Episode 54: Understanding Brain Imaging in Parkinson’s Disease

Dan Keller 0:08

Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

For the past two centuries, Parkinson's disease has been diagnosed and followed through its progression based largely on a person's symptoms, but symptoms can vary, and they're limited in predicting the course of the disease. Therefore, recent studies have turned to brain imaging using new technological tools, looking for ways to better assess the disease, predict its progression, and evaluate potential drugs to treat it or slow its progression. Dr. Jon Stoessl of the University of British Columbia in Canada uses Positron Emission Tomography to research chemical biomarkers in the brain, such as dopamine. For these purposes, he says, standard practice in neurology uses imaging such as Magnetic Resonance Imaging, or MRI, of brain structures to make a diagnosis, but PD requires additional imaging technologies, since MRI is not particularly helpful to make that diagnosis.

Dr. Jon Stoessl 1:47

But it may be very helpful to exclude other conditions that might sometimes masquerade as Parkinson's. Unfortunately, most of the imaging is not 100% reliable from that perspective, so a lot of our interest has been in research applications to better understand the progression of Parkinson's, to understand the complications of the disease and of its treatment, and really importantly these days, as a biomarker, to look at the effect of disease-modifying therapies. So I won't really talk too much about MRI from that perspective, although, as I already suggested, there has been a lot of development in the use of MRI as a biomarker, and so that's definitely an area worth watching.

Our own use of PET (Positron Emission Tomography) has been partly to understand disease complications and the complications of treatment; that's allowed us to look at things like the role of other neurotransmitters besides dopamine in the brain, or the pattern in which dopamine is released, because it's not just a question of too little, it's also how it's handled by the brain. And so that's led to some important insights. I think, as a fascinating sideline to that story, we were able to demonstrate that placebos given to people with Parkinson's probably have their impact by causing the release of dopamine, despite the fact that people with Parkinson's shouldn't have much dopamine to release in the brain. That's a side story, a particularly interesting one.

One can use the imaging to study the way the brain compensates for the deficits that happen in Parkinson's. So it's important to remember that Parkinson's doesn't just happen overnight. This is a process that evolves over many years, probably, and as a result, the brain will try to compensate for the loss of dopamine neurons. Some brains are probably better able than others to compensate, so we can study those changes in the brain. But I think at this stage, probably the biggest interest is as a biomarker, so to detect Parkinson's before it becomes clinically manifest, and then, as I said, to look at the effects of various interventions.

We're now at a stage where, more than any time before, I think there is realistic hope that we may have treatments that could slow the progression of Parkinson's. But in order to do that, we need several things, and one of them is early detection, because if you wait until people have advanced disease, the horses have fled the barn. We also need some kind of independent objective readout of the impact of the therapy, and molecular imaging does provide that with certain caveats.

But additionally, as people develop new treatments, they want to know whether those treatments are having the effect that they actually anticipated. So you can have a drug that you think has target X; it may work in a test tube, it may work in a mouse, but you don't actually know whether it's getting into the brain and doing what you hope it is in a human. So the imaging may allow a quick way to look at that before committing to a very large-scale clinical trial. So there are several ways in which we can do this. The traditional way is to look at dopamine function in the brain; both PET and Single-Photon Emission Computed Tomography (SPECT) will allow one to do that using a variety of different approaches. That is still extremely useful, but the downside is that it's not entirely reliable as a marker of disease progression, and indeed, a lot of the changes that occur in Parkinson's and that are responsible for much of the disability may be occurring in non-dopamine systems. So we need to move beyond that.

Dan Keller 6:16

Now, when we think of PET traditionally, the imagers use glucose that has a radioactive tag on it, and you can see what cells are metabolizing glucose—which ones are active metabolically. Are we talking about that looking at dopaminergic areas that way, or can you actually follow with PET dopamine itself?

Dr. Jon Stoessl 6:39

You can do both. So glucose was probably the original PET tracer some 40 years ago. And it's interesting you should ask that, because although we've traditionally thought that glucose use in the brain was occurring in the neurons themselves, at the synapse where one neuron communicates with the next neuron, in fact, there's recent evidence to suggest that the glucose use may actually be in the supporting cells of the brain, the astrocytes, although it still reflects the activity of the synapse.

So that doesn't give you a direct handle on dopamine, but it may still be very useful for diagnosis, because unlike dopamine imaging, glucose imaging may help differentiate between Parkinson's and the other Parkinson-like conditions. But if you want to look at dopamine itself, you can look at compounds that are actually taken up by the dopamine neuron, or you can study dopamine release in the brain using other molecules that have been tagged with radioactivity. So I still think this is an enormously useful approach, but we're now moving into other areas, either looking at other chemicals in the brain or trying to look at the underlying pathology.

One area of interest is inflammation in the brain. There are a variety of tags for imaging, particularly for PET, where one can hopefully look at inflammation in the brain. Turns out it's not that simple, unfortunately, and interpreting the results is even more challenging. The Holy Grail for the field is probably to be able to study the abnormal deposition of protein. Neurodegenerative diseases are all associated with abnormal deposition of abnormally folded protein. So in the case of Alzheimer's disease, it would be amyloid and probably tau. In the case of Parkinson's disease, it's alpha-synuclein. And up until now, we have not had good tools for studying alpha-synuclein deposition. That may be changing. There have been some recent developments in that area, and if that's borne out, and if it turns out to be an important marker of disease, then that could be a real game changer.

Neurons that produce dopamine project into various parts of the brain. Can you correlate, either in an individual or in a bunch of individuals, of population deficits that occur—neurologic deficits—with what you see on PET? That's a great question. And overall, there is a loose correlation. So if you look at the motor area of the striatum, where the dopamine projections are lost in Parkinson's, there is overall a correlation between the degree of dopamine deficit and the severity of the clinical findings. So that sounds good.

The more challenging side is that if you look within an individual over time or across a group of individuals over time, the amount of change in clinical function doesn't correlate all that well with the amount of change in the dopamine readout that you get by doing the imaging. And there have been a number of instances where you can show an improvement in the scan that does not correlate with clinical improvement. So, for instance, in transplant patients who had improvement in the appearance of the scan but their clinical function did not actually, unfortunately, improve. So this is still a bit of an unresolved issue.

Now, the other side of your question is: does dopamine have different functions in different parts of the brain? And yes. So I talked before about the placebo effect. We know that dopamine plays an extremely important role in signaling reward, or in particular, the anticipation of reward in the brain, and that's an area of the brain that's just millimeters away from the part that regulates motor function. And so you can indeed look at that. We think that's how the placebo effect is mediated, but also in people who have abnormal responses to medication, who may develop an impulse control disorder, there may be excessive responsiveness to certain types of stimulation. But importantly, these are tools that not only tell us about Parkinson's disease in illness, but tell us more about the normal function of the brain in health.

Dan Keller 11:40

When you do a scan, is there any potential benefit to the patient, or is this just research? At this point?

Dr. Jon Stoessl 11:48

I would say for most patients, the types of scans that we're doing are for overall benefit to the community and to learning more about Parkinson's. As you know, people with Parkinson's are highly motivated to improve the health of their confreres, and often do this purely for altruistic reasons, rather than for personal benefit. There are occasions when it may be useful to do this type of imaging for individual benefit, if you're having a lot of trouble with a diagnosis. So, for instance, the FDA has approved SPECT scan to differentiate between Parkinson's and essential tremor. So in some people, that may be a valuable application.

There are other times when it's hard to know exactly. For instance, some people may have a functional disorder where there isn't an organic disease, but it may appear that they have Parkinson's, so a scan may help resolve that issue. Or some people may be on medications that could produce the symptoms of Parkinson's. Of course, the logical thing to do is to try and withdraw those medications. That's either not always possible, or it may take a long time for the effects of the medications to wash out, and so a scan may be helpful in that instance.

Dan Keller 13:14

If someone wanted to participate in this kind of research, can you assure them that the amount of radiation is safe?

Dr. Jon Stoessl 13:21

It's a very small amount of radiation. We're talking about really close to the amount of background radiation that one would get in the environment. There are guidelines throughout the world, really; the US has a certain limit for what's deemed reasonable. That turns out to be considerably higher than what is typically permitted at my own institution or in Europe. Part of this has to do with some controversy over the relationship between radioactivity and risk.

The most likely relationship, in my view, is that you need to get up to a certain amount of radiation, which is a lot more than you would ever get exposed to in these types of tests, and then all hell breaks loose. But the more conservative approach, which some ethics boards choose to pursue, is that there's a linear relationship, so that if you get exposed to 100 units of radiation, and we know that's bad, that if you get exposed to one unit, it's 1/100 as bad. That seems scientifically unlikely to me, but it's something that's very difficult to prove.

Besides early work, preclinical work, animal work that might show you whether a drug that you're interested in or a chemical compound that might be a potential drug could work or not, does the knowledge you gain from doing your imaging show you where you should target drugs and what receptors—I mean what drugs to pick? I think that's always a bidirectional issue. It, in my view, should never be that you go from the test tube to the rat to the human in one direction. I think you kind of pose the questions in both directions, and as you learn something new by studying people who actually have the disease, that may give you new questions that are most easily dealt with by going back to an animal model or to the test tube. So you're constantly going back and forth. And I think many of the centers that do the best work work in that fashion, where you actually have clinicians, imagers, preclinical scientists, fundamental scientists, all working together, where they share the information as they acquire it.

Dan Keller 15:51

One of the catchwords over the last couple decades has been "bench to bedside"—bringing stuff from the lab to the bedside, with a lot of development in between. This sounds like "bedside to bench." Sort of completes the circle.

Dr. Jon Stoessl 16:05

I think it does need to work in a circle. You need bidirectional transfer of knowledge. It doesn't generally work all that well [one way].

Dan Keller 16:12

Right? That's more of "keep your fingers crossed." Have we missed anything important to add?

Dr. Jon Stoessl 16:17

Now, ironically, it's an area that was very exciting 30 to 40 years ago, then fell into perhaps less interest as other imaging modalities emerged, and now we may be seeing an upswing, because we have new tools where we can ask questions that we could not address with other modalities. And I think it's also true that we shouldn't be asking ourselves "either/or." We shouldn't be saying, "Is it MRI or is it PET?" We need to combine as many approaches as possible to try and understand what's going on in the brain.

In fact, I often get asked by people, "Well, what would be the one tool you would use if you want to assess the severity and progression of Parkinson's?" and my answer to that will always be: it isn't going to be one approach. I firmly believe that you require a panel of approaches. And we now also have emerging technology combining PET and MRI in a single scanner. And that will actually not only be of clinical utility, but I think will allow one to ask a lot of really interesting fundamental questions that could not have been addressed by doing one or the other, or even by trying to combine the two in separate scans.

Dan Keller 17:39

Very good. Thank you.

Dr. Jon Stoessl 17:40

Thank you very much.

Dan Keller 17:49

For more information on advances in imaging for PD and recent results, visit the Parkinson's Foundation blog, "What's Hot in PD" at parkinson.org/imaging-blog written by Michael Okun, National Medical Director of the Parkinson's Foundation. It's titled "The Importance of Imaging Biomarkers to Diagnose and Track Parkinson's Disease Progression." He reviews some interesting results on predicting disease progression using MRI, and also notes the potential for imaging to lead to more definitive and meaningful clinical trials.

Also on the blog, you can read about a study the Parkinson's Foundation funded studying fatigue through brain imaging at parkinson.org/fatigue-grant. As always, PD information specialists are available on our helpline. They can answer questions and provide information about this topic or anything else having to do with Parkinson's. You can reach them at 1-800-4PD-INFO if you have any questions about the topics discussed today. Or if you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback at the Parkinson's Foundation.

Our mission is to help every person diagnosed with Parkinson's live the best possible life. Today, to that end, we'll be bringing you a new episode in this podcast series every other week. Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO. That's 1-800-473-4636. Thank you for listening.

A. Jon Stoessl is Professor & Head of Neurology and Co-Director of the Djavad Mowafaghian Centre for Brain Health at UBC. He holds a Tier 1 Canada Research Chair in Parkinson’s, is Deputy Editor of Movement Disorders and sits on numerous other editorial boards including Lancet Neurology. He chairs the Scientific Advisory Board of the Parkinson’s Foundation and is President of the World Parkinson Coalition and a Member of the Order of Canada. Dr. Stoessl uses positron emission tomography to study Parkinson’s, including imaging biomarkers, the basis for complications of treatment and mechanisms of the placebo effect.