Biological rationale linking Retinal AF to disease
The retina is a part of the central nervous system, originating as an outgrowth of the developing brain and shares many similarities with the brain. The retina is easily accessible for direct and noninvasive imaging with high spatial resolution and sensitivity, providing an ideal diagnostic target.15,16 It has been shown that Aβ plaques occur in the retinas in addition to the brains of Alzheimer’s sufferers, and furthermore exhibit autofluorescence that is easily visible with slightly modified standard ophthalmic equipment. There is potential to visualize amyloid at an earlier point in disease progression based on histologic evidence showing retinal amyloid's existence in early-state cases of disease. 17
Aβ appears in the neural retina due to the same processing pathways of amyloid precursor protein (APP) into amyloid beta fragments as occurs in the brain18. In the retina, APP is synthesized by retinal ganglion cells.19,20 In addition to the production of Aβ in place, the connection of the retina and brain via the optic nerve presents the possibility of retrograde (or anterograde) transport of intracellular amyloids and APP.
The presence of amyloid beta in the neural retina of Alzheimer’s patients has been demonstrated by multiple research groups. In 2011, Koronyo et al. reported that Aβ plaques were present in the retina of subjects who had postmortem confirmation of AD diagnosis using histology. Their work used immunohistochemistry labeling of Aβ in the retina and found plaque concentrations and morphology similar to those in the brain, in stark contrast with the absence of plaques in the retinas and brains of a group of non-AD subjects.
In an independent study of 16 post mortem eyes and brains from 16 donors with neurological disorders, including 13 with AD, Campbell et al. report that amyloid deposits were present in all the AD eyes and neither of the two non-AD eyes.21 Subsequently Campbell et al. reported that retinal amyloid had a 100% sensitivity for AD in a group of matched eyes and brains from 26 donors analyzed post mortem.15 Campbell’s method was analogous to Koronyo et al. in that ex vivo staining of human retinas was conducted on retinal flat mounts and the retinal area surveyed for evidence of Aβ.
In 2017 Koronyo et al. published further work showing the strong correlation between retinal and cerebral plaque load in AD subjects and non-AD matched controls, and the significantly larger retinal amyloid burden in AD subjects versus controls, using post-mortem histology. In addition, retinal autofluorescent imaging was used for the first time qualitatively and quantitatively to demonstrate with high significance that both autofluorescent spot quantity and spot intensity was greater in AD patients than in younger, healthy controls.23
Additional studies have further demonstrated the potential for retinal AF measurement as a diagnostic tool in AD. In a feasibility study, Ngolab et al. showed that retinal AF quantification correlated in a strong and positive way with amyloid PET standardized uptake value ratio (SUVr), and clearly separated amyloid positive from amyloid negative subjects.24 Retinal AF quantification was shown by Dumitrascu et al. to correlate negatively with hippocampal volume and positively with increasing cognitive decline as measured by standardized cognitive tests.25 Kile et al. showed the feasibility of using retinal AF to detect changes in cerebral amyloid for patients undertaking an AD disease modifying therapy.26
Retinal Autoflourescence Measurement
NeuroVision Imaging, has developed a first of its kind, groundbreaking eye imaging system for measuring autofluorescence (AF) in the retina – Afina® Retinal Autofluorescence Measurement Software coupled with the Retia™ AF retinal camera. The Afina software is a medical device intended to import autofluorescence images of the retina from a qualified ophthalmic camera and then process those images to highlight areas of brighter autofluorescence relative to the background autofluorescence of the retina. The areas of brighter autofluorescence (spots) are counted as well as the total count of the pixels with brighter autofluorescence. Afina and Retia are market cleared by FDA in the United States.
Sources of autofluorescence in the fundus that can be detected:
- The main source of autofluorescence in the fundus is lipofuscin (LF) in the retinal pigment epithelium (RPE).17 LF is a byproduct of the visual cycle degradation pathway and is resistant to enzymatic degradation. Although a normal part of retinal metabolism, various physiological conditions or pathologies can accelerate the rate at which LF accumulates. This makes the presence of lipofuscin a potential early indicator of degenerative retinal diseases.
- Drusen, which consist primarily of lipofuscin, can be expected to produce hyperfluorescent spots. However, their location underneath the RPE means their signal is heavily modulated by the melanin in the RPE. The primary effect of drusen under an intact RPE is to physically distort the RPE layer, resulting in a distorted RPE AF signal.
- Amyloid beta is deposited in the inner retina and around the retinal vessels and exhibits fluorescence in the visible range.28 In particular, full-length amyloid beta (AB1-42) exhibits blue light (>420) autoflurorescence in senile plaques and cerebral amyloid angiopathy (truncated deposits do not). 29
- Collagen and elastin proteins in the sclera and choroid can contribute to the AF signal of patients with geographic atrophy (GA), where the RPE has failed and is absent in places. The contribution of these proteins to AF can be around 6% for dark-pigmented humans and 15% for light-pigmented humans.30
- Vitelliform lesions form round yellow, retinal lesions consisting of shed outer segment debris in the extracellular space. They accumulate between the photoreceptor tips and the RPE. This is a lipofuscin-like material anterior to the RPE. 31
- Optic disc drusen consist of extracellular mitochondria in a protein matrix that if superficial, may produce AF. 31
Autofluorescent (AF) amyloid beta (Aβ) deposits appear in the retina concurrently with the brain and can be imaged non-invasively with a high-resolution ophthalmic instrument16, and there is potential to visualize amyloid at an earlier point in disease progression based on histologic evidence showing retinal amyloid’s existence in early-stage cases of disease – probable and possible Alzheimer’s Disease.10 Retinal amyloid assessment of brain amyloid status has potential clinical utility in patients being evaluated for dementia when used as a screening test to help identify those who may require an amyloid PET scan for ruling out an Alzheimer’s diagnosis, and for helping identify subjects for inclusion in clinical studies.
Color Fundus Image Analysis
NeuroVision is developing another AI software product intended for importing, processing and displaying of retinal images and for the measurement of ocular features in those images of the retina, with the goal of allowing doctors to practice best-in-class medicine through better identification and management of retinal diseases. There are many diseases that may affect the a person's eyesight. Two of the most prevalent are age-related macular degeneration and diabetic retinopathy, which combine to cause loss of eyesight in millions of people worldwide. The earliest signs of each disease are very small abnormalities that develop in the retina. Robust image processing and analysis has the potential to allow for early retinal disease detection. Enhanced visualization and quantification of abnormal retinal features may improve single visit identification as an aid in diagnosing and monitoring of disease over time.
Color Fundus Image
Green-channel with bright and dark abnormal retinal features segmented
Investigational Device(s). Limited by Federal (or United States) law to investigational use.