Building a Community-Academic Partnership to Improve Underrepresented Group Awareness of Parkinson’s Disease and Research

BACKGROUND: Members of underrepresented groups (URGs) are more likely to have delays in PD diagnosis and less likely to receive specialized care when compared to non-Hispanic Caucasians. URGs are not proportionately represented in PD clinical research. Barriers to optimal diagnosis and treatment and research participation are multifaceted but include insufficient community knowledge of PD and research. OBJECTIVES: To establish a community-academic partnership (CAP) for increasing knowledge of Parkinson’s Disease (PD) and research opportunities in underrepresented Chicago communities. Here, we describe the development, structure, and outcomes of this pilot program. METHODS: The Chicago Movement Coalition (CMC) was established with academic leaders from two Chicago institutions, community leaders, people with PD and care-partners from two URG-predominant communities. Two community focus groups identified community needs regarding PD and PD research, informing the development of an educational intervention. Educational workshops (EW) were developed and executed to increase knowledge of PD symptoms, treatment, available resources, and research opportunities. RESULTS: Qualitative analysis from two focus groups with 13 participants identified themes related to PD knowledge, perceptions of clinical research and the CMC, and EW ideas. Four community EWs were completed with 162 total participants. Of 97 completed pre- and post-workshops surveys, 98% were satisfied with the workshop and 94% felt more comfortable understanding PD signs, symptoms and treatments. CONCLUSIONS: The CMC is a novel CAP established to address inequities in PD. The coalition experience can be used to inform and structure future community-engaged education and research initiatives aiming to decrease PD clinical and research disparities

Digital mobility sub-study in the Parkinson's Progressive Marker Initiative (PPMI) study

This poster details the gait sub-study project in PPMI. The sub-study aims to test the feasibility and validity of digital mobility data for enrichment of the prodromal screening and to assess the sensitivity of these measures to early phase progression in prodromal and recently diagnosed patients with Parkinson’s disease. The poster details the protocol and the initial preliminary results of the first 21 participants. The post5er was presented in the Movement Disorders Society Conference held in Copenhagen, Denmark in Sept 2023

Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures.

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding

Identifying prodromal symptoms at high specificity for Parkinson’s disease

IntroductionTo test drugs with the potential to prevent the onset of Parkinson’s disease (PD), it is key to identify individuals in the general population at high risk of developing PD. This is often difficult because most of the clinical markers are non-specific, common in PD but also common in older adults (e.g., sleep problems).ObjectiveWe aimed to identify the clinical markers at high specificity for developing PD by comparing individuals with PD or prodromal PD to healthy controls.MethodsWe investigated motor and non-motor symptoms (Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 1 and 2 items) in 64 prodromal PD and 422 PD individuals calculating the odds ratios, adjusting for age and gender, for PD and prodromal PD versus 195 healthy controls. Symptoms at high specificity were defined as having an adjusted odds ratio ≥ 6.ResultsConstipation had an adjusted odds ratio, 6.14 [95% CI: 2.94–12.80] showing high specificity for prodromal PD, and speech difficulties had an adjusted odds ratio, 9.61 [95% CI: 7.88–48.81] showing high specificity for PD. The proportion of participants showing these specific markers was moderate (e.g., prevalence of constipation was 43.75% in prodromal PD, and speech difficulties was 33.89% in PD), suggesting these symptoms may make robust predictors of prodromal PD and PD, respectively.DiscussionClinical markers at high specificity for developing PD could be used as tools in the screening of general populations to identify individuals at higher risk of developing PD

The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort.

ObjectiveThe Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.MethodsA total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.ResultsApproximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P < 0.01).InterpretationPPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial

BACKGROUND: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor. OBJECTIVE: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD). METHODS: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. RESULTS: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants. CONCLUSION: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF

Genetic Testing in Parkinson's Disease

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines.</p

Technology in Parkinson's disease:challenges and opportunities

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder