Pathogenesis Of Normal Tension Glaucoma Research Articles

Exploring the role of apolipoprotein E gene promoter polymorphisms in susceptibility to normal-tension glaucoma in a Korean population

Glaucoma, particularly primary open-angle glaucoma (POAG), poses a significant global health concern. Distinguished by intraocular pressure (IOP), POAG encompasses high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Apolipoprotein E (APOE) is a multifaceted protein with roles in lipid metabolism, neurobiology, and neurodegenerative diseases. However, controversies persist regarding the impact of APOE single-nucleotide polymorphisms (SNPs) on open-angle glaucoma and NTG. This study aimed to identify APOE-specific SNPs influencing NTG risk. A cohort of 178 patients with NTG recruited from Uijeongbu St. Mary’s Hospital and 32,858 individuals from the Korean Genome and Epidemiology Study (KoGES) cohort were included in the analysis. Genotype and haplotype analyses were performed on three promoter SNPs (rs449647, rs769446, and rs405509) and two exonic SNPs (rs429358 and rs7412) located on chromosome 19. Among the five SNPs, rs769446 genotypes exhibited significant differences between cases and controls. The minor allele C of rs769446 emerged as a protective factor against NTG. Furthermore, haplotype analysis of the five SNPs revealed that the A-T-G-T-T haplotype was a statistically significant risk factor for NTG. This study indicated an association between APOE promoter SNPs and NTG in the Korean population. Further studies are required to understand how APOE promoter SNPs contribute to NTG pathogenesis.

Normal-Tension Glaucoma and Potential Clinical Links to Alzheimer's Disease.

Glaucoma is a group of optic neuropathies and the world's leading cause of irreversible blindness. Normal-tension glaucoma (NTG) is a subtype of glaucoma that is characterized by a typical pattern of peripheral retinal loss, in which the patient's intraocular pressure (IOP) is considered within the normal range (<21 mmHg). Currently, the only targetable risk factor for glaucoma is lowering IOP, and patients with NTG continue to experience visual field loss after IOP-lowering treatments. This demonstrates the need for a better understanding of the pathogenesis of NTG and underlying mechanisms leading to neurodegeneration. Recent studies have found significant connections between NTG and cerebral manifestations, suggesting NTG as a neurodegenerative disease beyond the eye. Gaining a better understanding of NTG can potentially provide new Alzheimer's Disease diagnostics capabilities. This review identifies the epidemiology, current biomarkers, altered fluid dynamics, and cerebral and ocular manifestations to examine connections and discrepancies between the mechanisms of NTG and Alzheimer's Disease.

Molecular genetics of inherited normal tension glaucoma.

Normal tension glaucoma (NTG) is a complex optic neuropathy characterized by progressive retinal ganglion cell death and glaucomatous visual field loss, despite normal intraocular pressure (IOP). This condition poses a unique clinical challenge due to the absence of elevated IOP, a major risk factor in typical glaucoma. Recent research indicates that up to 21% of NTG patients have a family history of glaucoma, suggesting a genetic predisposition. In this comprehensive review using PubMed studies from January 1990 to December 2023, our focus delves into the genetic basis of autosomal dominant NTG, the only known form of inheritance for glaucoma. Specifically exploring optineurin ( OPTN ), TANK binding kinase 1 ( TBK1 ), methyltransferase-like 23 ( METTL23 ), and myocilin ( MYOC ) mutations, we summarize their clinical manifestations, mutant protein behaviors, relevant animal models, and potential therapeutic pathways. This exploration aims to illuminate the intricate pathogenesis of NTG, unraveling the contribution of these genetic components to its complex development.

Pharmaceutical Approaches to Normal Tension Glaucoma.

Normal tension glaucoma (NTG) is defined as a subtype of primary open-angle glaucoma (POAG) in which the intraocular pressure (IOP) values are constantly within the statistically normal range without treatment and represents approximately the 30-40% of all glaucomatous cases. The pathophysiology of this condition is multifactorial and is still not completely well known. Several theories have been proposed to explain the onset and progression of this disease, which can be divided into IOP-dependent and IOP-independent factors, suggesting different therapeutic strategies. The current literature strongly supports the fundamental role of IOP in NTG. The gold standard treatment for NTG tends to be based on the lowering IOP even if "statistically normal". Numerous studies have shown, however, that the IOP reduction alone is not enough to slow down or stop the disease progression in all cases, suggesting that other IOP-independent risk factors may contribute to the NTG pathogenesis. In addition to IOP-lowering strategies, several different therapeutic approaches for NTG have been proposed, based on vaso-active, antioxidant, anti-inflammatory and/or neuroprotective substances. To date, unfortunately, there are no standardized or proven treatment alternatives for NTG when compared to traditional IOP reduction treatment regimes. The efficacy of the IOP-independent strategies in decreasing the risk or treating NTG still remains inconclusive. The aim of this review is to highlight strategies reported in the current literature to treat NTG. The paper also describes the challenges in finding appropriate and pertinent treatments for this potentially vision-threatening disease. Further comprehension of NTG pathophysiology can help clinicians determine when to use IOP-lowering treatments alone and when to consider additional or alternatively individualized therapies focused on particular risk factors, on a case-by-case basis.

The Differences in the Pattern of OCT and OCTA Examinations between Early Normal- and High-Tension Pseudoexfoliative Glaucoma.

Purpose. The aim of this study was to compare the results of optical coherence tomography angiography (OCTA) and optical coherence tomography (OCT) examinations in patients with normal-tension glaucoma (NTG) in comparison to high-tension pseudoexfoliative glaucoma (HTG) patients at the early stage of glaucoma. Material and methods. The studied groups consisted of patients in the early stage of NTG (70 eyes) and the early stage of HTG (71 eyes). In NTG and HTG groups, a detailed ophthalmic examination was performed. Optic disc OCT with peripapillary RNFL measurements and OCTA examination with the evaluation of the macula and optic disc were performed for all participants using Zeiss Cirrus 5000. Results. NTG and HTG groups were statistically similar as far as the MD was concerned, and both groups had early glaucoma. When evaluating the RNFL thickness, the only statistical difference between early NTG and HTG was observed in the thicknesses in the temporal sector of peripapillary RNFL, with thinner values in the NTG group (53.94 vs. 59.94, p = 0.0071). When the OCTA results of the macula and optic disc were evaluated, there were no statistical differences between early NTG and HTG. Conclusions. The vascular density and flow parameters assessed in OCTA were equal between early NTG and HTG, and therefore the involvement of vascular factors in NTG pathogenesis could not be confirmed. Our results confirm the preponderance of more frequent temporal RNFL involvement in early NTG.

Vasoreactivity of the optic nerve head, nailfold, and facial skin in response to cold provocation in normal-tension glaucoma patients

BackgroundThe dysfunction of optic nerve head (ONH) hemodynamics has been suggested to be involved in the pathogenesis of normal-tension glaucoma (NTG). The aim of this study was to compare vasoreactivity in the ONH, nailfold, and facial skin in response to cold-water provocation in NTG patients and healthy controls.MethodsWe performed cold-water provocation in 14 eyes of 14 NTG patients and 15 eyes of 15 age-matched control subjects. Laser speckle flowgraphy-derived tissue-area mean blur rate (MT), skin blood flowmetry-derived pulse wave amplitude (PA), nailfold capillaroscopy-derived nailfold capillary diameter, and other clinical parameters were recorded at baseline and 4 and 6 min after the cold stimulus. We compared changes (as percentages) in these variables in the NTG and control subjects with a linear mixed-effects model and evaluated correlations between these changes with Spearman’s rank correlation coefficient.ResultsThe interaction term between the NTG group (reference, control group) and the 4-min protocol step (reference, baseline) significantly affected the changes in MT, nailfold capillary diameter and PA (β = -9.51%, P = 0.017, β = -20.32%, P = 0.002; β = + 18.06%, P = 0.017, respectively). The change in MT was positively correlated with the change in nailfold capillary diameter, and negatively correlated with the change in PA (r = 0.39, P = 0.036; r = -0.40, P = 0.031, respectively).ConclusionNTG patients showed abnormal vasoconstriction in the ONH and nailfold and vasodilation in the facial skin in response to cold-water provocation.

METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma.

Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-knock-in (Mettl23+/G and Mettl23G/G) and -knockout (Mettl23+/- and Mettl23-/-) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor α target gene that was critical for RGC homeostasis through the negative regulation of NF-κB-mediated TNF-α and IL-1β feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

Regulatory mechanisms of retinal ganglion cell death in normal tension glaucoma and potential therapies.

Normal tension glaucoma (NTG) is a multifactorial optic neuropathy characterized by normal intraocular pressure, progressive retinal ganglion cell (RGC) death, and glaucomatous visual field loss. Recent studies have described the mechanisms underlying the pathogenesis of NTG. In addition to controlling intraocular pressure, neuroprotection and reduction of RGC degeneration may be beneficial therapies for NTG. In this review, we summarized the main regulatory mechanisms of RGC death in NTG, including autophagy, glutamate neurotoxicity, oxidative stress, neuroinflammation, immunity, and vasoconstriction. Autophagy can be induced by retinal hypoxia and axonal damage. In this process, ischemia can cause mutations of optineurin and activate the nuclear factor-kappa B pathway. Glutamate neurotoxicity is induced by the over-stimulation of N-methyl-D-aspartate membrane receptors by glutamate, which occurs in RGCs and induces progressive glaucomatous optic neuropathy. Oxidative stress also participates in NTG-related glaucomatous optic neuropathy. It impairs the mitochondrial and DNA function of RGCs through the apoptosis signal-regulating kinase-JUN N-terminal kinase pathway. Moreover, it increases inflammation and the immune response of RGCs. Endothelin 1 causes endothelial dysfunction and impairment of ocular blood flow, promoting vasospasm and glaucomatous optic neuropathy, as a result of NTG. In conclusion, we discussed research progress on potential options for the protection of RGCs, including TANK binding kinase 1 inhibitors regulating autophagy, N-methyl-D-aspartate receptor antagonists inhibiting glutamate toxicity, ASK1 inhibitors regulating mitochondrial function, and antioxidants inhibiting oxidative stress. In NTG, RGC death is regulated by a network of mechanisms, while various potential targets protect RGCs. Collectively, these findings provide insight into the pathogenesis of NTG and potential therapeutic strategies.

Relationship between Androgen Deprivation Therapy and Normal-Tension Glaucoma in Patients with Prostate Cancer: A Nationwide Cohort Study.

PurposeThis study assessed the relationship between newly developed normal-tension glaucoma (NTG) and androgen deprivation therapy (ADT) in patients with prostate cancer.Materials and MethodsA retrospective population-based cohort study was performed. During the period between 2008 and 2017, a total of 218203 prostate cancer patients were identified in a nationwide claims database in the Republic of Korea. The final analysis included 170874 patients (42909 in the ADT group, 127965 in the control group) after applying the inclusion and exclusion criteria. The incidences of NTG according to ADT duration were compared with controls. Exact matching was conducted to adjust comorbidities between cohorts. Cox proportional hazard regression models were performed after controlling for latent confounding factors, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of NTG according to ADT were obtained.ResultsIn the matched cohort, the ADT group was associated with a significantly reduced risk of NTG in multivariable analysis compared to the control group. The risk of NTG decreased in patients who underwent ADT for less than 2 years (HR=0.824; 95% CI, 0.682–0.995; p=0.0440) and in those using ADT over 2 years (HR=0.796; 95% CI, 0.678–0.934; p=0.0051), compared to the controls.ConclusionMedical castrations for patients with prostate cancer results in a lower incidence of newly diagnosed NTG compared to no ADT. These findings suggest that testosterone may be involved in the pathogenesis of NTG.

Inflammatory responses by retinal astrocytes during pathogenesis of normal-tension glaucoma

Inflammatory responses by retinal astrocytes during pathogenesis of normal-tension glaucoma

Profiles of microRNA in aqueous humor of normal tension glaucoma patients using RNA sequencing

We aimed to identify and compare microRNAs (miRNAs) from individual aqueous humor samples between normal-tension glaucoma (NTG) patients and normal controls. Aqueous humor (80 to 120 µl) was collected before cataract surgery. Six stable NTG patients and seven age-matched controls were included in the final analysis. RNA sequencing was conducted for RNA samples extracted from the 13 aqueous humor samples, and bioinformatics analysis was employed for the miRNA targets and related pathways. Two hundred and twenty-eight discrete miRNAs were detected in the aqueous humor and consistently expressed in all samples. Eight significantly upregulated miRNAs were found in the NTG patients compared to the controls (fold-change > 2, p < 0.05). They were hsa-let-7a-5p, hsa-let-7c-5p, hsa-let-7f-5p, hsa-miR-192-5p, hsa-miR-10a-5p, hsa-miR-10b-5p, hsa-miR-375, and hsa-miR-143-3p. These miRNAs were predicted to be associated with the biological processes of apoptosis, autophagy, neurogenesis, and aging in the gene ontology categories. The related Kyoto encyclopedia of genes and genomes pathways were extracellular matrix-receptor interaction, mucin-type O-glycan biosynthesis, biotin metabolism, and signaling pathways regulating the pluripotency of stem cells. The differentially expressed miRNA in the NTG samples compared to the controls suggest the possible roles of miRNA in the pathogenesis of NTG. The underlying miRNA-associated pathways further imply novel targets for the pathogenesis of NTG.

High Pulse Wave Velocity Is Associated With Decreased Macular Vessel Density in Normal-Tension Glaucoma.

PurposeTo investigate the relationship between pulse wave velocity (PWV) and retinal vessel density (VD) measured by optical coherence tomography angiography (OCTA) in patients with normal-tension glaucoma (NTG).MethodsThis retrospective study included 103 patients with NTG and 109 healthy controls who underwent glaucoma examination and PWV measurements. Each group was classified into two subgroups according to a brachial-ankle PWV of 1400 cm/s. NTG was diagnosed when the maximum untreated intraocular pressure was < 21 mmHg on three repeated measurements obtained at different times in the presence of glaucomatous optic discs (neuroretinal rim thinning and excavation), peripapillary retinal nerve fiber layer defects, and glaucomatous visual field defects. Healthy controls did not have glaucomatous optic discs or visual field defects and exhibited normal retinal nerve fiber layer thickness. The interval between glaucoma examination and PWV measurements did not exceed six months. Univariate and multivariate logistic regression analyses were performed to identify factors associated with high PWV.ResultsPWV was higher in the NTG group than in the control group, while peripapillary VD and macular VD (mVD) were lower (all P < 0.05). Stepwise logistic regression analysis revealed that high PWV was significantly associated with age, mean arterial pressure (MAP), and mVD in the NTG group. Meanwhile, high PWV was significantly associated with age, MAP, and low-density lipoprotein cholesterol levels in healthy controls.ConclusionsHigh PWV is associated with decreased mVD in NTG patients, suggesting that systemic arterial stiffness might be involved in the pathogenesis of NTG.

Are Generalized Reduced Cerebrospinal Fluid Dynamics and Optic Nerve Sheath Compartmentation Sequential Steps in the Pathogenesis of Normal-Tension Glaucoma? [Response to Letter

Are Generalized Reduced Cerebrospinal Fluid Dynamics and Optic Nerve Sheath Compartmentation Sequential Steps in the Pathogenesis of Normal-Tension Glaucoma?

Are Generalized Reduced Cerebrospinal Fluid Dynamics and Optic Nerve Sheath Compartmentation Sequential Steps in the Pathogenesis of Normal-Tension Glaucoma? [Letter

Are Generalized Reduced Cerebrospinal Fluid Dynamics and Optic Nerve Sheath Compartmentation Sequential Steps in the Pathogenesis of Normal-Tension Glaucoma? [Letter

Proteomic analysis of aged and OPTN E50K retina in the development of normal tension glaucoma.

Progressive degeneration of retinal ganglion cells (RGCs) is a major characteristic of glaucoma, whose underlying mechanisms are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal tension glaucoma (NTG), directly affecting RGCs without high intraocular pressure and causing severe glaucomatous symptoms in clinical settings. A systematic analysis of the NTG mouse model is crucial for better understanding of the underlying pathological mechanisms for glaucoma. To elucidate proteomic and biochemical pathway alterations during NTG development, we established an OPTN E50K mutant mouse model through CRISPR/Cas9. Retinal proteins from resulting mice exhibiting glaucomatous phenotypes were subject to tandem mass tag-labeled quantitative proteomics and then analyzed through bioinformatics methods to characterize the molecular and functional signatures of NTG. We identified 6364 quantitative proteins in our proteomic analysis. Bioinformatics analysis revealed that OPTN E50K mice experienced protein synthesis dysregulation, age-dependent energy defects and autophagy-lysosome pathway dysfunction. Certain biological features, including amyloid deposition, RNA splicing, microglia activation and reduction of crystallin production, were similar to Alzheimer's disease. Our study is the first to describe proteomic and biochemical pathway alterations in NTG pathogenesis during disease advancement. Several proteomic signatures overlapped with retinal changes found in the ad mice model, suggesting the presence of common mechanisms between age-related degenerative disorders, as well as prospective new targets for diagnostic and therapeutic strategies.

Modern approach to the diagnosis of normal tension glaucoma taking into account the features of its pathogenesis

Normal tension glaucoma was isolated as a separate clinical form of primary open-angle glaucoma at the end of the 20th century. In the article, various points of view on the development of this most difficultly diagnosed variety of glaucoma, as well as modern concepts of the pathogenesis of normal tension glaucoma which determine the strategy of a new approach to its diagnosis, are reviewed in the historical aspect.

Modern approach to the diagnosis of normal tension glaucoma taking into account the features of its pathogenesis

Normal tension glaucoma was isolated as a separate clinical form of primary open-angle glaucoma at the end of the 20 th century. In the article, various points of view on the development of this most difficultly diagnosed variety of glaucoma, as well as modern concepts of the pathogenesis of normal tension glaucoma which determine the strategy of a new approach to its diagnosis, are reviewed in the historical aspect.

ABCA1の機能不全は正常眼圧緑内障発症リスクを上昇させる

ABCA1の機能不全は正常眼圧緑内障発症リスクを上昇させる

Modern view on normal-tension glaucoma

Glaucoma is a chronic progressive optic neuropathy that causes irreversible loss of visual functions. From the clinical point of view, normal-tension glaucoma (NTG) is regarded in Russian taxonomy as a clinical form of standard primary open-angle glaucoma in which the IOP values stay within the normal range, but the typical progressive visual functions loss is still present. The results of the latest studies put in question the traditional views of NTG pathophysiology that are based solely on intraocular pressure values. New capabilities of diagnostic visualization of central nervous system have considerably broadened our knowledge of the NTG development mechanisms. This article reviews current understanding of the pathogenesis of NTG and its connection to vascular and immune factors, translaminar pressure difference etc. The review also considers the relationship between glaucoma and cognitive defects associated with Alzheimer's and Parkinson's diseases.Глаукома представляет собой хроническую прогрессирующую оптическую нейропатию, характеризующуюся необратимой потерей зрительных функций. С клинической точки зрения в российской классификации нормотензивная глаукома рассматривается как клиническая разновидность обычной первичной открытоугольной (ПОУГ) глаукомы, при которой внутриглазное давление остается внутри условно нормального диапазона, но с прогрессией типичных глаукомных изменений зрительных функций. Результаты последних исследований ставят под сомнение традиционную патофизиологическую картину нормотензивной глаукомы, базирующуюся исключительно на показателях офтальмотонуса. Новые возможности диагностической визуализации центральной нервной системы значительно расширили наши знания о механизмах развития глаукомы нормального давления. В обзоре обсуждаются современные представления о патогенезе нормотензивной глаукомы, связанные с такими факторами, как сосудистые, иммунные, разница трансламинарного давления и т.д. Также рассмотрена взаимосвязь между глаукомой и когнитивными нарушениями, возникающими при болезнях Альцгеймера и Паркинсона.

New morphometric criteria in the study of pathogenesis of normal-tension glaucoma

Studying the factors that contribute to the disturbance of transmembrane pressure gradient is a topical task in the research of pathogenesis of normal-tension glaucoma (NTG). To measure and compare the thickness and depth of lamina cribrosa (LCT and LCD), as well as optic nerve subarachnoid space width (ONSASW) in patients with NTG and healthy individuals. The first group included 12 patients (23 eyes) aged from 58 to 74 years (average age 66.8±3.2 years) with NTG who all had normal intraocular pressure and arterial hypotension. The second (control) group consisted of 11 healthy individuals (22 eyes) aged from 51 to 69 years (average age 56.2±4.2 years). All patients underwent structural and functional assessment of the optic nerve head using OCT RTVue-100 (Optovue, USA), as well as Humphrey Visual Field Analyzer (HFA II 745i, Germany-USA) and our modification of Frequency Doubling Technology perimetry. In all subjects the central corneal thickness (CCT) was measured by Pentacam HR (Oculus, Germany), the LCT and LCD were measured by EDI (Enhanced Depth Imaging) mode of Topcon 3D OCT 2000 (Japan). To measure the ONSASW we used a cross-sectional image of the optic nerve taken 3 mm behind the eyeball with Magnetic Resonance Imaging (Siemens Magnetom Symphony 1.5 T, Germany). Statistically significant difference was found between the 1st and 2nd groups in the average LCT (217.60±36.92 and 345.86±33.29 μm respectively; p=0.0000), LCD (435.00±86.31 and 367.31±87.00 μm, respectively; p=0.014) and ONSASW (1.27±0.13 and 1.44±0.19 mm respectively; p=0.004); the difference wasn't significant in the average CCT (543.26±31.52 and 557.50±24.92 μm respectively; p=0.11). Patients with NTG had significantly higher value of the LCD with significantly lower values of the LCT and ONSASW compared with healthy individuals, which confirms the importance of these morphometric criteria in the study of NTG pathogenesis.