Tear Analysis May Reveal Neurodegenerative Disease Biomarkers

Eye exams have long provided optometrists with a portal to their patients’ systemic health, and clinicians may soon add tear analysis to their armamentarium of methods used to gather patient data. From observing pupillary reaction to fundus evaluation, the optometrist is not only amassing information on their patients’ vision and ocular health, they are also gathering data that may potentially provide a glimpse into their cardiovascular or neurological health. Since the eye is an extension of the central nervous system (CNS), it may have the potential to reveal neurodegenerative diseases. During the last decade, 2 noninvasive imaging methods, optical coherence tomography (OCT) and OCT-angiography (OCT-A), have been widely researched as strategies for detecting neurodegenerative diseases. While these imaging methods show promise for identifying these diseases, a noninvasive biomarker may be found in a more accessible part of the eye — the tears.

Neurodegenerative diseases affect millions of people worldwide and since older age contributes to this risk, they are becoming more prevalent as life expectancy increases.¹ The two most common neurodegenerative diseases are Parkinson Disease and Alzheimer disease.¹ Diagnosing neurodegenerative disease is difficult due to overlapping symptomatology, especially in the early stages of disease. To aid in diagnosis, functional brain imaging or invasive tests like lumbar puncture are often required.² The latest research is focused on identifying biomarkers in bodily fluids like cerebral spinal fluid (CSF) and blood. However, collecting CSF is a highly invasive procedure, and blood composition is not only complex, but has reduced CNS-derived biomarkers due to the blood brain barrier.³ Tear collection, however, may provide clinicians with a less invasive strategy for obtaining proteomic biomarkers. With their ease in collection and close relation to the CNS, tears may be the new frontier.⁴

Alzheimer Disease

Alzheimer disease is the most common cause of dementia in adults and the fifth leading cause of death in Americans aged 65 years and older.⁵ This neurodegenerative disease is caused by an abnormal buildup of protein in the brain cells. Amyloid-beta and tau are 2 such proteins responsible for building plaques around the cells and forming tangles within the cells, respectively. The most common sign of Alzheimer Disease in its early stage is life-disrupting memory loss. Visual symptoms can include trouble with depth perception, tracking, and contrast sensitivity. 

Ancillary Testing for Alzheimer Disease

OCT and OCT-A have been a focal point of research for early biomarker detection of Alzheimer Disease. A 2019 investigation that used spectral domain-OCT revealed thinning of the ganglion cell inner plexiform layer (GCIPL), ganglion cell complex (GCC), peripapillary retinal nerve fiber layer (RNFL), and choroid among individuals with Alzheimer disease compared with individuals who did not have the disease.⁶ Another investigation using OCT-A showed lower whole and parafoveal vessel densities in patients with Alzheimer disease compared with control group participants without the disorder.⁷

Tear Biomarkers for Alzheimer Disease 

Although this technology may lead clinicians to suspect Alzheimer disease during an earlier stage, the disease can only be definitively diagnosed postmortem. While imaging devices can provide a method of noninvasively obtaining potential neurodegenerative disease biomarkers, the ocular surface may also be a source of easy-to-access biomarkers for early disease. Amyloid precursor protein, and the peptides it releases upon degradation, are being investigated as potential biomarkers for the disease that can be obtained through tear analysis, as these peptides may be present in the tears of individuals with Alzheimer disease.^4,8,9 A 2019 investigation found that corneal fibroblasts and corneal epithelium expressed amyloid precursor protein in patients with Alzheimer disease, highlighting the possibility that the ocular surface holds a key to identifying Alzheimer disease and its progression.¹⁰ 

These proteomic composition changes, along with decreased tear breakup time (TBUT), lower Schirmer test values and increased tear flow rate may identify patients with Alzheimer disease^.11,12 While further research is needed, these results suggest that the ocular surface may be the future of Alzheimer disease diagnosis and monitoring.

Parkinson Disease

Following Alzheimer disease, Parkinson disease is the second most common neurodegenerative disease in the United States.¹³ This disorder involves a degeneration of dopamine neurons and a buildup of alpha-synuclein proteins. This neurodegeneration leads to a clinical presentation of tremors and slow, rigid movements. Common visual symptoms include dry eye and diplopia, which clinicians can manage with dry eye therapies and prism spectacles, respectively.

Ancillary Testing for Parkinson Disease

Clinicians can observe retinal changes associated with Parkinson disease through OCT analysis. Reduced RNFL thickness and foveal changes, such as thinning and broadening of the pit, have been linked to the disorder.^14,15 The inner retinal layer — a layer containing dopaminergic amacrine cells — can also demonstrate significant thinning in Parkinson disease.¹⁶ Since dopamine is a key player in regulating certain visual processes, it makes sense that retinal changes are linked to Parkinson disease. OCT-A may reveal microvasculature changes, including superficial capillary plexus vessel density and perfusion density reductions.¹⁷ The challenge with these findings, however,  is  the lack of specificity to the disease.

Tear Biomarkers for Parkinson Disease

Parkinson disease researchers have also turned to the tears looking for disease biomarkers. Research involving patients with the disease reveals a significant reduction in corneal nerve density and the presence of alpha-synuclein in the basal tears of these individuals.^18,19,20 TBUT and Schirmer test scores are also significantly lower in patients with Parkinson disease and corneal staining and Ocular Surface Disease Index (OSDI) scores are significantly higher.^21,22 These findings likely correlate with a reduced blink rate, a common sign of Parkinson Disease due to the dysfunction of the dopaminergic pathway.²³  

Optometry’s Evolving Role in Patient Care

“Understanding neurodegenerative diseases and their markers is such an important topic right now,” according to Kelly K. Nichols, OD, MPH, PhD, FAAO, a vision researcher specializing in dry eye disease and dean of the University of Alabama at Birmingham School of Optometry. “It would be wonderful if the proteome of the tears could help with early diagnosis. At a minimum, the knowledge that dry eye signs and symptoms may occur in patients with these disorders may shed light on one more aspect of impact on quality of life that can be managed by an optometrist.”

Although research has yet to determine adequate specificity and sensitivity for these neurodegenerative disease-related biomarkers, optometrists should stay up to date on this evolving research. While it is important for clinicians to provide symptom management, eye care professionals must also incorporate testing that may support early diagnosis and monitoring of these complex diseases.

This article originally appeared on Optometry Advisor