The Parkinson's Disease Biomarker: A Critical Missing Link for Diagnosing PD and Tracking Disease Progression
What are biomarkers?
A biomarker is generally defined as a measure of a biological process or other feature that can be correlated with some aspect of normal body function, an underlying disease process, or a response to a treatment. For example, blood pressure can be objectively and easily measured and acts as a biomarker of both normal cardiovascular function, and (when high) of potential cardiovascular disease.
Parkinson’s is a complex disease with many potential underlying causes that may differ among individuals. For this reason, a biomarker (or set of biomarkers) for PD likely will require sophisticated methods of measurement. Researchers are working to identify several types of biomarkers:
- Disease trait biomarker: predicts the likelihood that a given individual will get PD and may be present even in the absence of actual disease (e.g., genetic predisposition).
- Disease state biomarker: a 'diagnostic' marker that a given individual has PD (particularly useful for distinguishing PD from other PD-like diseases or for identifying individuals in the earliest stages of the disease).
- Disease rate biomarker: a marker of disease progression over time (particularly important for developing treatments that can slow or stop a disease).
- Translational biomarkers: may predict whether an individual will respond to a particular treatment or not, or whether a drug is reaching and acting on its biological target. Biomarkers of this type are critical for drug development although not directly related to the disease process itself.
Why are biomarkers important?
The lack of clear and reliable biomarkers for Parkinson’s disease that can accurately identify individuals with PD, measure disease progression and monitor treatment effects is one of the greatest hurdles to developing new treatments — particularly those aimed at slowing, stopping or preventing the disease. Additionally, a biomarker that can identify people with or at risk for PD could make it possible to intervene with protective and preventative therapies (once these become available) before significant dopamine neuron loss has occurred.
Without a biomarker there is currently no way to make a definitive Parkinson’s diagnosis in a living patient. Physicians who suspect PD rely on measures including a tool called the United Parkinson’s Disease Rating Scale (UPDRS), a clinical test whose results may point to a PD diagnosis. The UPDRS, however, lacks the necessary sensitivity and objectivity to definitively establish the presence of Parkinson’s or to track disease progression.
The benefit of biomarkers is clear, and the need remains urgent to identify a marker or markers that could be used in clinical trials and ultimately ’be reliable enough for physicians to make informed decisions about appropriate care and/or preventive measures.
What stands in the way of development of biomarkers?
One of the greatest roadblocks to the identification and validation of a Parkinson’s biomarker is the critical need for longitudinal studies that can measure disease in well-characterized populations of individuals.
Longitudinal studies involve selecting a group of patients who exhibit specific traits of interest and then observing them at regular intervals over an extended period of time to measure changes in those traits and correlate these changes to the status of each patient’s health or disease. Such studies are large, expensive and difficult to fund. Additionally, standardized procedures for collecting biological samples and clinical measures must be established to allow the testing of biomarkers at multiple clinical sites and in studies involving large numbers of patients.’
What biomarkers are being developed for Parkinson's disease?
An ideal Parkinson’s biomarker would be a direct measure of dopamine cell loss in the brain, but we are currently unable to measure this non-invasively in humans. Research is ongoing to identify markers that accurately measures underlying disease process (or effect of treatment). Current chief avenues of pursuit include:
- Brain imaging markers (e.g., PET/SPECT, MRI, ultrasonography) use indirect measures of dopamine neuron function, but do not have sufficient resolution to measure cell numbers. Leading neuroimaging markers for PD involve measuring dopamine function in the brain including DATscan and other ways to measure dopamine activity. These dopamine-based markers may provide a way to monitor disease in its earliest stages. Additionally, MRI measures of the brain are also being developed as PD biomarkers.
- Markers taken from blood, urine, cerebral spinal fluid or tissue biopsies can be used to identify genetic, protein or other chemical and molecular ‘signatures’ of the disease. While these markers are not observed in the brain directly, they may provide a window to evaluate what is going on in the brain. Leading biological markers include measures of antioxidants such as urate or measures of proteins linked to PD through genetics such as alpha-synuclein and DJ-1.
- Clinical measures (e.g., tests of motor ability, presence of disease-associated symptoms such as olfactory deficits, sleep disorders, constipation or early speech problems) can be good markers, but it may be necessary to combine more than one for reliable results. These measures are also not necessarily Parkinson’s-specific but may provide a means for detecting early stages of PD or tracking disease progression.
Overall, it is likely that a combination of markers (clinical, imaging, and biologics) measured in the same individuals will be needed to develop useful biomarkers for PD. Currently, however, due to the lack of validated biological markers, most therapeutic clinical trials currently use some form of clinical measure (such as the UPDRS) to determine whether a treatment is working.
However, clinical measures may be subjective, may vary from day to day, and are very sensitive to symptom-masking effects of drugs, which can make it difficult to measure underlying disease-modifying effects sought in neuroprotective trials.
How is The Michael J Fox Foundation addressing the challenge of developing PD biomarkers?
The development of accurate biomarkers of PD progression is needed to accelerate the development of disease-modifying therapies – therapies that prevent, slow or reverse the progression of the disease. Because of this critical need, MJFF has worked with the scientific community to develop a large-scale, multi-site clinical study to test and verify promising biomarkers — The Parkinson’s Progression Markers Initiative (PPMI).
Sponsored by MJFF, is an ambitious $40 million, five-year project. PPMI will be carried out over five years at 19 clinical sites — 15 across the United States and four in Europe — in 400 de novo Parkinson’s patients (patients who are newly diagnosed and have not yet taken PD medication) and 200 healthy age-matched controls. It will be led by principal investigator Ken Marek, PhD, President and Senior Scientists at the Institute for Neurodegenerative Disorders in New Haven, Connecticut.
Enrollment is expected to begin at selected sites in spring 2010 and will continue for approximately two years. Participants will undergo four patient visits in their first year, with visits twice a year thereafter. Each visit will include different tests, assessments and biologics sampling, including motor, neuropsychiatric and cognitive assessments; DatSCAN, MRI imaging, DTI (diffusion tensor imaging, a specialized form of MRI), and blood, CSF, urine and DNA sampling.
In addition, verification studies will be conducted on promising lead biological markers such as alpha-synuclein levels. Biological samples will be banked for future studies. All data will be made widely available to the research community throughout the course of the study through a web portal.
MJFF is developing this project as a private-public partnership and hopes to recruit additional funders for the study in 2010.
What is The Michael J. Fox Foundation's view on biomarkers?
With investments of about $25 million to date, The Michael J. Fox Foundation is a field leader in the search for a PD biomarker. Our research has lead to the development of promising biomarkers but significant work is required through the PPMI to verify and further develop these leads into tools that can be used to inform clinical trials of novel therapies.
We believe the advent of a biomarker will be a critical stride toward better treatments and a cure. This advance will allow researchers to identify affected individuals early in the disease course and reliably track the disease as it progresses. Suitable markers will also improve clinical trials by allowing for tailored recruitment of well-defined patient groups, something not currently possible, which will reduce the variability and uncertainty inherent in current clinical trials.
For more information on Foundation investments in biomarker research, please search our Funded Studies Database.April 21, 2010
