Photobiomodulation & Ketogenic Diet for Treatment of Mid-periphery Retinal Disorders for Alzheimer's Disease Prevention

As part of the central nervous system (CNS), the retina shares key structural and functional features with the brain, making it a potential portal into a patient's medical future. Since the cerebral and retinal microvasculature are strikingly similar, the condition of retinal vasculature has been considered a proxy for cerebral vascular health. Retinal nerve fiber layer thinning, loss of retinal ganglion cells and optic disc changes may be associated with Alzheimer's disease (AD). Additionally, drusen formation in the macula has been shown to potentially predict AD severity. While the macula has been the primary focus of research for retinal abnormalities, the peripheral retina may be the earliest predictor of neurodegeneration via dry AMD (age-related macular degeneration) and diabetic retinopathy (DR). Ultra-widefield (UWF) retinal imaging has been shown to identify early biomarkers for AD and its progression. Peripheral hard drusen formation and changes to the vasculature beyond the posterior pole are associated with the pathogenesis of AD. A recent clinical trial found a significantly higher prevalence of the hard drusen phenotype within the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%)[p = 0.04]. Analyzing the peripheral retina for biomarkers of neurodegeneration such as drusen formation and vascular pathology offers a foundational diagnostic standard for preventative care. The proposed intervention purposes to inhibit the pro-inflammatory cascade in the retinal and cerebral vasculature via restoration of mitochondrial signaling, metabolic substrate flexibility and reduction of oxidative stress using a clinically prescribed ketogenic dietary protocol concurrent with photobiomodulation.

Deterioration in metabolic energy pathways is a prominent feature of AD, Parkinson's disease (PD), retinitis pigmentosa (RP), diabetic retinopathy, dry AMD, glaucoma and cerebellar atrophy. Common etiological mechanisms of neurodegenerative disorders of the eye and the CNS include mutations in the DJ-1 and Myc-Modulator (MM-1) genes and impaired mitochondrial signaling. Photobiomodulation (PBM) therapy, pulsating frequencies of 660nm and 810nm, has been shown to generate vasoprotective, neuroprotective, immunomodulatory and regenerative effects on mitochondrial function, cellular respiration, and improve retinal and cerebral vascularity. Recent studies have shown significant outcomes using PBM in the treatment of AMD, diabetic retinopathy, Stargardt disease, Leber's hereditary optic neuropathy, Parkinson's disease and Alzheimer's disease. Common to the etiology of each of these disease states is oxidative stress, an inflammatory cascade and activation of apoptotic pathways. Photobiomodulation proves to be both pro-oxidant in the short-term and antioxidant in the long term to potentiate a hormetic dose response. Likewise, PBM modulates inflammation via the immune regulatory pathways, reduces risk for retinal vascular dysfunction and offers protection from photoreceptor cell death. In primary astrocytes, improved immune regulation attenuates cerebral inflammation and oxidative stress induced by beta amyloid and initiates reparative action on protein misfolding by activating/modulating metabolic control over folding/unfolding.

Neuro-modulatory outcomes are well documented for ketogenic nutritional protocols; most recently, dietary ketosis has been shown to mediate Type 2 Diabetes Mellitus (T2DM), significantly reduce systemic inflammation, restore endocrine homeostasis and improve peripheral and cerebral insulin sensitivity. A recent study demonstrating the neuroprotective effects of a ketogenic diet on glaucoma suggests that increased insulin sensitivity protects retinal ganglion cell structure and function, reduces NF-KB p65 nuclear translocation and inhibits expression of pro-inflammatory molecules. The 8-week ketogenic nutritional intervention resolved energy demand and ameliorated inflammation by stimulating HCAR1-ARRB2 (Hydroxycarboxylic acid receptors-Arrestin beta -2) signaling pathways.

The rapidly increasing demand for healthcare among America's aging population warrants novel, integrative strategies focused on non-invasive treatments to ensure patient compliance and maximize health span concurrent with lifespan. Photobiomodulation therapy combined with multidisciplinary lifestyle modifications, such as ketogenic nutritional protocols, offered to patients in the optometry setting provides a viable therapeutic approach for healthcare providers on the front-line of diabetes care. The PBM intervention features both a diagnostic tool for prevention and a treatment model for retinal/cerebral microvasculature diseases common to aging: AD, PD, diabetic retinopathy, AMD, glaucoma and retinitis.

The study will explore the impact of photobiomodulation, pulsating at frequencies of red (660nm) and near-infrared (810nm), concurrent with a ketogenic dietary protocol (serum ketones @ .5 - 2.0 mmol/L) to mediate vascular features of diabetic retinopathy, diabetic macular edema, age-related macular degeneration (AMD), mid-peripheral drusens, visual acuity and retinal disorders. Red and near-infrared light (NIR) via light-emitting diode (LED) treatment promotes retinal healing and improves visual acuity by augmenting cellular energy metabolism, enhancing mitochondrial function, increasing cytochrome C oxidase activity, stimulating antioxidant protective pathways and promoting cell survival. LED therapy directly benefits neurons in the retina, the lateral geniculate nucleus and the visual cortex; likewise, a ketogenic dietary protocol shows metabolic and neuro-modulatory benefits within the CNS, most notably as treatment for refractory epilepsy. Photobiomodulation has been approved as a non-significant risk (NSR) modality for the treatment of eye disorders.