Monday, October 3, 2022

Parkinson’s Progression Markers Initiative

Ppmi Study Goals And Objectives

Parkinsons PPMI Participants Share Their Experiences

The primary objective of this study is to identify clinical, imaging and biologic markers of PD progression for use in clinical trials of disease-modifying therapies. The specific aims to accomplish the primary objective are: Develop a comprehensive and uniformly acquired clinical and imaging dataset and biological samples that can be used to estimate the mean rates of change and the variability around the mean of clinical, imaging and biomic outcomes in early PD patients, prodromal PD subjects, and PD subjects with a LRKK2, GBA or SNCA mutation. Investigate existing and identify novel clinical, imaging, and biomic Parkinson disease progression markers to identify quantitative individual measures or combination of measures that demonstrate optimum interval change in PD patients in comparison to healthy controls, SWEDD subjects, Prodromal subjects, PD subjects with a LRRK2, GBA or SNCA mutation, unaffected LRRK2, GBA or SNCA mutation carriers, or in sub-sets of PD patients defined by baseline assessments, progression milestones and/or rate of clinical, imaging, genetic mutations, or biomic change. Conduct preliminary verification studies on promising biological markers using stored collected samples.

New Insights Into The Disease’s Progression

These modeling decisions have allowed us to gain more insights into disease states and progression pathways. The results suggest that a patients state can vary in several factors, including the ability to perform activities of daily living issues around slowness of movement, tremor and postural instability and non-motor symptoms such as depression, anxiety, cognitive impairment and sleep disorders.

We have found that the results support the hypothesis of diverse progression pathways, as indicated by the many disease trajectories weve observed. However, the AI model is still able to make accurate predictions. Having learned the model using one dataset, it was able to successfully predict an advanced state of Parkinsons disease associated with outcomes such as dementia and the inability to walk unassisted.

Because of the diversity of experiences in Parkinsons disease, we hope that by enabling such predictions, the model can help in patient management and provide more specific inclusion criteria and outcome definitions during clinical trial design.

There is still a lot of work to do, though. For example, we hope to refine the model to provide even more granular characterization of disease states by incorporating emerging biomarker assessments including genomic and neuroimaging measurements.

We are humbled to be a part of Michael J. Foxs vision for Parkinsons research and hope that together we will make a meaningful impact on the lives of patients around the world.

The Parkinson’s Progression Markers Initiative

Objective/Rationale:Currently there is no definitive diagnostic test for Parkinsons disease in a live patient, and no way to track disease progression on a biological level. These gaps have ramifications on personal disease management and on drug development. Findings from trials testing new PD therapeutics rely predominantly on outcomes measured through clinical observation, and there are limits on stratifying patients for trials. Reliable and well-validated biological markers of the disease would dramatically improve patient care and accelerate our understanding of PD, speeding therapeutic development.

During the past two decades much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Given the recent advances in the studies of molecular genetics, neurobiology, imaging technology and radiochemistry and the recognition that the lack of PD biomarkers has created a roadblock for further studies of disease-modifying therapies, there has been increasing consensus that a major initiative to develop PD progression biomarkers is both necessary and feasible.

In response, in 2010, The Michael J. Fox Foundation launched a longitudinal, multi-center clinical study the Parkinsons Progression Markers Initiative to collect clinical, imaging and biologic data to identify and validate biomarkers of Parkinsons disease progression.

Anticipated Outcome: PPMI seeks to achieve the following goals:

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Genetic Cohort: Parkinson’s Disease Subjects

  • Patients must have at least two of the following: resting tremor, bradykinesia, rigidity OR either asymmetric resting tremor or asymmetric bradykinesia
  • A diagnosis of Parkinson disease for 7 years or less at Screening
  • Hoehn and Yahr stage < 4 at Baseline
  • Male or female age 18 years or older
  • Willingness to undergo genetic testing and to be informed of genetic testing results Confirmation of mutation in LRRK2, GBA or SNCA
  • For subjects taking any drugs that might interfere with dopamine transporter SPECT imaging must be willing and able from a medical standpoint to hold the medication for at least 5 half-lives prior to screening DatSCANTM imaging
  • Ppmi: The Study That Could Change Everything

    Parkinsons Progression Markers

    The Parkinson’s Progression Markers Initiative is changing how patients, families, doctors and scientists think about brain disease. Now it needs you.

    The Michael J. Fox Foundation launched PPMI in 2010 to better understand Parkinson’s and advance new treatments. Since then, the study has changed how research is done and what scientists know about the brain. It is a cornerstone of our understanding of disease and has heavily influenced clinical trials.

    PPMI follows people with and without Parkinson’s over time to learn more about how disease starts and changes. That information may lead to insights and tools that can help better diagnose, treat and even prevent brain disease. The study sharesits data set themost robustin Parkinson’s research with scientists to speed breakthroughs.

    This landmark initiative is only possible through partnerships. Leaders across the field and nearly 40 funding partners have helped shape PPMI. Most importantly, more than 1,400 participants enrolled in PPMI over its first decade. Many of those people continue in the study.

    Today, with more therapies in testing, PPMI is expanding. The study has added an online platform to gather data from more than 100,000 people. It is following volunteers atmore sites in more countries. More data can help advance us closer to better treatments and prevention.

    Join the study that could change everything.

    Find answers to common questions here.

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    Key Deliverables And Results

    The impact of the PPMI study reaches across Parkinsons research:

    Analysis of the PPMI dataset and biosamples has led to seminal research findings driving study focus and design. For example, people with Parkinsons show significant, progressive loss of dopamine activity as measured by DaTscan in the first years after a diagnosis. And, predictive models and biological findings are helping to subtype the population.

    Cornerstone for Validation and Collaboration

    As PPMI makes its data available to the broad research community, many turn to this resource for discovery and validation of findings. PPMI data has been downloaded more than 2.8 million times.

    In addition, the rigorous, standardized data and biosample collection across study sites established by PPMI have been adopted by the broader Parkinsons field, enabling cross-study comparisons. The Accelerating Medicines Partnership Parkinsons disease program launched in 2018 by the National Institutes of Health with MJFF and five industry collaborators and managed by the Foundation for the NIH is exploring molecular fingerprints in biofluids from Parkinsons patients using samples collected through PPMI and other studies that modeled its methods.

    Model for Trial Design

    What Is The Parkinson’s Progression Markers Initiative

    The Parkinsons Progression Markers Initiative is a longitudinal research study aiming to identify biomarkers of Parkinsons disease and its progression. The study is led by the Michael J. Fox Foundation for Parkinsons Research, and Verily joined as a research partner in 2018. This is one of two longitudinal Parkinsons research programs that Verily is supporting. The other is the Personalized Parkinson’s Project.

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    Study Specific Data Contribution

    The following variables and associated data are specific to the PPMI study and are available for analysis as part of AMP PD. These variables have not been harmonized across cohorts, but are relevant to Parkinson’s Disease research:

    Assessment/Category
    DaTSCAN SPECT Visual Interpretation Assessment Report
    Summarized Imaging Data DTI DTI Measure

    Ibm And The Michael J Fox Foundation Use Ai To Help Predict Progression Of Parkinsons Disease

    The Parkinsons Journey – Understanding Progression

    New research published in Lancet Digital Health details a new AI model that groups typical symptom patterns of Parkinsons disease. The model also predicts the progression of these symptoms in timing and severity by learning from longitudinal patient data.

    Chances are, you know that Michael J. Foxthe actor who played Marty McFly in the iconic Back to the Future movieshas Parkinsons disease. But when he first disclosed his condition in 1998, the world gasped. He revealed that he had been diagnosed seven years earlier, at the age of 29. Just a few years later, in 2000, Fox launched The Michael J. Fox Foundation for Parkinsons Research to help search for treatments and a cure for this condition that affects an estimated more than six million people, globally.

    Since then, MJFFs team of in-house neuroscientists and business strategists have been working side-by-side with science and technology researchers, clinicians, industry partners and patients around the world to fund the most promising research to better understand and treat the disease. In July 2018, a unique partnership was launched between the Foundation and IBM Research to apply machine learning to advance scientific breakthroughs.

    Our aim is to use AI to help with patient management and clinical trial design. These goals are important because, despite Parkinsons prevalence, patients experience a unique variety of motor and non-motor symptoms.

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    Study Organization And Governance

    The PPMI steering committee is responsible for all aspects of study conduct and directs the study through the clinical, imaging, genetics, bioanalytic, biorepository, statistics, and bioinformatics cores. The steering committee includes PD clinical and biomarker experts, study core leaders, MJFF, and industry scientists.

    Mjff Funds 36 Studies Totaling $63m

    The large-scale expansion of PPMI promises to change our understanding of Parkinsons disease diagnosis and enable the development of new PD therapeutics,Ken Marek, MD, the principal investigator of PPMI, said in a press release.

    PPMI data will provide researchers globally the tools to uncover key biological and clinical changes that occur both once PD has begun and more importantly even before symptoms arise with the ultimate goal of disease prevention, Marek added.

    The original PPMI study was launched in 2010 by The Michael J. Fox Foundation for Parkinsons Research . The aim of this observational study is to better understand how Parkinsons develops and progresses by collecting data on people at every stage of disease, with healthy volunteers serving as a comparative control group.

    The expanded study is also sponsored by the MJFF, in collaboration with the Institute for Neurodegenerative Disorders, a nonprofit research center based in Connecticut.

    According to the foundation, PPMI has generated the most robust Parkinsons data set and biosample library in the world in its first decade. These data are freely available to researchers worldwide multiple safeguards are in place to remove any identifying information and ensure participants privacy. Up to date, PPMI has enrolled and followed more than 1,400 participants.

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    Michael J Fox Foundation Announces Major Expansion Of Parkinson’s Progression Markers Initiative Landmark Study Toward Better Treatments And Prevention Of Disease

    — $450-million study aims to triple enrollment at nearly 50 sites across 12 countries, plus recruit 100,000 participants online

    — Any U.S. resident over age 18 is needed — especially individuals over age 60 without Parkinson’s

    — Launched in 2010, PPMI has enrolled and followed more than 1,400 participants to date, creating an unparalleled open-access data set that is now a cornerstone of Parkinson’s research

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    How Are You Making It Happen

    Parkinson

    Weve built devices, algorithms and analytic outputs that capture relevant and reliable measurements from the human body to aid in the diagnosis and management of conditions like Parkinsons disease. Parkinsons disease looks different from person to person, and within the same person from hour to hour, so its important to develop reliable methods for capturing information continuously and over time.

    For the PPMI study, were using the investigational Verily Study Watch to collect new data types and identify digital biomarkers, which have the potential to enhance researchers abilities to better define diagnostic markers and Parkinsons disease progression. Ultimately, we hope to help researchers and therapeutic partners accelerate the development of treatments and support clinicians with better real-time disease monitoring to guide treatment and improve outcomes.

    Michael J. Fox and Todd Sherer, MJFF CEO with MJFF and Verily team members during a visit to Verily’s headquarters in 2017

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    Parkinsons Progression Markers Initiative Data Science Modeling Group

    Our Challenge

    Existing diagnoses for complex brain disorders such as Parkinsons disease focus on understanding clusters of major symptoms. In order to drive progress in the development of new treatments, it is important to understand the role of specific biological processes in the onset and progression of Parkinsons. While much progress has been made in identifying and assessing Parkinsons biomarkers during the past two decades, there remains no fully validated biomarkers of Parkinsons progression. Reliable and well-validated biomarkers that reflect underlying biological changes and predict disease progression would dramatically improve patient care and accelerate research into both Parkinsons biology and novel treatments.

    Our Goal

    To integrate and analyze clinical and biologic measures to track disease progression in early stage Parkinsons patients and genetic cohorts to support the development of new disease-modifying therapies for use in clinical trials.

    Our Solution
    Next Steps

    Financial Disclosures Of All Authors

    John Siebyl served as a consultant receiving consulting fees from GE Healthcare, Piramal Imaging, Roche, and Biogen. Dr. Siebyl has received research funding from MJFF.

    Andrew Singleton was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project ZO1 .

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    Parkinson Progression Marker Initiative New Science/new Cohorts

    K. Marek, A. Siderowf, T. Simuni, L. Chahine, K. Kieburtz, B. Mollenhauer, D. Galasko, K. Merchant, E. Brown, C. Coffey, R. Dobkin, T. Foroud, K. Poston, E. Flagg, S. Chowdhury, C. Tanner

    Category:Parkinsons Disease: Clinical Trials

    Objective: The Parkinson Progression Marker Initiative is expanding its cohorts and exploring additional biomarkers of PD progression to test hypotheses of the underlying molecular pathobiology of PD, enable modeling of PD progression to identify clinical and/or biologic data driven PD progression sub-sets, and to inform studies testing PD therapeutics.

    Background: The PPMI study was launched in 2010 and has made substantial progress to establish a robust clinical and biomarker data set and biosample repository that has contributed to the study design of numerous planned and ongoing clinical trials in PD. A major goal of the expanded PPMI is to identify biomarker signatures across the PD continuum from prodromal to moderate PD. The overall goal of PPMI is to identify markers of disease progression for use in clinical trials of therapies to reduce progression of PD disability.

    To cite this abstract in AMA style:

    Mov Disord.

    Parkinson’s Progression Markers Initiative Data Challenge

    Dr. Kenneth Marek on the Parkinson’s Disease Biomarker Initiative

    The Parkinson’s Progression Markers Initiative has generated a comprehensive, standardized, longitudinal set of clinical, biological and imaging data unique to the Parkinson’s disease field and ripe for novel and innovative exploration. Study sponsor The Michael J. Fox Foundation seeks to stimulate analysis of this robust dataset while offering an opportunity for cross-disciplinary collaboration.

    The PPMI Data challenge offers $50,000 in total prizes, awarding a $25,000 cash prize to each question.

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    Genotyping And Quality Control

    For the Immunochip there is existing data on 524 successfully genotyped PPMI subjects . For NeuroX there is existing data on 619 successfully genotyped subjects , and concordance between self-reported and genetically ascertained sex). This data is readily available for analyses by qualified researchers after a brief application process that can be found at . Once approved, any researcher with a valid login can activate the data access link below. The individual level genotype data for these arrays is available as plink binary files on the PPMI website .

    The genotypes of variants typed both on Immunochip and NeuroX arrays were compared and these showed an extremely high genotype concordance rate between the two platforms . The rs7412 variant of APOE was also genotyped on NeuroX and this genotype showed ~99.3% concordance with the custom TaqMan genotyping across 5 redundant probes. Rs429358 could not be assayed accurately using currently available array technology, but using a proxy we were able to achieve > 90% accuracy to tag the APOE epsilon-4 haplotype.

    Smart Deep Brain Stimulators

    Surgically implanted deep brain stimulators use electrical impulses to improve symptoms such as tremor and rigidity. But these stimulators cannot be directly monitored, so results are measured by the subjective reports of patients. In 2020, the Food and Drug Administration approved Medtronics new stimulator with BrainSense technology, which can sense and record the brains electrical signals. Its ADAPT-PD trial is now testing whether the BrainSense recordings can be used to adjust stimulation automatically.

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    Edmond J Safra Core Programs For Pd Research

    Twice a year, MJFF calls for applications to its funding programs, which are the vehicle for quickly directing donor-raised capital to the many promising research studies that need support.

    Get the latest news and updates from the Foundation directly to your inbox.

    The Michael J. Fox Foundation launched its $100-million flagship study, the Parkinson’s Progression Markers Initiative , in 2010. PPMI is now expanding to grow its base of 1,400 volunteers contributing data and samples over time to 4,000 participants at 50 global sites.

    PPMI aims to understand and measure the changes in Parkinson’s disease at its earliest stages even before motor symptoms appear and as the disease progresses. The goal is to develop better tests to facilitate earlier and more accurate diagnosis, and game-changing therapies that may help slow, stop or prevent the disease.

    PPMI makes de-identified data and biosamples available to the broad research community to speed breakthroughs. Data has been downloaded more than 6 million times, and the study has received more than 200 biosample requests. With the PPMI data, scientists already have identified predictors of certain symptoms and speed of progression and noted changes in brain scans that may help diagnose or track Parkinson’s. The study is also setting the standard for clinical trial procedures and is the basis for other large-scale collaborations designed to learn more about PD.

    Learn more and enroll today.

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