Brain-retina axis in neurodegeneration: Metabolic overlaps for diagnosis and therapy

For higher vertebrate embryonic phase of cell development, the brain, spinal cord, retina, and optic nerve form the main interconnected parts of the central nervous system. As cell division occurs, with aging, these complex body parts gradually degenerate, and it rarely affects an organ in isolation.^[1] This complex process is relevant to organs coordinated by a neuron network; therefore, the brain-retina axis is potentially vulnerable to this degeneration, and it is the main cause of cognitive decline and vision loss, leading to a high mortality rate. Increasing evidence shows that the brain and retina are metabolically interconnected,^[2] and many neurodegenerative disorders manifest in both tissues because of the similarity of cell types, metabolic demands, and vulnerability pathways. Because of this, the brain retina undergoes continuous oxidative metabolism and maintains high mitochondrial density. Between these organs is the unfolded protein response (UPR), which maintains protein homeostasis in the endoplasmic reticulum (ER) through the ER stress-induced dysfunction of the inositol-requiring enzyme 1-X-box binding protein 1 pathway regulating protein folding and inflammatory signaling, and protein kinase RNA-like ER kinase-Eukaryotic Initiation Factor 2a pathways, which suppress protein synthesis under stress. Hence, when these pathways are dysregulated, it induce susceptible to metabolic dysfunction, oxidative stress, and impaired immune defense, leading to diabetes pathways.^[3]

The brain neurodegenerative diseases affect the brain cells due to progressive loss of neurons, therefore leading to a decline in cognition and memory of individuals. This condition includes Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, and it affects more than 26 million people in 2006, with majority between middle and old age, and with the number estimated to increase by 4 times by 2050 due to increase in life expectancy.^[1] Similarly, the neuroretina degeneration is a functional indicator of vision loss in diabetic patients, characterized by asymptomatic features before progression, with clinical features used to categorize non-proliferative and proliferative diabetic retinopathy (NPDR and PDR). Both brain neurodegeneration and neuroretina degeneration have diverse morphological manifestations, yet they comprise the cell body, dendrites, and an axon, which form synaptic tight junction architecture and control the microenvironment from immune insult through the blood–brain barrier and blood-retinal barrier, respectively.

With advancement in aging research, the eye represents the window to access the brain pathology using different biomarkers including tau protein, advanced glycation end-product (AGE), vascular endothelial growth factors, and amyloid-b (Ab) deposition in the brain; a landmark of neuropathologic AD diagnosed in the retina, retinal ganglionic cells (RGC), and retinal nerve fiber layer, and these markers is age-dependent.^[4] Furthermore, the brain’s ability to interpret visuals begins from the eye retina, which processes the visual stimuli into electric stimuli by coordination of neurons in the histological layer, i.e., photoreceptors (rods and cones), bipolar cells, amacrine cells, horizontal cells, and RGC. These stimuli, with the help of the optic nerve, reach the lateral geniculate body of the thalamus, which further transmits them to the visual cortex for visual interpretation.

Altogether, the pathologies of both brain-retina neurodegeneration are unique, with imaging requirement that indicates the advancement of modalities such as magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid such as tau and Ab proteins, opening a new frontier of knowledge on how the brain neurodegeneration progresses from the retina indicator. Similarly, neuroretina degeneration is identified using structural imaging modalities such as fundus photography, optical coherence tomography (OCT), and OCT angiography, alongside functional assays including electroretinography and pupillometry. Emerging retinal molecular biomarkers further enhance early detection of structural and functional decline, offering a noninvasive window into brain health. These methods are increasingly used in clinical research.

Currently, there are well-established and documented models of brain neurodegeneration to differentiate types of cognitive and memory decline condition,^[5] but current neuroretina degeneration models rely heavily on models and systems exposed to chemical, dietary, genetic, or surgical stressors developed primarily for NPDR and PDR, often missing the asymptomatic early functional deficit phase of neuroretina decline.^[6] Strategies to expand the new frontier of research on neuroretina degeneration model are underway,^[7] as the functional and structural deterioration of neuroretina has been linked with cognitive decline of brain neurodegenerative disorder through UPR molecular pathways.^[2,3] Thus, using this visual pathway from the eye lens to the retina, across the neuron to the brain can help with mapping of clinically relevant differential metabolic markers for diagnosis of posterior retina and the brain neurodegenerative disorder.

Because neuroretina degeneration affects the working-age population, and brain neurodegeneration is unique to individuals aged 65 and above, brain-retina defect is likely to increase the risk of long-lasting neurodegenerative disease epidemic in the near future, hence the need to improve the diagnosis and therapy of brain-retina neurodegeneration. Across the globe, life expectancy of patients with brain-retina neurodegeneration is significantly reduced compared to healthy patients, and a strong contributing factor to this is aging coupled with diabetes mellitus.^[3] Therefore, brain-retina neurodegeneration may persist across the human lifespan because the current knowledge on the metabolic signature of these comorbidities cannot be captured only based on current imaging modalities used for standardized diagnostic assessment.

Furthermore, the discrepancy between technological capability and clinical implementation reflects the validation gap rather than technical limitations. Although advanced imaging modalities can provide extraordinary resolution and non-invasive assessment capabilities that are useful for brain-retina axis structural diagnosis. However, standardization of both imaging modalities and evaluation of predictive biomarkers remained incomplete, limiting widespread clinical adoption beyond research settings. Therefore, to improve brain-retina axis neurodegenerative therapy, the underexplored molecular metabolic markers shared between the brain and retina must be well established, with the inclusion of imaging and functional screening, essential as a promising clinical tool to validate the progression of brain-retina neurodegenerative disorders for effective therapy.