Hot Topic: Prodromal Parkinson's disease

Dr. Eva Schäffer: Hello. Thank you very much for inviting me

Dr. Eduardo de Pablo Fernandez: Excellent. So let's just start from the beginning. We sometimes-- we know that there are different stages and different phases in Parkinson's disease, but sometimes the labels and the names can be a bit confusing. So what is prodromal Parkinson's disease?

Dr. Eva Schäffer: At the moment when we diagnose [00:01:00] Parkinson's disease according to the typical motor symptoms we see, bradykinesia, rigidity, or resting tremor, we are actually quite late in the course of the disease because we know that years before we see the manifest motor symptoms, we have a phase of ongoing neurodegeneration where alpha-synucleinopathy, which is a pathological hallmark of Parkinson's disease, is spreading throughout the central and also peripheral nervous system in Parkinson's disease.

And in early years before the typical manifest motor symptoms can be diagnosed and can be seen, there might be some early symptoms which show early ongoing neurodegeneration. And these early prodromal symptoms can, for example, be isolated REM sleep behavior disorder or hyposmia. And the phase where we have ongoing neurodegeneration, where we have these early symptoms that can be non-motor symptoms or very [00:02:00] small or non-mot- symptoms, is called the prodromal phase of the disease.

Dr. Eduardo de Pablo Fernandez: So you made an interesting point there. We have this conception in the past that the prodromal phase of Parkinson's disease was mainly related to non-motor symptoms. But obviously, before we can reach the diagnosis and the motor abnormalities present with a full picture of parkinsonism there may be some subtle clinical features and also some subtle abnormalities that we can now detect with electronic devices or further methods.

So I think it's important to emphasize that also the motor abnormalities and motor symptoms are part of the prodromal phase. Okay how can we identify prodromal Parkinson's disease both in, in clinical practice and in clinical research?

Dr. Eva Schäffer: Yeah. It's still not that easy. So first of all, we have to say that we have prodromal Parkinson's disease criteria published by the Movement Disorder Society, but they are a research criteria, so they are not [00:03:00] intended to be used in the clinics, which is very important. So we should be very careful if we try to diagnose in clinical practice prodromal Parkinson's disease and be also very careful how we tell this to our patients.

So first of all, we have clinical symptoms that may be a sign of prodromal Parkinson's disease. The most important and most specific prodromal symptoms is still isolated REM sleep behavior disorder. If you have the sleep disorder, you have a very high probability of getting Parkinson's disease or MSA, dementia with Lewy bodies.

And then we have more unspecific prodromal symptoms. And specifically, if we only make clinical assessments, we have to be very careful because hyposmia, depression, constipation are quite unspecific prodromal symptoms. So for clinical practice, isolated REM sleep behavior disorder is the most important prodromal marker, and we hope, of course, in the future that we can combine it with a biomarker so that we can actually [00:04:00] diagnose prodromal PD better. 

Dr. Eduardo de Pablo Fernandez: Excellent. So you mentioned some of the more specific clinical presentations, but still there is some overlap, and this can be the prodromal presentations of other synucleinopathies, most commonly multiple system atrophy. So I guess that is still very challenging in the prodromal phase or more even than in the clinical phase.

As you mentioned, some of the diagnostic tests, and obviously this is a, a rapidly evolving field, but some of the i-investigations have been incorporated into the prodromal diagnostic criteria that you mentioned. But there has been new developments, particularly with the synuclein seeding assay.

How do you think this new investigations will help with the early identification of prodromal Parkinson's disease?

Dr. Eva Schäffer: I personally think this will help a lot. We also see a very high sensitivity and specificity for alpha-synuclein seeding assay, specifically at the moment for CSF and for skin biopsies. [00:05:00] However, we are al- we also getting increasing knowledge. There are uh, a lot of recent publications showing that a positive alpha-synuclein test could also be in other diseases.

We see it in some cases of Alzheimer's disease or other neurodegenerative diseases. So in the future, I personally think it has to be a combination of clinical presentation and a biomarker. But then these biomarkers will help us a lot to definitely diagnose prodromal Parkinson's disease, because at the moment, we have not only the issue that we not only have the problem that the clinical symptoms alone are hard to interpret, but additionally, if we see, for example, isolated REM sleep behavior disorder, we do not know yet when an individual will get Parkinson's disease.

So the time to conversion is also an issue, and we hope that if we combine biomarkers and clinical symptoms, maybe we can also close that gap of knowledge.

Dr. Eduardo de Pablo Fernandez: So that you mentioned that a couple of [00:06:00] points as well that obviously these investigations come with challenges and we will discuss a bit more of that a bit later today. But one point that I wanted to discuss with you is how do we approach the diagnosis of prodromal Parkinson's disease?

How do we discuss the risk of a conversion to manifest Parkinson's disease?

Dr. Eva Schäffer: So the most important aspect is actually an ethical aspect, because at the moment, if we diagnose prodromal Parkinson's disease, this does not translate into a pharmacological disease-modifying treatment, meaning you diagnose something with an ongoing neurodegenerative disease that will happen sometime in the future, but you cannot offer any pharmacological treatment.

So the most important thing for clinical practice is that you try to find out if your patient actually wants to know that he has a high risk of developing Parkinson's disease. This would be the very first step. And there are, of course, [00:07:00] very different patients. Some have already read all about it in the Internet, and they want to know everything about their REM sleep behavior disorder if they get Parkinson's disease or not.

But we also have a lot of patients that say, "I do not want to know anything." So this is the first important step you have to approach. And then if you have individuals where you suspect REM sleep behavior disorder, you would have to diagnose it with polysonography, so to have a clearly confirmed REM sleep behavior disorder.

And then it's very different in different countries because you can add additional diagnostics, but it's not clarified in international criteria yet. You can, for example, if you have an individual that really wants to know very much in detail his risk of developing Parkinson's disease, you can, for example, add in DaTscan, which will increase the probability a little bit more.

And we have some data showing that if you have a positive DaTscan, the time to conversion is a little bit closer. You can also add in some countries the-- an [00:08:00] alpha-synuclein seeding test, but again, it's not in daily clinical practice yet. So at the moment if you have a patient with isolated REM sleep behavior disorder, the clinical diagnosis and follow-up of REM sleep behavior disorder is the most important part you can do, and then try to find out if he wants to know an increased risk.

We are not there yet, I think, to definitely diagnose an individual in the prodromal phase in daily clinical practice

Dr. Eduardo de Pablo Fernandez: That's something to highlight. One thing that you mention as well is that we can estimate the risk of prodromal Parkinson's disease, but we are not still very good at determining the timing on the progression of the disease. How do you approach that when discussing the risk disclosure with people with prodromal Parkinson's disease?

The uncertainty as, as some of these people probably will never develop very disabling symptoms or requiring any symptomatic treatment with [00:09:00] dopaminergic drugs. So how do you approach this with the patients?

Dr. Eva Schäffer: So there are a few steps you can go with the patients. The first step I already mentioned is ask what they want to know and the depth of knowledge they want to know. And if they want to know that they have an upcoming risk, you have to clearly state that at the moment we do not know when their time, their personal time to convert would be, but that you can offer to follow up then.

This would be the ideal that you offer regular follow-ups. But I would openly discuss with them that at the moment we do not know yet when they will convert, probably in the future. And what is most important thing you should do if you diagnose someone in the prodromal phase, or tell them that they have a high probability or high risk of being in the prodromal phase, then you should automatically tell them that they actually can do something for themselves and then we move on to the topic of lifestyle.

Because we actually have a disease-modifying treatment and this is our lifestyle, moderate intensity exercise, enough [00:10:00] sleep, mediterranean diet. And if you try to diagnose someone in the prodromal phase, this is, to my opinion, an absolutely must that you tell them that they can actually do something for themselves.

Dr. Eduardo de Pablo Fernandez: That's a very important point and one of the critics that some argue is that what is the point of making a diagnosis when you cannot offer any pharmacological options? But there is still a lot of lifestyle changes and non-pharmacological treatments that we can we can offer. I don't know if you could expand a bit on that?

Dr. Eva Schäffer: Yeah, sure. So there are pros and cons for diagnosing or trying to diagnose someone in the prodromal phase. And one of the most important pros is that you can tell them you can change your lifestyle and maybe then you can slow down your disease in the prodromal phase. And the most important aspects we know from many studies are moderate intensity exercise, whatever you like to do.

The Mediterranean diet has the best data for being neuroprotective and reducing [00:11:00] neuroinflammation, oxidative stress, all kind of pathological mechanisms that are important for Parkinson's disease. Enough sleep is very important. Cognitive training, stress management, these are very important lifestyle options that actually have the ability to slow down the disease in the prodromal phase.

So this is the most important thing you can tell them. There are other pros. An additional pro is, for example, that you can actually take care of symptomatic treatment. We have a lot of individuals with REM sleep behavior disorder that suffer a lot from the sleep disorder, so you can treat that. You can treat constipation, orthostatic hypotension, depression.

So many of them actually have a high disease burden, although they are only in the prodromal phase, but they have a non-motor symptom burden, so you can treat that. And of course, another pro is that if they convert to Parkinson's disease, you can diagnose it very fast and then treat them fast and well, so this is also a [00:12:00] pro.

Dr. Eduardo de Pablo Fernandez: Sort of disease-modifying, non-pharmacological treatments can be offered, a timely management of the symptoms related to that prodromal stage. And I would like also to discuss a bit the importance of people with prodromal Parkinson's disease taking part in research.

Obviously this offers a great window op- of opportunity for the development of biomarkers at earlier stages and also clinical trials for early interventions. I think probably as the last question you mentioned that we are getting better at getting the identification and understanding the risk of Parkinson's disease in, these patients.

I don't know whether you-- I would like to get your thoughts in how things will be moving in this field in the near future, if you have anything to add?

Dr. Eva Schäffer: I mean, our main goal is that we identify individuals in the prodromal phase and then can offer them pharmacological disease-modifying treatment. And at the same time, we do not find a disease-modifying pharmacological treatment because we test [00:13:00] all our pharmacological options in the clinical phase, and it might be too late to actually have significant effects.

So I think we are very close to diagnosing individuals in the prodromal phase and the combination of clinical and biomarkers, and that we are very close to include these individuals in disease-modifying pharmacological studies. We already have ongoing non-pharmacological interventional trials which is really great.

Cognitive training in Germany, we have multi-domain lifestyle intervention for prodromal individuals, so we already have that. And I think it will start very soon that we also use pharmacological studies, and this is the next step that is very close.

Dr. Eduardo de Pablo Fernandez: I think it's very promising to hear that there are more and more interventional trials in people with prodromal Parkinson's disease. Thank you very much Dr. Eva Schäffer for joining us today, and I hope all the listeners enjoyed. Thank you very much. Bye-bye for now.

Dr. Eva Schäffer: Bye. Thank [00:14:00] you.