Searching for the “cholesterol” of Parkinson's disease (PD), the federal government is providing funding for a collaborative initiative to identify biomarkers to help diagnose the movement disorder earlier in the disease process and use the markers to monitor disease progression and test potential therapies.
The Parkinson's Disease Biomarkers Program has awarded grants to nine research teams that will work independently and collectively on developing biomarkers and assessment tools. [See “Research Teams: The Parkinson's Disease Biomarker Program.”] The National Institute of Neurological Disorders and Stroke is sponsoring the program.
It is too early to know whether any of the markers in development or markers yet to be identified would be able to routinely diagnose and monitor the disease across a large and clinically diverse patient population. The hope is to find biomarkers that, like cholesterol or high blood pressure, could flag a person at risk.
As part of the effort, scientists will be designing tools to gather and store the data, and collecting specimens from patients to identify and test markers specific to the disease. They will also look to the clinical exam to see whether they can develop biomarkers that could quantifiably measure changes in symptoms from one person to the next.
Katrina Gwinn, MD, a program director at the NINDS, said that the program does not compete with the biomarker initiative established several years ago by The Michael J. Fox Foundation. The Parkinson's Progression Markers Initiative (PPMI) is collecting biological samples and clinical data from 400 patients and 200 controls and placing the data in a repository. Scientists are then able to access the data to test potential biomarkers that would be useful in clinical trials.
Dr. Gwinn said that the NINDS effort is more about developing and testing new ideas for biomarkers. Sharing the data is critical as the growing resource will have enough power to make substantial claims about a specific biomarker.
While so much is known about the pathophysiology of the disease, the field has been struggling to find a single biomarker that could be used across the patient population to definitively diagnose the disease — 10 to 15 percent of patients are ultimately deemed to have another neurological disorder — and follow the progression of the disease. Also, Dr. Gwinn said that the lack of a biomarker could have led to the failure of a number of trials testing neuroprotective agents as it was difficult to measure effectiveness without the proverbial yardstick.
The seeds for this federal biomarker program were planted in 2010 when scores of researchers and clinicians were called to Bethesda to begin mapping out how such a program might work. Dr. Gwinn said that they borrowed methods from scientists studying Alzheimer's disease, traumatic brain injury, cancer, and autism, which are part of federal databases supported by the National Institutes of Health. The National Database for Autism Research, for example, had succeeded in collecting large amounts of data that was fed into a system of Global Unique Identifiers (GUID) and a data-sharing framework called Data Dictionary. This enabled scientists to grow and link data and mine the information for future discoveries.
The PD collaborative will use similar methods as they hunt for biomarkers, Dr. Gwinn added. The data collection and management from all studies generated by the funding will be standardized. This is no easy task. Administrators have to clean the combined data and ensure that the patients and controls can't be identified. They need to know how the data is handled at each site and how to verify the quality of the data.
There are many considerations in figuring out what a given biomarker can actually do. Is it something that can pick up the disease before the onset of motor symptoms? Can it catch a change at six months or two years? Will it be an office-based test? Will the biomarker track the progression of the disease?
The NIH Center for Information Technology built an online data-sharing platform for the biomarker initiative. The biological samples will be banked in the NINDS Human Genetics Repository at the Coriell Institute for Medical Research.
“By giving researchers access to data and resources, we hope to stimulate biomarker discovery efforts across the Parkinson's research community,” said Margaret Sutherland, PhD, a program director at NINDS. Dr. Sutherland and Dr. Gwinn are the lead scientific officers on several the Parkinson's Disease Biomarkers Program projects.
For more information about the Parkinson's Disease Biomarkers Program, visit http://pdbp.ninds.nih.gov.
RESEARCH TEAMS: THE PARKINSON'S DISEASE BIOMARKER PROGRAM
For the most part, the new grants went to people already searching for Parkinson's disease (PD) biomarkers, but a few of the recipients were new to the field and arrived to the table with technical tools used in other research fields:
- Vladislav Petyuk, PhD, of the Battelle Pacific Northwest Laboratories in Richland, WA, has been developing mass spectrometry to study proteins and said he was drawn into PD as an opportunity to use this tool to “non-invasively detect Lewy bodies during a person's life.” Such a tool could be a way to measure disease progression and would be useful to test the benefits of experimental treatments. They will also look for brain-specific proteins that are markers for Lewy bodies.
- The test would be the equivalent of detecting amyloid-beta in the brain or cerebrospinal fluid of Alzheimer's patients, Dr. Petyuk said, and his group, in collaboration with colleagues at Rush University, will obtain samples from the Religious Orders Study and Memory and Aging Project.
- F. Dubois Bowman, PhD, and his colleagues at Emory University in Atlanta are developing the statistical tools to analyze data accumulated from brain imaging, genetic, molecular and clinical tests. The tools will be utilized to see whether any of the information from these tests could be used as a biomarker to predict the course of PD.
- Alice Chen-Plotkin, MD, of the University of Pennsylvania, and her colleagues have been conducting genomic screens to identify genetic variations in patients with PD, and looking for specific changes in mRNA expression or micro-RNA expression. They found that epidermal growth factor levels in plasma predict cognitive decline in PD. They are now testing this potential biomarker in a larger number of patients. They are also confirming other candidate biomarkers, and drawing on new techniques to measure levels of more than 400 proteins in blood.
- At Johns Hopkins University, Ted Dawson, MD, PhD, and his colleagues are looking for biochemical changes in blood and cerebrospinal fluid that can be linked to some of the non-motor complaints like sleep and cognition. Their work studying molecular mechanisms in PD has turned up other leads in search of biomarkers, including changes in nitric oxide signaling and a pathway to programmed cell death linked to PD.
- Dwight German, PhD, and Richard Dewey, PhD, of the University of Texas Southwestern Medical Center at Dallas, are looking for changes in levels of antibodies and blood/CSF proteins as the disease progresses.
- Xuemei Huang, MD, PhD, of Pennsylvania State University, and her colleagues are using magnetic resonance imaging (MRI) to identify structural and chemical changes in the brain, including iron accumulation.
- Clemens Scherzer, MD, of Brigham and Women's Hospital, and colleagues at Harvard University are looking for changes in the activity of non-coding, “dark matter” genes at work in brain. They will work with PD experts at the Harvard NeuroDiscovery Center, which has already enrolled about 2,000 individuals. Dr. Scherzer has identified an intriguing transcriptional biomarker for Huntington's disease.
- Andrew West, PhD, of the University of Alabama at Birmingham, is using the new federal funding to continue studying the leucine-rich repeat kinase 2 (LRRK2) protein and other proteins in urine. They are able to measure microscopic structures called exosomes. Dr. West and his colleagues have identified several LRRK2 inhibitors that they are now testing as neuroprotectants against the disease.
- Jing Zhang, MD, PhD, of the University of Washington in Seattle, is focusing attention on markers in CSF and blood.