Macula Society 2023: Evangelos S. Gragoudas Award and Lecture

Inês Laíns, MD, PhD
Massachusetts Eye and Ear
Boston, MA

Dr. Inês Laíns was awarded the prestigious Evangelos S. Gragoudas Award at the 2023 Macula. Society Meeting in Miami, Florida for her work entitled “Plasma Metabolomic Profiles Associated with Progression of Age-Related Macular Degeneration.”  Congratulations!

Why did you develop this study?

Laíns: As many of the readers know, age-related macular degeneration (AMD) remains a leading cause of blindness worldwide. Clinically, some patients remain very stable for years, while others progress to the late blinding forms of AMD. The reasons behind this variability remain poorly understood. Several genetic and environmental factors have been linked to AMD progression. However, their interlinks and functional consequences remain only partially understood. This has important consequences for clinical care. Namely, there are currently limited strategies to halt AMD progression and treat the non-exudative forms of AMD. We need a better understanding of the pathophysiology of AMD progression to be able to develop new treatment targets.

Our group hypothesized that plasma metabolomics, the qualitative and quantitative analysis of metabolites (<1-1.5 KDa), could contribute to address these challenges. Metabolites are the downstream product of the genome and its interaction with environmental exposures; therefore, the metabolome is thought to closely relate to disease phenotype, especially in multifactorial diseases, such as AMD. Indeed, our group and others had previously described that patients with AMD have a distinct plasma metabolomic profile as compared to controls. To our knowledge, no prior studies have evaluated how plasma metabolomic profiles relate to AMD progression. The goal of this study was to analyze the association between plasma metabolomic profiles and progression of AMD over a three-year period.

How was the study designed?

Laíns: This was a prospective longitudinal study including patients with early or intermediate AMD and a control group. All study participants had a complete ophthalmological exam and imaging at baseline and three years later. At both study visits, fasting blood samples were collected and processed for metabolomic profiling, which was done by Metabolon, Inc using mass spectrometry. AMD progression was defined as any change at three-years in AMD status based on color fundus photographs. Additionally, we also assessed associations between plasma metabolomic profiles and changes in rod-mediated dark adaptation (DA), a promising functional outcome in AMD.

What did we find?

 Laíns: Our results revealed that both baseline levels and three-year changes of metabolites in the (i) pentose and glucoronate interconversions pathway and (ii) pregnenolone steroids were associated with AMD progression. The association of metabolites in the pentose and glucoronate interconversions pathway with progression of AMD is an interesting finding, and points to the role of oxidative stress in the pathogenesis of this disease. The pentose phosphate pathway is thought to represent a primary source of nicotinamide adenine dinucleotide phosphate (NADPH) in the retina, and studies have shown that, when this pathway is disturbed, the antioxidant capacity of the RPE cells is impaired. Our findings on associations between levels of androgenic and pregnanediol steroids and AMD progression at 3 years also point to the role of oxidative stress in this disease. Sex hormones are produced in the retina and estrogens are believed to have an antioxidant and anti-inflammatory role, while testosterone, progesterone and their metabolites appear capable of modulating neurotransmission.

Additionally, we used dark adaptation as a functional outcome and observed that baseline and changes in glutamine and in the alanine, aspartate and glutamate pathway were associated with 3-year changes in DA. These findings are not surprising given that consistent work has shown that changes in metabolites in the glutamate pathway are seen in AMD. Additionally, previous studies have described that glutamate can induce rod apoptosis. Glutamate is an important excitatory neurotransmitter for the visual pathway, including the retina. However, through excitotoxicity, it can lead to rod photoreceptor cell death, which is at least partially mediated by oxidative stress.

What is the take home message?

Laíns: In summary, this work suggests that baseline plasma metabolites and changes in plasma metabolites are associated with AMD progression at 3 years, and that metabolomics can be an useful tool to better understand the pathophysiology of AMD progression. In particular, while several metabolomic pathways were identified, all of them have a converging biological link to oxidative stress. This suggests that oxidative stress may play a particularly important role in the progression of AMD both at a structural and functional level. Further studies with larger sample sizes and longer follow-up periods are required to clarify the results of this pilot work, and hopefully to help identifying potential therapeutic targets for this blinding disease.