Although glaucoma is the leading cause of irreversible blindness, there is a “significant unmet need” for the identification of glaucoma-related biomarkers that has the potential to improve clinical testing for early diagnosis and disease progression, according to a review published in Progress in Retinal and Eye Research. The discovery of such biomarkers could, according to the authors, “allow for timely intervention in the clinic to assist in predicting prognosis and monitoring treatment response, as well as for more rapid early-phase clinical trial design.” 

Molecular biomarkers are an “enticing” target, as recent studies have advanced the clinical understanding of glaucomatous neurodegeneration pathophysiology, the research shows. Despite an advanced understanding of the molecular and cellular mechanisms that initiate and drive the neuronal injury of retinal ganglion cells, the cross-talk between degenerative pathways, and the contribution of these pathways to functional and structural loss, remain unknown. 

Currently, researchers are debating the best pathway to identify these necessary biomarkers. The location of glaucoma neurodegeneration makes biopsy clinically implausible; surveying vitreous fluid and serums are less invasive, but these sites — including the aqueous humor and tear film — are “slightly more distant” for molecular biomarkers. Therefore, optical imaging, focusing on retinal ganglion cell dendrites within the inner plexiform layer, cell bodies in the ganglion cell layer, and axons in the nerve fiber layer and optic nerve head are “particularly attractive” due to the noninvasive nature of imaging. 


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Fundoscopy observations suggest that defects in the nerve fiber layer might be the earliest available clinical signs of glaucomatous optic nerve atrophy. The retinal ganglion axon, then, may represent a “locus of pathology” in glaucoma. Red-free fundus photography, though, is qualitatively and subjectively interpreted, necessitating better imaging and quantification metrics for nerve fiber layer defects. 

Adaptive optics ophthalmoscopy allows clinicians to create in vivo visualization of retinal structures beyond those available with conventional optical coherence tomography (OCT) and fundus photography, and may represent another imaging option. However, interpretation of en face adaptive optics-enhanced OCT images can be challenging due to interference with high-contrast grains or speckles. Adaptive optics imaging is powerful, but has some limitations that prevent its widespread implementation and clinical use. 

Magnetic resonance imaging (MRI) is another option to measure renal ganglion cell axon degeneration via the optic nerve or optic tract. MRI-based protocols like diffusion tensor imaging can detect abnormalities in intracranial myelination, which have been investigated and have demonstrated “variable correlations” with RNFL thickness as measured by OCT. MRI also has the potential to reveal downstream degeneration of renal ganglion cell axons in visual pathways to the brain. 

Another site ripe for investigation is the inner plexiform layer, which may hold clues to both glaucoma pathophysiology and biomarker development, with numerous functional and molecular pathways tied to inner plexiform layer synapses. Comparatively few studies, though, report on inner plexiform layer changes in glaucoma, likely due to limitations in commercial OCT. 

Dye-based detection of retinal ganglion cells undergoing apoptosis is an “exciting approach” for researchers, with supportive early data. A recent phase 1 clinical trial, for example, successfully demonstrated that the detection of apoptosing retinal cells is a minimally invasive signal that correlates with disease severity. 

The evaluation of patients’ blood flow, oxygen, and metabolic dysregulation can be important starting points for biomarker research. Oxygen metabolism, for example, is impaired in early glaucoma, possibly even before structural changes occur. Studies of oxygenation and flow in glaucoma have benefited from the development of advanced techniques like depth-resolved Doppler OCT to quantify blood flow within arteries and veins. Progress towards using optical coherence tomography angiography (OCT-A) as a biomarker for glaucoma diagnosis or progression detection has also advanced in recent years. 

Finally, the authors have noted that the molecular and cellular mechanisms that are involved in retinal ganglion cell neuronal injury can be detected in tear film, aqueous humor, and vitreous body and blood serums. Utilizing these available tissues and fluids might increase the scientific understanding of glaucoma pathophysiology and speed the identification of treatment targets for drug development. 

“Despite the existence of clinically adopted biomarkers for the diagnosis and treatment of glaucoma, the need for new biomarkers with higher sensitivity and specificity remains,” the research says. “Disease impact could be dramatically reduced through early diagnosis and improved management. Sensitive biomarkers…could also reduce the duration of clinical trials, as well as improve the evaluation of efficacy through improved patient selection.” 

“Although formal validation of novel biomarkers for these purposes is expected to take years of longitudinal clinical testing in properly designed trials, we propose that merging biomarker testing as exploratory endpoints in therapeutic trials may accelerate their path to utility,” the research concludes. 

Reference

Beykin G, Norica AM, Srinivasan VJ, Dubra A, Goldberg JL. Discovery and clinical translation of novel glaucoma biomarkers. Prog Retin Eye Res. 2021;80:100875.