Parkinson's Disease Clinical Trials Research Articles

Validating new symptom emergence as a patient-centric outcome measure for PD clinical trials

IntroductionTracking of emergent symptoms (ES) in de novo Parkinson Disease (PD) patients using Parts Ib and II of the MDS-UPDRS rating scale has been proposed as an outcome measure for PD clinical trials, based on observations in the Safety, Tolerability and Efficacy Assessment of Isradipine for PD (STEADY-PD3) clinical trial. MethodsIndividual item-level data was extracted from the SURE-PD3 study (coded as “PD-1018” in the C-path pooled dataset). We sought to confirm the observations made in the STEADY-PD3 dataset by analyzing data from a different Phase 3 clinical trial, the Phase 3 Study of Urate Elevation in Parkinson Disease (SURE-PD3), in which MDS-UPDRS was assessed more frequently than the 12-month intervals in STEADY-PD3, using similar methodology. ResultsWe were able to broadly validate results that demonstrated the frequency of ES, lack of impact of the introduction of symptomatic medications, and in the reduction in sample size required to demonstrate slowing of disease progression at a group level compared with the traditional total MDS-UPDRS summed score scoring methods. Counts of ES generally correlated modestly with summed MDS-UPRDS scores, both for the various sub-parts and for the overall scale as well. However, instability of individual item responses, especially during the first 6 months of observation complicated the assessment of the temporal evolution and stability of ES over time in the course of the SURE-PD3 study. ConclusionFurther validation using data sets with frequent administration of MDS-UPDRS is necessary to assess value of this approach as an outcome measure in PD clinical trials.

Sample size planning for estimating the global win probability with precision and assurance

Randomized controlled trials commonly employ multiple endpoints to collectively assess the intended effects of the new intervention on multiple aspects of the disease. Focusing on the estimation of the global win probability (WinP), defined as the (weighted) mean of the WinPs across the endpoints that a treated participant would have a better outcome than a control participant, we propose a closed-form sample size formula incorporating pre-specified precision and assurance, with precision denoted by the lower limit of confidence interval and assurance denoted by the probability of achieving that lower limit. We make use of the equivalence of the WinP and the area under the receiver operating characteristic curve (AUC) and adapt a formula originally developed for the difference between two AUCs to handle the global WinP. Unequal variances between treatment groups are allowed. Simulation results suggest that the method performs very well. We illustrate the proposed formula using a Parkinson's disease clinical trial design example.

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

The Parkinson's Disease Composite of Executive Functioning: A Measure for Detecting Cognitive Decline in Clinical Trials.

Executive functioning is one of the first domains to be impaired in Parkinson disease (PD), and the majority of patients with PD eventually develop dementia. Thus, developing a cognitive endpoint measure specifically assessing executive functioning is critical for PD clinical trials. The objective of this study was to develop a cognitive composite measure that is sensitive to decline in executive functioning for use in PD clinical trials. We used cross-sectional and longitudinal follow-up data from PD participants enrolled in the PD Cognitive Genetics Consortium, a multicenter setting focused on PD. All PD participants with Trail Making Test, Digit Symbol, Letter-Number Sequencing, Semantic Fluency, and Phonemic Fluency neuropsychological data collected from March 2010 to February 2020 were included. Baseline executive functioning data were used to create the Parkinson's Disease Composite of Executive Functioning (PaCEF) through confirmatory factor analysis. We examined the changes in the PaCEF over time, how well baseline PaCEF predicts time to cognitive progression, and the required sample size estimates for PD clinical trials. PaCEF results were compared with the Montreal Cognitive Assessment (MoCA), individual tests forming the PaCEF, and tests of visuospatial, language, and memory functioning. A total of 841 participants (251 no cognitive impairment [NCI], 480 mild cognitive impairment [MCI], and 110 dementia) with baseline data were included, of which the mean (SD) age was 67.1 (8.9) years and 270 were women (32%). Five hundred forty five PD participants had longitudinal neuropsychological data spanning 9 years (mean [SD] 4.5 [2.2] years) and were included in analyses examining cognitive decline. A 1-factor model of executive functioning with excellent fit (comparative fit index = 0.993, Tucker-Lewis index = 0.989, and root mean square error of approximation = 0.044) was used to calculate the PaCEF. The average annual change in PaCEF ranged from 0.246 points per year for PD-NCI participants who remained cognitively unimpaired to -0.821 points per year for PD-MCI participants who progressed to dementia. For PD-MCI, baseline PaCEF, but not baseline MoCA, significantly predicted time to dementia. Sample size estimates were 69%-73% smaller for PD-NCI trials and 16%-19% smaller for PD-MCI trials when using the PaCEF rather than MoCA as the endpoint. The PaCEF is a sensitive measure of executive functioning decline in PD and will be especially beneficial for PD clinical trials.

Exclusion of older patients from randomized clinical trials in Parkinson's disease.

Prevalence of Parkinson's disease (PD) increases with age. The purpose of this study was to evaluate the eligibility criteria in randomized clinical trials (RCTs) in PD, especially those limiting the enrollment of older adults. We examined RCTs of pharmacological and non-pharmacological anti-parkinsonian interventions registered with ClinicalTrials.gov and started from 2013 through 2022. Primary outcome was proportion of RCTs with an upper age limit of 85years of age or less. Secondary outcome was proportion of RCTs with other exclusion criteria. Associations between trial characteristics and the presence of the age limits were determined using logistic regression. Our study included 420 RCTs. Two hundred thirty-nine (57%) of these had an upper age limit of 85years of age or less. Proportion of these trials significantly increased over time. The odds of the presence of an upper age limit were significantly associated with the investigational site location, phase, and timeframe for theprimary endpoint assessment. Three hundred fifty-six (85%) trials had other eligibility criteria limiting the enrollment of older patients; these often (n = 285; 68%) included cognitive impairment. Overall, 386 (92%) RCTs either explicitly excluded older adults or had criteria indirectly limiting their enrollment. Underrepresentation of older patients in clinical trials in PD considerably reduces the generalizability of their results. Some eligibility criteria should be modified to enable the investigators to assess the benefits and harms of new therapeutic interventions in older adults. This problem is important in view of rapidly growing number of older patients with PD.

Assessing Uptake of the Core Outcome Set in Randomized Controlled Trials for Parkinson's Disease: A Systematic Review.

Parkinson's Disease (PD) affects more than 10 million individuals, with increasing incidence worldwide. As PD's incidence rises, research funding is increasing substantially. PD's core outcome set (COS) provides standardization for PD clinical trial outcomes, improves research quality, and study comparability. Our study aimed to analyze COS uptake rate before and after the PD COS publication. We searched ClinicalTrials.gov to retrieve phase III/IV adult PD trials published between 2013-2023. Screening for inclusion and data extraction occurred in a masked, duplicate fashion. Trial characteristics and COS uptake rate were extracted from this sample. In our 111 included trials, the COS uptake rate was highest for the 'Walking and Balance' outcome and lowest for the 'Hospital Admissions' outcome. Overall, there was a non-significant monthly increase of 0.26% (P = 0.266, CI = [-0.20, 0.72]) in "COS-defined outcome" measurement when comparing pre- and post-COS publication. Our study found no significant increase in COS uptake in PD clinical trials. We found multiple outcomes to be vastly unmeasured and heterogeneity among the measurement instruments used. These findings complicate standardizing and comparing RCT outcomes. Overcoming these barriers is vital to improving the usefulness of PD research.

Ferroptosis in Parkinson's disease: Molecular mechanisms and therapeutic potential.

Parkinson's Disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), leading to motor and non-motor symptoms. While the exact mechanisms remain complex and multifaceted, several molecular pathways have been implicated in PD pathology, including accumulation of misfolded proteins, impaired mitochondrial function, oxidative stress, inflammation, elevated iron levels, etc. Overall, PD's molecular mechanisms involve a complex interplay between genetic, environmental, and cellular factors that disrupt cellular homeostasis, and ultimately lead to the degeneration of dopaminergic neurons. Recently, emerging evidence highlights ferroptosis, an iron-dependent non-apoptotic cell death process, as a pivotal player in the advancement of PD. Notably, oligomeric α-synuclein (α-syn) generates reactive oxygen species (ROS) and lipid peroxides within cellular membranes, potentially triggering ferroptosis. The loss of dopamine, a hallmark of PD, could predispose neurons to ferroptotic vulnerability. This unique form of cell demise unveils fresh insights into PD pathogenesis, necessitating an exploration of the molecular intricacies connecting ferroptosis and PD progression. In this review, the molecular and regulatory mechanisms of ferroptosis and their connection with the pathological processes of PD have been systematically summarized. Furthermore, the features of ferroptosis in PD animal models and clinical trials targeting ferroptosis as a therapeutic approach in PD patients' management are scrutinized.

GV-971 attenuates α-Synuclein aggregation and related pathology.

Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ). GV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.

How should we be using biomarkers in trials of disease modification in Parkinson's disease?

The recent validation of the α-synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson's disease has formed the backbone for a proposed staging system for incorporation in Parkinson's disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson's disease patients into trials (as distinct from patients with non-Parkinson's disease parkinsonism or non-Parkinson's disease tremors). There remain, however, further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson's disease, namely: optimizing the distinction between different α-synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; a sensitive means of confirming target engagement; and the early prediction of longer-term clinical benefit. For example, levels of CSF proteins such as the lysosomal enzyme β-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer's disease-like pathology (detectable through CSF levels of amyloid-β42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline in Parkinson's disease even in its later stages. The exploitation of additional biomarkers to the α-synuclein seed amplification assay will, therefore, greatly add to our ability to plan trials and assess the disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson's disease. However, correlation with clinical progression does not necessarily equate to causation, and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson's disease.

Procedure-Related Complications in Sham Surgeries for Parkinson's Clinical Trials: A Meta-analysis.

Double-blind, sham-controlled neurosurgical trials for neurodegenerative disorders are debated as an ethical dilemma, particularly regarding subjects randomized to the sham surgery group with general anesthesia. The objective of this study was to examine the safety of sham surgeries in Parkinson's disease (PD) clinical trials through complications related to the procedure. A systematic review and meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Rates and odds ratios (OR) were compared using random effects analysis. Seven studies, all randomized, double-blind, sham surgery-controlled trials, with 309 patients with PD, were qualitatively and quantitatively analyzed: 141 patients in sham groups and 168 patients in the experimental arms of gene or cell therapy trials. Sham subjects had lower rates of gastrointestinal, positioning, incision-site, respiratory (hypoxic or hypercapnic respiratory failure), cardiovascular, thromboembolism, postoperative cognitive decline, skull fracture, and intracranial or spinal complications when compared with active treatment subjects. Sham subjects, however, had a higher rate of perioperative respiratory infections, such as pneumonia or sinusitis. Further, sham subjects were less likely to experience postoperative cognitive decline (OR, 0.23; 95% confidence interval [CI]: 0.11-0.47), intracranial or spinal complications (OR, 0.10; 95% CI: 0.01-0.75), total major morbidity (OR, 0.30; 95% CI: 0.19-0.47), or overall complications (OR, 0.59; 95% CI: 0.47-0.75) when compared with patients receiving experimental therapy. Patients with PD in the sham surgery control arm of cell transplantation or gene therapy clinical trials have a low risk of procedure-related adverse events overall and fewer complications than patients in the experimental groups. There were no reported deaths attributed to sham surgery-controlled PD clinical trials. © 2023 International Parkinson and Movement Disorder Society.

Integrated safety summary from Phase 3 clinical trials of IPX203, an extended-release carbidopa-levodopa formulation, in Parkinson disease (P1-11.006)

Integrated safety summary from Phase 3 clinical trials of IPX203, an extended-release carbidopa-levodopa formulation, in Parkinson disease (P1-11.006)

Chapter 19 - Role of novel endpoints and evaluations of response in Parkinson disease

With progress in our understanding of Parkinson disease (PD) and other neurodegenerative disorders, from clinical features to imaging, genetic, and molecular characterization comes the opportunity to refine and revise how we measure these diseases and what outcome measures are used as endpoints in clinical trials. While several rater-, patient-, and milestone-based outcomes for PD exist that may serve as clinical trial endpoints, there remains an unmet need for endpoints that are clinically meaningful, patient centric while also being more objective and quantitative, less susceptible to effects of symptomatic therapy (for disease-modification trials), and that can be measured over a short period and yet accurately represent longer-term outcomes. Several novel outcomes that may be used as endpoints in PD clinical trials are in development, including digital measures of signs and symptoms, as well a growing array of imaging and biospecimen biomarkers. This chapter provides an overview of the state of PD outcome measures as of 2022, including considerations for selection of clinical trial endpoints in PD, advantages and limitations of existing measures, and emerging potential novel endpoints.

Does clinically measured walking capacity contribute to real-world walking performance in Parkinson's disease?

ObjectiveThe study examined how clinically measured walking capacity contributes to real-world walking performance in persons with Parkinson's disease (PD). MethodsCross-sectional baseline data (n = 82) from a PD clinical trial were analyzed. The 6-Minute Walk Test (6MWT) and 10-Meter Walk Test (10MWT) were used to generate capacity metrics of walking endurance and fast gait speed, respectively. An activity monitor worn for seven days was used to generate performance metrics of mean daily steps and weekly moderate intensity walking minutes. Univariate linear regression analyses were used to examine associations between each capacity and performance measure in the full sample and less and more active subgroups. ResultsWalking capacity significantly contributed to daily steps in the full sample (endurance: R2=.13, p < .001; fast gait speed: R2=.07, p = .017) and in the less active subgroup (endurance: R2 =.09, p = .045). Similarly, walking capacity significantly contributed to weekly moderate intensity minutes in the full sample (endurance: R2=.13, p < .001; fast gait speed: R2=.09, p = .007) and less active subgroup (endurance: R2 = .25, p < .001; fast gait speed: R2 =.21, p = .007). Walking capacity did not significantly contribute to daily steps or moderate intensity minutes in the more active subgroup. ConclusionsWalking capacity contributed to, but explained a relatively small portion of the variance in, real-world walking performance. The contribution was somewhat greater in less active individuals. The study adds support to the idea that clinically measured walking capacity may have limited benefit for understanding real-world walking performance in PD. Factors beyond walking capacity may better account for actual walking behavior.

Ferroptosis in Parkinson's disease: glia-neuron crosstalk.

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.

Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways

Biallelic (homozygous or compound heterozygous) glucocerebrosidase gene (GBA) mutations cause Gaucher disease, whereas heterozygous mutations are numerically the most important genetic risk factor for Parkinson disease (PD) and are associated with the development of other synucleinopathies, notably Dementia with Lewy Bodies. This phenomenon is not limited to GBA, with converging evidence highlighting further examples of autosomal recessive disease genes increasing neurodegeneration risk in heterozygous mutation carriers. Nevertheless, despite extensive research, the cellular mechanisms by which mutations in GBA, encoding lysosomal enzyme β-glucocerebrosidase (GCase), predispose to neurodegeneration remain incompletely understood. Alpha-synuclein (A-SYN) accumulation, autophagic lysosomal dysfunction, mitochondrial abnormalities, ER stress and neuroinflammation have been proposed as candidate pathogenic pathways in GBA-linked PD. The observation of GCase and A-SYN interactions in PD initiated the development and evaluation of GCase-targeted therapeutics in PD clinical trials.

Novel Approach to Movement Disorder Society-Unified Parkinson's Disease Rating Scale Monitoring in Clinical Trials: Longitudinal Item Response Theory Models.

ABSTRACTBackgroundAlthough nontremor and tremor Part 3 Movement Disorder Society–Unified Parkinson's Disease Rating Scale items measure different impairment domains, their distinct progression and drug responsivity remain unstudied longitudinally. The total score may obscure important time‐based and treatment‐based changes occurring in the individual domains.ObjectiveUsing the unique advantages of item response theory (IRT), we developed novel longitudinal unidimensional and multidimensional models to investigate nontremor and tremor changes occurring in an interventional Parkinson's disease (PD) study.MethodWith unidimensional longitudinal IRT, we assessed the 33 Part 3 item data (22 nontremor and 10 tremor items) of 336 patients with early PD from the STEADY‐PD III (Safety, Tolerability, and Efficacy Assessment of Isradipine for PD, placebo vs. isradipine) study. With multidimensional longitudinal IRT, we assessed the progression rates over time and treatment (in overall motor severity, nontremor, and tremor domains) using Markov Chain Monte Carlo implemented in Stan.ResultsRegardless of treatment, patients showed significant but different time‐based deterioration rates for total motor, nontremor, and tremor scores. Isradipine was associated with additional significant deterioration over placebo in total score and nontremor scores, but not in tremor score. Further highlighting the 2 separate latent domains, nontremor and tremor severity changes were positively but weakly correlated (correlation coefficient, 0.108).ConclusionsLongitudinal IRT analysis is a novel statistical method highly applicable to PD clinical trials. It addresses limitations of traditional linear regression approaches and previous IRT investigations that either applied cross‐sectional IRT models to longitudinal data or failed to estimate all parameters simultaneously. It is particularly useful because it can separate nontremor and tremor changes both over time and in response to treatment interventions.

Chapter 27 - The subthalamic nucleus and the placebo effect in Parkinson's disease

The study of the placebo effect, or response, is related to the investigation of the psychologic component of different therapeutic rituals. The high rate of placebo responses in Parkinson's disease clinical trials provided the impetus for investigating the underlying mechanisms. Ruling out spontaneous remission and regression to the mean through the appropriate experimental designs, genuine psychologic placebo effects have been identified, in which both patients' expectations of therapeutic benefit and learning processes are involved. Specifically, placebo effects are associated with dopamine release in the striatum and changes in neuronal activity in the subthalamic nucleus, substantia nigra pars reticulata, and motor thalamus in Parkinson's disease, as assessed through positron emission tomography and single-neuron recording during deep brain stimulation, respectively. Conversely, verbal suggestions of clinical worsening or drug dose reduction induce nocebo responses in Parkinson's disease, which have been detected at both behavioral and electrophysiologic level. Important implications and applications emerge from this new knowledge. These include better clinical trial designs, whereby patients' expectations should always be assessed, as well as better drug dosage in order to reduce drug intake.

Repurposing GLP-1 Receptor Agonists for Parkinson's Disease: Current Evidence and Future Opportunities.

The global burden of chronic disorders such as Parkinson's disease (PD) has rapidly increased over recent decades. Despite an increasing understanding of PD pathophysiology, there are no effective therapies capable of stopping or slowing the progression of this neurological condition. It has been suggested that type 2 diabetes mellitus (T2DM) may be a risk factor for PD and comorbid T2DM may worsen PD symptoms, as well as accelerate neurodegeneration. In fact, the similar pathological mechanisms shared by PD and T2DM have inspired several studies on the therapeutic potential of T2DM drugs against PD, among which glucagon-like peptide-1 receptor (GLP-1R) agonists are promising candidates. Here, we highlight the mechanisms linking T2DM and PD, as well as the links between insulin resistance (IR) and PD patients' risk of developing cognitive deficits. We also briefly review the effects of GLP-1R agonists on PD and discuss how the successful use of these substances in preclinical models of PD has paved the way for PD clinical trials. We further discuss how recent evidence on the beneficial effects of dulaglutide on cognitive function of T2DM patients may have important implications for PD drug repurposing.

A validated measure of rigidity in Parkinson's disease using alternating finger tapping on an engineered keyboard

IntroductionReliable and accurate measures of rigidity have remained elusive in remote assessments of Parkinson's disease (PD). This has severely limited the utility of telemedicine in the care and treatment of people with PD. It has also had a large negative impact on the scope of available outcomes, and on the costs, of multicenter clinical trials in PD. The goal of this study was to determine if quantitative measures from an engineered keyboard were sensitive and related to clinical measures of rigidity. MethodsSixteen participants with idiopathic PD, off antiparkinsonian medications, and eleven age-matched control participants performed a 30 second repetitive alternating finger tapping task on an engineered keyboard and were assessed with the Unified Parkinson's Disease Rating Scale – motor (UPDRS-III). ResultsThe speed of the key release was significantly slower in the PD compared to control cohorts (p < 0.0001). In the PD cohort key release speed correlated with the lateralized upper extremity UPDRS III rigidity score (r = - 0.58, p < 0.0001), but not with the lateralized upper extremity tremor score (r = - 0.14, p = 0.43). ConclusionsThis validated measure of rigidity complements our previous validation of temporal metrics of the repetitive alternating finger tapping task with the UPDRS III, bradykinesia and with the ability to quantify tremor, arrhythmicity and freezing episodes, and suggests that 30 seconds of alternating finger tapping on a portable engineered keyboard could transform the treatment of PD with telemedicine and the precision of multicenter clinical trials.

Race, language, and technology status: How to close the gap in Parkinson's Disease research participation

Objective: Minority patients are routinely under-represented in Parkinson's Disease (PD) clinical trials. In a 2008 review of PD trials, only 8% of subjects were non-white, compared to 20% of the non-white US population over age 601. As a compliment to the FIRE-UP PD study, the Boston University Patient Initiative aims to assess whether providing translated study documents reduces barriers to patient participation.