Biomarkers for Parkinson Disease

Bret S. Stetka, MD: Hello. I am Dr. Bret Stetka, Editorial Director of Medscape Neurology, and I am here today with Dr. Ken Marek. Dr. Marek is President and Senior Scientist at the Institute for Neurodegenerative Disorders, and he also leads the Parkinson's Progression Markers Initiative (PPMI) in collaboration with the Michael J. Fox Foundation for Parkinson's Research. Dr. Marek, welcome.

Kenneth Marek, MD: Thank you very much.

Dr. Stetka: I would like to talk to you today about the diagnosis of Parkinson disease. Although unfortunately, we have no cure yet, a lot of encouraging research is going on with respect to Parkinson diagnosis and monitoring disease progression, particularly with biomarkers and imaging. Can you review for us which biomarkers have been linked with the disease so far?

Dr. Marek: A wide array of biomarkers for Parkinson disease have been developed over the past decade. I can put them into 3 different categories.
The first category is clinical markers. These are clinical features that occur outside of the normal cardinal features of Parkinson disease -- so these are not motor abnormalities, but nonmotor abnormalities, such as loss of smell, autonomic dysfunction, depression, or change in cognition. Second, there are imaging biomarkers like MRI, but more productively, PET and SPECT imaging have provided us with tools that can identify the dopamine loss in Parkinson disease and track that loss.

Finally, there are biologic markers. These are markers in the blood and spinal fluid that may be particularly valuable in identifying early Parkinson disease and tracking the disease as well.

Dr. Stetka: Which of these biomarkers, if any, are being used in the clinic, or are most of them investigational at this point?

Dr. Marek: Many of the biomarkers for Parkinson disease are still investigational or even exploratory, but there are now markers that have made their way into the clinic. The most widely used is an imaging biomarker that is now available in the United States and Europe commercially called the DaTscan™ (GE Healthcare; Arlington Heights, Illinois). It targets the dopamine transporter protein, which is a protein on the dopamine nerve cell, and it has proven to be very useful in identifying early disease, and in a research setting in tracking disease.

It's important to emphasize that although these markers are available, they are not necessary for every patient, because most patients still can be identified clinically. But for those difficult cases, these biomarkers have now proven to be very useful as diagnostic tools.

Dr. Stetka: What about simpler biomarkers, such as olfactory dysfunction or sleep disorders? Are people screening for these in primary care yet, or are they still investigational?

Dr. Marek: An exciting aspect of Parkinson disease has been that the disease has broadened from a disorder of motor dysfunction and perhaps even beyond a disorder of central nervous system dysfunction to a more widespread disease of the nervous system. Such problems as olfactory dysfunction and autonomic dysfunction of cardiac or gastrointestinal neurons have begun to be useful predominantly as research tools, but hopefully soon will become more useful as clinical adjuncts to a diagnosis, and we will be able to identify individuals at risk for Parkinson disease at an earlier stage.

Newer Targets in Neuroimaging

Dr. Stetka: Let's move on to neuroimaging. I know that several groups, including your own, are researching various neuroimaging approaches in Parkinson disease. For example, some groups are trying to develop an alpha-synuclein tracer to localize Lewy body pathology. Can you review for us some of the more promising imaging studies that are under way?

Dr. Marek: Neuroimaging in Parkinson disease has had a fairly long history. In part, we have been very fortunate because the dopamine deficit in Parkinson disease has offered us a number of neuroimaging targets, and those targets are very useful, but as you suggest, newer targets are perhaps going to be even more useful. Such targets as alpha-synuclein and inflammatory changes that occur in Parkinson disease might be approaching the actual underlying pathology of the disease, so they are exciting tools that are just being developed. They are not here with us yet, but we would expect that they will be coming along over the next couple of years and will significantly change our ability to detect and monitor Parkinson disease.

Common Ground in Neurodegenerative Disease

Dr. Stetka: There is a good deal of overlap among Alzheimer disease, Parkinson disease, and dementia with Lewy bodies, in terms of pathology. Do you see a day when a patient with a suspected neurodegenerative disease undergoes a battery of these biomarker or imaging tests to evaluate his or her risk for a particular condition, and how far off might that day be?

Dr. Marek: It is very intriguing that many neurodegenerative diseases seem to have some commonality with respect to etiology, as well as many of the symptoms that are manifested, and it is very likely that some of the biomarkers we are identifying for Parkinson disease could be useful in other disorders, such as Alzheimer disease and Lewy body disease. The reverse is also true. Results of ongoing efforts in Alzheimer disease may inform our work in Parkinson disease. An example of that is the research focused on spinal fluid markers in Parkinson disease. In that study, we are using the identical markers that were used in studies of Alzheimer disease and Lewy body disease. Comparing biomarkers among these disorders can be very informative.

Dr. Stetka: The ultimate goal of many of these biomarker studies is to facilitate more effective, earlier treatment. Can you speak about the broader implications of these studies in terms of how they may one day affect the management of Parkinson disease?

Dr. Marek: The entire goal of this study is to help us to accelerate therapies. The general way in which we can do that is by simply having tools that can be used to objectively measure disease, but the more specific way is that many of these biomarkers will hopefully identify subsets of individuals who may be affected in different ways. For example, some individuals with Parkinson disease might have more of a synuclein problem, whereas others have more of a LRRK2 problem. Using these biomarkers to direct therapy will also be extremely valuable in making those therapeutic trials more likely to be effective.
Dr. Stetka: Are there any therapeutic avenues you find particularly promising at this point?
Dr. Marek: A number of therapeutic avenues are promising, and many of them focus on our recent understanding of the genetics of Parkinson disease. We now understand that there are different genetic mutations that contribute to risk in Parkinson disease, and these afford us an opportunity to develop targeted therapies. Therapies focused on alpha-synuclein or LRRK2 are the 2 most prominent genetically derived therapeutic targets, but there are other more general approaches, such as looking at growth factors, that also have merit in Parkinson disease.

Dr. Stetka: It is great to know that this research is ongoing. Do you have any final thoughts?

Dr. Marek: I would encourage readers to take a look at the PPMI Website. We want everyone to contribute and be involved in this program.

Dr. Stetka: Dr. Marek, thanks so much for coming today. I hope that you can come back and update us on all of this exciting Parkinson disease research.

Dr. Marek: I look forward to doing that. Thank you very much.