Director of the Division of Movement Disorders at the USC Keck School of Medicine

Mark Lew, MD

"Tears are a noninvasive process to collect. It’s a relatively inexpensive set of tests to run compared with other types of biofluids and biotissues. I think we have a tremendous amount of potential."

Despite the progress made within the space, there remains an urgent need for reliable diagnostic and prognostic biomarkers for patients with Parkinson disease (PD). Traditionally, the diagnosis of PD relies on clinical symptoms, which hampers the detection of the earliest phases of the disease—the time when treatment with forthcoming disease-modifying therapies could have the greatest therapeutic effect. Thus far, evidence has suggested that the value of cerebrospinal fluid and blood biomarkers reflect the pathophysiology of PD; however, most clinicians have agreed that it will take a combination of biomarkers to produce the most effective model.

A new method using reflex tears has emerged as a potential diagnostic biomarker for the disease. In a study presented at the 

2022 American Academy of Neurology (AAN) Annual Meeting

, April 2-7, in Seattle, Washington, oligomeric α-synuclein levels were found to be significantly elevated across different disease durations of PD, including early, intermediate, and late stage. Led by 

, this expanded on previous findings which first identified the increased levels and was also the first presentation of tear fluid evaluation in patients with PD stratified by disease duration.

Lew, the director of the Division of Movement Disorders at the USC Keck School of Medicine, sat down with 

 at AAN 2022 to discuss how the community has perceived these findings, albeit relatively early in the research process. He detailed the advantages of this approach, and why there are distinct differences with biomarkers from other neurodegenerative disorders.

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

Videos

The director of the Division of Movement Disorders at the USC Keck School of Medicine discussed the early reactions behind reflex tears as a potential biomarker for Parkinson disease. [WATCH TIME: 2 minutes]

The Need to Find Valuable Parkinson Disease Biomarkers: Mark Lew, MD

"Our results have been replicated by ourselves in several different populations and we know that there’s a substantial difference in oligomeric alpha-synuclein compared with healthy controls. We’re at a point now where we can look at these atypical syndromes. Had we done that earlier, I don’t think there would have been any validity because our assay was still in its infancy."

In a preliminary study, a group of investigators found significantly elevated levels of oligomeric alpha synuclein in both basal tears and reflex tears in patients with Parkinson disease (PD) vs healthy controls (HCs). Although that study had a homogenous sample related to disease duration, a new analysis evaluated whether the protein composition of reflex tears differs based on disease stage. To do so, reflex tears were collected in 77 early-stage (disease duration, 0-4 years), 43 intermediate-stage (5-8 years), and 50 late-stage PD cases and 67 HCs.

These protein levels were significantly increased by 5.4-fold in tears of early PD (4.28 [±0.75] ng/mg tear protein; 

<.001), 4.0-fold in tears of intermediate PD (3.23 [±0.54] ng/mg tear protein; 

<.001), and 3.1-fold in tears of late PD (2.44 [±0.40] ng/mg tear protein; 

<.001) relative to HCs (0.80 [±0.24] ng/mg tear protein). The findings indicated that oligomeric synuclein levels in tear fluid do not distinguish the stage of PD.

, this is the first time that tears have been evaluated as a biomarker for PD, thus prompting the need for further validation. At the 

, April 2-7, in Seattle, Washington, Lew, director of the Division of Movement Disorders at the USC Keck School of Medicine, sat down to discuss the next steps needed to expand on these findings. He stressed research looking at atypical presentations of the disease and warned that the field needs to proceed with caution, as this research wades into relatively uncharted waters.

The director of the Division of Movement Disorders at the USC Keck School of Medicine discussed the efforts needed to validate tears as a biomarker in patients who don’t present with typical Parkinson disease. [WATCH TIME: 4 minutes]

Validating Tears as a Biomarker in Atypical Presentations of Parkinson Disease: Mark Lew, MD

“It’s extremely important that if we have a biomarker, it can discern the difference between Parkinson disease and the atypical syndromes, both in the synucleinopathies and the tauopathies. We need to look at [multiple system atrophy], Lewy body disease, [progressive supranuclear palsy], and corticobasal syndrome as well.”

There has been little movement in the field of disease-modifying therapies for patients with Parkinson disease (PD), mainly because it has been difficult to identify the correct biomarker or group of biomarkers needed to target to show change. Using an unanesthetized Schirmer’s test, a group of investigators, led by 

, looked at the protein composition of reflex tears and found elevated levels of oligomeric α-synuclein, a biomarker long-believed to show neurodegeneration.

The first study, which concluded a few years ago, identified the elevated levels, while a new analysis showed that the increased levels do not discriminate between various stages of early-, intermediate-, and late-stage PD.

, April 2-7, in Seattle, Washington, the new analysis further validated previous findings and suggested sustained levels of oligomeric α-synuclein throughout disease process.

Lew, director of the Division of Movement Disorders at the USC Keck School of Medicine, sat down with 

 at AAN 2022 to discuss the next steps in expanding on these results. He emphasized starting clinical trials in patients with other neurodegenerative disorders such as Alzheimer disease, multiple system atrophy, and Lewy body disease.

Click here for more coverage of AAN 2022.

The director of the Division of Movement Disorders at the USC Keck School of Medicine provided insight on the next steps in how we can expand on tears as a valuable biomarker for neurodegenerative diseases. [WATCH TIME: 4 minutes]

The Future of Tears as a Biomarker for Neurodegenerative Disorders: Mark Lew, MD

"It made sense to try and look at the proteinaceous constituents of tear fluid. Additionally, tear fluid is easy to collect. It’s noninvasive, inexpensive. It’s not like when you do a lumbar puncture, which is a much more involved ordeal, there’s risk of contamination with blood, saliva is dirty, issues with blood and collection. It’s much safer and less expensive to do."

, April 2-7, in Seattle, Washington, investigators assessed whether the protein composition of reflex tears differs in patients with Parkinson disease (PD) stratified by disease duration. The study collected reflex tears of 77 men and women in early (disease duration, 0-4 years), 43 intermediate (5-8 years), and 50 late (greater than 9 years) stages of PD and 67 healthy controls. All told, oligomeric α-synuclein levels found in tear fluid did not discriminate between various stages of PD based on disease duration compared with HC.

Values measured by enzyme-linked immunosorbent assay, or ELISA, showed a 5.4-fold increase in oligomeric α-synuclein in those with early-stage PD (4.28 [±0.75] ng/mg tear protein; 

<.001), a 4.0-fold increase for intermediate PD (3.23 [±0.54] ng/mg tear protein; 

<.001) and a 3.1-fold increase for late-stage PD (2.44 [±0.40] ng/mg tear protein; 

<.001). Led by Mark Lew, MD, the study expanded on previous findings which first identified these elevated protein levels in both basal tears and reflex tears.

, Lew, director of the Division of Movement Disorders at the USC Keck School of Medicine, echoed the thoughts of other movement disorder experts, noting the dire need for biomarkers of PD that can formalize diagnosis and show medication response. He also provided background on the previous that led to this new analysis, how tears are collected, and the advantages they bring over traditional biomarkers.

The director of the Division of Movement Disorders at the USC Keck School of Medicine commented on the potential of reflex tears as a critical biomarker of Parkinson disease. [WATCH TIME: 6 minutes]

Mark Lew, MD

Articles

The Need to Find Valuable Parkinson Disease Biomarkers: Mark Lew, MD

Validating Tears as a Biomarker in Atypical Presentations of Parkinson Disease: Mark Lew, MD

The Future of Tears as a Biomarker for Neurodegenerative Disorders: Mark Lew, MD

The Motivations for Using Tears to Confirm Parkinson Disease Diagnosis: Mark Lew, MD

Latest News