Is the Eye an Extension of the Brain in Central Nervous System Disease?

Since 1950, global average life expectancy has been steadily increasing at a rate of more than 3 years per decade (with the exception of the 1990s), with accompanying growth in age-related neurodegenerative diseases, such as Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and stroke. The limited capacity of self-repair of the adult mammalian central nervous system (CNS) and the general lack of preventive and restorative treatments for these conditions lead to progressive debilitation and eventually death. Not only does this result in a diminished quality of life for patients (and their families) but also impacts society by placing tremendous demands on social welfare and health systems. How to “ensure healthy lives and promote well-being for all at all ages,” one of the Sustainable Development Goals for 2030, adopted by the United Nations General Assembly, is thus a challenge to be tackled by the next generation of researchers, clinicians, and policy makers

Redefining clinical outcomes and endpoints in glaucoma

Introduction: Increasing life expectancy and ageing populations across the world are causing the number of glaucoma patients to rise dramatically. With longer lifespans also comes the need to improve the timeframe and accuracy with which we can diagnose, monitor and treat patients, ensuring longevity of vision contributes to a meaningful quality of life. Current markers used in glaucoma practice are in many cases suboptimal in their ability to accurately identify glaucomatous damage in time to prevent irreversible optic neuropathy. // Areas covered: This review summarises the important properties of successful biomarkers and surrogates, and relates this to how intraocular pressure, visual field testing, and imaging have been refined to improve early diagnosis and progression analysis of glaucoma patients. Secondly, we discuss newer concepts in imaging, genetics, and quality of life measures which may provide biomarkers and surrogate endpoints with which to develop novel treatments in the future. // Expert commentary: We summarise the key relevant points in glaucoma research, and the current techniques being trialled that are most likely to lead to valuable biomarkers for the future

Investigational neuroprotective compounds in clinical trials for retinal disease

INTRODUCTION: The death of retinal neurons causes permanent and irreversible vision loss, severely impairing quality of life. By targeting toxic conditions which cause neuronal death, such as oxidative stress and ischaemia, neuroprotective agents provide utility in slowing or stopping sight loss resulting from eye disease. While clinical use of neuroprotectants remains limited, there are a few promising compounds presently in early clinical trials (pre-phase III) which may fulfil exciting new therapeutic roles. Search terms relating to neuroprotection and eye disease were used on ClinicalTrials.gov to identify relevant compounds. AREAS COVERED: This review focuses research supporting neuroprotective compounds in eye diseases which range from preclinical stages to phase II, as listed on the clinicaltrials.gov database. The compounds under discussion, namely NGF, Saffron, Ubiquinone, and CNTF, are discussed in terms of potential clinical applications in the near future. EXPERT OPINION: Until recently, the major challenge in neuroprotection research has been the successful translation from basic research to the clinic. A number of potential neuroprotective molecules have progressed to ophthalmology clinical trials in the last few years, with defined mechanisms of action - saffron and CoQ10 - targeting the mitochondria, and both CNTF and NGF showing anti-apoptotic effects. Enhancements in trial design and choice of patient cohorts in these chronic diseases using proof-of-concept trials with enriched patient populations and surrogate endpoints should increase drug development speed. A further important consideration is optimising drug delivery approaches with improvements in individualised management and patient compliance. Progress in all these areas means that neuroprotective strategies have a much improved chance nowadays of translational success

Detecting Apoptosis as a Clinical Endpoint for Proof of a Clinical Principle

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarise the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase

Visual and Ocular Manifestations of Alzheimer's Disease and Their Use as Biomarkers for Diagnosis and Progression

Alzheimer's disease (AD) is the most common form of dementia affecting the growing aging population today, with prevalence expected to rise over the next 35 years. Clinically, patients exhibit a progressive decline in cognition, memory, and social functioning due to deposition of amyloid β (Aβ) protein and intracellular hyperphosphorylated tau protein. These pathological hallmarks of AD are measured either through neuroimaging, cerebrospinal fluid analysis, or diagnosed post-mortem. Importantly, neuropathological progression occurs in the eye as well as the brain, and multiple visual changes have been noted in both human and animal models of AD. The eye offers itself as a transparent medium to cerebral pathology and has thus potentiated the development of ocular biomarkers for AD. The use of non-invasive screening, such as retinal imaging and visual testing, may enable earlier diagnosis in the clinical setting, minimizing invasive and expensive investigations. It also potentially improves disease management and quality of life for AD patients, as an earlier diagnosis allows initiation of medication and treatment. In this review, we explore the evidence surrounding ocular changes in AD and consider the biomarkers currently in development for early diagnosis

Retinal correlates of neurological disorders

Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research

Detection of macular atrophy in age-related macular degeneration aided by artificial intelligence

INTRODUCTION: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment worldwide. The endpoint of AMD, both in its dry or wet form, is macular atrophy (MA) which is characterized by the permanent loss of the RPE and overlying photoreceptors either in dry AMD or in wet AMD. A recognized unmet need in AMD is the early detection of MA development. AREAS COVERED: Artificial Intelligence (AI) has demonstrated great impact in detection of retinal diseases, especially with its robust ability to analyze big data afforded by ophthalmic imaging modalities, such as color fundus photography (CFP), fundus autofluorescence (FAF), near-infrared reflectance (NIR), and optical coherence tomography (OCT). Among these, OCT has been shown to have great promise in identifying early MA using the new criteria in 2018. EXPERT OPINION: There are few studies in which AI-OCT methods have been used to identify MA; however, results are very promising when compared to other imaging modalities. In this paper, we review the development and advances of ophthalmic imaging modalities and their combination with AI technology to detect MA in AMD. In addition, we emphasize the application of AI-OCT as an objective, cost-effective tool for the early detection and monitoring of the progression of MA in AMD

Glaucoma: the retina and beyond

Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain

Glaucoma: Hot topics in Pharmacology

BACKGROUND: Glaucoma comprises a group of neurodegenerative diseases resulting in retinal ganglion cell death within the optic nerve head. It is projected to affect almost 80 million people worldwide by 2020. The condition's asymptomatic nature translates to over half of glaucoma sufferers being unaware of their condition. By the time of diagnosis, irreversible blindness is likely to have occurred. Prime areas of glaucoma research therefore include identification and optimization of risk factors for the disease, accurate and early diagnostic tools and novel therapeutic methods. METHODS: The goal of this review was to summarize main areas of latest glaucoma research into risk factors of glaucoma, diagnostic tools and treatments. PubMed was used to search for terms including glaucoma risk factors, glaucoma diagnostics, glaucoma treatment, glaucoma drug delivery and glaucoma IOP. RESULTS: The evidence for risk factors of low CSF pressure, IOP, smoking, vascular risk factors and light toxicity is described. Latest diagnostic and monitoring techniques for glaucoma include SD-OCT, DARC and IOP telemetry. Current and emerging medical and surgical treatments in glaucoma are discussed. Rho kinase inhibitors have the potential to both lower IOP and also provide neuroprotection, several of which are in clinical trials. Several other new medical treatments such as calcium channel blockers and neurotrophic agents also have the capacity to provide neuroprotection. Minimally Invasive Glaucoma Surgery (MIGS) devices provide an improved safety profile compared to traditional trabeculectomy; the latest ab interno and ab externo devices are described. Novel drug delivery methods, including punctual plugs and contact lenses, help overcome the challenges with patient adherence. CONCLUSION: The ultimate goals are to reduce the individual patient risk factors associated with glaucoma, diagnose the condition early and to find treatments that not only reduce IOP but also reverse neurodegeneration of RGCs. The usage of combinations of novel medical and surgical treatments may help maximize IOP reduction and neuroprotection

Ophthalmic sensing technologies for ocular disease diagnostics

Point-of-care diagnosis and personalized treatments are critical in ocular physiology and disease. Continuous sampling of tear fluid for ocular diagnosis is a need for further exploration. Several techniques have been developed for possible ophthalmological applications, from traditional spectroscopies to wearable sensors. Contact lenses are commonly used devices for vision correction, as well as for other therapeutic and cosmetic purposes. They are increasingly being developed into ocular sensors, being used to sense and monitor biochemical analytes in tear fluid, ocular surface temperature, intraocular pressure, and pH value. These sensors have had success in detecting ocular conditions, optimizing pharmaceutical treatments, and tracking treatment efficacy in point-of-care settings. However, there is a paucity of new and effective instrumentation reported in ophthalmology. Hence, this review will summarize the applied ophthalmic technologies for ocular diagnostics and tear monitoring, including both conventional and biosensing technologies. Besides applications of smart readout devices for continuous monitoring, targeted biomarkers are also discussed for the convenience of diagnosis of various ocular diseases. A further discussion is also provided for future aspects and market requirements related to the commercialization of novel types of contact lens sensors