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Biomarkers and Parkinson’s Disease
By Stephanie Lessig, MD, Assistant Clinical Professor VAMC/UCSD Department of Neurosciences
A biomarker is defined as an “objectively measured indication of normal biologic process, pathogenic process, or drug response”. An example of a biomarker is following the hemoglobin A1C level to measure how well diabetes is controlled. In Parkinson’s Disease (PD), there are no biomarkers in use either to diagnose PD or to follow the disease over time. Currently, a diagnosis of PD is based on clinical features. This has been one of the difficulties in developing treatment, particularly to protect the brain.
Developing biomarkers is a leading area of research in PD at present. Some promising methods, and their current state of development, are described below.
On January 14, 2011, the FDA approved the use of DaT scans “for the detection of dopamine transporters (DaT) in the brains of adult patients with suspected Parkinsonian syndromes”. DaT (Dopamine transporters) scans use a radioactive dye (ioflupane, 123I) to detect the presence of dopamine transporters in the brain. Dopamine is the chemical in the brain known to be deficient in PD. In patients with PD, therefore, DaT are significantly reduced, causing a reduced signal in the brain compared to someone without PD.
Currently, DaT scans are not essential to diagnose PD, but can be used in cases where the diagnosis is questionable. The presence of DaT varies between individuals; therefore, what may appear as a reduction in DaT in one person may be normal for someone else. Research is ongoing regarding the usefulness of DaT scans in distinguishing PD from other parkinsonian syndromes (such as essential tremor or progressive supranuclear palsy), and in detecting progression of PD.
Cerebral spinal fluid (CSF) bathes the brain and spinal cord and can be sampled via a lumbar puncture (spinal tap). Because CSF flows around the brain it carries proteins made by the brain. Alpha-synuclein is one of these proteins; it is a normal protein, used and processed by the brain, and can be measured in the CSF of all people. In PD, alpha-synuclein is abnormally deposited in the brain. Abnormal aggregates (clumps) of alpha-synuclein lead to the pathology seen in the brains of PD patients. Because alpha-synuclein is deposited in the brain in PD, there is less in the CSF than in people without PD. Studies have found lower levels of CSF alpha-synuclein in PD compared to people without PD.
While the risk of developing PD in people who have a family member with PD is difficult to define, over a dozen genes have been identified that correlate with the development of PD. These discoveries have enabled scientists to further study PD at the cellular level, in attempts to determine mechanisms of disease. While there is no single gene that positively diagnoses or causes PD, new discoveries in gene linkage (finding genes and proteins linked to PD patients) is an ongoing area of research. In order to perform such linkage analysis, DNA from multiple patients with PD, with diverse ethnic and geographic backgrounds, is needed.
While each of these tests has been explored independently, it is not known which will be the most reliable and useful to help to diagnose or track progression in PD, or if a combination of tests will be needed. To this end, the Michael J. Fox Foundation has initiated an international study involving both PD patients and patients of similar age without PD, in order to distinguish which tests most reliably distinguish PD patients from non-PD patients, and to see how these tests change over time in PD and non-PD. This study is called the Parkinson’s Progression Markers Initiative (PPMI), and its primary objective is to identify biomarkers for PD (http://www.ppmi-info.org/). The goal is to study patients in the earliest stage of diagnosis of PD, who do not yet require medication for PD. This study will examine the markers mentioned above, and will collect information about sleep, smell abilities and cognitive function at baseline and repeated during 3 years of follow-up. Currently 17 sites across the US are conducting this study, including UCSD. If you are newly diagnosed with Parkinson’s and interested in becoming involved in an upcoming study, please contact Deborah Fontaine at (858) 622-5806.