Lains I, Mendez KM, Gil JQ, Miller JB, Kelly RS, Barreto P, Kim IK, Vavvas DG, Murta JN, Liang L, Silva R, Miller JW, Lasky-Su J, Husain D.
Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration. J Clin Med 2022;11(4)
AbstractWe and others have shown that patients with different severity stages of age-related macular degeneration (AMD) have distinct plasma metabolomic profiles compared to controls. Urine is a biofluid that can be obtained non-invasively and, in other fields, urine metabolomics has been proposed as a feasible alternative to plasma biomarkers. However, no studies have applied urinary mass spectrometry (MS) metabolomics to AMD. This study aimed to assess urinary metabolomic profiles of patients with different stages of AMD and a control group. We included two prospectively designed, multicenter, cross-sectional study cohorts: Boston, US (n = 185) and Coimbra, Portugal (n = 299). We collected fasting urine samples, which were used for metabolomic profiling (Ultrahigh Performance Liquid chromatography-Mass Spectrometry). Multivariable logistic and ordinal logistic regression models were used for analysis, accounting for gender, age, body mass index and use of AREDS supplementation. Results from both cohorts were then meta-analyzed. No significant differences in urine metabolites were seen when comparing patients with AMD and controls. When disease severity was considered as an outcome, six urinary metabolites differed significantly (p < 0.01). In particular, two of the metabolites identified have been previously shown by our group to also differ in the plasma of patients of AMD compared to controls and across severity stages. While there are fewer urinary metabolites associated with AMD than plasma metabolites, this study identified some differences across stages of disease that support previous work performed with plasma, thus highlighting the potential of these metabolites as future biomarkers for AMD.
Li Y, Hall NE, Pershing S, Hyman L, Haller JA, Lee AY, Lee CS, Chiang M, Lum F, Miller JW, Lorch A, Elze T.
Age, Gender, and Laterality of Retinal Vascular Occlusion: A Retrospective Study from the IRIS® Registry. Ophthalmol Retina 2022;6(2):161-171.
AbstractPURPOSE: Retinal vascular occlusion is a leading cause of profound irreversible visual loss, but the understanding of the disease is insufficient. We systematically investigated the age, gender, and laterality at the onset of retinal artery occlusion (RAO) and retinal vein occlusion (RVO) in the Intelligent Research in Sight (IRIS®) Registry. DESIGN: Retrospective registry cohort. PARTICIPANTS: Patients with retinal vascular occlusion participating in the IRIS® Registry. METHODS: Patients who received a diagnosis of retinal vascular occlusion between 2013 and 2017 were included. Those with unspecified gender or laterality were excluded when conducting the relevant analyses. Patients were categorized into RAO, with subtypes transient retinal artery occlusion (TRAO), partial retinal artery occlusion (PRAO), branch retinal artery occlusion (BRAO), and central retinal artery occlusion (CRAO), and into RVO, with subtypes venous engorgement (VE), branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO). Age was evaluated as a categorical variable (5-year increments). We investigated the association of age, gender, and laterality with the onset frequency of retinal vascular occlusion subtypes. MAIN OUTCOME MEASURES: The frequency of onset of RAO and RVO subtypes by age, gender and laterality. RESULTS: A total of 1 251 476 patients with retinal vascular occlusion were included, 23.8% of whom had RAO, whereas 76.2% had RVO. Of these, 1 248 656 and 798 089 patients were selected for analyses relevant to gender and laterality, respectively. The onset frequency of all subtypes increased with age. PRAO, BRAO, CRAO, and CRVO presented more frequently in men (53.5%, 51.3%, 52.6%, and 50.4%, respectively), whereas TRAO, VE, and BRVO presented more frequently in women (54.9%, 56.0%, and 54.5% respectively). All RAO subtypes and BRVO showed a right-eye onset preference (TRAO, 51.7%; PRAO, 54.4%; BRAO, 53.5%; CRAO, 53.4%; and BRVO, 51.0%), whereas VE and CRVO exhibited a left-eye onset preference (53.3% and 50.9%, respectively). CONCLUSIONS: Although retinal vascular occlusion incidence increases with age regardless of subtypes, we found various subtype-specific disease-onset differences related to gender and, in particular, ocular laterality. These findings may improve understanding of the specific cause of retinal vascular occlusions of different subtypes and their relationships with structural and anatomic asymmetries of the vascular system.
Lin JB, Halawa OA, Husain D, Miller JW, Vavvas DG.
Dyslipidemia in age-related macular degeneration. Eye (Lond) 2022;36(2):312-318.
AbstractLipid-rich drusen are the sine qua non of age-related macular degeneration (AMD), the leading cause of blindness in older adults in the developed world. Efforts directed at uncovering effective therapeutic strategies have led to the hypothesis that altered lipid metabolism may play a pathogenic role in AMD. This hypothesis is supported by the fact that: (1) drusen, the hallmark histopathologic feature of AMD, are composed of lipids, (2) polymorphisms of genes involved in lipid homeostasis are associated with increased odds of AMD, (3) metabolomics studies show that patients with AMD have alterations in metabolites from lipid pathways, and (4) alterations in serum lipid profiles as a reflection of systemic dyslipidemia are associated with AMD. There is strong evidence that statins, which are well described for treating dyslipidemia and reducing risk associated with cardiovascular disease, may have a role for treating certain cohorts of AMD patients, but this has yet to be conclusively proven. Of interest, the specific changes in serum lipoprotein profiles associated with decreased cardiovascular risk (i.e., high HDL levels) have been shown in some studies to be associated with increased risk of AMD. In this review, we highlight the evidence that supports a role for altered lipid metabolism in AMD and provide our perspective regarding the remaining questions that need to be addressed before lipid-based therapies can emerge for specific cohorts of AMD patients.
Lužnik Marzidovšek Z, Blanco T, Sun Z, Alemi H, Ortiz G, Nakagawa H, Chauhan SK, Taylor AW, Jurkunas UV, Yin J, Dana R.
The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critical for Corneal Endothelial Cell Protection and Graft Survival after Transplantation. Am J Pathol 2022;192(2):270-280.
AbstractCorneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.