Differentiating patients with atypical parkinsonisms from idiopathic Parkinson disease (PD) can be a significant challenge for clinicians in clinical practice because of the similar symptoms presented in each of them. For instance, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit an overlap of pathological features and have various phenotypic variants. Therefore, it is important for providers to make an accurate diagnosis to determine the most effective treatment and management approach for patients. Prior research even indicated that inappropriate treatment, because of misdiagnosis, provides limited benefits to patients, complicating care and increasing the disease burden.1
At the 3rd Annual Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 22-25, 2024, David Shprecher, DO, MSci, FAAN, delivered a presentation on diagnostic insights in atypical parkinsonism. He discussed methods for clinicians to differentiate the clinical and pathological features of each atypical parkinsonian syndrome from idiopathic PD. Additionally, he highlighted key indicators that may signal atypical parkinsonism and evaluated recent advancements in diagnostics and treatments.
In a new iteration of NeuroVoices, Shprecher, the director of movement disorders at the Banner Sun Health Research Institute, sat down with NeurologyLive® at the Congress to discuss the current limitations of diagnostics tests such as the Syn-One skin biopsy test and cerebral spinal fluid (CSF) test for synuclein biomarkers. Shprecher, who also serves as a clinical associate professor at University of Arizona-Phoenix, spoke about how the current biomarkers help differentiate between synucleinopathies and tauopathies. Furthermore, he talked about future developments anticipated in minimally invasive biomarker testing for neurodegenerative diseases.
NeurologyLive: Could you provide an overview of your talk that you presented at ATMRD on diagnostic pearls and atypical Parkinson?
Top Clinical Takeaways
- Synuclein biomarkers, including SYN-One skin biopsy and cerebral spinal fluid tests, show high sensitivity in detecting Parkinson disease but have limitations in differentiating from other proteinopathies.
- There is a need for further studies involving larger, diverse cohorts and independent validation to confirm the utility of these biomarkers.
- The development of minimally invasive tests, such as blood biomarkers or imaging ligands, holds significant potential for improving the diagnosis and management of neurodegenerative diseases.
David Shprecher, DO, MSci, FAAN: First of all, thanks so much for your interest in the ATMRD program. I was able to kick off the symposium today with the first CME talk in diagnostic pearls and atypical Parkinsonism. I also touched briefly on some of the updates and diagnostic criteria for atypical Parkinsonian disorders and some of the clinical pearls and management. It's an exciting time because we're just at the cusp of having biomarkers that can help us more reliably differentiate what the underlying changes in the nervous system are while patients are still alive, when it really matters to them.
What are the main takeaways from your talk that clinicians should be thinking about regarding developments in diagnostics?
While the data is very promising for synuclein biomarkers—both the Syn-One skin biopsy test and the CSF test from Amperon—we still don't have studies that compare patients with synucleinopathy to those with tauopathies and some of these other proteinopathies. We still need a little bit more time to study the utility of these tests in differentiating some of those tough cases. [In addition,] we want to recognize the limitations of the data sets that are still out there. That said, the synuclein biomarker in the Parkinson Progression Markers Initiative (PPMI) showed extraordinarily high sensitivity, 99%, in clinically well-defined patients with PD who also had anosmia using the University of Pennsylvania smell identification test. We were able to very clearly identify classic patients with PD that show misfolded alpha-synuclein in the CSF that can be confirmed during life with a test that isn't terribly invasive, but we would like something a little less invasive, if possible.
Another important limitation there is we still don't know in other cohorts where patients present with the classic “not reading the textbook” approach to things where they don't have all of the classic features of PD. What's the utility attest in those cases? We don't have any autopsy confirmed cohorts yet, so there are still some limitations. Another thing to emphasize with this, and also with the Syn-One biopsy test, is that we do have 2 well defined, relatively large cohorts for both biomarkers but these studies haven't necessarily been confirmed by independent groups with separate cohorts and separate labs.
When it comes to the Syn-One biopsy test, an important limitation is that all of the participants enrolled were very well defined patients with synucleinopathies, PD, dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy. There were no patients with some of the other atypicals, the tauopathies, for example. In addition, there were very well defined healthy controls, but the healthy controls, on average, were younger than the disease patients. That is a limitation of the data. Still, it is a useful test in select cases, but we really need to understand the limitations of the test. That is just another piece of information. It's not a simple yes or no answer either you have synucleinopathy or you don't and that there isn't anything else going on.
What other developments for enhanced diagnostics should the clinical community look forward to?
We really would like to see tests that are minimally invasive, that could be therefore more broadly available and broadly utilized. If the Syn-One biopsy test could be studied in a much larger cohort, such as the PPMI cohort, that would be very helpful. I would be very excited to see that happen. I think another area that would be super exciting—if it can happen—is if we could have a blood biomarker, of course, for synucleonopathy, or even for tauopathy, that would be what we consider our most minimally invasive test, other than maybe an imaging ligand. We're still a ways off from a synuclein imaging ligand.
Are there any closing remarks that you have regarding your presentation and regarding the Congress?
There are 2 imaging ligands just to keep an eye on. First of all, there is a synuclein imaging ligand that, while it doesn't necessarily differentiate all synucleinopathies, does show promise specifically separating multiple system atrophy from the other synucleinopathies. Another exciting development is we have several different tau ligands in development. Some are mainly being developed for Alzheimer disease, but one in particular from Molecular Life Sciences is also showing promise because of a different pattern of deposition in PSP. Where it clearly differentiates people with the classic presentation of Richardson syndrome from, say, PD or healthy controls. This is now being studied in a much larger cohort of neurodegenerative disease patients who are all at end of life and also consented for brain autopsy. Hopefully, over the next few years, we’ll have autopsy-confirmed data about the utility of this ligand for identifying these 4 repeat telepathies like PSP or CBD during life, when it matters the most to our patients.
Transcript edited for clarity. Click here to view more NeuroVoices.
REFERENCES
1. McFarland NR. Diagnostic Approach to Atypical Parkinsonian Syndromes. Continuum (Minneap Minn). 2016;22(4 Movment Disorders):1117-1142. doi:10.1212/CON.0000000000000348
