NeuroVoices: Mark Lew, MD, on the Validation of Tears as a Biomarker for Parkinson Disease

Mark Lew, MD

This is a 2-part interview. Click here to view part 1.

Biomarkers are a critical component for early diagnosis and clinical intervention for patients with Parkinson disease (PD); however, finding these biomarkers has been a challenge for the field. Several various biomarkers for PD have been developed, but their specificity and sensitivity are not ideal when applied to individuals. A group of investigators may be on the break of a new biomarker, by collecting human tears.

A few years ago, the team, led by Mark Lew, MD, found significantly elevated levels of oligomeric α-synuclein in both basal tears and reflex tears in patients with PD vs controls using Schirmer tests. That patient sample was homogenous to disease duration, whereas in a new analysis presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, the protein composition of reflex tears were evaluated based on early (0-4 years), intermediate (5-8 years), or late (greater than 9 years) stages of the disease.¹

At the conclusion of the analysis, each group of patients had significantly increased levels of oligomeric alpha synuclein, but the levels did not discriminate from each other. While the new data validated their original findings, Lew, who is the director of the Division of Movement Disorders at the USC Keck School of Medicine, believes the next step is assessing atypical populations. In a new iteration of NeuroVoices, Lew discussed the next steps in justifying tears as a valuable biomarker for PD, and provided background on the advantages this approach brings to the field and why clinicians should be excited about these early results.

NeurologyLive^®: Is the next step for this biomarker a validation effort?

Mark Lew, MD: [Yes], validation. The main criticism that we’ve received as we submitted our work for publication was that we haven’t looked at it as a potential biomarker in an atypical population. Their response would be, “Well that’s very nice that you found this, but what about the atypicals?” We have nothing, no way. That’s much harder to diagnose than Parkinson disease. Can your potential biomarkers in tears piece that up for us? Our response has always been, you have to start from the ground and work up. We’re finally at that point where we’re confident with the assay, we’ve done it several times over in a huge group of patients. Our results have been replicated by ourselves again in several different populations and we know there’s a substantial difference in oligomeric alpha synuclein compared with healthy controls.

We’re at a point where we can look at these atypical syndromes. Had we done that earlier, I don’t think there would be any real validity because our assay was still in its infancy. That’s the main project for us. We fortunately received some federal funding to try to develop a new, more sensitive assay to detect oligomeric alpha synuclein, specifically in tears. Again, nobody’s done this. There’s a real steep learning curve to this. We’re also looking at different formats, we’re looking at mRNA sequencing.

I think the future of not just our tear research, but of biomarker research is that there’s going to be a signature. There may be four or five different proteins or factors that we use together and say, this suggests that this person has Parkinson disease or MSA (multiple system atrophy) or corticobasal syndrome. Looking at mRNA sequencing is another way to be able to evaluate large numbers of potentially other proteins as well. We have a lot going on, it’s really exciting, and we have a great team of people. I’m just a cog in the wheel, we have a huge team of basic scientists working on this. It takes a village.

Although relatively early in its research, how is the Parkinson disease community reacting to this? Do they believe this is a valuable biomarker that could fit in the space?

I think it would be crass of me to say, “We’re the best,” but the reality of that is that tears are a noninvasive process to collect. It’s a relatively inexpensive set of tests to run compared with other types of biofluids and bio-tissues. We have a tremendous amount of potential. I think that people are waiting, as I said, to see how our assay looks with the atypical syndromes. I don’t think there’s going to be one unique test, it’s probably going to be a handful of things that we look at, which is why we’re expanding to other proteins, more than looking at oligomeric alpha synuclein. People are also waiting for a multicenter validation to see if this can be done at other places. We have to provide them with that data and move forward with this.

Transcript edited for clarity. Click here for more iterations of NeuroVoices.

REFERENCE
1. Lew M, Janga S, Ju Y, et al. Biomarkers for Parkinson disease with reflex tears stratified by disease duration. Presented at: 2022 AAN Annual Meeting; April 2-7, Seattle, Washington. Abstract 3750