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Understanding corticobasal syndrome: Clinical and neuroimaging characteristics to unlock the underlying pathology

June 10, 2024
Dr. Michele Matarazzo interviews Dr. Jacy Parmera about her recently published article on the clinical and neuroimaging characteristics of patients with corticobasal syndrome, with a focus on the potential correlation with the underlying neuropathological causes. Read the article »


[00:00:05] Michele Matarazzo: Hello and welcome to the MDS podcast, the official podcast of the International Parkinson and Movement Disorder Society. I am Michele Matarazzo, the editor in chief of the podcast. And today we have the privilege of speaking with Jacy Parmera, movement disorder neurologist from the University of Sao Paulo School of Medicine in Brazil.

She's the first author of an article titled Probable 4-Repeat Tauopathy Criteria Predict Brain Amyloid Negativity, Distinct Clinical Features, and FDG-PET/MRI Neurodegeneneration Patterns in Corticobasal Syndrome, that was published very recently on the Movement Disorder Clinical Practice. Welcome to the podcast, Jacy.

[00:00:40] Jacy Parmera: Hello, thank you for the opportunity to be here.

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[00:00:43] Michele Matarazzo: Okay, so I would like to start with an overview of the corticobasal syndrome. Could you explain us what it is, why it's important? What are the clinical features, the normal progression and evolution of the disease, and also the management and what the underlying pathology is?

[00:00:57] Jacy Parmera: Yeah, well, a corticobasal syndrome, I used to say that it is a diagnostic conundrum. It is an atypical parkinsonian syndrome characterized by a combination of progressive asymmetric Parkinsonism with dystonia and myoclonus and cortical features such as apraxia, cortical sensory deaths, aniline phenomenon, and other language and cognitive dysfunction. So the current criteria, the Armstrong criteria, state that a probable CBS may have an asymmetrical progressive presentation with at least two motor signs among rigidity and bradykinesia, dystonia, or myoclonus associated with at least It's two cortical signs among apraxia, cortical sensory deaths, and alien limb phenomenon.

So CBS is related to multiple underlying pathologies. And what we know from previous studies is that clinical features cannot reliably distinguish them. So CBD and PSP which are four repeat tauopathies are the most common underlying pathologies.

[00:02:13] Michele Matarazzo: So just make sure that everybody is following CBD is corticobasal degeneration, right?

And PSP is progressive cerebral palsy. Yeah.

[00:02:22] Jacy Parmera: Yeah, exactly. So corticobasal degeneration, which is a pathological diagnosis and progressive supernuclear palsy are the most common underlying pathologies and they are classified as four repeat tauopathies. So the tauopathies are classified according to the predominance of the tau isoform.

And Alzheimer's disease is also an underlying possible pathology found in approximately 20 to 25 percent of cases. PSP accounts for approximately 30 to 40 percent of cases. It depends on the clinical pathological studies. Well, and there is a huge overlap among these diseases and among tauopathies, and it's usually difficult to guess and to know with certainty the underlying pathology.

So we usually need to add biomarkers in this investigation.

[00:03:22] Michele Matarazzo: So you're already showing us that that's a complicated disease. And also it's not complicated just from the clinical standpoint, but also from the underlying pathology and possibly also the management and the progression of the disease is quite complicated, right?

[00:03:37] Jacy Parmera: Yeah, exactly. Well currently we don't have any specific treatment related to these pathologies both for repeat tauopathies corticobasal degeneration and progressive supernuclear palsy and Alzheimer's disease as well. They don't have any specific and disease modifying treatment. So we usually work with symptomatic treatments.

Usually we try L DOPA and symptomatic treatments for parkinsonism and for cognitive dysfunction.

[00:04:11] Michele Matarazzo: Awesome. Now let's dive into the article itself, starting from the background. So this is a complex and comprehensive study on corticobasal syndrome. Well, you've said it already. We call it CBS from now on. And you also, you specifically study some biomarkers including, well, clinical evaluations and also different neuroimaging characteristics and biomarkers.

First of all, What is the evidence that those neuroimaging modalities, the FDG PET, the amyloid PET, and the MRI have or can have a role in the evaluation of CBS or in general in tauopathies?

[00:04:43] Jacy Parmera: Yes. Well this is a specific PET ligands such as amyloid PET and tau tracers. They are leading biomarkers as they disclose the underlying pathology. So amyloid PET in CBS is really important. a valuable tool indeed because it is it can distinguish AD cases and regarding FDG PET, it is interesting because neuropathology modulates metabolism.

So specific metabolic patterns have been shown for each parkinsonian syndrome. So the typical PSP presentation, for example, show hypometabolism in the midbrain, basal ganglia, frontal lobes, and CBD shows an asymmetrical frontal parietal hypometabolism. However, CBS on the other hand, shows a more complex set of patterns likely due to underlying pathologist. And more recent studies, but it's interesting, have suggested that FDG PET might be useful in distinguishing underlying pathologies in CBS. A previous study from our group, published in the Movement Disorder Journal in 2021, showed that FDG PET has a high specificity in distinguishing AD and no AD CBS. And there are also studies showing the usefulness of FDG PET in distinguishing PSP clinical variants.

And regarding MRI, there are also some multi modal studies that have demonstrated CBS structural pattern that may suggest underlying pathology.

[00:06:12] Michele Matarazzo: Perfect. I think one of the advantages here is rather than one specific modality is is that you're using different types of neuroimaging. And so the multi modal approach is definitely an advantage here. And just as we are discussing about biomarkers for CBS there are some other biomarkers both in neuroimaging and not neuroimaging biomarkers that are also quite interesting for CBS.

I just want you to comment a little bit on that. Maybe CSF analysis could be interesting. And also, I don't know, maybe dopamine imaging or tau PET imaging. What do you think the role of these other biomarkers could be when evaluating a CBS case?

[00:06:52] Jacy Parmera: Yeah, well, at CSF, as, as amyloid PET can differentiate CBS due to AD underlying pathology from other pathologies. And this is interesting in the CBS clinical routine. And TauPET Indeed, might become the most interesting, the ideal biomarker for CBS and for repeat tauopathies is in the near future. However it's important to mention that only second generation Tau PET tracers such as the PI 2620 and others demonstrate good specificity to detect for repeat tauopathies.

And dopamine ligands on the other hand, they don't differentiate quite well a typical parkinsonian neurodegenerative syndromes.

[00:07:42] Michele Matarazzo: Great. Now, can you guide us through the methodology of your study? How many subjects and what types of analysis did you perform?

[00:07:49] Jacy Parmera: Yeah, basically we performed a prospective clinical evaluation in 32 patients diagnosed with probable CBS according to Armstrong criteria. And we performed a comprehensive motor and cognitive assessment. So at the moment of the clinical evaluation, we decided to apply the criteria for probable 4 repeat tauopathy that was proposed in the MDS PSP criteria published in 2017.

So this criteria aimed to address the phenotypic overlap between PSP and CBD. So, it's criteria includes cases, obviously, of probable PSP with a predominant speech language phenotype, and PSP with a CBS phenotype. So, we classified our CBS patients in our cohort as 4 repeated tauopathy, when they, in addition to the CBS phenotype, they presented ocular motor dysfunction, such as vertical gaze palsy or slow virtual circuits.

And after that, we split the patients according to these criteria, blinded to, neuroimaging and all patients underwent amyloid PET. imaging. And we assess the frequencies of positive and negative amyloid PET in both groups and the clinical differences among both groups. And we also performed FDG PET and VBM MRI quantitative group analysis.

[00:09:21] Michele Matarazzo: And what were the main results of the study?

[00:09:23] Jacy Parmera: Well, I think that our main finding was that the probable for repeated tauopathy criteria were highly specific to predict negative amyloid PET among CBS patients showing more than 90 percent of specificity. Remarkably, such specificity was similar to a previous post mortem validation study. And concerning clinical results the patients classified as 4 repeat tauopathy presented dysarthria and motor perseveration, more often than patients who did not fulfill the criteria.

And both dysarthria and perseveration have been linked to tauopathy and mostly to PSP and In terms of neuroimaging patterns, both groups showed distinct neuroimaging patterns. And CBS patients classified as 4 repeat tauopathy, they showed a pattern closely related to tauopathies.

[00:10:16] Michele Matarazzo: So now that you have those findings, how do you think those should be applied, or those should impact the clinical practice?

[00:10:23] Jacy Parmera: Yes from a clinical perspective, our findings show that the clinical concept of 4 repeat tauopathies might be a clinical useful tool to distinguishing CBS cases due to for repeat tauopathies and CBS due to AD. But more important than that, actually, I think that we highlighted the clinical value of ocular motor dysfunction in CBS showing that it is a clinical signature and it might point towards 4 repeat tauopathies as an underlying pathology.

[00:10:56] Michele Matarazzo: Well, I think that's a very good take home message. So there's something very easy to do that we normally do in our routine clinical practice is looking at the eye movements of the patient that could help us understand what's the underlying pathology. Or at least we could get closer to what's really happening in the brain of the patient.

And that's something I guess, very important, especially as we approach in the future, possible clinical trials or possible treatments that could be selective to one underlying pathology or the other, right.

[00:11:26] Jacy Parmera: Yeah, exactly. That was our goal, to do a clinical and study.

[00:11:32] Michele Matarazzo: Now, going to the other part of the study, which are the metabolic and the atrophy patterns, what did you find, and did you expect those patterns or did you have any unexpected finding any region that you did not expect to see there?

[00:11:45] Jacy Parmera: Yeah, CBS patients classified as 4 repeat tauopathy. They showed that an interesting markedly frontal hypometabolism extending to supplementary motor area and basal ganglia. So compared to health, healthy controls and they showed brain atrophy at the anterior cingulate and basal ganglia. And those patterns were indeed previously associated to tauopathies, mostly to PSP.

And CBS patients that did not fulfill the criteria, they showed a more general hypometabolism in posterior temporal parietal regions, possibly due to the presence of AD cases. So there was any unexpected finding, but our observations suggest that most patients classified as 4 repeat , tauopathies might have an underlying, PSP pathology.

[00:12:39] Michele Matarazzo: And do you think you could be able to differentiate patients just based on the neuroimaging findings in an accurate manner? I mean, based on what I know, not on amyloid obviously, but I mean, based on FDG and or atrophy on a patient level, not on a group level, obviously.

[00:12:55] Jacy Parmera: I guess that if we want to have better accuracy I think we will need multimodal studies. So I don't think that clinical alone can distinguish and FDG alone can distinguish the FDG PET and MRI as well. But I think that if we take all of them together, the accuracy might be improved.

And I think that it should be addressed in, some studies. It was not the purpose of our research, but I think it's an interesting idea.

[00:13:28] Michele Matarazzo: Great. Now, is there anything else that you want to share with our listeners? Or do you have any further research ideas on this topic for the future?

[00:13:35] Jacy Parmera: Yeah, I just would like to mention here my mentors, Professor Sonia Brucki Professor of Neurology, who helped me a lot with the clinical data and methodology, and Professor Artur Coutinho, Professor of Nuclear Medicine, and he guided me a lot through neuroimaging methodology and it guided me through the research project.

And so concerning for the research ideas, we are currently working on establishing new cohorts of atypical parkinsonian syndrome and not only CBS, but also PSP and MSA at the University of Sao Paulo. And I strongly believe that It is important to study these diseases, these rare diseases across different countries.

[00:14:20] Michele Matarazzo: Perfect. Well, Jacy, it's been a pleasure discussing your article with you. Thank you very much for joining us today.

[00:14:27] Jacy Parmera: Thank you.

[00:14:28] Michele Matarazzo: We have had Dr. Jacy Parmera and we have discussed the article Probable 4-Repeat Tauopathy Criteria Predict Brain Amyloid Negativity, Distinct Clinical Features, and FDG-PET/MRI Neurodegeneneration Patterns in Corticobasal Syndrome from the Movement Disorder Clinical Practice.

Download and the read the article that is available on the website of the journal. And thank you all for listening

Special thank you to:

Dr. Jacy Parmera MD, PhD 
Movement Disorders Group, Department of Neurology, University of São Paulo 

Michele Matarazzo, MD 

Neurologist and clinical researcher HM CINAC

Madrid, Spain

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