The inner blood retinal barrier in ocular disease and circadian regulation: its role in age related macular degeneration development and other neuro-ophthalmology disorders

Abstract

Age related macular degeneration (AMD) is one of the most common causes of irreversible sight loss worldwide. The initial pathophysiological events that occur in AMD are poorly understood, with most research focusing on the outer blood retinal barrier (oBRB), choroid and RPE dysfunction. This research is focused on circadian regulation of inner blood retinal barrier (iBRB) permeability, and how dysfunction of this barrier may be one of the initiating events in photoreceptor/RPE stress and AMD development. There is a gap in knowledge of the disease process and an unmet need for an effective therapeutic agent that can target these aberrant processes at an early stage of disease. The tight junction (TJ) protein claudin-5, which cycles in a circadian manner, is thought to be central to the maintenance of iBRB integrity. Fluorescein signal at the macula can act as a proxy for iBRB integrity. Previous work has shown that there is a circadian associated fluorescein signal differential present in young healthy controls under 30 years. An increased fluorescein signal at the macula is present in the evening compared to the morning in this group. Results from this research show this is not present in age matched controls and AMD participants suggesting that the circadian dependant iBRB kinesis present in younger people may decrease with ageing and may be further decreased or arrested fully in AMD. We believe this may be one of the early initiating factors in AMD pathogenesis. A more permanently open or "leaky" iBRB may contribute to increased photoreceptor/RPE stress and commence the cycle of pathophysiological events leading to AMD development. Claudin-5 is the dominant TJ protein not only in the iBRB but also in the blood brain barrier (BBB). Some neurological diseases have demonstrated abnormal and increased BBB permeability. It follows therefore due to the molecular similarities between the BBB and iBRB, dysfunction in iBRB permeability may also be evident in these conditions. The healthy young control dataset from the IRCP allows a comparison between iBRB permeability in these neurological conditions and healthy controls. Visual Snow (VS) syndrome is a condition defined by the subjective reporting of constant positive visual phenomenon or "static background" in both eyes. No assessment of the iBRB is evident in the literature. We therefore carried out ocular assessment and imaging of participants with VS symptoms. We have observed an increased permeability of the iBRB when compared to healthy young controls. In conclusion, the iBRB permeability is highly dynamic in many conditions including AMD and VS, and that abnormal permeability may be a significant factor in the pathogenesis of these conditions. Studies have also begun investing the role of the iBRB in other neuro ophthalmology conditions such as Tuberous Sclerosis, traumatic brain injury and other rare neurological conditions.