the Anticholinergic Cognitive Burden (ACB) scale and the ACB score, were used to calculate the anticholinergic burden from prescriptions. We identified commonly prescribed drugs contributing to anticholinergic effects and correlated the cumulative ACB score with cognitive impairment (Movement Disorder Society-Unified Parkinson's Disease Rating Scale item 1.1) and FOG (Movement Disorder Society-Unified Parkinson's Disease Rating Scale items 2.13 and 3.11). We recruited 287 patients with PD (68.9% male) with a mean age of 56.9 ± 11.8 years and a duration of symptoms 6.3 ± 6.9 years. Median ACB score was 4 (range 0-12). A total of 164 (58.4%) patients had total ACB score > 3. ACB score > 3 was independently associated with cognitive impairment (Odds Ratio, 2.55; 95% confidence interval, 1.43-4.53; P < 0.001) and FOG using patient-reported measures (Odds Ratio, 3.192; 95% Confidence Interval, 1.68-6.07; P < 0.001) and objective measures (odds ratio, 2.41; 95% confidence interval, 1.27-4.6, P = 0.007). Patients with PD are exposed to significant anticholinergic burden from drugs prescribed for PD and non-PD indications. Higher anticholinergic burden is associated with cognitive impairment and FOG even in younger patients with PD.

A Study for Expanding Application Sites for Rotigotine Transdermal Patch.

The rotigotine transdermal patch (RTP) is a dopamine agonist used to treat Parkinson's disease (PD). Some PD patients cannot continue RTP treatment due to application site reactions. We explored sites for RTP where application site reactions are less severe than those in the six approved application sites. Thirty PD patients (12 men, mean age = 76 years) who underwent RTP at the approved sites and had some application site reactions were enrolled in this study. When applying the RTP to the approved application sites for more than four weeks (pre-RTP) and then on the shin for the following four weeks (post-RTP), skin reactions, itching evaluated using the skin irritation score, motor symptoms, clinical global impressions scale, and plasma rotigotine concentration were examined. The mean visual analogue scale and skin irritation score in the post-RTP group were significantly lower than those in the pre-RTP group. The mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score in the post-RTP group was slightly but significantly lower than that in the pre-RTP group. Plasma rotigotine concentration in the post-RTP group was slightly but significantly lower than that in the pre-RTP group. These results indicate that the shin can be a useful application site for RTP.

"Does the Response to Morning Medication Predict the ADL-Level of the Day in Parkinson's Disease?"

Background Individuals with Parkinson's Disease (PD) have bradykinesia during mobility tasks in the morning before intake of dopaminergic treatment and have difficulties managing Activities of Daily Living (ADLs). Early morning off (EMO) refers to off-states in the morning where the severity of bradykinesia is increased and causes a decrease in mobility related to wearing off of effects of medication. Measurements from devices capable of continuously recording motor symptoms may provide insight into the patient's response to medication and possible impact on ADLs. Objectives To test whether poor or slow response to medication in the morning predicts the overall ADL-level and to assess the association between change in bradykinesia score (BKS) and the risk of having disabilities within three selected ADL-items. Methods In this cross-sectional study, the sample consists of 34 patients with light to moderate PD. Data collection encompasses measurements from the Parkinson KinetiGraph, and the ADL-limitations are assessed by the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part II. Results The association between UPDRS- II and BKS from the algorithm was −0.082 (p < 0.01), 95% CL:−0.113; −0.042). The individuals experienced disabilities in performing “Speech” (p=0.004) and “Doing hobbies” (p=0.038) when being slow or poor responders to dopaminergic therapy. The PD patients' L-dopa equivalent dose seems to be a strong predictor of the ADL-level in the morning. Conclusion Slow response to the medication dosages in the morning is correlated with disabilities in the overall ADL-level in PD. The combination of PD-drugs and precise, timely dosages must be considered in the improvement of the ADL-level in PD patients.