Plasma GDF-15 concentration is not elevated in open-angle glaucoma.

AIM: Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease. METHODS: Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn's multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models. RESULTS: Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15. CONCLUSION: The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients.

Nicotinamide Deficiency in Primary Open-Angle Glaucoma.

Purpose: To investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG). Methods: Plasma of 34 POAG individuals was compared to that of 30 age- and sex-matched controls using a semiquantitative method based on liquid chromatography coupled to high-resolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls. Results: Using the semiquantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to controls and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 µM (median: 0.12 µM; range, 0.06-0.28 µM) in the POAG group (-30%; P = 0.022) and 0.19 µM (median: 0.18 µM; range, 0.08-0.47 µM) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (-33%; P = 0.011) in the replicative cohort with mean concentrations of 0.14 µM (median: 0.14 µM; range, 0.09-0.25 µM) in the POAG group, and 0.19 µM (median: 0.21 µM; range, 0.09-0.26 µM) in the control group. Conclusions: Glaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.

Serum vitamin D status is associated with the presence but not the severity of primary open angle glaucoma.

OBJECTIVES: Vitamin D is involved in visual health and function. Our objective was to determine whether age-related vitamin D insufficiency was associated with the presence and the severity of primary open angle glaucoma (POAG) in a case-control study of older adults. STUDY DESIGN: Case-control study. MAIN OUTCOME MEASURES: One hundred fifty cases diagnosed with moderate-to-severe POAG (mean, 75.1 ± 8.5 years; 42.0% female) and 164 healthy controls (mean, 73.0 ± 7.9 years; 59.8% female) were included. POAG diagnosis was based on classical diagnostic criteria of optic nerve cupping and/or RNFL thinning, measured with optical coherence tomography. Severe POAG was defined as Humphrey visual field mean deviation (MD) worse than -12 dB. Vitamin D insufficiency was defined as serum 25OHD ≤ 75 nmol/L. Age, gender, mean arterial pressure, vitamin D supplementation, visual acuity, and intraocular pressure were used as potential confounders. RESULTS: POAG cases had lower mean serum 25OHD concentration than controls (42.9 ± 25.7 nmol/L versus 49.4 ± 29.5 nmol/L, P=0.039) and a greater prevalence of vitamin D insufficiency (90.7% versus 82.3%, P=0.032). Increased mean serum 25OHD concentrations were associated with lower POAG frequency, even after adjustment for potential confounders (OR=0.89 per 10 nmol/L of 25OHD, P=0.045). Similarly, vitamin D insufficiency was associated with POAG (OR=2.09, P=0.034). Among POAG cases, no 25OHD difference was observed between moderate and severe POAG cases (respectively, 39.2 ± 23.3 nmol/L versus 45.1 ± 26.7 nmol/L, P=0.188); and no between-group difference regarding the prevalence of vitamin D insufficiency (88.9% versus 94.0%, P=0.313). CONCLUSIONS: Decreased serum 25OHD concentration was associated with POAG. There was no 25OHD difference between moderate and severe POAG.

Relationship between glaucoma and selenium levels in plasma and aqueous humour.

AIM: The aim of the study was to compare selenium levels in plasma and aqueous humour in subjects with and without primary open-angle glaucoma (POAG). METHODS: Forty-seven POAG cases and 54 controls in this case-control study were recruited from surgery patients at the University Physician's Ophthalmology Clinic in Tucson, Arizona, USA. Aqueous humour and plasma selenium were determined by high-performance liquid chromatography ion channel plasma mass spectrometry (HPLC ICP-MS). Potential confounders were assessed via a questionnaire. Biological samples were collected and processed at surgery and analysed for selenium content after collection was complete. Outcome measures included the odds of glaucoma in relationship to plasma selenium, aqueous humour selenium, and the ratio of levels of aqueous humour selenium to plasma selenium. RESULTS: Tertile of selenium and its relationship to POAG was examined. After adjustment for common glaucoma risk factors, the odds of glaucoma in the highest tertile of plasma selenium (OR = 11.3; p = 0.03) and the middle tertile of aqueous humour selenium (OR = 0.06; p = 0.02) was significantly associated with glaucoma. CONCLUSION: Although a causal pathway cannot be inferred from our analysis, our data, added to that of others, suggest that the pathology is selenium-related.

Clinical evaluation of the neuroprotective effect of alpha-tocopherol against glaucomatous damage.

PURPOSE: To evaluate the vasoregulatory effect of antioxidant alpha-tocopherol on retina via protein kinase C pathway. METHODS: Thirty glaucomatous patients (60 eyes) were included in this study. The patients were divided into three groups. For patients in Group A, tocopherol was not supplemented in their therapy. Patients in Groups B and C received 300 and 600 mg/day of oral alpha-tocopherol acetate, respectively. The ultimate blood tocopherol levels were confirmed via high-performance liquid chromatography assay. Progression of the disease for each subject was monitored via visual field measurements and color Doppler imaging of ophthalmic and posterior ciliary arteries at the beginning and at the 6th and 12th months of this study. RESULTS: The average differences between the pulsatility indexes (PI) and resistivity indexes (RI) of both ophthalmic arteries (OA) and posterior ciliary arteries (PCA) of Groups B and C were significantly lower than those of Group A at months 6 and 12. In trial groups, RI decreases observed in PCAs at months 6 and 12 and PI decreases observed in OAs at the 6th month were statistically significant. Differences of mean deviations with visual fields in Groups B and C were highly significantly lower than that of Group A. CONCLUSIONS: Alpha-tocopherol deserves attention beyond its antioxidant properties for protecting retina from glaucomatous damage.

Decreased response of plasma cortisol to intravenous metyrapone in ocular hypertension and primary open-angle glaucoma.

PURPOSE: To determine if there is a difference in response to metyrapone, which blocks the conversion of 11-deoxycortisol to cortisol in the adrenal gland between normals and ocular hypertensives (OH) plus primary open-angle glaucomas (POAG) without pigmented angles. METHODS: Intravenous metyrapone was given to 20 normals and 15 ocular hypertensives plus primary open-angle glaucomas without pigmented angles. Blood samples were obtained at 4, 6, and 8 hours after administration of intravenous metyrapone for analyses of 11-deoxycortisol and cortisol. RESULTS: The ocular hypertensives plus primary open-angle glaucoma group showed significantly lower cortisol values compared with the normal group at 6 hours (P = 0.002) but not at 4 or 8 hours. There were no significant differences between the two groups for 11-deoxycortisol values at 4, 6, or 8 hours. The percent decrease of plasma cortisol from baseline was significantly greater for the ocular hypertensives plus open-angle glaucoma group compared with the normals at 4 hours (P = 0.010) and 6 hours (P = 0.0004). Significant negative correlations were observed for the total group of subjects between levels of plasma cortisol at 6 hours and intraocular pressure, worse eye (P = 0.029), percent area of cupping, worse eye (P = 0.045), pallor, worse eye (P = 0.001), and visual field loss, worse eye (P = 0.048), so that the less the plasma cortisol, the greater the abnormality of the glaucomatous parameters. Multivariate analyses with the 6-hour plasma cortisol level as the dependent variable showed that the only significant (P = 0.0004) independent variable was the percent area of pallor, worse eye, associated with a smaller level of plasma cortisol at 6 hours. Similarly, the multiple regression models using the percent change from baseline of the 6-hour plasma cortisol value showed a significant association of larger percent decreases of plasma cortisol in the ocular hypertensives plus open-angle glaucoma compared with the normals. CONCLUSIONS: The ocular hypertensives plus primary open-angle glaucoma subjects show greater adrenal inhibition to metyrapone in the synthesis of cortisol from 11-deoxycortisol compared with normals. This observation suggests an adrenal abnormality in the ocular hypertensive plus primary open-angle glaucoma subjects.

Plasma homocysteine is elevated in patients with exfoliation syndrome.

PURPOSE: To compare plasma homocysteine concentrations among patients with exfoliation syndrome, exfoliative glaucoma, normal-tension glaucoma, and normal control subjects without vascular or inflammatory ocular disease or glaucoma. DESIGN: Cross-sectional study. METHODS: We tested 25 patients with exfoliation syndrome, 50 with exfoliative glaucoma, 25 with normal-tension glaucoma, and 24 control subjects. Fasting plasma homocysteine concentrations were measured by fluorescence polarization immunoassay. Patients using vitamin supplements or medications known to alter serum homocysteine were excluded. RESULTS: Homocysteine levels were higher in both exfoliatin groups compared with controls (exfoliation syndrome: P =.003; exfoliative glaucoma: P =.009); levels in normal-tension glaucoma were higher than but not significantly different from those in controls (P =.2). Hyperhomocysteinemia was present in 16 of 25 (64%) exfoliation syndrome patients, 28 of 50 (56%) exfoliative glaucoma patients, 13 of 25 (52%) normal-tension glaucoma patients, and 7 of 24 (29.2%) controls (P =.005). Multiple logistic regression analyses comparing exfoliation syndrome and exfoliative glaucoma patients with controls indicated that elevated plasma homocysteine concentration was a significant risk factor for exfoliation syndrome, in both those patients (odds ratios per 1.0 micromol/l increase in plasma homocysteine concentrations = 1.47; 95% confidence interval [CI] = 1.08-2.0) and in exfoliative glaucoma patients (odds ratio = 1.3; 95% CI = 1.07-1.6). Although exfoliative glaucoma and normal-tension glaucoma patients were not significantly different with respect to hyperhomocysteinemia, logistic regression modeling of exfoliative glaucoma vs normal-tension glaucoma patients showed that an increased homocysteine concentration was a significant risk factor for exfoliation syndrome in the presence of glaucoma (odds ratio per 1.0 micromol/l increase in homocysteine = 1.2, 95% CI = 1.0-1.4). These relationships were not affected by adjustment for potential confounding due to sex, history of hypertension, or other factors. RESULTS: Elevated plasma homocysteine, a risk factor for cardiovascular disease, is more common in exfoliation syndrome and exfoliative glaucoma patients than healthy controls. Patients with exfoliation syndrome may benefit from measurement of homocysteine levels.

Association of ocular pressure and optic disc cup volume with red blood cell sodium-potassium ATPase inhibition.

PURPOSE: To determine if there were significant differences between the number of red blood cell ouabain binding sites in normals and untreated ocular hypertensives plus one open-angle glaucoma patient. METHODS: We measured the binding of (3)H ouabain to erythrocyte membranes of 23 normals, 25 ocular hypertensives and one open-angle glaucoma. We also measured the levels of plasma cortisol and digoxin in these subjects. Characteristics of cupping of the optic disc and thickness of the retinal nerve fiber layer, as well as area of optic disc pallor of these subjects were measured by stereophotogrammetry and by computerized image analysis from single and stereo photographs. RESULTS: The number of (3)H ouabain binding sites was observed to be significantly less in the ocular hypertensives and one glaucoma compared to the normals (p = 0.0009). In multi-variate analyses, to determine what other factors affected this difference, there was a significant negative association with mean intraocular pressure (p = 0.003) (average of both eyes) and total cup volume (average of both eyes) (p = 0.005), diagnosis of ocular hypertension and glaucoma (p = 0.0005) and male gender (p = 0.019). There was a significant positive association with plasma cortisol levels (p = 0.048), and diastolic blood pressure (p = 0.037). CONCLUSIONS: The number of (3)H ouabain binding sites in red blood cells decreases significantly with increasing ocular pressure and increasing cup volume indicating the possible presence of an increased systemic endogenous digoxin-like inhibitor and/or difference in the isozymes of Na(+), K(+)-ATPase which may be associated with increased levels of plasma cortisol in ocular hypertensives and glaucomas.

Blood viscosity in primary open-angle glaucoma.

To determine whether hemorrheologic factors play a part in optic nerve cupping and visual field loss in glaucoma, blood viscosity was measured at three shear rates in 27 patients with primary open-angle glaucoma and 18 healthy control subjects matched for sex, mean arterial blood pressure and smoking habits. The study was conducted between 1984 and 1986. The mean viscosity was significantly higher in the glaucoma group than in the control group at all three shear rates. The possible relevance of raised blood viscosity as a causal factor in optic nerve cupping in patients with glaucoma is discussed.