Age-related Macular Degeneration (AMD) Clinical Trial
Official title:
Photobiomodulation & Ketogenic Diet for Treatment of Mid-periphery Retinal Disorders (Diabetic Retinopathy, Dry AMD, Hard Drusen Formation) for Alzheimer's Disease Prevention
The study will explore the impact of photobiomodulation (PBM), pulsating at frequencies of red (660nm) and near-infrared (810nm)(NIR), concurrent with a ketogenic dietary protocol (serum ketones @ .5 - 2.0 mmol/L) to mediate vascular features of diabetic retinopathy (DR), diabetic macular edema (DME), age-related macular degeneration (AMD), mid-peripheral drusens, visual acuity and retinal disorders. Red and near-infrared light 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.
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.
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