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

February 28, 2019 updated by: Bristlecone Health, Inc.

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Male or Female (age 18-80)

Previously diagnosed with MetS and/or T2DM as measured by possessing at least 2 of the following physiological measures: type II diabetes, BMI >30, HgA1c > 5.7, waist/height ratio >.6, fasting glucose > 125

Previously diagnosed with at least one of the following: mid-peripheral drusen formation, diabetic retinopathy (DR), age-related macular degeneration (AMD) or diabetic macular edema

Exclusion Criteria:

Previously diagnosed with Alzheimer's disease (AD), dementia or Parkinson's disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental group
Subjects in the experimental group will receive clinically prescribed meal plans designed to facilitate prolonged benign dietary ketosis (BDK) purposed at glucose regulation, improved insulin sensitivity and restored metabolic flexibility. Photobiomodulation therapy, via Joovv red light/infrared LED device, will be administered three times per week, 20 minutes per session.
Behavioral: Photobiomodulation
Photobiomodulation therapy, via Joovv red light/infrared LED device, three days/week, 20 minutes per session for experimental and control groups.
Behavioral: Ketogenic diet
Experimental group will follow a clinically prescribed ketogenic diet.
Active Comparator: Control group
Subjects in the control group will follow current dietary protocol (Standard American Diet- SAD). Photobiomodulation therapy,via Joovv red light/infrared LED device, will be administered three times per week, 20 minutes per session.
Behavioral: Photobiomodulation
Photobiomodulation therapy, via Joovv red light/infrared LED device, three days/week, 20 minutes per session for experimental and control groups.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Diabetic Retinopathy (DR) pathology
Time Frame: 36 weeks
Improvement in number and severity of hemorrhages and hard and soft exudates as measured by the Daytona Plus (Panoramic Ophthalmoscope P200T)
36 weeks
Diabetic Macular Edema (DME) pathology
Time Frame: 36 weeks
Lower incidence of macular edema as measured by Optos Daytona Plus (Panoramic Ophthalmoscope P200T) and Optovue XR Avanti 3 OCT (Ocular Coherence Tomography) Imaging Systems
36 weeks
Dry Age-related Macular Degeneration (AMD) pathology
Time Frame: 36 weeks
Reduction in size and number of drusen in early and intermediate stages of Dry AMD pathology as measured byOptos Daytona Plus (Panoramic Ophthalmoscope P200T) and Optovue XR Avanti 3 OCT (Ocular Coherence Tomography) Imaging Systems
36 weeks
Hard Drusen in the Mid-periphery pathology
Time Frame: 36 weeks
Reduction in size and/or density of drusen as measured by the Optos Daytona Plus (Panoramic Ophthalmoscope P200T)
36 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
HgA1c
Time Frame: 36 weeks
Assessment of changes in HgA1c (Hemoglobin A1c) over time. Ranges: <5.7%
36 weeks
Fasting Insulin
Time Frame: 36 weeks
Assessment of changes in fasting insulin over time. Ranges: < 2.6-11.1 mU/L
36 weeks
Fasting Glucose
Time Frame: 36 weeks
Assessment of changes in fasting glucose over time. Ranges 74-100 mg/dL
36 weeks
HOMA-IR
Time Frame: 36 weeks
Assessment of changes in HOMA-IR over time. Ranges <1.0
36 weeks
Triglycerides/HDL ratio
Time Frame: 36 weeks
Assessment of changes in triglycerides/HDL ratio over time. Ranges <2.0
36 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bristlecone Health, Inc.

Collaborators

University of Minnesota

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 23, 2019

Primary Completion (Anticipated)

September 30, 2020

Study Completion (Anticipated)

September 30, 2020

Study Registration Dates

First Submitted

February 24, 2019

First Submitted That Met QC Criteria

February 27, 2019

First Posted (Actual)

March 1, 2019

Study Record Updates

Last Update Posted (Actual)

March 4, 2019

Last Update Submitted That Met QC Criteria

February 28, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Bristlecone-002

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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