Parkinson’s Disease Biomarker Program Recruits 1,000th Subject Reply

Posted by Story Landis

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Last month the 1,000th subject was enrolled in the Parkinson’s Disease Biomarkers Program (PDBP), marking a major milestone in the efforts of NINDS to develop a method to predict the early onset—and track the progression—of this debilitating neurological disorder.

We have made considerable progress in developing treatments, but people with Parkinson’s still suffer. While current treatments are most effective at alleviating early symptoms of the disease, symptoms in later stages are less responsive, and no intervention has been found to slow disease progression or prevent it. Like many neurological diseases, the search for better Parkinson’s treatments has been hindered by the fact that symptoms—including uncontrollable shaking, rigidity, and impaired balance—only start appearing well after the disease has begun to cause significant changes in the brain.

This photomicrograph of the substantia nigra reveals a rust-colored Lewy body, an abnormal aggregate of protein that develops inside neurons in Parkinson’s disease. Credit: Wikicommons, Suraj Rajan

Currently, we cannot identify the biological signature of the disease—the accumulation of aggregates of a protein called synuclein (so-called Lewy bodies) inside neurons and the loss of neurons in specific regions of the brainstem—in living people. Finding biological signatures in blood or other body tissues or fluids that can be detected in patients would allow us to track the progression of disease, and, importantly, give us a way to quantify the effectiveness of potential therapies over the course of treatment. Ideally a biomarker would enable screening for the presymptomatic stage of the disease, and subsequent testing of therapies that delay or prevent disability from ever occurring. Such signatures, or biomarkers, may take the form of proteins or other molecules created by the body; a good example is cholesterol, which is often used as a biomarker linked to heart disease, or high blood levels of glucose, which serves as a biomarker for diabetes. The exciting advances in PET scan tracers to label protein aggregates in the brain of living persons with Alzheimer’s disease may also blaze a path toward similarly useful tracers to label aggregates of synuclein in persons with Parkinson’s disease.

Since symptoms get worse over time, developing biomarkers for Parkinson’s could lead to earlier diagnosis and help spur the development of treatments to slow progression of the effects of Parkinson’s. The ultimate hope is that by combining biomarker signatures with drug discovery efforts, the Parkinson’s research community will uncover a cure for the more than one million people in the United States afflicted with the disease. So far, several candidate biomarkers for Parkinson’s have been proposed, but to date none has been proven to predict disease onset or progression reliably.

Dr. Paul Zimmet discusses his experience as a patient in the NINDS Parkinson's Disease Biomarkers Program.

Launched in January 2013, the NINDS Parkinson’s Disease Biomarkers Program (PDBP) aims to accelerate the search for biomarkers through eleven research projects. Seven of the research sites also collect clinical samples using a standardized methodology for the collection of blood, DNA, and cerebral spinal fluid (CSF). These biological samples are stored at the NINDS Repository; scans of subjects’ brains taken with PET and MRI imaging, and clinical information such as medications and neurological exam results, are also collected and shared online among PDBP researchers via a web-based bioinformatics tool called the Data Management Resource (DMR). This state-of-the-art tool received the 2014 Best Overall Excellence.Gov Award in recognition of the best government information technology system.

The PDBP DMR accelerates the search for biomarkers by streamlining the sharing of the collected patient data with the entire community of Parkinson’s disease researchers, even those who are not part of the program. In addition, researchers can use the DMR tool to request that biological samples be shipped from the NINDS Repository to their labs for further study. We anticipate that this resource will become a launching pad for a variety of additional projects exploring multiple approaches to developing treatments for neurological diseases. As such, we strongly encourage any and all researchers working on Parkinson’s to utilize this incredible resource.

The eleven PDBP research groups (see bottom of post for brief project descriptions) are using the program’s aggregated data to test existing candidate biomarkers, discover new candidate biomarkers, and develop tools to streamline the collection and analysis of samples collected from patients. Additional research groups will join the program in the coming year.

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Click this image to see an infographic describing the Parkinson’s Disease Biomarkers Program.

In just over 18 months, the program has recruited more than 1,000 subjects (see infographic), around 600 with a diagnosis of Parkinson’s and 400 age-matched controls. To date, approximately 1,500 biological samples and 380 MRIs have been collected. By the end of the five-year program 1,500 subjects—900 with Parkinson’s and 600 controls—are expected to be enrolled, with each individual contributing clinical data and biological samples at least twice a year. Given that these numbers are well ahead of schedule, this project has so far been a remarkable accomplishment. The real measure of success for the program, however, will be how many researchers make use of this wonderful resource and what advances emerge from their studies.

This NINDS biomarker project complements previously established efforts supported by the Michael J. Fox Foundation (MJFF), which is sponsoring two biomarker projects of its own. The MJFF Parkinson’s Progression Marker Initiative (PPMI) has enrolled 800 individuals since it began in 2010, while the Fox Investigation For New Discovery of Biomarkers (BioFIND) launched in 2012 with the goal of collecting biological samples from 120 Parkinson’s patients and 120 age-matched controls. Working together, NINDS and MJFF have assembled powerful teams of patients, investigators and resources to attack this scientific problem.

I very much appreciate the contribution of each and every individual who has participated, and continues to participate, in the biomarker program. The time and energy these folks have devoted are critical to the program’s success. Take, for example, Dr. Paul Zimmet, the first subject enrolled in the study. Paul was a dentist with his own practice when he was diagnosed with Parkinson’s seven years ago. Soon after his diagnosis, Paul enrolled in his first Parkinson’s study and has to date been part of a dozen different studies to help researchers improve diagnosis and find better treatments. Please watch the video above to learn more about the biomarker program and hear more about why Paul enrolled and his experience in the study.

For more information about the program, please visit:

NINDS website about Parkinson’s disease

NINDS Parkinson’s Disease Biomarkers Program

NINDS Parkinson’s Disease Biomarkers Program Recruitment Brochure (PDF)

NINDS Parkinson’s Disease Biomarkers Program Infographic (PDF)

Video of a subject describing his experience in Parkinson’s Disease Biomarkers Program

 

Brief Description of PDBP projects:

Roy Alcalay, Ph.D., Columbia University, New York
Given the variability in symptoms and prognoses across Parkinson’s patients, many researchers theorize that there are several subtypes of the disease. Dr. Alcalay’s group is searching for genetic markers that can identify individuals with various subtypes.

F. Dubois Bowman, Ph.D., Columbia University, New York
This group is developing statistical tools to analyze data from brain imaging, genetic, molecular and clinical tests, in order to discover biomarkers which, in combination, can better predict the course of Parkinson’s disease than a single biomarker might be able to do.

Alice Chen-Plotkin, M.D., University of Pennsylvania, Philadelphia
This team seeks to confirm several candidate biomarkers they have identified, and search for others by using a novel, broad-ranging approach to measure the levels of more than 400 proteins in blood.

Ted Dawson, M.D., Ph.D., Johns Hopkins University, Baltimore
This team seeks to gain a clearer picture of the early clinical features of Parkinson’s – including changes in cognition and sleep – and to correlate those changes with potential biomarkers in blood and CSF.

Dwight German, Ph.D., and Richard Dewey, Ph.D., University of Texas Southwestern Medical Center at Dallas
Based on evidence that immune responses play a role in Parkinson’s, the researchers will investigate whether disease progression is related to changing levels of antibodies and other proteins in blood and CSF.

Xuemei Huang, M.D., Ph.D., Pennsylvania State University, University Park
This team will seek to determine whether state-of-the-art magnetic resonance imaging (MRI) scans can reveal subtle structural and chemical changes in the brain, including iron accumulation, during Parkinson’s.

Vladislav Petyuk, Ph.D., Battelle Pacific Northwest Laboratories, Richland,Washington
This group will seek to identify new components of the Lewy bodies that accumulate in the brain during Parkinson’s, and then use ultra-sensitive methods to see if any of these proteins have leaked into CSF or blood.

Clemens Scherzer, M.D., Brigham and Women’s Hospital, and Harvard University, Boston
This team will investigate whether Parkinson’s is associated with changes in the activity of non-coding, “dark matter” genes (which do not make proteins) in brain tissue, blood and CSF. The team also will integrate the PDBP with a Parkinson’s biomarkers study at the Harvard Neurodiscovery Center, which has already enrolled about 2,000 individuals.

Andrew West, Ph.D., University of Alabama at Birmingham
This team discovered that the Parkinson’s-related protein LRRK2 and many other proteins can be detected in urine, within microscopic structures called exosomes; they will investigate whether exosome-related proteins can serve as biomarkers.

David Vaillancourt, Ph.D., University of Florida, Gainsville
Dr. Vaillancourt and his team are using non-invasive imaging techniques that enable them to take snapshots of an individual’s brain at different stages of disease. These snapshots not only enable them to look at changes in the appearance of the brain, but also in how the brain is functioning and interacting with its various anatomical regions associated with movement and cognition.

Jing Zhang, M.D., Ph.D., University of Washington, Seattle
CSF appears to contain potential biomarkers, but blood is easier to obtain. Therefore, this group’s strategy is to conduct an expanded search for biomarkers in CSF and then search again for the strongest candidates in blood.

 

NINDS Launches New Translational Funding Programs Reply

Posted by Rajesh Ranganathan and Story Landis

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New treatments for the hundreds of disorders that affect the brain are too few and far between. One reason for this lack of treatments is that we do not yet understand how the brain and nervous system work at a fundamental level (see our recent blog post about the need to support basic science). In addition, when potential treatments for nervous system disorders are discovered in the laboratory, researchers in academia often lack the expertise and access to critical infrastructure required to develop a new drug, biologic agent, or device to the point where the biotech/pharma industry will pursue it further. Compounding the problem, and reflected in statistics for pharmaceutical development, is that treatments for brain disorders have particularly long clinical development and approval times (8.8 years) and a low clinical approval success rate (~8%). With such deep risks in terms of time and money, pharma has dialed back early-stage investments in drug development for neurological diseases, despite the large number of people affected who urgently need new and better treatments. Taken together, these factors mean that the clinical application of many promising potential therapies is never fully explored.

bp_neurotherapeutics_logo_smNINDS has supported researchers through the discovery and preclinical phases of therapeutic development with several research funding mechanisms, including those developed by the Institute’s Office of Translational Research (OTR). Recognizing the need to play a bigger role in bridging the gap between the discovery of a potential therapy and its development and clinical testing, NINDS staff thoroughly assessed the strengths and weaknesses of our existing programs. Based on that assessment and in consultation with the community, NINDS has just launched three carefully crafted funding programs, each tailored to specific treatment modalities—the Blueprint Neurotherapeutics Network for small molecules, CREATE (Cooperative Research to Enable and Advance Translational Enterprises) Bio, and CREATE Devices. These new milestone-driven programs offer support for preclinical development and potentially small clinical trials and allow researchers in academia and small companies the opportunity to play a more active part in translating their basic neuroscience discoveries into treatments. We hope novel therapies advanced through these programs will become attractive enough to hand off to biotech/pharma companies, which can then lead later-stage development and testing and ultimately produce treatments approved for use in humans. More…

Back to Basics: A call for fundamental neuroscience research 10

Posted by Story Landis

NINDS supports a broad range of research projects, from basic studies of the nervous system to large Phase III clinical trials. Several years ago, we embarked on an institute-wide planning process to analyze and optimize our investments in basic, translational, and clinical research. Triggered by the observation that between 2003 and 2008, NINDS funding for R01s decreased by 10%, we extended our analyses to determine how our extramural funds are distributed across the spectrum of basic and applied research, and whether that distribution has changed over time.

To perform the analysis, we developed simple definitions of basic and applied research (listed at the end of this post) that could be applied as unambiguously and reproducibly as possible. We also divided each of these broad categories into two subcategories—basic/basic, basic/disease-focused, applied/translational, and applied/clinical. Expert neuroscientists, including program directors, scientific review officers, and other members of our staff then assigned funded projects to these subcategories based on careful reading of abstracts, specific aims, and, when necessary, additional sections of the grant application. Because a single application often proposed research in more than one subcategory, we assigned percentages of a grant to each subcategory as appropriate; for example, a grant could be described as 75% basic/basic and 25% basic/disease-focused.

Our analysis covered the period between 1997 and 2012 to ensure that any trends we observed did not reflect a short-term response to a particularly good or bad funding year. This analysis included most of the new and competing continuation grants issued each year. The specific funding mechanisms that we included are described below. Since this was an extremely labor-intensive task (and our staff have day jobs!), we selected eight years within this period for review.

Our first finding was that between 1997 and 2012, NINDS expenditures on applied research as a fraction of total competing research budget increased from 13% to 29% while the proportion of basic research declined from 87% to 71% (Figure 1). Continue reading…