Dr. Sara Schaefer:
Hello, and welcome to the December, 2021 edition of the MDS podcast, the official podcast of the International Parkinson and Movement Disorder Society.
Today, we are lucky enough to have two guests with us: Dr. Cecelia Peralta, neurologist and movement disorder specialist at CEMIC University Hospital in Buenos Aires, Argentina; and associate professor of neurology at the CEMIC Medical University; and also a member of the MDs Neuroimaging Study Group in movement disorders. As well as Professor Antonio Strafella, the Krembil-Rossy Chair and chair of research in the division of neurology in the University Health Network at the University of Toronto. They will be speaking with us about their article published in Movement Disorders: Clinical Practice, entitled "Pragmatic Approach on Neuroimaging Techniques for the Differential Diagnosis of Parkinsonisms." I look forward to learning a lot from them today, and I hope you do too. Thank you for joining us, both of you.
We have talked in the past on this podcast about how differentiating Parkinson's disease from atypical Parkinsonisms, especially early in the disease, can be difficult and how this stymies both research and optimal patient care. In the article, you talk about the imaging modalities that already exist and some up-and-coming imaging modalities that may be used in the future to assist with differentiating these conditions. Let's start with what is already used most commonly in practice.
One thing that struck me about the paper is that you recommended MRI brain in all patients with Parkinsonism, even if classic idiopathic PD is suspected. I must confess that if someone comes in with very straightforward PD, I don't always get an MRI and often make the diagnosis and start treatment at the very first visit. The recommendations in the paper are that the MRI should be used at least once over the course of the disease, just to rule out secondary causes. What exactly do you recommend to practitioners in terms of the timing of this? Do you think it should be obtained even prior to making a diagnosis?
Read full transcript [00:02:05] Dr. Cecilia Peralta:
Yes, we believe that it is kind of good practice, although it is not obligatory, but it's a good practice, to have a brain MRI of patients in the workup of the diagnosis of Parkinson's disease. Sometimes patients themselves ask for an imaging, and also their families. And we recommend to have at least one MRI in the course of the disease to rule out alternative diagnosis or to rule out secondary causes such as vascular lesions or space occupying lesions or hydrocephalus or traumatic or toxic or metal depositions or demyelinating diseases, space occupying lesions — I mean, other causes that may simulate or may present like a Parkinsonian syndrome, but may not be in the end, a true degenerative Parkinsonism. The other thing is that, if possible, nowadays it will be useful to include susceptibility weighted imaging within the MRI because ion imaging can give us some clues to the diagnosis and differential diagnosis, especially between Parkinson's disease and atypical Parkinsonism.
Also I have to say, or I must say that an MRI is not an approved biomarker for diagnosis or differential diagnosis. This is something important. It's an important concept that we have to take into account. But, we can use in clinical practice and in certain context integrated with the clinical features and with the clinical diagnostic criteria, for the diagnosis and for the differential diagnosis of Parkinsonism.
[00:03:53] Dr. Sara Schaefer:
Let's talk about differentiating degenerative Parkinsonism from non-degenerative Parkinsonism. One way we look at that, obviously, is through MRI to see if there are other things like vascular lesions that can explain the Parkinsonism that would make it non-degenerative. And you mentioned the SWI — are you referring to the loss of the DNH signal on 3T MRIs in PD versus healthy controls?
[00:04:21] Dr. Cecilia Peralta:
Yes, yes. This is a useful sign that can be used in the differentiation from degenerative, from non-degenerative Parkinsonism. We also have clinical clues. The presence of typical features and a good response to a dopaminergic trial, this leads us to think of a typical and degenerative Parkinsonian syndrome.
But if these features are absent or are unclear, then we can use DNH imaging, which is basically lost in Parkinson's patients and also in atypical Parkinson's disease. So, it's not useful for differentiation between typical Parkinson's disease and atypical Parkinsonism, but it can be useful for the differentiation between degenerative Parkinsonism, and non-degenerative Parkinsonism or other conditions.
[00:05:17] Dr. Sara Schaefer:
So, what we're referring to here is the loss of the dorsal nigral hyperintensity on SWI, of a 3T or higher MRI that you can see in degenerative Parkinsonisms both PD and atypical versus healthy controls. In the paper, that's cited as having a 100% sensitivity. And you also mentioned in the paper that the Movement Disorder Society clinical diagnostic criteria for PD notes that a normal DaTscan, which is another thing we use to differentiate degenerative versus non-degenerative Parkinsonism, that a normal DaTscan is an absolute exclusion criteria for PD. So do I take this to mean that these two imaging modalities, or two signs, both a DaTscan and the dorsal nigral hyperintensity sign, or lack thereof in the case of Parkinsonisms, are near-perfect in their differentiation between degenerative and non-degenerative Parkinsonism, even in early disease?
[00:06:23] Dr. Antonio Strafella:
That's actually, Sara, a very important question. In my personal practice, and when I see a patient, of course, I always take into consideration different kinds of information. So definitely if we have certain abnormalities with imaging, whether it's DaTscan or sophisticated MRI acquisitions, like of course, the one that Dr. Peralta just mentioned, definitely is very important information for my clinical decision, but I think that also you have to take into consideration the clinical correlations of these findings in order to have a more congruent approach in your final decisions.
So definitely for me, the imaging acquisitions are important, but are not the only one that will guide my final decision. So abnormalities, of course, in the DNH plus changes in, DaTscanning, those are relevant, but your clinical information has to be integrated with these findings. So, it is usually my approach on a day-to-day practice.
[00:07:33] Dr. Sara Schaefer:
So I'm just trying to really pin you down here. So despite the clinical diagnostic criteria, you would say that these SWEDDs, or scans without evidence of dopamine deficit, in patients truly who have PD that that does exist?
[00:07:52] Dr. Antonio Strafella:
We know that, I think, up to 10% sometimes of these patients may have a normal imaging finding. That's why I think neuroimaging is relevant in this case. If you're able to identify some of these patients that have a normal functioning of let's say the presynaptic terminal and a C-level with some features that are suggestive of some kind of Parkinsonism I think all this has to be taken into consideration as a whole. Whether it's a primary degeneration or secondary forms of degeneration, definitely imaging in this case becomes relevant. And so I would endorse having at least a DaTscan or that together with an MRI for guiding your decisions, yes. In the most difficult situations.
[00:08:34] Dr. Sara Schaefer:
Definitely, I agree that looking at the whole picture is very important in these patients where one thing may not give us exactly everything that we need in terms of diagnostic accuracy. Most of us are familiar with the typical signs we see on MRI brain and patients with atypical Parkinsonism, like the hot cross bun sign, the hummingbird sign, unilateral cortical atrophy in corticobasal syndrome, and those types of things. Can you discuss how we can quantify some of these features a bit more objectively to aid in diagnosis and some of the other signs on 3T or even 1.5T MRI that we can use to aid in a specific diagnosis?
[00:09:18] Dr. Cecilia Peralta:
You know, brain imaging is sort of relevant to demonstrate metering atrophy or palms atrophy and middle cerebellar peduncle atrophy or superior cerebellar peduncle atrophy, and those changes are hyperintensities at those levels. And it's also useful to rule out alternative diagnosis. As we know, PSP is sometimes the atypical Parkinsonian disorder that gives us the most difficult challenge in terms of differential diagnosis. And, recently, it has been published two set of measures that have been found to be very useful to differentiate PSP from PD and front MSA. And these two measures are the midbrain to pons ratio and the MRI Parkinsonism index, which is calculated by multiplying the pons to midbrain area ratio by the middle cerebellar peduncle width to superior cerebellar peduncle width ratio. And you get a value of 12.9, and if it is increased, it is very suggestive of PSP, particularly in those patients with a vertical supranuclear gaze palsy or PSP Steele-Richardson-Olszewski syndrome. And it's very useful to differentiate from PD, and also from MSA. And in this regard, the MDS PSP Study Group indicated that these MRI PI and the midbrain to pons ratio are the most reliable biomarkers for the diagnosis of PSP, Steele-Richardson-Olszewski syndrome.
And I think one of the good things of the paper, if you look at the figures, you have practical explanations on how to measure a superior cerebellar peduncle because, I mean, sometimes it's not easy. You find it in the papers, but you don't know in practical terms, how, in which plane, you are going to measure that. So I think in the figures, if you look at the figures, this is, I find personally very useful that information, in which planes you have to look at: what is the normal width of the superior cerebellar peduncle? What is the normal width of the middle cerebellar peduncle? How to measure them. I think this information is quite useful for daily practice to have at hand.
And something similar happens too with MSA, as well, where the pattern of brain atrophies located, particularly affecting the putamen and the middle cerebellar peduncle, together with some hyperintensities, the hot cross buns sign, and then middle cerebellar peduncle hyperintensity and the putaminal brain sign, which reflects the atrophy of the posterior putamen.
[00:12:04] Dr. Sara Schaefer:
So you mentioned lots of calculations and practical guides to help a practitioner go into the MRI and actually make these calculations. I was wondering as I was reading this, how you see in the future, in terms of, if there will be any kind of automation of these types of calculations of various diameters and widths and areas of brain tissue to aid a movement disorders neurologist or radiologist in proper diagnosis if they don't have, potentially, the time or expertise to sit there measuring for all their patients.
[00:12:40] Dr. Cecilia Peralta:
Oh, yes. I mean, there are ongoing projects directed to automated measurements of these indices and ratios. I think one of the future aspects of imaging would be the access to automated measurements of these indexes and all these brain volumes that can help in the diagnosis. And [Dr.] Antonio [Strafella], if you want to add further on this.
[00:13:05] Dr. Antonio Strafella:
Indeed, the future of these techniques and approaches is probably based on the success of potential platforms that will allow to have automated calculations of these different measures. And, because as you just mentioned, most of the centers and probably won't have either the expertise or sometimes the technology to make these sophisticated analysis or measures. So having an automated approach with certain platforms would allow a more wide distribution of these techniques.
I know that a number of centers have tried to implement this and eventually will become more and more available.
[00:13:48] Dr. Sara Schaefer:
That sounds great. [Dr.] Cecilia [Peralta] coming back to you, all the findings that you mentioned with the putaminal atrophy, et cetera, would they generally be present early in the disease course? Or would you expect some of these other features that we're familiar with, like the hot cross bun sign and things like that, then in early disease, the sensitivity would be low?
[00:14:10] Dr. Cecilia Peralta:
Oh, yes, definitely. In early disease, the sensitivity is low. And in fact, this is a problem or a limitation, let's say, of these imaging biomarkers. Approximately half of atypical Parkinsonian patients wont' present the signs early in the disease. However, there's some papers published that have shown that changes seen in MSA, this putaminal atrophy and hyper intensity , in around 30% of MSA patients, can be present inclusive when not all the clinical diagnostic criteria are fully developed. So I think that one of the ideas behind the paper when we discussed with the neuroimaging group was to help the general neurologist and also the radiologist, how to read in detail, an MRI or a pet scan, because you shouldn't, you have lots of information, but you need to know where to look, what to look, how to make sure, to be able to get all the information that the biomarker can give to you.
[00:15:19] Dr. Sara Schaefer:
You go through some flow sheets as part of the paper of how to approach a patient with Parkinsonism, including using combinations of MRIs, DaTscans, FTG-PET; what is the difference between these two algorithms? Are they mostly related to what is available at individual institutions?
[00:15:40] Dr. Cecilia Peralta:
Uh, well I think there's no specific difference. I mean, they are in fact different, because they're different methods, and then you can use one or the other one, according to what is available. Of course, again, another important concept is that the only approved biomarker to be used in clinical practice for the differential diagnosis of PD from essential tremor is DaTscan. It's a marker of the dopamine transporter with SPECT using Ioflupane. This is very important to have into account. This is the official approval. The other things we can use in clinical practice, we can use in certain contexts or according what is available to us.
[00:16:22] Dr. Sara Schaefer:
And [Dr.] Antonio [Strafella], can you talk through some of the things that might be coming down the pike in terms of neuroimaging for these patients, particularly highlighting imaging modalities that you think will become clinically relevant or are more likely to become clinically relevant in the coming year?
[00:16:40] Dr. Antonio Strafella:
Yes, yes. So of course, the field of neuroimaging at the moment I will say is actually exploding in the sense that in the pipeline, there are a number of interesting developments that could be clinically useful in the near future. You're probably very much aware of tau imaging, of course, and for PSP and the CBD, or let's say for our pathology in general. In the last five years, there's been a great interest in developing certain radio tracers that are able to image these pathologies of atypical Parkinsonism.
And of course now we are moving into the second generation of tau tracers, and at least three or four new potential tracers that have been tested. And among those, probably there is one or two that are emerging more — without naming one specifically — but certainly there've been a number of publications the last six months that seemed to be very much suggestive that these are the traits that can be useful for diagnosis of PSP and corticobasal degeneration. And again, the problem that these tracers had in the past was the off target binding, which now was the new generation of tracers seems to be less and less.
So definitely we're moving into an area of great interest from a clinical point of view, and definitely now one of the largest task that the neuroimaging community is involved in is trying to identify also a tracer for alpha-synuclein. Of course most of the studies at the moment are still at the preclinical level, but it seems that there might be a chance in the near future to have some clinical trials that will be exploring the possibility of these new to ready tracers for, for alpha-synuclein.
So definitely I would say the next five years there will be great developments in the field. And I look forward to see how we can implement more and more neuroimaging in general, whether it's an MRI or molecular imaging into the clinical practice, because I think that will have a great impact on our clinics for our patients.
[00:18:52] Dr. Sara Schaefer:
Well, in terms of tau PET, if I remember our interview correctly from 2019 at the Movement Disorder Society meeting, I think you sound a bit more optimistic about it than you did then, so that's certainly encouraging.
[00:19:07] Dr. Antonio Strafella:
Yes, I definitely am, because that was probably still the beginning of a tau imaging. And that was actually most of the work done in the first generation of the tracer. But now we are in the second generation, we are aware of the problems and I think we are moving in the right direction, even though there are always new challenges that we have to face, but I think now we are in a better position than we were three or four years ago, yes.
[00:19:34] Dr. Sara Schaefer:
That's very encouraging. All right. Well, is there anything else you guys want to add before we sign off?
[00:19:40] Dr. Cecilia Peralta:
I would say I agree, totally with [Dr.] Antionio [Strafella], that the neuroimaging field is very dynamic. It's a lot of developments. Tau PET probably will be one of the most promising areas of development in the next years, but also the basic biomarker studies such as MRI and high-field MRI, which are emerging now are very promising as well. We hope that they can enter more and more in the daily clinical practice to improve our ability to better diagnose and treat our patients. And of course I want to acknowledge to all the co-authors who did a great job writing the paper.
And also, I hope that the general neurologist community may find the paper useful to improve these basics skills that are needed to have a pragmatic approach on how to read an MRI, how to look for all these signs, and how to use this for the better of our patients.
[00:20:44] Dr. Sara Schaefer:
Yes, I would echo that the paper itself is very practical in terms of giving any provider, a clinical approach to these patients and trying to come up with a good, accurate diagnosis as early as possible, including the flow sheets and a lot of figures that show the imaging findings in great detail. So I do encourage all of our listeners to go to the paper as well for those practical tips.
Thank you so much for joining us, and you have a good day.
[00:21:18] Dr. Antonio Strafella:
Thank you for inviting us, Sara.