• Flow area
• OCTA
• Pseudoexfoliation syndrome
• Pseudoexfoliative glaucoma
• Vascular density

• Humans
• Exfoliation Syndrome/physiopathology
• Tomography, Optical Coherence/methods
• Cross-Sectional Studies
• Female
• Male
• Aged
• Choroid/blood supply
• Choroid/diagnostic imaging
• Middle Aged
• Retinal Vessels/diagnostic imaging
• Fluorescein Angiography/methods
• Case-Control Studies

• Exfoliation glaucoma
• Exfoliation syndrome
• Genetics
• LOXL1
• Post-GWAS

• Exfoliation Syndrome/genetics
• Exfoliation Syndrome/physiopathology
• Humans
• Genome-Wide Association Study
• Animals

• R01 EY023242 NEI NIH HHS
• R01 EY032960 NEI NIH HHS
• P30 EY031631 NEI NIH HHS
• R21 EY033961 NEI NIH HHS
• R21 EY028671 NEI NIH HHS

• cardiovascular disease
• cerebrovascular disease
• glaucoma
• homocysteine
• loxl-1 gene
• manifestations
• pseudoexfoliative material

• DNA methylation
• Glaucoma
• Pseudoexfoliation
• SNPs
• microRNAs

• Humans
• Exfoliation Syndrome/genetics
• Exfoliation Syndrome/metabolism
• Exfoliation Syndrome/pathology
• Genome-Wide Association Study
• Glaucoma/genetics
• Risk Factors
• Epigenesis, Genetic

• aqueous humor
• exfoliation glaucoma
• glaucoma
• homocysteine
• primary open-angle glaucoma

• R01EY023242 NIH HHS

• Exfoliation syndrome
• GTEx
• GWAS
• TWAS
• predicted expressions
• transcriptomics

• Humans
• Exfoliation Syndrome/genetics
• Exfoliation Syndrome/complications
• Exfoliation Syndrome/metabolism
• Amino Acid Oxidoreductases/genetics
• RNA, Messenger
• Mutation, Missense
• Gene Expression
• Polymorphism, Single Nucleotide
• DNA-Binding Proteins/genetics
• B7 Antigens/genetics

• R35 HG010718 NHGRI NIH HHS
• T32 EY021453 NEI NIH HHS
• 5T32EY021453 T32
• R35HG010718 NIH HHS
• NIH

• metabolomics
• glaucoma
• case-control study

• Aged
• Case-Control Studies
• Cortisone
• Exfoliation Syndrome/diagnosis
• Female
• Follow-Up Studies
• Humans
• Lysophosphatidylcholines
• Male
• Metabolomics
• Phosphatidylethanolamines
• Plasmalogens
• Triglycerides

• R01 EY015473 NEI NIH HHS
• R01 HL123915 NHLBI NIH HHS
• R01 HL155742 NHLBI NIH HHS
• R01 HL141826 NHLBI NIH HHS
• R01 EY020928 NEI NIH HHS
• U01 CA167552 NCI NIH HHS
• UM1 CA186107 NCI NIH HHS

• Inflammation
• neutrophil
• pseudoexfoliation
• red cell distribution width

Exfoliation glaucoma (XFG) is the most recognizable form of secondary open-angle glaucoma associated with a high risk of blindness. This disease is characterized by white flaky granular deposits in the anterior chamber that leads to the elevation of intraocular pressure (IOP) and subsequent glaucomatous optic nerve damage. Conventionally, XFG is known to respond poorly to medical therapy, and surgical intervention is the only management option in most cases. Various genetic and nongenetic factors are known to be linked to the development of XFG. Despite decades of research on the genetic factors in exfoliation syndrome (XFS) by study groups and global consortia involving different ethnic populations, the pathogenesis of XFS and the mechanism of onset of glaucoma still remains an unsolved mystery. The key lies in understanding how the function of a gene (or set of genes) is altered by environmental triggers, along with other molecular events that underlie the key disease attributes, namely, oxidative stress and the disruption of the blood–aqueous barrier (BAB). It remains a challenge to evolve a theory encompassing all factions of molecular events occurring independently or parallelly that determine the disease manifestation (phenotype) or the stage of the disease in the eye (or in any tissue) in exfoliation. Our enhanced understanding of the underlying molecular pathophysiology of XFG, beyond the known genes or polymorphisms involved in the disease, will lead to improved diagnosis and management and the ability to recognize how the environment influences these key events that lead to the disease phenotype or disease progression. This review summarizes the recent observations and discoveries of four key factors that may hold the answers to the non-lysyl oxidase-like 1 (LOXL1) mechanisms behind XFG pathogenesis, namely, the epigenetic factor miRNA, disordered autophagy along with the potential involvement of mitochondrial mutations, and a compromised aqueous–blood barrier.

• Desmosine
• Elastin synthesis
• Extracellular matrix
• Lens capsule
• Lysyl Oxidase
• Pseudoexfoliation syndrome

• biomarkers
• blood serum
• early diagnosis
• eye tissues
• glaucoma
• metabolomics
• ocular fluids
• omics sciences
• proteomics

• Cátedra Rafael del Pino en Oftalmología Fundación Rafael del Pino
• IDE/2019/000289 Gobierno del Principado de Asturias

• Cardiovascular diseases
• Diabetes mellitus
• Exfoliation glaucoma
• Exfoliation syndrome

Pseudoexfoliation syndrome (XFS) is stress- or inflammation-induced elastosis accompanied by excessive production of microfibrils and their deposition in the anterior segment of the eye. Approximately 60–70 million people are affected by XFS worldwide. It is a component of a systemic disorder, considered a major risk factor for accelerated cataract formation, cataract surgery complications and development of glaucoma, which untreated or inadequately treated may lead to blindness. Moreover, XFS has been associated with cardiovascular and cerebrovascular morbidity, dementia, sensorineural hearing loss and pelvic organ prolapse. The pathogenesis of XFS has not been fully elucidated yet. Aqueous humor (AH) is a transparent fluid filling the anterior and posterior chambers of the eye. Determination of AH metabolites that are characteristic for XFS may provide valuable information about the molecular background of this ocular disorder. The aim of this study was to compare the composition of AH in XFS and non-XFS patients undergoing cataract surgery. The AH samples from 34 patients (15 with XFS and 19 without) were analyzed using liquid chromatography coupled to a Quadrupole Time-of-Flight mass spectrometer (LC-QTOF-MS). The obtained metabolic fingerprints were analyzed using multivariate statistics. Eleven statistically significant metabolites were identified. Compared with the non-XFS group, the AH of patients with XFS contained significantly lower levels of amino acids and their derivatives, for example, arginine (−31%, VIP = 2.38) and homo-arginine (−19%, VIP = 1.38). Also, a decrease in the levels of two acylcarnitines, hydroxybutyrylcarnitine (−29%, VIP = 1.24) and decatrienoylcarnitine (−46%, VIP = 1.89), was observed. However, the level of indoleacetaldehyde in XFS patients was significantly higher (+96%, VIP = 2.64). Other significant metabolites were two well-recognized antioxidants, ascorbic acid (−33%, VIP = 2.11) and hydroxyanthranilic acid (−33%, VIP = 2.25), as well as S-adenosylmethionine, a compound with anti-inflammatory properties (−29%, VIP = 1.93). Metabolic pathway analysis demonstrated that the identified metabolites belonged to eight metabolic pathways, with cysteine and methionine metabolism as well as arginine and proline metabolism being the most frequently represented. XFS can be associated with enhanced oxidative stress and inflammation, as well as with the disturbances of cellular respiration and mitochondrial energy production. Implementation of non-targeted metabolomics provided a better insight into the still not fully understood pathogenesis of XFS.

• aqueous humor
• mass spectrometry
• metabolomics
• ophthalmology
• pseudoexfoliation syndrome

• Anterior chamber depth
• Homocysteine
• Pseudoexfoliation
• Pseudoexfoliation glaucoma

• Epigenetics
• Extracellular matrix
• Glaucoma
• Lysyl oxidase like 1
• Pseudoexfoliation

Optical coherence tomography angiography allows a detailed evaluation of retinal and choroidal microvascular structures without the need for a contrast agent. Pseudoexfoliation syndrome is a condition that leads to anatomical and functional losses due to accumulation of degraded abnormal fibrillar material in the intraocular and extraocular tissues. Histopathological studies have shown that the accumulation of Pseudoexfoliation syndrome material in the vascular structures may play a role in different ocular pathologies such as retinal vein occlusion, iris hypoperfusion, anterior segment hypoxia, retinal arterial occlusion, and neovascular glaucoma.

To evaluate and compare flow and vascular density in the retina and choroid in eyes with Pseudoexfoliation syndrome, fellow eyes without Pseudoexfoliation syndrome, and healthy eyes using optical coherence tomography angiography.

Case control study.

The study included 35 eyes with Pseudoexfoliation syndrome of 35 Pseudoexfoliation syndrome patients, 32 fellow eyes without Pseudoexfoliation syndrome of 32 unilateral Pseudoexfoliation syndrome patients, and 35 eyes of healthy control subjects. Flow area and vascular density in the superficial capillary plexus and deep capillary plexus were measured by optical coherence tomography angiography as three separate parameters: total, parafoveal, and foveal. Choroidal thickness and foveal avascular zone area were measured for each patient.

There were significant differences between the Pseudoexfoliation syndrome eyes and control eyes in total, parafoveal, and foveal flow and vascular density in the superficial capillary plexus (p<0.05 for all), while there were no significant differences between these groups in any of the flow or vascular density values in the deep capillary plexus (p>0.05). None of the superficial capillary plexus and deep capillary plexus flow and vascular density values showed significant differences between Pseudoexfoliation syndrome eyes and non-Pseudoexfoliation syndrome fellow eyes or between the non-Pseudoexfoliation syndrome fellow eyes and control eyes (p>0.05). Choroidal thickness was significantly lower in Pseudoexfoliation syndrome eyes compared to control eyes. Foveal avascular zone area was significantly enlarged in Pseudoexfoliation syndrome eyes compared to control eyes in both the superficial and deep layers (p<0.05).

Pseudoexfoliation syndrome eyes exhibit significant damage to the retinal and choroidal vascular structures.

• pseudoexfoliation
• Choroid
• optical coherence tomography angiography
• retina
• vascular structure

Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid homocysteine (Hcy), is implicated in glaucoma, a disease characterized by increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here we analyzed the role of NRF2, a master regulator of the antioxidant response, in Hhcy-induced RGC death in vivo and in vitro. By crossing Nrf2^−/− mice and two mouse models of chronic Hhcy (Cbs^+/- and Mthfr^+/- mice), we generated Cbs^+/-Nrf2^−/− and Mthfr^+/-Nrf2^−/− mice and performed systematic analysis of retinal architecture and visual acuity followed by assessment of retinal morphometry and gliosis. We observed significant reduction of inner retinal layer thickness and reduced visual acuity in Hhcy mice lacking NRF2. These functional deficits were accompanied by fewer RGCs and increased gliosis. Given the key role of Müller glial cells in maintaining RGCs, we established an ex-vivo indirect co-culture system using primary RGCs and Müller cells. Hhcy-exposure decreased RGC viability, which was abrogated when cells were indirectly cultured with wildtype (WT) Müller cells, but not with Nrf2^−/− Müller cells. Exposure of WT Müller cells to Hhcy yielded a robust mitochondrial and glycolytic response, which was not observed in Nrf2^−/− Müller cells. Taken together, the in vivo and in vitro data suggest that deleterious effects of Hhcy on RGCs are likely dependent upon the health of retinal glial cells and the availability of an intact retinal antioxidant response mechanism.

•

Oxidative stress is linked to homocysteine (Hcy)-induced retinal ganglion cell death.

• Cystathionine β-synthase
• Ganglion cells
• Glaucoma
• Homocysteine
• Hyperhomocysteinemia
• Methylene tetrahydrofolate reductase
• Mouse
• NRF2
• Retina

• caffeine
• cataract
• eye
• glaucoma
• intraocular pressure

• Exfoliative glaucoma
• Hyperhomocysteinemia
• Mouse
• Optic neuropathy
• Oxidative stress
• Retinal glial cells

• Alcohol
• Antioxidants
• Caffeine
• Diet
• Dietary supplements
• Glaucoma
• Intraocular pressure
• Nutrition
• Obesity

• Cataract
• Cataracte
• Glaucoma
• Glaucome
• Glaucome exfoliatif
• Hypertonie oculaire
• Ocular hypertension
• Pseudoexfoliation glaucoma
• Pseudoexfoliation syndrome
• Syndrome pseudo-exfoliatif

• Adult
• Aged
• Aged, 80 and over
• Female
• Follow-Up Studies
• Glaucoma, Open-Angle/complications
• Glaucoma, Open-Angle/diagnosis
• Glaucoma, Open-Angle/physiopathology
• Humans
• Intraocular Pressure/physiology
• Macula Lutea/pathology
• Macular Edema/diagnosis
• Macular Edema/etiology
• Macular Edema/physiopathology
• Male
• Middle Aged
• Phacoemulsification
• Prospective Studies
• Pseudophakia/complications
• Pseudophakia/diagnosis
• Tomography, Optical Coherence/methods
• Visual Acuity

• CACNA1A
• LOXL1
• animal models
• exfoliation syndrome
• homocysteine

• Amino Acid Oxidoreductases/genetics
• Exfoliation Syndrome/complications
• Exfoliation Syndrome/genetics
• Exfoliation Syndrome/metabolism
• Glaucoma, Open-Angle/etiology
• Humans
• Prevalence
• Protein-Lysine 6-Oxidase/metabolism

• coffee consumption
• dietary folate
• environmental factors
• exfoliation syndrome
• latitude effect
• solar exposure

• Amino Acid Oxidoreductases/genetics
• Amino Acid Oxidoreductases/metabolism
• Environment
• Exfoliation Syndrome/enzymology
• Exfoliation Syndrome/etiology
• Glaucoma, Open-Angle/enzymology
• Glaucoma, Open-Angle/etiology
• Humans

• R01 EY020928 NEI NIH HHS
• EY020928 NEI NIH HHS

Pseudoexfoliation (PEX) syndrome is a well-recognized late-onset disease caused by a generalized fibrillopathy. It is linked to a broad spectrum of ocular complications including glaucoma and perioperative problems during cataract surgery. Apart from the long-known intraocular manifestations, PEX deposits have been found in a variety of extraocular locations and they appear to represent a systemic process associated with increased cardiovascular and cerebrovascular morbidity. However, as published results are inconsistent, the clinical significance of the extraocular PEX deposits remains controversial. Identification of PEX deposits in the heart and the vessel wall, epidemiologic studies, as well as, similarities in pathogenetic mechanisms have led to the hypothesis of a possible relation between fibrillar material and cardiovascular disease. Recent studies suggest that PEX syndrome is frequently linked to impaired heart and blood vessels function. Systemic and ocular blood flow changes, altered parasympathetic vascular control and baroreflex sensitivity, increased vascular resistance and decreased blood flow velocity, arterial endothelial dysfunction, high levels of plasma homocysteine and arterial hypertension have all been demonstrated in PEX subjects. Common features in the pathogenesis of both atherosclerosis and PEX, like oxidative stress and inflammation and a possible higher frequency of abdominal aorta aneurysm in PEX patients, could imply that these grey-white deposits and cardiovascular disorders are related or reflect different manifestations of the same process.

• Pseudoexfoliation
• Cardiovascular disease
• Cerebrovascular disease
• Coronary artery disease
• Homocysteine

Pseudoexfoliation syndrome is a primarily ophthalmological disorder caused by deposition of whitish-gray protein on the lens, iris, and multiple other eye tissues. There is increasing evidence over the previous years that pseudoexfoliation syndrome is a systemic disorder with various extraocular manifestations and has recently been linked to several cardiovascular disorders. The present article aims to summarize the current knowledge on cardiovascular implications of this well-described clinical entity.

• Cardiovascular
• Coronary disease
• Pseudoexfoliation syndrome

• LOXL1
• exfoliation syndrome
• glaucoma

• Amino Acid Oxidoreductases/genetics
• Exfoliation Syndrome/complications
• Exfoliation Syndrome/diagnosis
• Exfoliation Syndrome/genetics
• Genetic Predisposition to Disease
• Hearing Loss, Sensorineural/complications
• Hearing Loss, Sensorineural/etiology
• Humans
• Vascular Diseases/complications