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Introduction: Parkinson's disease represents a burdensome condition with complex manifestations. A licensed, standardized paper-based questionnaire is completed by both patients and physicians to monitor the progression and state of the disease. However, integrating the obtained scores into digital systems still poses a challenge., Methods: Paper-based handwriting is intuitive and an efficient mode of human-computer interaction. Accordingly, we transformed a consumer-grade tablet into a device where an exact digital copy of the disease-specific questionnaire can be filled with the supplied pen. Utilizing a small convolutional neural network directly on the device and trained on MNIST data, we translated the handwritten digits to appropriate LOINC codes and made them accessible through a FHIR-compatible HTTP interface., Results: When evaluating the usability from a patient-centric point of view, the System Usability Score revealed an excellent rating (SUS = 83.01) from the participants. However, we identified some challenges associated with the magnetic pen and the flat design of the device., Conclusion: In setups where certified medical devices are not required, consumer hardware can be used to map handwritten digits of patients to appropriate medical standards without manual intervention through healthcare professionals.

Background and Objectives : Currently, no tool exists to predict clinical outcomes in patients with advanced Parkinson's disease (PD) under levodopa-carbidopa intestinal gel (LCIG) treatment. The aim of this study was to develop a novel deep neural network model to predict the clinical outcomes of patients with advanced PD after two years of LCIG therapy. Materials and Methods : This was a longitudinal, 24-month observational study of 59 patients with advanced PD in a multicenter registry under LCIG treatment from September 2019 to September 2021, including 43 movement disorder centers. The data set includes 649 measurements of patients, which make an irregular time series, and they are turned into regular time series during the preprocessing phase. Motor status was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (off) and IV. The NMS was assessed by the NMS Questionnaire (NMSQ) and the Geriatric Depression Scale (GDS), the quality of life by PDQ-39, and severity by Hoehn and Yahr (HY). Multivariate linear regression, ARIMA, SARIMA, and Long Short-Term Memory-Recurrent NeuralNetwork (LSTM-RNN) models were used. Results : LCIG significantly improved dyskinesia duration and quality of life, with men experiencing a 19% and women a 10% greater improvement, respectively. Multivariate linear regression models showed that UPDRS-III decreased by 1.5 and 4.39 units per one-unit increase in the PDQ-39 and UPDRS-IV indexes, respectively. Although the ARIMA-(2,0,2) model is the best one with AIC criterion 101.8 and validation criteria MAE = 0.25, RMSE = 0.59, and RS = 0.49, it failed to predict PD patients' features over a long period of time. Among all the time series models, the LSTM-RNN model predicts these clinical characteristics with the highest accuracy (MAE = 0.057, RMSE = 0.079, RS = 0.0053, mean square error = 0.0069). Conclusions : The LSTM-RNN model predicts, with the highest accuracy, gender-dependent clinical outcomes in patients with advanced PD after two years of LCIG therapy.

Introduction: Several studies have reported iron accumulation in the basal ganglia to be associated with the development of Parkinson's Disease (PD). Recently, a few trials have examined the efficacy of using the iron-chelating agent Deferiprone (DFP) for patients with PD. We conducted this meta-analysis to summarize and synthesize evidence from published randomized controlled trials about the efficacy of DFP for PD patients., Methods: A comprehensive literature search of four electronic databases was performed, spanning until February 2023. Relevant RCTs were selected, and their data were extracted and analyzed using the RevMan software. The primary outcome was the change in the Unified Parkinson's Disease Rating Scale (UPDRS-III)., Results: Three RCTs with 431 patients were included in this analysis. DFP did not significantly improve UPDRS-III score compared to placebo (Standardized mean difference -0.06, 95% CI [-0.69, 0.58], low certainty evidence). However, it significantly reduced iron accumulation in the substantia nigra, putamen, and caudate as measured by T2*-weighted MRI (with high certainty evidence)., Conclusion: Current evidence does not support the use of DFP in PD patients. Future disease-modification trials with better population selection, adjustment for concomitant medications, and long-term follow up are recommended., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: According to many reports, multidisciplinary comprehensive care alleviates Parkinson's disease (PD) more frequently than any other standard care, though the results were found to vary greatly., Material and Methods: A systematic literature search up to July 2022 was performed and 1234 related studies were evaluated. The chosen studies comprised 1115 subjects with PD who participated in baseline trials; 633 of them were under multidisciplinary comprehensive care, while 482 were under standard care. Odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (95% CIs) were calculated to measure the results of multidisciplinary comprehensive care for PD by the contentious and dichotomous approaches with a random or fixed influence model employed., Results: The use of multidisciplinary comprehensive care resulted in significantly better health-related quality of life (HRQL) (MD: -3.17; 95% CI: -5.98--0.35, p = 0.03) and Unified Parkinson's Disease Rating Scale (UPDRS) score (MD: -5.25; 95% CI: -10.14--0.37, p = 0.04) compared to the standard care for subjects with PD. Nevertheless, no significant difference was found between multidisciplinary comprehensive care and standard care for subjects with PD regarding medication dosage (MD: 0.31; 95% CI: -0.72-1.34, p = 0.56) and caregiver strain (MD: -0.51; 95% CI: -1.69-0.67, p = 0.40)., Conclusion: Outpatient multidisciplinary comprehensive care models may improve patient-reported HRQL and UPDRS score; nevertheless, no significant difference was found in terms of medication dosage and caregiver strain compared to the standard care for subjects with PD. The small sample size of 2 out of 7 analyzed studies and the small number of studies in certain comparisons requires attention when analyzing the results.

Background: The clinical utility and safety of sargramostim has previously been reported in cancer, acute radiation syndrome, autoimmune disease, inflammatory conditions, and Alzheimer's disease. The safety, tolerability, and mechanisms of action in Parkinson's disease (PD) during extended use has not been evaluated., Methods: As a primary goal, safety and tolerability was assessed in five PD patients treated with sargramostim (Leukine ® , granulocyte-macrophage colony-stimulating factor) for 33 months. Secondary goals included numbers of CD4 + T cells and monocytes and motor functions. Hematologic, metabolic, immune, and neurological evaluations were assessed during a 5-day on, 2-day off therapeutic regimen given at 3 μg/kg. After 2 years, drug use was discontinued for 3 months. This was then followed by an additional 6 months of treatment., Results: Sargramostim-associated adverse events included injection-site reactions, elevated total white cell counts, and bone pain. On drug, blood analyses and metabolic panels revealed no untoward side effects linked to long-term treatment. Unified Parkinson's Disease Rating Scale scores remained stable throughout the study while regulatory T cell number and function were increased. In the initial 6 months of treatment, transcriptomic and proteomic monocyte tests demonstrated autophagy and sirtuin signaling. This finding paralleled anti-inflammatory and antioxidant activities within both the adaptive and innate immune profile arms., Conclusions: Taken together, the data affirmed long-term safety as well as immune and anti-inflammatory responses reflecting clinical stability in PD under the sargramostim treatment. Confirmation in larger patient populations is planned in a future phase II evaluation., Trial Registration: ClinicalTrials.gov: NCT03790670, Date of Registration: 01/02/2019, URL: https://clinicaltrials.gov/ct2/show/NCT03790670?cond=leukine+parkinson%27s&draw=2&rank=2 ., (© 2023. The Author(s).)

The rehabilitation evaluation of Parkinson's disease has always been the research focus of human assistive systems. It is a research hotspot to objectively and accurately evaluate the gait condition of Parkinson's disease patients, thereby adjusting the actuators of the human-machine system and making rehabilitation robots better adapt to the recovery process of patients. The rehabilitation evaluation of Parkinson's disease has always been the research focus of rehabilitation robots. It is a research hotspot to be able to objectively and accurately evaluate the recovery of Parkinson's disease patients, thereby adjusting the driving module of the human-machine collaboration system in real time, so that rehabilitation robots can better adapt to the recovery process of Parkinson's disease. The gait task in the Unified Parkinson's Disease Rating Scale (UPDRS) is a widely accepted standard for assessing the gait impairments of patients with Parkinson's disease (PD). However, the assessments conducted by neurologists are always subjective and inaccurate, and the results are determined by the neurologists' observation and clinical experience. Thus, in this study, we proposed a novel machine learning-based method of automatically assessing the gait task in UPDRS with wearable sensors as a more convenient and objective alternative means for PD gait assessment. In the design, twelve gait features, including three spatial-temporal features and nine kinematic features, were extracted and calculated from two shank-mounted IMUs. A novel nonlinear model is developed for calculating the score of gait task from the gait features. Twenty-five PD patients and twenty-eight healthy subjects were recruited for validating the proposed method. For comparison purpose, three traditional models, which have been used in previous studies, were also tested by the same dataset. In terms of percentages of participants, 84.9%, 73.6%, 73.6%, and 66.0% of the participants were accurately assigned into the true level with the proposed nonlinear model, the support vector machine model, the naive Bayes model, and the linear regression model, respectively, which indicates that the proposed method has a good performance on calculating the score of the UPDRS gait task and conformance with the rating done by neurologists.

We sought to design a data visualization platform to represent the Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) item scores in an easy-to-use display without modification of the raw data or summary scores. Score items for Parts I, II, and IV were arranged as separate inline blocks, while Part III item blocks were arranged in an anatomical fashion. A color scale was created to represent symptom severity and changes observed from one exam to another. We have found the visualization helpful for quickly defining the most troublesome symptoms and their anatomical location enabling communication of the results and interpretations.

Objective: To determine the effects of walking meditation (WM) on functional performance, disease severity, and anxiety in Parkinson's disease (PD). Design: This was a randomized controlled trial. Settings: The study was conducted at a regional hospital. Subjects /I nterventions: Thirty-three participants with PD were randomly allocated to the control (CON) group ( n Gait velocity, Timed Up and Go, five times sit to stand (FTSTS) test, Unified Parkinson's Disease Rating Scale (UPDRS), and the percentage of participants with anxiety (Hospital Anxiety and Depression Scale-part anxiety [HADS-A] ≥8). n  = 17). Participants in the WM group were asked to perform WM monthly under supervision and encouraged to practice at home at least 3 days/week for 12 weeks. Outcome measurements: Gait velocity, Timed Up and Go, five times sit to stand (FTSTS) test, Unified Parkinson's Disease Rating Scale (UPDRS), and the percentage of participants with anxiety (Hospital Anxiety and Depression Scale-part anxiety [HADS-A] ≥8). Results: Both groups showed reduced gait velocity ( p  < 0.05), although impairment of the FTSTS ( p  < 0.05) score was observed only in the CON group. A significant enhancement within and between groups in the total UPDRS and UPDRS part II scores was observed only in the WM group. The percentage of participants with anxiety (HADS-A ≥ 8) decreased significantly only in the WM group ( p  < 0.05), compared with the baseline and after 12 weeks. There was no loss to follow-up in the WM group, and the participation rate of training was 3.2 days/week. Conclusions: Home-based WM can encourage high rates of exercise adherence, reduce disease severity, lower the percentage of participants with anxiety, and might be suitable during disease endemic and/or pandemic in PD. The protocol was registered on Thaiclinicaltrials.org (Identifier: TCTR20201009001).

Background: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson's disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG., Objective: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes., Methods: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome., Results: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement., Conclusion: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.

Background: Increasing evidence connects the gut microbiome to Parkinson's disease (PD) etiology, but little is known about microbial contributions to PD progression and its clinical features., Objective: We aim to explore the association between the gut microbiome with PD, and the microbial association with PD-specific clinical features., Methods: In a community-based case-control study of 96 PD patients and 74 controls, microbiome data were obtained from 16S rRNA gene sequencing of fecal samples, and analyzed for microbial diversity, taxa abundance, and predicted functional pathways that differed in PD patients and controls, and their association with PD-specific features (disease duration, motor subtypes, L-DOPA daily dose, and motor function)., Results: PD patients' gut microbiome showed lower species diversity (p = 0.04) and were compositionally different (p = 0.002) compared to controls but had a higher abundance of three phyla (Proteobacteria, Verrucomicrobiota, Actinobacteria) and five genera (Akkermansia, Enterococcus, Hungatella, and two Ruminococcaceae) controlling for sex, race, age, and sequencing platform. Also, 35 Metacyc pathways were predicted to be differentially expressed in PD patients including biosynthesis, compound degradation/utilization/assimilation, generation of metabolites and energy, and glycan pathways. Additionally, the postural instability gait dysfunction subtype was associated with three phyla and the NAD biosynthesis pathway. PD duration was associated with the Synergistota phylum, six genera, and the aromatic compound degradation pathways. Two genera were associated with motor function., Conclusion: PD patients differed from controls in gut microbiome composition and its predicted metagenome. Clinical features were also associated with bacterial taxa and altered metabolic pathways of interest for PD progression.

Background: Assessment of motor signs in Parkinson's disease (PD) requires an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous monitoring for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic., Objective: Investigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD., Methods: Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years., Results: QDG-RAFT metrics showed differences between PD and controls and provided correlated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment, and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy and showed differences between akinetic-rigid and tremor-dominant phenotypes, as well as people with and without FOG., Conclusions: QDG is a reliable technology, which could be used in the clinic or remotely. This could improve access to care, allow complex remote disease management based on data received in real time, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive motor metrics needed for therapeutic trials.

Aims: The multipart Unified Parkinson's Disease Rating Scale is the standard instrument in clinical trials. A sum of scores for all items in 1 or more parts of the instrument is usually analysed. Without accounting for relative importance of individual items, this sum of scores conceivably does not optimize the power of the instrument. The aim was to compare the ability to detect drug effect in slowing down motor function deterioration, as measured by Part III of the Scale-motor examinations-between the item scores and the sum of scores., Methods: We used data from 423 patients in a Parkinson's disease progression trial to estimate the symptom severity by item response modelling; modelled symptom progression using the severity and the sum of scores; and conducted simulations to compare the sensitivity of detecting a broad range of hypothetical drug effects on progression using the severity and the sum of scores., Results: The severity endpoint was far more sensitive than the sum of scores for detecting treatment effects, e.g. requiring 275 vs. 625 patients per arm to achieve 60% probability of trial success for detecting a range of potential effects in a 2-year trial. Nontremor items related to the left side of the body seemed most informative. The domain relevance of tremor items appeared questionable., Conclusion: This analysis generated clear evidence that longitudinal modelling of item scores can enhance trial efficiency and success. It also called for reassessing the placement of the tremor items in the instrument., (© 2021 British Pharmacological Society.)

Background: Neuroinflammation plays a pathogenic role in Parkinson's disease (PD). Immunotherapies that restore brain homeostasis can mitigate neurodegeneration by transforming T cell phenotypes. Sargramostim has gained considerable attention as an immune transformer through laboratory bench to bedside clinical studies. However, its therapeutic use has been offset by dose-dependent adverse events. Therefore, we performed a reduced drug dose regimen to evaluate safety and to uncover novel disease-linked biomarkers during 5 days/week sargramostim treatments for one year., Methods: Five PD subjects were enrolled in a Phase 1b, unblinded, open-label study to assess safety and tolerability of 3 μg/kg/day sargramostim. Complete blood counts and chemistry profiles, physical examinations, adverse events (AEs), immune profiling, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, T cell phenotypes/function, DNA methylation, and gene and protein patterns were evaluated., Findings: Sargramostim administered at 3 μg/kg/day significantly reduced numbers and severity of AEs/subject/month compared to 6 μg/kg/day treatment. While MDS-UPDRS Part III score reductions were recorded, peripheral blood immunoregulatory phenotypes and function were elevated. Hypomethylation of upstream FOXP3 DNA elements was also increased., Interpretation: Long-term sargramostim treatment at 3 μg/kg/day is well-tolerated and effective in restoring immune homeostasis. There were decreased numbers and severity of AEs and restored peripheral immune function coordinate with increased numbers and function of Treg. MDS-UPDRS Part III scores did not worsen. Larger patient numbers need be evaluated to assess conclusive drug efficacy (ClinicalTrials.gov NCT03790670)., Funding: The research was supported by community funds to the University of Nebraska Foundation and federal research support from 5 R01NS034239-25., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Published by Elsevier B.V.)

Objective: Advancing age and greater number of medical comorbidities are well-known risk factors for higher rates of surgical complications and undesirable outcomes. We sought to determine the risk of increasing medical comorbidities on surgical outcomes for patients with Parkinson disease undergoing deep brain stimulation (DBS) surgery., Methods: We retrospectively reviewed 107 consecutive patients who underwent DBS for Parkinson disease at Ochsner Medical Center in 2008-2018. Patients were stratified into 3 groups based on Elixhauser comorbidity index (ECI) at the time of surgery: 0, 1, or ≥2. Outcome measures were changes in Unified Parkinson's Disease Rating Scale III scores, changes in medications, and surgical complications. Analysis of variance, paired t test, and nonparametric equivalents were used for statistical analysis., Results: Of patients, 31 (29.0%) had ECI score 0, 44 (41.1%) had ECI score 1, and 32 (29.9%) had ECI score ≥2. For all groups, Unified Parkinson's Disease Rating Scale III scores decreased significantly postoperatively (P = 0.0014, P < 0.0001, P < 0.0001). All groups had a reduction in mean levodopa equivalent daily dose after surgery; however, only the group with ≥2 comorbidities achieved statistical significance (P = 0.0026). The rate of postoperative complications was significantly correlated with comorbidity score on univariate logistic regression analysis (P = 0.0425)., Conclusions: Our findings indicate that DBS is efficacious in patients with multiple medical comorbidities. However, patients with ≥1 medical comorbidities may be more likely to have complications. The most common observed complication was wound infection. Patients with medical comorbidities may still benefit significantly from DBS when performed at experienced centers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: This study aims to evaluate the base-peak difference in levodopa response for detecting patients with motor fluctuations in Parkinson's disease (PD)., Methods: Two independent PD samples were evaluated at baseline and 2 h after the administration of the usual morning dose of levodopa using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). The presence of motor fluctuations was defined by the UPDRS-IV. We quantified the magnitude of motor variation as absolute (Δ) and percentage (Δ%) change in UPDRS-III scores. Optimal cut-offs for each index distinguishing patients with or without fluctuations were calculated on the exploratory population. The accuracy of the identified cut-offs was then verified in a testing population., Results: In the exploratory population (N = 26), the optimal cut-off for detecting fluctuations was a Δ of 6 points and a Δ% of 18.4%. When we applied the identified thresholds to the testing population (N = 139), we found a sensitivity of 93.8% (95% CI: 89.7 to 97.8) and a specificity of 91.2% (95% CI: 86.5 to 95.9) for Δ, 83.3% (95% CI: 77.1 to 89.5) and 86.8% (95% CI: 81.2 to 92.4) for Δ%, respectively., Conclusions: The assessment of levodopa usual morning dose response through the base-peak evaluation represents an accurate method for detecting parkinsonian patients with motor fluctuations, and for defining the Minimal Important Difference (MID) in levodopa response suggesting the presence of motor fluctuations in PD patients demanding further therapeutic interventions.

In recent years, there is an increasing interest in building e-health systems. The systems built to deliver the health services with the use of internet and communication technologies aim to reduce the costs arising from outpatient visits of patients. Some of the related recent studies propose machine learning-based telediagnosis and telemonitoring systems for Parkinson's disease (PD). Motivated from the studies showing the potential of speech disorders in PD telemonitoring systems, in this study, we aim to estimate the severity of PD from voice recordings of the patients using motor Unified Parkinson's Disease Rating Scale (UPDRS) as the evaluation metric. For this purpose, we apply various speech processing algorithms to the voice signals of the patients and then use these features as input to a two-stage estimation model. The first step is to apply a wrapper-based feature selection algorithm, called Boruta, and select the most informative speech features. The second step is to feed the selected set of features to a decision tree-based boosting algorithm, extreme gradient boosting, which has been recently applied successfully in many machine learning tasks due to its generalization ability and speed. The feature selection analysis showed that the vibration pattern of the vocal fold is an important indicator of PD severity. Besides, we also investigate the effectiveness of using age and years passed since diagnosis as covariates together with speech features. The lowest mean absolute error with 3.87 was obtained by combining these covariates and speech features with prediction level fusion. Graphical Abstract Framework for the proposed UPDRS estimation model.

Objectives: The aim of the present study was to determine the relations of clinical symptoms with nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We examined the severity of motor symptoms and freezing of gait (FOG), falls and overactive bladder (OAB) in PD patients and their relations with striatal dopamine transporter (DAT) binding., Patients and Methods: Thirty-two untreated PD patients (14 men and 18 women with a mean age of 71.4 ± 7.2 years) were included in this study. Clinical assessments were performed by using Unified Parkinson's Disease Rating Scale (UPDRS) and overactive bladder symptom score (OABSS), and striatal dopamine transporter (DAT) binding was measured by 123 I-FP-CIT SPECT., Results: The results showed that striatal DAT availability was significantly lower in the high UPDRS motor score group, high akinetic-rigid score group, FOG group, and OAB group than in the low UPDRS motor score group, low akinetic-rigid score group, non-FOG group, and non-OAB group. However, the results also showed that there was no significant difference in striatal DAT availability between the high tremor score group and low tremor score group or between the faller group and non-faller group., Conclusions: The severity of bradykinesia and axial symptoms and the existence of FOG and OAB in untreated PD patients are related to a decrease in striatal DAT availability. Severity of tremors and occurrence of falls are not related to a decrease in striatal DAT availability. The mechanisms underlying the clinical symptoms of PD involve not only dopaminergic pathways but also non-dopaminergic pathways., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study is intended to explore the associations between nutritional status and molecular biomarkers and the clinical severity of Parkinson's disease (PD), as well as to examine the differences in related factors between PD patients with normal nutrition and those with at risk for malnutrition. A cross-sectional assessment of 82 consecutive outpatients with PD was conducted using the mini nutritional assessment (MNA), Unified Parkinson's Disease Rating Scale (UPDRS), and the Hoehn and Yahr scale to determine the nutritional status, the clinical severity of PD, and the stage of the disease. Recordings of blood samples collected after 12 h of overnight fasting were also assessed in terms of serum levels of glycated hemoglobin (HbA1c), blood urea nitrogen (BUN), creatinine, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), hemoglobin (Hgb), folate, and vitamin B12. All participants were divided into normal nutrition and malnutrition risk groups via the MNA scores to compare the above-mentioned parameters. The results showed that the total MNA score was significantly correlated with some parts of the UPDRS scale (e.g., Sections 1 and 2) and the levels of HbAlc in PD patients and those with risk for malnutrition, with significantly lower weight and body mass index (BMI), and with lower levels of Hgb and HDL. Higher levels of cholesterol were observed in the malnutrition risk group as compared with the normal nutrition group. The findings suggest that the clinical severity of PD is associated with nutritional status. Body weight, BMI, and the levels of Hgb, cholesterol, and HDL could be, at least partially, important biological markers to monitor malnutrition and the progression of the disease.

Objectives: The aim of the present study was to determine the relationships of drooling with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relationships of drooling with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography( 123 I-FP-CIT SPECT)., Patients and Methods: Thirty-five untreated PD patients (14 men and 21 women with a mean age of 71.9 ± 7.2 years) were included in this study. The patients were divided into a drooler group and non-drooler group. They underwent clinical assessments and 123 I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS)., Results: The results showed that UPDRS motor score (p = 0.002) and akinetic-rigid score (p = 0.008) were higher and that striatal DAT availability (p = 0.03) was lower in the drooler group than in the non-drooler group. However, tremor score, age, and duration of PD showed no significant differences between the drooler group and non-drooler group., Conclusions: Drooling in untreated PD is related to an increase in motor symptoms (especially bradykinesia and axial symptoms) and to reduction of striatal DAT availability., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Malnutrition is an essential problem in the late stage of PD. Lowering of body mass is seen in 30% of patients, and malnutrition or the risk of malnutrition in 24% and 60%, respectively., Objectives: The aim of the study was an analysis of the relationships between the parameters of the nutritional stage and the advancement of clinical symptoms in PD patients., Material and Methods: A total of 40 patients (18 men, 22 women) with PD were analyzed, mean age: 70.7 years. In all patients, structured anamnesis, Nutrition Risk Screening (NRS 2002), body mass index (BMI), morphology, and basic biochemical tests were conducted. Skin fold thickness was also measured. The results were referred to the score of different scales., Results: The study showed a lot of correlations between the severity of PD, mostly motor symptoms in the Unified Parkinson's Disease Rating Scale (UPDRS), and parameters characterizing the patient's nutritional status. We revealed a correlation between malnutrition and PD duration, and l-DOPA frequency intake. The global score of parts I, II and III of UPDRS were correlated with the nutritional status. The results confirmed the existence of more severe smell change and taste impairment in the late stage of PD, with more pronounced malnutrition., Conclusions: The duration of PD, motor and non-motor PD symptoms, and the frequency of l-DOPA intake closely correlate with the nutritional status. Understanding of the multifactorial interdependence might be useful in the estimation of the algorithm for monitoring the nutritional status of PD patients and taking early nutritional intervention.

Background: Deep brain stimulation (DBS) surgery for Parkinson's disease (PD) is usually performed as awake surgery allowing sufficient intraoperative testing. Recently, outcomes after asleep surgery have been assumed comparable. However, direct comparisons between awake and asleep surgery are scarce., Objective: To investigate the difference between awake and asleep surgery comparing motor and nonmotor outcome after subthalamic nucleus (STN)-DBS in a large single center PD population., Methods: Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively., Results: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems "freezing" and "speech" were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups., Conclusions: Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery., (© 2018 International Neuromodulation Society.)

Objectives: The aim of the present study was to determine the relation of urinary dysfunction with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relation of overactive bladder (OAB) symptoms with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography ( 123 I-FP-CIT SPECT)., Patients and Methods: Thirty-one untreated PD patients (12 men and 19 women with a mean age of 71.2 ± 6.7 years) were included in this study. Patients were evaluated with overactive bladder symptom score (OABSS) and divided into an OAB group and Non-OAB group. They underwent clinical assessments and 123 I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS)., Results: The results showed that UPDRS motor score (p = 0.01) and akinetic-rigid score (p = 0.002) were higher and that striatal DAT availability (p = 0.01) was lower in the OAB group than in the Non-OAB group. However, tremor score, age, and duration of PD showed no significant differences between the OAB group and Non-OAB group., Conclusions: Urinary dysfunction in untreated PD is related with increase in motor symptoms (especially bradykinesia and axial symptoms) and reduction of striatal DAT availability., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Recent studies have shown similar clinical outcomes between Parkinson disease (PD) patients treated with deep brain stimulation (DBS) under general anesthesia without microelectrode recording (MER), so-called “asleep” DBS, and historical cohorts undergoing “awake” DBS with MER guidance. However, few studies include internal controls. This study aims to compare clinical outcomes after globus pallidus internus (GPi) and subthalamic nucleus (STN) DBS using awake and asleep techniques at a single institution., Methods: PD patients undergoing awake or asleep bilateral GPi or STN DBS were prospectively monitored. The primary outcome measure was stimulation-induced change in motor function off medication 6 months postoperatively, measured using the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III). Secondary outcomes included change in quality of life, measured by the 39-item Parkinson’s Disease Questionnaire (PDQ-39), change in levodopa equivalent daily dosage (LEDD), stereotactic accuracy, stimulation parameters, and adverse events., Results: Six-month outcome data were available for 133 patients treated over 45 months (78 GPi [16 awake, 62 asleep] and 55 STN [14 awake, 41 asleep]). UPDRS-III score improvement with stimulation did not differ between awake and asleep groups for GPi (awake, 20.8 points [38.5%]; asleep, 18.8 points [37.5%]; p = 0.45) or STN (awake, 21.6 points [40.3%]; asleep, 26.1 points [48.8%]; p = 0.20) targets. The percentage improvement in PDQ-39 and LEDD was similar for awake and asleep groups for both GPi (p = 0.80 and p = 0.54, respectively) and STN cohorts (p = 0.85 and p = 0.49, respectively)., Conclusions: In PD patients, bilateral GPi and STN DBS using the asleep method resulted in motor, quality-of-life, and medication reduction outcomes that were comparable to those of the awake method.

Objectives: To provide a quantitative estimation of motor fluctuations in PD through a 12-h Waking-day Motor Assessment (WDMA) and to develop new WDMA-based tools, the Motor Fluctuation Indices., Methods: Two independent samples of PD patients (exploratory population N = 51, testing population N = 109) were examined. Patients underwent a WDMA using the Unified Parkinson's Disease Rating Scale (UPDRS) and were classified as either having or not having motor fluctuations. To quantify motor fluctuations, the Worsening Index (WI), the Mean Fluctuation Index (MFI) and the Coefficient of Variation (CV) were computed. The optimal cut-off for each index distinguishing patients with or without fluctuations was calculated on the exploratory population. Cut-offs' accuracy was then verified in the testing population., Results: Optimal cut-off scores to differentiate stable patients from fluctuating ones were 8.3 for WI, 5 for MFI and 12.9 for CV. Sensitivity and a specificity were 91.2% (95%CI: 85.9 to 96.5) and 87.8% (95%CI: 81.7 to 93.9) for WI; 75% (95%CI: 66.9 to 83.1) and 90.2% (95%CI: 84.7 to 95.8) for MFI; 69.1% (95%CI: 60.4 to 77.8) and 95.1% (95%CI: 91.1 to 99.2) for CV. Patients with a larger magnitude of fluctuation had higher values for all three indices, whereas patients with multiple daily fluctuations presented only higher WI values., Conclusions: WDMA-derived Motor Fluctuation Indices may represent reliable tools for evaluating and quantifying the severity of motor fluctuations in PD patients. Even if WDMA is a time-consuming procedure, the detection of Motor Fluctuation Indices could be helpful in assessing therapeutic efficacy on motor fluctuations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: This Phase IV, double-blind, randomized, parallel-group study characterized the dose-response and tolerability of fixed doses of ropinirole prolonged release (PR)., Patients & Methods: Subjects with early Parkinson's disease (PD) received placebo or ropinirole PR 2, 4, 8, 12 or 24 mg once daily, up-titrated to randomized or highest tolerated dose, maintained for 4 weeks., Results: The primary end point was not met (change from baseline in Unified PD Rating Scale motor score). However, because the data were not normally distributed, prespecified nonparametric analysis of covariance suggested ropinirole PR (8 and 12 mg/day) was effective in treating motor symptoms. The adverse event profile was consistent with the known safety profile of ropinirole PR. There was no impulse control disorder reported. Although a higher than previously reported rate of sudden onset of sleep events was reported, these were not dose dependent and were likely to have been influenced by the method of data collection., Conclusion: The adverse event profile was consistent with the known safety profile of ropinirole PR and ropinirole PR (8 or 12 mg/day) improved motor symptoms of early PD.

Background: Parkinson disease (PD) is a common neurodegenerative disease in elderly patients that may be treated with deep brain stimulation (DBS). DBS is an accepted surgical treatment in PD patients <70 years that demonstrates marked improvement in disease symptomology. Patients ≥70 years historically have been excluded from DBS therapy. Our objective is to evaluate the short- and long-term outcomes in patients with PD ≥70 years who underwent DBS at our center., Methods: In our single-center study, we retrospectively assessed a prospective registry of patients with PD treated with DBS who were ≥70 years old at the time of their procedure. Univariate analyses and 1-sample paired t test were used to evaluate data. Motor scores were evaluated with the Unified Parkinson's Disease Rating Scale III, and the effects on medication requirements were evaluated with levodopa equivalence daily doses (LEDD)., Results: Thirty-seven patients were followed for an average of 42.2 months post-DBS. The average ages at diagnosis and at the time of DBS surgery were 63.05 years and 72.45 years, respectively. Significant reductions in the average Unified Parkinson's Disease Rating Scale III score were observed (preoperative 31.8; postoperative 15.6; P < 0.0001). Significant reductions in the average LEDD (preoperative 891.94 mg; postoperative 559.6 mg; P = 0.0008) and medication doses per day (preoperative 11.54; postoperative 7.97; P = 0.0112) also were present., Conclusion: DBS is effective in treating elderly patients with PD. Patients experienced improvement in motor function, LEDD, and medication doses per day after DBS. Our results suggest that DBS is an effective treatment modality in elderly patients with PD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Subthalamic nucleus (STN) local field potential (LFP) recordings demonstrate beta (13-30Hz) band oscillations in Parkinson's disease (PD) defined as elevations of spectral power. The amount of attenuation of beta band power on therapeutic levels of high frequency (HF) deep brain stimulation (DBS) and/or dopaminergic medication has been correlated with the degree of improvement in bradykinesia and rigidity from the therapy, which has led to the suggestion that elevated beta band power is a marker of PD motor disability. A fundamental question has not been answered: whether there is a prolonged attenuation of beta band power after withdrawal of chronic HF DBS and whether this is related to a lack of progression or even improvement in the underlying motor disability. Until now, in human PD subjects, STN LFP recordings were only attainable in the peri-operative period and after short periods of stimulation. For the first time, using an investigational, implanted sensing neurostimulator (Activa® PC+S, Medtronic, Inc.), STN LFPs and motor disability were recorded/assessed after withdrawal of chronic (6 and 12month) HF DBS in freely moving PD subjects. Beta band power was similar within 14s and 60min after stimulation was withdrawn, suggesting that "off therapy" experiments can be conducted almost immediately after stimulation is turned off. After withdrawal of 6 and 12months of STN DBS, beta band power was significantly lower (P<0.05 at 6 and 12months) and off therapy UPDRS scores were better (P<0.05 at 12months) compared to before DBS was started. The attenuation in beta band power was correlated with improvement in motor disability scores (P<0.05). These findings were supported by evidence of a gradual increase in beta band power in two unstimulated STNs after 24months and could not be explained by changes in lead impedance. This suggests that chronic HF DBS exerts long-term plasticity in the sensorimotor network, which may contribute to a lack of progression in underlying motor disability in PD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Parkinson's disease (PD) is an oxidative stress-mediated degenerative disorder. Elevated plasma homocysteine (Hcy) is frequently found in the levodopa-treated PD patients, is associated with disease progression and is a marker of oxidative stress. Whey protein is a rich source of cysteine, and branched-chain amino acids (BCAA). It has been shown that supplementation with Whey protein increases glutathione synthesis and muscle strength., Objectives and Methods: In this study, we conducted a placebo-controlled, double-blind study (NCT01662414) to investigate the effects of undenatured Whey protein isolate supplementation for 6months on plasma glutathione, plasma amino acids, and plasma Hcy in PD patients. Clinical outcome assessments included the unified Parkinson's disease rating scale (UPDRS) and striatal L-3,4-dihydroxy-6-(18)F-fluorophenylalanine (FDOPA) uptake were determined before and after supplementation. 15 patients received Whey protein, and 17 received Soy protein, served as a control group., Results: Significant increases in plasma concentration of reduced glutathione and the ratio of reduced to oxidized glutathione were found in the Whey-supplemented patients but not in a control group. This was associated with a significant decrease of plasma levels of Hcy. The plasma levels of total glutathione were not significantly changed in either group. Plasma BCAA and essential amino acids (EAA) were significantly increased in the Whey-supplemented group only. The UPDRS and striatal FDOPA uptake in PD patients were not significantly ameliorated in either group. However, significant negative correlation was observed between the UPDRS and plasma BCAA and EAA in the pre-supplemented PD patients., Conclusion: This study is the first to report that Whey protein supplementation significantly increases plasma reduced glutathione, the reduced to oxidized glutathione ratio, BCAAs and EAAs in patients with PD, together with a concomitant significant reduction of plasma Hcy. However, there were no significant changes in clinical outcomes. Long-term, large randomized clinical studies are needed to explore the benefits of Whey protein supplementation in the management of PD patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: The aim of the present study was to determine the associations of motor symptoms in untreated Parkinson's disease (PD) with urinary dysfunction. We therefore examined the association between the overactive bladder symptom score (OABSS) and Unified Parkinson's Disease Rating Scale (UPDRS)., Patients and Methods: Thirty-one untreated PD patients without dementia (12 men and 19 women with a mean age of 72.0±6.7years) were included in this study. Their urinary tract dysfunctions were rated using the OABSS. The motor symptoms of all patients were also assessed using UPDRS., Results: OABSS had significant correlations with UPDRS motor score (Spearman's rho=0.39, p=0.03) and akinetic-rigid score (Spearman's rho=0.47, p=0.01). However, OABSS showed no significant correlation with tremor score, age, or duration of PD., Conclusions: Higher OABSS was consistently associated with increase in severity of motor disorders, especially akinetic-rigid score, in the study participants., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This study aimed to examine whether the volume of the olfactory bulbs and tracts (OB & T) on magnetic resonance imaging (MRI) is useful for differentiating Parkinson's disease (PD) from PD-related disorders., Methods: The study group comprised 13 patients with PD, 11 with multiple system atrophy (MSA), five with progressive supranuclear palsy, and five with corticobasal degeneration (PSP/CBD). All patients were evaluated using the odor stick identification test for Japanese (OSIT-J), (123)I-meta-iodobenzylguanidine (MIBG) scintigraphy, and brain MRI. OB & T areas on 1-mm-thick coronal images were measured and summed for volumes. We examined relationships between olfactory function and volume, and cardiovascular dysautonomia. We defined the cut-off values for OSIT-J score or MIBG uptake and OB & T volume to discriminate PD from PD-related disorders and calculated the proportional rate of PD in four categorized groups., Results: OB & T volume was smaller in PD than in MSA or PSP/CBD (p < 0.05 each). The cut-off for detecting PD patients was OSIT-J score <8, heart/mediastinum ratio <1.6, and OB & T volume <270 mm(3). In the group with OSIT-J score <8 and OB & T volume <270 mm(3), the proportion of PD patients among all patients with PD-related disorders was 91%. The rate of probable PD gradually increased as OSIT-J score and OB & T volume decreased (p < 0.001)., Conclusions: Although preliminary, these data obtained from a combined morphological and functional evaluation of OB or cardiovascular dysautonomia could be useful for further differential of PD and other PD-related disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson's disease (PD) with mild symptom severity., Background: Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson's Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716)., Methods: Post hoc analysis of patients at Hoehn and Yahr 1-2; groups defined by treatment received in 6-month double-blind studies: 'Rotigotine-Rotigotine' received rotigotine (n = 221), 'Placebo-Rotigotine' received placebo (n = 125)., Results: At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: -8.5 ± 10.6 'Rotigotine-Rotigotine', -7.7 ± 9.0 'Placebo-Rotigotine.' After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in 'Rotigotine-Rotigotine', and ∼ 21 months in 'Placebo-Rotigotine.' At the time mean UPDRS II + III had crossed baseline in 'Placebo-Rotigotine' (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to 'Rotigotine-Rotigotine' change from baseline was -3.89 (95% CI -6.94, -0.84); p = 0.013., Conclusions: In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.

Object: Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). The globus pallidus internus (GPi) and the subthalamic nucleus (STN) are commonly targeted by this procedure. The purpose of this meta-analysis was to compare the efficacy of DBS in each region., Methods: MEDLINE/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library were searched for English-language studies published before April 2013., Results: of studies investigating the efficacy and clinical outcomes of DBS of the GPi and STN for PD were analyzed., Results: Six eligible trials containing a total of 563 patients were included in the analysis. Deep brain stimulation of the GPi or STN equally improved motor function, measured by the Unified Parkinson's Disease Rating Scale Section III (UPDRSIII) (motor section, for patients in on- and off-medication phases), within 1 year postsurgery. The change score for the on-medication phase was 0.68 (95% CI - 2.12 to 3.47, p > 0.05; 5 studies, 518 patients) and for the off-medication phase was 1.83 (95% CI - 3.12 to 6.77, p > 0.05; 5 studies, 518 patients). The UPDRS Section II (activities of daily living) scores for patients on medication improved equally in both DBS groups (p = 0.97). STN DBS allowed medication dosages to be reduced more than GPi DBS (95% CI 129.27-316.64, p < 0.00001; 5 studies, 540 patients). Psychiatric symptoms, measured by Beck Depression Inventory, 2nd edition scores, showed greater improvement from baseline after GPi DBS than after STN DBS (standardized mean difference -2.28, 95% CI -3.73 to -0.84, p = 0.002; 3 studies, 382 patients)., Conclusions: GPi and STN DBS improve motor function and activities of daily living for PD patients. Differences in therapeutic efficacy for PD were not observed between the 2 procedures. STN DBS allowed greater reduction in medication for patients, whereas GPi DBS provided greater relief from psychiatric symptoms. An understanding of other symptomatic aspects of targeting each region and long-term observations on therapeutic effects are needed.

The aims of this study were to assess the peripapillary retinal nerve fiber layer (RNFL) thickness in patients with Parkinson's disease (PD), to determine its correlation with disease severity, and to define a simple biomarker for predicting clinical severity. One hundred two eyes from 52 patients affected by PD were compared with 97 eyes from 50 age-comparable controls. In all patients, peripapillary RNFL thickness was measured by optical coherence tomography (OCT). We used the Unified Parkinson's Disease Rating Scale (UPDRS) total score and measured responses in the on medication state. Eyes from patients with PD had a statistically significant decrease in average peripapillary RNFL thickness compared with control eyes (P < 0.001). This reduction was observed in every quadrant (inferior, superior, nasal [P < 0.001], and temporal [P = 0.017]) in patients with PD. Furthermore, a strong inverse correlation was found between the PD severity measured according to the UPDRS score and the average peripapillary RNFL thickness (r = -0.615; P < 0.001) and PD duration (r = -0.303; P = 0.002). From these results, we defined a regression equation that predicts the UPDRS score from the above-mentioned variables: UPDRS = 81.6 + 29.6 * log PD duration (years) - 0.6 * RFNL thickness (μm). We observed that, as the evolution and severity of PD progress, the peripapillary RNFL layer thickness, as evaluated by OCT, gradually diminishes. These results suggest that the average peripapillary RNFL thickness measured by OCT might be useful as a biomarker to detect the early onset and progression of PD., (Copyright © 2013 Movement Disorder Society.)

The effect of Parkinson's disease (PD) on hand-eye coordination and corrective response control during reach-to-grasp tasks remains unclear. Moderately impaired PD patients (n=9) and age-matched controls (n=12) reached to and grasped a virtual rectangular object, with haptic feedback provided to the thumb and index fingertip by two 3-degree of freedom manipulanda. The object rotated unexpectedly on a minority of trials, requiring subjects to adjust their grasp aperture. On half the trials, visual feedback of finger positions disappeared during the initial phase of the reach, when feedforward mechanisms are known to guide movement. PD patients were tested without (OFF) and with (ON) medication to investigate the effects of dopamine depletion and repletion on eye-hand coordination online corrective response control. We quantified eye-hand coordination by monitoring hand kinematics and eye position during the reach. We hypothesized that if the basal ganglia are important for eye-hand coordination and online corrections to object perturbations, then PD patients tested OFF medication would show reduced eye-hand spans and impoverished arm-hand coordination responses to the perturbation, which would be further exasperated when visual feedback of the hand was removed. Strikingly, PD patients tracked their hands with their gaze, and their movements became destabilized when having to make online corrective responses to object perturbations exhibiting pauses and changes in movement direction. These impairments largely remained even when tested in the ON state, despite significant improvement on the Unified Parkinson's Disease Rating Scale. Our findings suggest that basal ganglia-cortical loops are essential for mediating eye-hand coordination and adaptive online responses for reach-to-grasp movements, and that restoration of tonic levels of dopamine may not be adequate to remediate this coordinative nature of basal ganglia-modulated function., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

In Parkinson's disease (PD) levodopa-associated changes in the power and long-range temporal correlations of beta oscillations have been demonstrated, yet the presence and modulation of genuine connectivity in local field potentials (LFP) recorded from the subthalamic nucleus (STN) remains an open question. The present study investigated LFP recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and after a single dose levodopa administration (ON). We utilized connectivity measures being insensitive to volume conduction (functional connectivity: non-zero imaginary part of coherency; effective connectivity: phase-slope index). We demonstrated the presence of neuronal interactions in the frequency range of 10-30 Hz in STN-LFP without a preferential directionality of interactions between different contacts along the electrode tracks. While the direction of neuronal interactions per se was preserved after levodopa administration, functional connectivity and the ventral-dorsal information flow were modulated by medication. The OFF-ON differences in functional connectivity were correlated with the levodopa-induced improvement in clinical Unified Parkinson's Disease Rating Scale scores. We hypothesize that regional neuronal interactions, as reflected in STN-LFP connectivity, might represent a basis for the intra-nuclear spatial specificity of deep brain stimulation. Moreover, our results suggest the potential use of volume conduction-insensitive measures of connectivity in STN-LFP as a marker of clinical motor symptoms in PD., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

External pacing cues, dopaminergic medication, and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) improve repetitive movements performed at low rates. When the pacing rate is increased to frequencies near 2 Hz and above, both external pacing cues and Parkinson's medication were shown to be ineffective at improving repetitive finger movement performance. It remains unclear if STN-DBS improves the performance of repetitive finger movements at high pacing rates. This study examined the effects of STN-DBS on the amplitude and rate of repetitive finger movement across a range of external pacing rates. Nine participants with STN-DBS (OFF and ON stimulation) and nine matched healthy adults performed repetitive index finger flexion movements paced by an acoustic tone that increased from 1.0 to 3.0 Hz. OFF stimulation, most subjects moved at rates that were substantially higher (hastening pattern) or lower (bradykinesia pattern) than the tone rate, particularly at high pacing rates. ON stimulation, movement rate improved in subjects with the bradykinesia pattern, but not in those with the hastening pattern. Overall, STN-DBS did not significantly affect movement rate. In contrast, STN-DBS significantly (p<0.05) improved movement amplitude across all pacing rates. These findings demonstrate that STN-DBS improves movement amplitude, but had no effect on the rate of movement in participants with a hastening pattern. Separately testing movement amplitude and movement rate using both high and low rate externally paced cues in the clinical environment may aid in the diagnosis and treatment of people with Parkinson's disease., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the impact of non-motor symptoms on health-related and perceived quality of life in Parkinson's disease (PD)., Methods: One hundred and fifty PD patients (57.3% males; 70.9±8.6years old) were included in this cross-sectional, monocenter, evaluation study. Multiple linear regression methods were used to evaluate the direct impact of non-motor symptoms (as assessed by the Non-Motor Symptoms Scale [NMSS]) on 1) the 39-item PD Quality of Life Questionnaire Summary Index score (PDQ-39SI), and 2) a subjective assessment of perceived quality of life (PQ-10), after adjusting for age, sex, mood (Beck Depression Inventory), disability (Schwab&England Activities of Daily Living Scale), and PD-specific motor dysfunction (ON-state Hoehn&Yahr/Unified Parkinson's Disease Rating Scale [UPDRS] part III, and motor complications [UPDRS part IV])., Results: Higher NMSS total scores were systematically associated with worse quality of life (for PDQ-39SI, p=0.013; for PQ-10, p=0.017). PD-specific motor dysfunction had a larger negative impact on health-related quality of life (PDQ-39SI) than non-motor symptoms (2.8% vs 0.7%). In contrast, the negative impact of non-motor symptoms on perceived quality of life (PQ-10) was larger than that found for PD-specific motor dysfunction (2.8% vs 0.9%). While the model for PDQ-39SI provided an adequate fit (adjusted R-squared, 0.83), a substantial proportion of the PQ-10 variance remained unexplained (adjusted R-squared, 0.48)., Conclusions: Non-motor symptoms have a direct negative impact on health-related and perceived quality of life in PD. Perceived quality of life is not adequately explained by motor and non-motor manifestations of the disease., (© 2013. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a common neurodegenerative disorder owing to loss of dopaminergic cells. Akinesia - one of the core symptoms of PD - is associated with exaggerated oscillations at beta frequency (13-30 Hz) within the subthalamic nucleus (STN). Thus, enhanced oscillations below 30 Hz are assumed to represent a pathophysiological marker of PD. However, recent data suggest that OFF medication exaggerated beta oscillations within basal ganglia (BG) cortical networks may serve for the compensation of BG dysfunctions. The STN is functionally connected to mesial prefrontal areas like the supplementary motor area (SMA). But, it is still not fully understood how enhanced beta oscillations within the BG exert dominance over the primary motor cortex (M1) thereby yielding motor impairment. The present study, therefore, investigates the effect of dopaminergic state on SMA-M1 functional connectivity using Magnetoencephalography (MEG). MEG data were recorded in 7 patients suffering from PD with preponderance of akinesia during isometric contraction of the right forearm and during rest. Coherence as a measure of functional connectivity between M1 and SMA was calculated OFF and ON medication and correlated with the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III) and with disease duration. During rest a significant positive correlation between disease duration and SMA-M1 coherence was found ON but not OFF medication. Conversely, during isometric contraction SMA-M1 coherence and UPDRS III were inversely correlated OFF but not ON medication explaining more than 80% of variance. The results favor the hypothesis that OFF medication exaggerated cortical coherence at beta frequency represents a compensatory mechanism rather than a pathophysiological marker per se., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Brain iron accumulation has been implicated in a host of chronic neurological diseases, including Parkinson's disease (PD). The elevated iron levels observed in the substantia nigra of PD subjects have been suggested to incite the generation of reactive oxygen species and intracellular α-synuclein aggregation, terminating in the oxidative neuronal destruction of this brain area. Thus, elucidation of the molecular mechanisms involved in iron dysregulation and oxidative stress-induced neurodegeneration is a crucial step in deciphering PD pathology and in developing novel iron-complexing compounds aimed at restoring brain iron homeostasis and attenuating neurodegeneration. This review discusses the involvement of dysregulation of brain iron homeostasis in PD pathology, with an emphasis on the potential effectiveness of naturally occurring compounds and novel iron-chelating/antioxidant therapeutic hybrid molecules, exerting a spectrum of neuroprotective interrelated activities: antioxidant/monoamine oxidase inhibition, activation of the hypoxia-inducible factor (HIF)-1 signaling pathway, induction of HIF-1 target iron-regulatory and antioxidative genes, and inhibition of α-synuclein accumulation and aggregation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55–65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized β and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of β-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN β amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3 , P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS. [ABSTRACT FROM AUTHOR]

Objective Neuropsychiatric symptoms (NPS) are common clinical features of patients with Parkinson's disease (PD). However, such symptoms in non-demented PD patients have scarcely been investigated. To address this issue, we describe the neuropsychiatric profile in PD patients with and without Mild Cognitive Impairment (MCI). Participants and Method Eighty non-demented PD patients were included. The patients were divided into two groups depending on the presence or absence of MCI (PD-MCI and PD-nMCI, respectively). MCI diagnosis was made according to the Movement Disorder Society Task Force Level I criteria. NPS were evaluated using the Neuropsychiatric Inventory (NPI). For each domain, the presence and magnitude of symptoms (frequency x severity) was calculated. The total NPI score was also computed, in which higher scores suggest greater behavioral disturbance. Results PD-nMCI (n = 59, 74%) and PD-MCI (n = 21, 26%) groups were similar in the disease stage and years since diagnosis. In contrast with the PD-nMCI group, participants in the PD-MCI group were older. Fourteen PD-MCI (66%) and 45 PD-nMCI (76%) patients reported at least one neuropsychiatric symptom in the previous month. In both groups, the most frequent NPS were sleep disorders, depression, anxiety, apathy, irritability, and disinhibition. Additionally, the proportion of these symptoms between groups did not differ significantly (p > 0.05). There was only a tendency of greater score in the disinhibition subscale in PD-MCI group (p < 0.02). In both groups, NPS were not associated with clinical variables (years since diagnosis, Unified Parkinson's Disease Rating Scale -III) after adjusting for age. Conclusions Preliminary findings suggest that NPS are frequent in PD patients independent of the degree of cognitive impairment, and they may encompass non-motor features of the clinical spectrum of the disease. Further longitudinal investigations are needed to determine whether such symptoms may predict the cognitive decline in these patients. [ABSTRACT FROM AUTHOR]