Safety and Efficacy of IPX203 in Parkinson's Disease: The RISE-PD Open-Label Extension Study.

BACKGROUND: IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved "Good On" time in patients with Parkinson's disease compared with immediate-release CD/LD. OBJECTIVES: To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study. METHODS: This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included Movement Disorder Society-Unified Parkinson's Disease Rating Scale and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded. RESULTS: Improvements in efficacy were maintained and dosing frequency and total daily dose remained stable through the trial. A total of 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment. CONCLUSIONS: In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adjusting for Underrepresentation Reveals Widespread Underestimation of Parkinson's Disease Symptom Burden.

BACKGROUND: Clinical research is limited by underrepresentation, but the impact of underrepresentation on patient-reported outcomes in Parkinson's disease (PD) is unknown. OBJECTIVES: To produce nationwide estimates of non-motor symptom (NMS) prevalence and PD-related quality of life (QOL) limitations while accounting for underrepresentation. METHODS: We performed a cross-sectional analysis of data from the Fox Insight (FI) study, an ongoing prospective longitudinal study of persons with self-reported PD. Using epidemiologic literature and United States (US) Census Bureau, Medicare, and National Health and Aging Trends Study data, we simulated a "virtual census" of the PD population. To compare the PD census to the FI cohort, we used logistic regression to model the odds of study participation and calculate predicted probabilities of participation for inverse probability weighting. RESULTS: There are an estimated 849,488 persons living with PD in the US. Compared to 22,465 eligible FI participants, non-participants are more likely to be older, female, and non-White; live in rural regions; have more severe PD; and have lower levels of education. When these predictors were incorporated into a multivariable regression model, predicted probability of participation was much higher for FI participants than non-participants, indicating a significant difference in the underlying populations (propensity score distance 2.62). Estimates of NMS prevalence and QOL limitation were greater when analyzed using inverse probability of participation weighting compared to unweighted means and frequencies. CONCLUSIONS: PD-related morbidity may be underestimated because of underrepresentation, and inverse probability of participation weighting can be used to give greater weight to underrepresented groups and produce more generalizable estimates. © 2023 International Parkinson and Movement Disorder Society.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Determination of optimal vibration dose to treat Parkinson's disease gait symptoms: A clinical trial.

Introduction: Most people with Parkinson's disease (PD) will experience gait problems. Previous studies demonstrated improved gait and balance after vibration stimulation was applied to the feet of PD patients. However, not all study participants showed improvement, perhaps due to sub-optimal vibration stimulus. Thus far, the optimal frequency and amplitude of vibration for mitigating gait dysfunction in PD have yet to be systematically explored. This study aimed to deliver vibration to the feet of 26 people with PD gait disturbances. We hypothesized that a global frequency, amplitude, and minimum duration of vibration therapy are required to improve PD gait issues. Methods: This was a phase Ib trial to identify optimal vibration parameters. Thirteen participants were recruited at Hoehn & Yahr (H&Y) stage II and 13 participants at stage III. Each group was randomly assigned to different frequency and amplitude settings prescribed by the central composite design methodology. Each participant received vibration for 18 min per walking session, for eight sessions spread over one week. Results: Results showed an optimal response to treatment for frequency (Hz) and amplitude (mm) of vibration based on the Functional Ambulation Performance score for stages II and III. In the H&Y stage II group, stabilization of outcomes occurred after the 4th treatment. This stabilization was not seen in stage III participants. Conclusions: A global frequency and vibration amplitude have been identified for treating PD gait disorders. Patients with more advanced disease may require a longer duration of therapy.

Consensus practice recommendations for management of gastrointestinal dysfunction in Parkinson disease.

BACKGROUND: Gastrointestinal (GI) dysfunction is a common non-motor feature of Parkinson disease (PD). GI symptoms may start years before the onset of motor symptoms and impair quality of life. Robust clinical trial data is lacking to guide screening, diagnosis and treatment of GI dysfunction in PD. OBJECTIVE: To develop consensus statements on screening, diagnosis, and treatment of GI dysfunction in PD. METHODS: The application of a modified Delphi panel allowed for the synthesis of expert opinions into clinical statements. Consensus was predefined as a level of agreement of 100 % for each item. Five virtual Delphi rounds were held. Two movement disorders neurologists reviewed the literature on GI dysfunction in PD and developed draft statements based on the literature review. Draft statements were distributed among the panel that included five movement disorder neurologists and two gastroenterologists, both experts in GI dysmotility and its impact on PD symptoms. All members reviewed the statements and references in advance of the virtual meetings. In the virtual meetings, each statement was discussed, edited, and a vote was conducted. If there was not 100 % consensus, further discussions and modifications ensued until there was consensus. RESULTS: Statements were developed for screening, diagnosis, and treatment of common GI symptoms in PD and were organized by anatomic segments: oral cavity and esophagus, stomach, small intestine, and colon and anorectum. CONCLUSIONS: These consensus recommendations offer a practical framework for the diagnosis and treatment of GI dysfunction in PD.

Efficacy of the iron-chelating agent, deferiprone, in patients with Parkinson's disease: A systematic review and meta-analysis.

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.

Parkinson's Disease Action Tremor Detection with Supervised-Leaning Models.

People with Parkinson's Disease (PD) have multiple symptoms, such as freezing of gait (FoG), hand tremors, speech difficulties, and balance issues, in different stages of the disease. Among these symptoms, hand tremors are present across all stages of the disease. PD hand tremors have critical consequences and negatively impact the quality of PD patients' everyday lives. Researchers have proposed a variety of wearable devices to mitigate PD tremors. However, these devices require accurate tremor detection technology to work effectively while the tremor occurs. This paper introduces a PD action tremor detection method to recognize PD tremors from regular activities. We used a dataset from 30 PD patients wearing accelerometers and gyroscope sensors on their wrists. We selected time-domain and frequency-domain hand-crafted features. Also, we compared our hand-crafted features with existing CNN data-driven features, and our features have more specific boundaries in 2-D feature visualization using the t-SNE tool. We fed our features into multiple supervised machine learning models, including Logistic Regression (LR), K-Nearest Neighbours (KNNs), Support Vector Machines (SVMs), and Convolutional Neural Networks (CNNs), for detecting PD action tremors. These models were evaluated with 30 PD patients' data. The performance of all models using our features has more than 90% of F1 scores in five-fold cross-validations and 88% F1 scores in the leave-one-out evaluation. Specifically, Support Vector Machines (SVMs) perform the best in five-fold cross-validation with over 92% F1 scores. SVMs also show the best performance in the leave-one-out evaluation with over 90% F1 scores.

FoG-Finder: Real-time Freezing of Gait Detection and Treatment.

Freezing of gait is a serious symptom of Parkinson's disease that increases the risk of injury through falling, and reduces quality of life. Current clinical freezing of gait treatments fail to adequately address the fall risk posed by freezing of gait symptoms, and current real-time treatment systems have high false positive rates. To address this problem, we designed a closed-loop, non-intrusive, and real-time freezing of gait detection and treatment system, FoG-Finder, that automatically detects and treats freezing of gait. To evaluate FoG-Finder, we first collected 716 freezing of gait events from 11 patients. We then compared FoG-Finder against other real-time systems with our dataset. Our system was able to achieve a 13.4% higher F1 score and a 10.7% higher overall accuracy while achieving a reduction of 85.8% in the false positive treatment rate compared with other validated real-time freezing of gait detection and treatment systems. Additionally, FoG-Finder achieved an average treatment latency of 427ms and 615ms for subject-dependent and leave-one-subject-out settings, respectively, making it a viable system to treat freezing of gait in the real-world.

Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Poster: Kinetic Tremor Measurement via IMU Sensing Data Analysis.

Tremor is a common symptom among all stages of Parkinson's Disease (PD) patients. To measure daily tremor events, we utilized IMU sensing data from wrists while PD patients were drawing. We secured 30 patients' IMU sensing data, following standard rating scale activities. With the collected data, we conducted data analysis for identifying any tremor episodes and extracting tremor amplitude. Our preliminary analysis and results show the potential of measuring kinetic tremors effectively. We plan to further analyze tremor events of PD patients via wearable sensing devices.

IMU Sensing Data-based Kinetic Tremor Detection in Parkinson's Disease Patients.

Tremor is a common symptom among Parkinson's disease (PD) patients at all stages. To measure tremor, we utilized IMU sensing data from the wrists while PD patients were drawing. With 30 patients' IMU sensing data obtained from standard tremor rating scale activities, we conducted data analysis for identifying any tremor episodes and extracting tremor amplitude. In this demo, we demonstrate that our preliminary analysis and results show the potential of measuring kinetic tremors effectively using these methods.

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

BACKGROUND: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications. OBJECTIVE: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients. METHODS: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients. RESULTS: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55). CONCLUSION: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.

Gastrointestinal features of Parkinson's disease.

Gastrointestinal (GI) symptoms are among the most common nonmotor manifestations of Parkinson's disease (PD), and they have many important ramifications for patients. The purpose of this review is to raise awareness of the full spectrum of GI symptoms in PD which include weight loss, sialorrhea, dysphagia, nausea, constipation, and defecatory dysfunction. We will discuss their practical significance, and outline a clear approach to their evaluation and management. A brief discussion about the impacts of commonly used medical and surgical PD therapies on GI symptom manifestation is also included.

Tardive dyskinesia.

OPINION STATEMENT: Tardive dyskinesia (TD) is iatrogenic (drug-induced); hence the best strategy is prevention. Try to limit exposure to any dopamine receptor blocking agents (DRBAs) if possible. These agents may be unavoidable in some psychiatric conditions such as schizophrenia, but alternative therapies can be used in many situations, such as in the treatment of depression, anxiety, gastrointestinal conditions, and other neurologic conditions, including migraines and sleep disorders. When DRBAs are necessary, physicians should prescribe the smallest possible dose and try to taper and stop the drug at the earliest signs of TD. Abrupt cessation should be avoided, as this can worsen symptoms of TD. Always discuss and document the possibility of TD as an adverse effect when starting patients on DRBAs. If TD is mild and tolerable, the withdrawal of the offending agent is possible, and exposure to DRBAs was short, physicians should consider avoiding treatment and waiting for spontaneous recovery. When treatment is necessary, tetrabenazine (TBZ) is considered a potential first-line agent and is known to be one of the most effective drugs in treating TD, but it is expensive and adverse effects such as depression, akathisia and parkinsonism frequently occur. Therefore, second-line agents with better tolerability profiles are often tried first in practice. These include amantadine, benzodiazepines, beta-blockers, and levetiracetam. When using TBZ, adverse effects should be aggressively monitored. (Depression often can be managed with antidepressants, for instance). In patients with psychosis, withdrawal of the antipsychotic may not be possible. Switching to clozapine or quetiapine is one option to minimize TD. When these agents are contraindicated and the patient must continue using other atypical antipsychotic drugs, try to add dopamine-depleting agents such as TBZ or reserpine, but watch for the development of parkinsonism. When the symptoms are focal, such as tongue protrusion or blepharospasm, botulinum toxin injections can be very effective if spontaneous recovery does not occur. As a last resort, when disabling, life-threatening symptoms of TD persist despite all of the above-mentioned methods, some advocate resuming treatment with the DRBA to suppress symptoms of TD. This has the potential to worsen TD in the long run.

Gastrointestinal Care of the Parkinson Patient.

This article reviews the most common gastrointestinal (GI) problems that occur in patients with Parkinson disease, including weight loss, drooling, dysphagia, delayed gastric emptying, constipation, and defecatory dysfunction. Appropriate workup and treatment options are reviewed in detail in order to provide clinicians with a comprehensive and practical guide to managing these problems in Parkinson disease patients. GI adverse effects of commonly used Parkinson disease motor medications are also reviewed.

Therapeutic approaches to cholinergic deficiency in Lewy body diseases.

Introduction: Cortical cholinergic denervation resulting from degeneration of the nucleus basalis of Meynert (NBM) is a primary contributor to cognitive impairment and neuropsychiatric symptoms in the Lewy body diseases Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). Considering the morbidity associated with cognitive impairment and neuropsychiatric symptoms in these diseases, it is important to investigate all potential therapies to improve these symptoms.Areas covered: The authors review the current landscape of pharmacological and surgical therapies for mitigating the cortical cholinergic deficiency in PD, PDD, and DLB.Expert opinion: The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are currently the primary pharmacological treatments available to improve cognition and associated neuropsychiatric symptoms in Lewy body diseases. Other possible pharmacological strategies include increasing acetylcholine release with 5-HT4 agonists or directly stimulating cholinergic receptors with muscarinic and nicotinic agonists. The side effect profile of muscarinic agonists is a deterrent to their future study, but 5-HT4 and nicotinic agonists deserve further investigation. Targeting the basal forebrain with either deep brain stimulation (DBS)- or cell-based therapies is another strategy to mitigate cortical cholinergic deficiency. Before NBM DBS studies continue, it will be important to resolve issues related to targeting, stimulation pattern, and duration.

An Integrated Review of Psychological Stress in Parkinson's Disease: Biological Mechanisms and Symptom and Health Outcomes.

Parkinson's disease (PD) is characterized by complex symptoms and medication-induced motor complications that fluctuate in onset, severity, responsiveness to treatment, and disability. The unpredictable and debilitating nature of PD and the inability to halt or slow disease progression may result in psychological stress. Psychological stress may exacerbate biological mechanisms believed to contribute to neuronal loss in PD and lead to poorer symptom and health outcomes. The purpose of this integrated review is to summarize and appraise animal and human research studies focused on biological mechanisms, symptom, and health outcomes of psychological stress in PD. A search of the electronic databases PubMed/Medline and CINAHL from 1980 to the present using the key words Parkinson's disease and stress, psychological stress, mental stress, and chronic stress resulted in 11 articles that met inclusion criteria. The results revealed significant associations between psychological stress and increased motor symptom severity and loss of dopamine-producing neurons in animal models of PD and between psychological stress and increased symptom severity and poorer health outcomes in human subjects with PD. Further research is needed to fully elucidate the underlying biological mechanisms responsible for these relationships, for the ultimate purpose of designing targeted interventions that may modify the disease trajectory.

Biobehavioral Framework of Symptom and Health Outcomes of Uncertainty and Psychological Stress in Parkinson Disease.

Parkinson disease (PD) is a debilitating, progressive neurodegenerative disorder characterized by complex motor and nonmotor symptoms that fluctuate in onset, severity, level of disability, and responsiveness to treatment. The unpredictable nature of PD and the inability to halt or slow disease progression may result in uncertainty and psychological stress. Uncertainty and psychological stress have important implications for symptom and health outcomes in PD. Uncertainty and psychological stress have been shown to worsen symptoms, functional capacity, and quality of life in chronic illnesses; however, the causal mechanisms have yet to be elucidated. We propose a biobehavioral framework for examining uncertainty and psychological stress in PD. The framework considers factors that may contribute to uncertainty and neuroendocrine-immune mechanisms of uncertainty and psychological stress that may influence symptom and health outcomes in PD, for the ultimate purpose of improving symptom and disease progression, functional capacity, and quality of life.

Control of arterial pressure by angiotensin II and nitric oxide at the onset of diabetes.

We have reported that the induction of diabetes in N(omega)-nitro-L-orginine methyl ester (L-NAME)-infused rats causes significant hypertension that is associated with increased plasma renin activity. This study tested the role of angiotensin II (Ang II) by clamping it chronically at baseline levels. The clamp consisted of an intravenous infusion of enalapril (10 mg/kg/d), which decreased mean arterial pressure (MAP) by approximately 20 mm Hg after 3 days, and adding chronic Ang II at 4 ng/kg/min, which restored MAP to normal. Chronic L-NAME infusion increased MAP to 127 +/- 1 and 132 +/- 2 mm Hg in normal and clamped rats, respectively, and induction of diabetes (streptozotocin) increased MAP progressively in normal rats to 161 +/- 8 mm Hg by day 12, whereas MAP in the clamped rats decreased progressively to 98 +/- 5 mm Hg by day 12. In non-L-NAME rats, MAP averaged 95 +/- 1 and 91 +/- 1 mm Hg for normal and clamped groups, respectively, before diabetes, and MAP was 10 to 13 mm Hg lower in the clamped versus normal rats midway through the diabetic period. This suggests that Ang II is important for maintaining blood pressure at the onset of diabetes, possibly to compensate for renal volume losses. Angiotensin II also is required for the hypertension caused by induction of diabetes in rats with chronic blockade of nitric oxide synthesis, but whether this is due to increased volume sensitivity in L-NAME-treated, vasoconstricted rats remains to be determined.