DARC: From Bench to Bedside

Tracing the path of an exploratory retinal biomarker.

Francesca M. Cordeiro, MD, PhD, MRCP, FRCOphth

Glaucoma Today

The management of chronic neurodegenerative diseases such as glaucoma, age-related macular degeneration (AMD), Alzheimer disease, Parkinson disease, and stroke is complicated by a similar set of challenges. These diseases cause significant disability, owing in part to their late diagnosis, the absence of appropriate screening tests, ineffective monitoring, and a lack of early clinical endpoints. Patients with neurodegenerative diseases progress slowly and are followed over long periods of time. Reliable indicators are therefore needed to measure disease progression and efficacy of treatment. In glaucoma, the gold standard for diagnosis is visual field testing. Visual field defects, however, can take years to develop, by which point at least 30% of the eye’s retinal ganglion cells (RGCs) may be lost. This inability to identify early disease is estimated to translate to about a 10-year delay in the diagnosis of glaucoma.1 Diagnostic delays affect patients with other neurodegenerative diseases as well. Parkinson disease is diagnosed only once a patient presents with symptoms, by which point 70% of dopaminergic receptors have typically been lost.2 With Alzheimer disease, the time between the start of the disease process and the development of memory loss is reported to be about 20 years.3 The detection of apoptosis and cell stress is a promising strategy for detecting neurodegenerative disease before irreversible damage occurs and for monitoring treatment response ahead of existing endpoints. This article reviews a novel retinal biomarker—the Detection of Apoptosing Retinal Cells (DARC)—and the potential for this to function as a surrogate endpoint in glaucoma and other conditions. BIOMARKERS AND ENDPOINTS A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.

The Parasympathetic Nervous System and DED

The connection between the two suggests dry eye is more than just a disease of the eye.

Hardeep K. Kataria, OD, FAAO, and Mila Ioussifova, OD, FAAO, CNS

Modern Optometry

The parasympathetic nervous system (PNS), involved in the “rest and digest” response, and the sympathetic nervous system, involved in the “fight or flight” response, are the two main divisions of the autonomic nervous system. The PNS operates in the craniosacral and sacral segments of the central nervous system, and involves the oculomotor (III), facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The primary neurotransmitters used by these nerves, acetylcholine (ACh) and vasoactive intestinal peptide (VIP), work together to promote the “rest and digest” functions of the body (eg, constricting pupils, slowing heart rate, and maintaining gut motility for digestion).1 The motor branch of the seventh nerve serves as part of the postganglionic parasympathetic pathway that innervates the lacrimal functional unit for tear production, distribution, and clearance. The lacrimal gland has mainly muscarinic ACh receptors, and the primary neurotransmitter responsible is ACh. Therefore, if we want to stimulate tear production in conditions such as aqueous-deficient dry eye disease (DED), we should focus on targeting the lacrimal gland tissue, nerve, receptor, and/or neurotransmitter.2 HOW ARE THE PNS AND DED CONNECTED? Because the PNS is mainly responsible for tear production in the lacrimal gland, when the superficial petrosal nerve is denervated, tear production is reduced by 70%. Conversely, when we stimulate the PNS, we can increase tear production.2 Additionally, the PNS plays a role in immune modulation, with the cholinergic antiinflammatory pathway linking the autonomic nervous system and the immune system, primarily through the parasympathetic nerves, especially the vagus nerve, along with ACh and its receptors. This pathway can activate and regulate immune cell functions, contributing to its antiinflammatory role and affecting the development of various autoimmune diseases.3 Anticholinergic medications, such as antihistamines and antidepressants, also downregulate the binding of ACh to its muscarinic receptor in the lacrimal gland, leading to overall reduced tear production.2 In conditions such as Sjögren syndrome, inflammation further reduces ACh release and tear production. Furthermore, the presence of muscarinic receptor antibodies that block ACh binding to the receptors may also lead to decreased tear production.4 It has been suggested that serum autoantibodies against muscarinic ACh may even serve as an early marker for Sjögren syndrome.5 Because serum ACh cannot be measured successfully, clinicians must use signs and symptoms to help guide treatment for these patients. It is worth mentioning that studies have confirmed the presence of VIP receptors in human meibomian gland acini that may be indicated in cell proliferation, and that exogenous application of VIP can stimulate goblet cell secretion; however, further data are needed to confirm the exact role of VIP in DED.6 Overall, the role of the PNS in aqueous-deficient dry eye is well established (its role in evaporative dry eye and the meibomian glands is less so).

A Global Community

Callan Navitsky, Editor-in-Chief

Glaucoma Today

Working in proximity to many trainees through YoungMD Connect, BMC’s platform for young and aspiring ophthalmologists, I regularly hear that one of the most appealing aspects of ophthalmology is its community feel. People in the field are perceived as welcoming, connected, and collegial. Although community may seem synonymous with closeness, the concept itself may be broader than that. For some, community is not defined solely by shared geography, nationality, or other social or cultural ties. In this issue of GT, ophthalmologists recount experiences in which they traveled abroad to serve and support others from different backgrounds, in different settings, and with different resources—but with a common goal to combat blindness. The anecdotes and photographs they share are snapshots of comprehensive initiatives and continuous collaborations. For example, after observing unmet needs in trabeculectomy care in Bali, Oluwatosin Smith, MD, is now working to establish a program within her home practice to address this obstacle. Annette L. Giangiacomo, MD, communicates regularly with providers she has met on past trips to remain an active part of their support team. Shawn Gulati, MD, MPH, is participating in a dedicated global ophthalmology fellowship.