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A study published in Cell Reports Medicine examined the role of homocysteine in glaucoma development and progression, including models of glaucoma, clinical data, and Mendelian randomization, and suggests that several B vitamins have a promising role as neuroprotective agents. Homocysteine elevations have been linked to a number of neurodegenerative diseases, but it has been difficult to determine if it is a causative agent or a biomarker for other pathological processes (or nutrient deficiencies), as evidence exists for both. Several studies suggest that people with glaucoma have higher homocysteine levels compared to controls, but the evidence has been mixed, with this recent study offering new insight into its role, as well as that of one-carbon metabolism.
One of the initial experiments described in this study involved intravitreal injection of various concentrations of homocysteine to determine the effect in models on retinal ganglion cells (RGCs), the cells whose dysfunction and death characterize glaucoma. Even at a very high physiological level, only a mild worsening of RGCs was observed, with no effect on intraocular pressure. This suggested that homocysteine itself was unlikely to drive the degradation of RGCs, though it may have subtle effects, including vascular dysfunction.
Next, this group performed a Mendelian randomization analysis to determine if genetic variants that are associated with serum homocysteine levels would affect susceptibility to glaucoma. This included 14 single-nucleotide polymorphisms (SNPs) in the MTHFR (methylenetetrahydrofolate reductase), MMACHC (vitamin B12 metabolism), MTR (methionine synthase), and other relevant genes, and included data for over 216,000 people for primary open-angle glaucoma, nearly 140,000 for intraocular pressure, and other related conditions. A genetic increase in homocysteine levels was not associated with glaucoma or any of the related conditions, suggesting that homocysteine may not be a driver of RGC dysfunction.
They also performed a secondary analysis of a large randomized clinical trial (United Kingdom Glaucoma Treatment Study) to determine if homocysteine levels were associated with more rapid progression of glaucoma. Here too, no effect was observed, suggesting that homocysteine is not a driver for glaucoma progression.
However, they also evaluated gene expression in another glaucoma model and found significant dysregulation of genes involved in one-carbon metabolism, i.e., pathways of transferring carbon, such as methylation, including the re-methylation of homocysteine to methionine. This dysregulation occurred early in the disease and continued through both moderate and severe disease. A comparison between healthy controls and people with glaucoma using single-cell RNA sequencing also pointed to dysregulated one-carbon metabolism, including dysregulation of genes involved in the activation of vitamin B6, the transport and metabolism of vitamin B12, as well as the metabolism of folate and choline in the retina.
Overall, this indicates that homocysteine may not be the driver of glaucoma, but instead is a biomarker for dysfunctional one-carbon metabolism, and it is the latter that may play a more direct role in glaucoma pathophysiology. To further test this hypothesis, they found that oral supplementation of B6, folic acid, B12, and choline had a moderately protective effect, increasing RGC survival in both acute and chronic hypertensive models of glaucoma. Lastly, the researchers used data from the UK Biobank to determine if dietary intake of the three B vitamins (data for choline were not available) was associated with glaucoma outcomes. No association between glaucoma incidence was observed, possibly limited by the use of 24-hour dietary recalls, known for inconsistencies.
Thus, the next step is a randomized clinical trial to evaluate the effectiveness of the supplementation of these vitamins for glaucoma, which has not yet been done. Indeed, no clinical trials evaluating the use of any of these vitamins for glaucoma have been conducted. One encouraging piece of data, though, is from a randomized and double-blind placebo-controlled trial evaluating the effect on the incidence of age-related macular degeneration with supplementation of 2.5 mg/d folic acid, 50 mg/d pyridoxine hydrochloride, and 1mg/d cyanocobalamin compared to placebo. This trial included over 5,200 female health professionals with preexisting cardiovascular disease or risk factors and followed them for an average treatment length of just over 7 years. The supplementation was associated with a 34% lower risk of developing macular degeneration during the study period.
Lastly, there has been one clinical trial evaluating a different B vitamin for glaucoma. Published in Clinical & Experimental Ophthalmology, this was a crossover double-blind trial evaluating the use of nicotinamide taken at 1.5 g/d for 6 weeks followed by 3.0 g/day for another 6 weeks (compared to placebo), and included 57 participants with glaucoma. The main outcome of the study was inner retinal function (assessed using electroretinography and perimetry). Although only a short-term study, all of the assessed variables were significantly improved with nicotinamide compared to placebo. Previous research indicates that nicotinamide adenine dinucleotide (NAD) declines in the retina with age, and models of glaucoma found that nicotinamide supplementation corrects much of the associated metabolic dysfunction, improving oxidative phosphorylation, metabolic stress, and even increasing mitochondrial size. Although larger and longer clinical trials are needed, several B vitamins appear quite promising for halting the progression of glaucoma and improving the underlying metabolic dysfunction.
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