Dataset Information

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

ABSTRACT:

Background

Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants.

Methods

Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing.

Results

Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers.

Conclusions

The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Skrahina V

PROVIDER: S-EPMC8246975 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

Skrahina Volha V Gaber Hanaa H Vollstedt Eva-Juliane EJ Förster Toni M TM Usnich Tatiana T Curado Filipa F Brüggemann Norbert N Paul Jefri J Bogdanovic Xenia X Zülbahar Selen S Olmedillas Maria M Skobalj Snezana S Ameziane Najim N Bauer Peter P Csoti Ilona I Koleva-Alazeh Natalia N Grittner Ulrike U Westenberger Ana A Kasten Meike M Beetz Christian C Klein Christine C Rolfs Arndt A

Movement disorders : official journal of the Movement Disorder Society 20201214 4

<h4>Background</h4>Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants.<h4>Methods</h4>Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a report ...[more]

PMID: 33314351

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Project description: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.

Project description:Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data. Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.

Project description:Introduction: Parkinson's disease (PD) is one of the most frequent causes of disability among older people, characterized by motor disorders, rigidity, and balance problems. Recently, dance has started to be considered an effective exercise for people with PD. In particular, Irish dancing, along with tango and different forms of modern dance, may be a valid strategy to motivate people with PD to perform physical activity. The present protocol aims to implement and evaluate a rehabilitation program based on a new system called "SI-ROBOTICS," composed of multiple technological components, such as a social robotic platform embedded with an artificial vision setting, a dance-based game, environmental and wearable sensors, and an advanced AI reasoner module. Methods and Analysis: For this study, 20 patients with PD will be recruited. Sixteen therapy sessions of 50 min will be conducted (two training sessions per week, for 8 weeks), involving two patients at a time. Evaluation will be primarily focused on the acceptability of the SI-ROBOTICS system. Moreover, the analysis of the impact on the patients' functional status, gait, balance, fear of falling, cardio-respiratory performance, motor symptoms related to PD, and quality of life, will be considered as secondary outcomes. The trial will start in November 2021 and is expected to end by April 2022. Discussions: The study aims to propose and evaluate a new approach in PD rehabilitation, focused on the use of Irish dancing, together with a new technological system focused on helping the patient perform the dance steps and on collecting kinematic and performance parameters used both by the physiotherapist (for the evaluation and planning of the subsequent sessions) and by the system (to outline the levels of difficulty of the exercise). Ethics and Dissemination: The study was approved by the Ethics Committee of the IRCCS INRCA. It was recorded in ClinicalTrials.gov on the number NCT05005208. The study findings will be used for publication in peer-reviewed scientific journals and presentations in scientific meetings.

Dataset Information

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

Background

Methods

Results

Conclusions

Publications

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

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