AS747 - Metabolomics and the Prospective analysis of age-related macular degeneration and the structural integrity of the retina

Investigator Names and Contact Information

Amy Millen (aemillen@buffalo.edu)

Introduction/Intent

SPECIFIC AIMS

The global burden of age-related vision impairment and vision loss is increasing as the world population ages.¹ Vision loss leads to reduced independence and work productivity, as well as increased depression and falls. Vision-threatening age-related macular degeneration (AMD) is a leading cause of vision loss in aging adults,² and it is estimated it will increase from 2 to 5.4 million from 2010 to 2050.³ Adherence to healthy dietary patterns⁴ is consistently shown to be associated with reduced risk of progression of AMD to vison loss.^5-11 And, findings from the Age-Related Eye Disease Study (AREDS) Clinical Trials have established that use of a high-dose antioxidant supplement formula is an effective clinical treatment to reduce blindness from AMD.¹² Together these findings have elucidated that foods and nutrients play a significant role in AMD progression. Researchers have identified metabolomic biomarkers of healthy diet patterns¹³ and metabolites have been associated with the consumption of healthy diet patterns, such as the Mediterranean diet, in observational studies.^14-19 Biomarkers are not prone to the same measurement error as dietary assessment tools such as food frequency questionnaires, food records, or 24-hour recalls.²⁰ Several studies have shown that there are differentiating metabolomic profiles between individuals with and without AMD;^21-29 however, these studies have not examined metabolites using a hypothesis-driven approach focused on diet. And, only one study of metabolomics and AMD was prospective, a small clinical study.²³

We propose to efficiently leverage existing resources from a well-characterized, prospective cohort study, the Carotenoids in Age-Related Eye Disease Study (CAREDS), to examine prospective associations between metabolomic signatures indicative of differentiating dietary patterns and the 15-year progression of AMD, 15-year changes in macular pigment optical density (MPOD), and assessment of retinal structural integrity 15 years later. CAREDS was designed to investigate the association between nutrition and AMD,³⁰ and is an ancillary study of the Women’s Health Initiative Observational Study. CAREDS baseline was conducted from 2001-2004 with a 15-year follow-up from 2016-2019 (CAREDS2). We have retinal photographs, measures of MPOD, and assessment of diet at baseline and follow-up. MPOD is a measure of retinal macular pigment concentrations comprised of carotenoids lutein and zeaxanthin and hypothesized to be inversely associated with reduced risk of AMD.³¹ Ocular coherence tomography (OCT) was conducted at follow-up and used to measure the thickness of retinal layers such as the ganglion cell complex (GCC) and the retinal nerve fiber layer (RNFL), both indicators of the structural integrity of the neurosensory retina.^32,33 Stored serum samples from 1997-2001, overlapping in time to CAREDS baseline from 2001-2004, will be assessed for metabolites with mass spectrometry (aqueous panel, lipid panel, and customized carotenoid analysis). We will derive healthy Metabolomic Dietary Pattern Scores (MDPS) using data reduction of a set (n=71) of pre-identified metabolomic markers of food and nutrient intake from feeding studies. We will also explore differences in the full spectrum of metabolites available on the panels (n~1,800) by quintile of each MDPS.

No studies of metabolomics and AMD include a full spectrum of the type and stage of AMD phenotypes, as well as these other indicators of retinal health. Research in CAREDS supports a role for diet in AMD, MPOD, and the structural integrity of the neurosensory retina, and our preliminary data shows we can derive MDPS in WHI OS participants. Our overarching hypothesize is that increasing healthy MDPS will be associated with a decreased risk of AMD, increased MPOD, and increased GCC and RNFL thickness. This study will deepen our understanding of associations between diet and retinal health independent from potential biases associated with self-reported dietary intake. Specifically, using data from the prospective CAREDS cohort, we propose to examine the associations between MDPS and:

• Aim 1: prevalent AMD at baseline (n=1,874) and the incidence of AMD over 15 years (n=706),
• Aim 2: MPOD at baseline (n=1,698) and changes in MPOD over 15 years (n=429), and
• Aim 3: the structural integrity of the neurosensory retina indicated by the thickness of the RNFL and GCC of the macula measured at the 15-year follow-up exam (n=473).

Findings from this proposed study will help us to identify novel dietary metabolites and metabolic pathways associated with the progression of AMD and the maintenance of the integrity of the retina with aging. Such findings could be used in a clinical setting to help identify patients most at risk for future development of retinal degeneration; help personalize the recommendations for dietary prevention in AMD. This robust study could provide a foundation of evidence needed to probe certain metabolites and their associated metabolic pathways for therapeutic interventions in drug trials or supplementation trials related to the maintenance of the integrity of the retina central to vision functioning.