Glaucoma is a complex neurodegenerative disease with many clinical subtypes. Some of its rare forms include pigmentary glaucoma, uveitic glaucoma and congenital glaucoma. While they all share common ...features of progressive retinal ganglion cell (RGC) loss, optic nerve damage and corresponding visual field loss, the exact mechanisms underlying glaucomatous neuron loss are not clear. This has largely hindered the development of a real cure for this disease. Elevated intraocular pressure (IOP) is a known major risk factor of glaucoma; however, progressive degeneration of RGCs and axons can also be found in patients with a normal IOP, i.e., normal tension glaucoma (NTG). Interestingly, patients who carry the gain‐of‐function mutation of the pro‐inflammatory gene TBK1 – tumor necrosis factor (TNF) receptor associated factor NF‐κB activator (TANK) binding kinase 1 – are at increased risk to develop NTG. This finding suggests a causal link between neuroinflammatory processes and glaucoma. Various studies have reported the presence of neuroinflammatory responses by microglia, astrocytes and other blood‐born immune cells in the optic nerve head (ONH) at early stages of experimental glaucoma. Inhibition of certain pro‐inflammatory pathways, particularly those associated with microglial activation, appears to be neuroprotective. In this review, we will focus on the inflammatory responses, in particular the proposed roles of microglia, in the pathogenesis of glaucoma.
An increasing number of artificial intelligence (AI) systems are being proposed in ophthalmology, motivated by the variety and amount of clinical and imaging data, as well as their potential benefits ...at the different stages of patient care. Despite achieving close or even superior performance to that of experts, there is a critical gap between development and integration of AI systems in ophthalmic practice. This work focuses on the importance of trustworthy AI to close that gap. We identify the main aspects or challenges that need to be considered along the AI design pipeline so as to generate systems that meet the requirements to be deemed trustworthy, including those concerning accuracy, resiliency, reliability, safety, and accountability. We elaborate on mechanisms and considerations to address those aspects or challenges, and define the roles and responsibilities of the different stakeholders involved in AI for ophthalmic care, i.e., AI developers, reading centers, healthcare providers, healthcare institutions, ophthalmological societies and working groups or committees, patients, regulatory bodies, and payers. Generating trustworthy AI is not a responsibility of a sole stakeholder. There is an impending necessity for a collaborative approach where the different stakeholders are represented along the AI design pipeline, from the definition of the intended use to post-market surveillance after regulatory approval. This work contributes to establish such multi-stakeholder interaction and the main action points to be taken so that the potential benefits of AI reach real-world ophthalmic settings.
•Trustworthy AI is the next step to facilitate AI integration in healthcare and, particularly, ophthalmology.•Several aspects need to be addressed so as to generate trustworthy AI systems.•Mechanisms can be applied along the AI design pipeline.•Collaboration of all stakeholders involved in AI for ophthalmic care is essential.
Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD ...for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium.
Pooled analysis of 4 case-control and 6 cohort studies.
Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium.
Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan-Meier analyses in population-based cohorts.
Age-related macular degeneration features and stage.
Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval CI, 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4-13.3), and of mixed late AMD was 12.2 (95% CI, 7.3-20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0-11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 μm (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen ≥ 125 μm (OR, 2.1; 95% CI, 1.5-3.0), up to an OR of 7.2 (95% CI, 3.8-13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2-5.4); risks of other characteristics were not different.
Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.
Retinal ischemic events, which result from occlusion of the ocular vasculature share similar causes as those for central nervous system stroke and are among the most common cause of acute and ...irreversible vision loss in elderly patients. Currently, there is no established treatment, and the condition often leaves patients with seriously impaired vision or blindness. The immune system, particularly T-cell–mediated responses, is thought to be intricately involved, but the exact roles remain elusive. We found that acute ischemia-reperfusion injury to the retina induced a prolonged phase of retinal ganglion cell loss that continued to progress during 8 weeks after the procedure. This phase was accompanied by microglial activation and CD4+ T-cell infiltration into the retina. Adoptive transfer of CD4+ T cells isolated from diseased mice exacerbated retinal ganglion cell loss in mice with retinal reperfusion damage. On the other hand, T-cell deficiency or administration of T-cell or interferon-γ–neutralizing antibody attenuated retinal ganglion cell degeneration and retinal function loss after injury. These findings demonstrate a crucial role for T-cell–mediated responses in the pathogenesis of neural ischemia. These findings point to novel therapeutic targets of limiting or preventing neuron and function loss for currently untreatable conditions of optic neuropathy and/or central nervous system ischemic stroke.
Recent studies suggest that the diabetes drug metformin has a protective effect on open-angle glaucoma (OAG) and age-related macular degeneration (AMD). However, studies have not addressed the ...critical issue of confounding by indication, and associations have not been evaluated in a large prospective cohort.
To determine the association between diabetes medication and the common eye diseases OAG, AMD, and cataract and to evaluate their cumulative lifetime risks in a large cohort study.
This cohort study included participants from 3 independent cohorts from the prospective, population-based Rotterdam Study between April 23, 1990, and June 25, 2014. Participants were monitored for incident eye diseases (OAG, AMD, cataract) and had baseline measurements of serum glucose. Data on diabetes medication use and data from ophthalmologic examinations were gathered.
Type 2 diabetes (T2D) and the diabetes medications metformin, insulin, and sulfonylurea derivatives.
Diagnosis and cumulative lifetime risk of OAG, AMD, and cataract.
This study included 11 260 participants (mean SD age, 65.1 9.8; 6610 women 58.7%). T2D was diagnosed in 2406 participants (28.4%), OAG was diagnosed in 324 of 7394 participants (4.4%), AMD was diagnosed in 1935 of 10 993 participants (17.6%), and cataract was diagnosed in 4203 of 11 260 participants (37.3%). Untreated T2D was associated with a higher risk of OAG (odds ratio OR, 1.50; 95% CI, 1.06-2.13; P = .02), AMD (OR, 1.35; 95% CI, 1.11-1.64; P = .003), and cataract (OR, 1.63; 95% CI, 1.39-1.92; P < .001). T2D treated with metformin was associated with a lower risk of OAG (OR, 0.18; 95% CI, 0.08-0.41; P < .001). Other diabetes medication (ie, insulin, sulfonylurea derivates) was associated with a lower risk of AMD (combined OR, 0.32; 95% CI, 0.18 to 0.55; P < .001). The cumulative lifetime risk of OAG was lower for individuals taking metformin (1.5%; 95% CI, 0.01%-3.1%) than for individuals without T2D (7.2%; 95% CI, 5.7%-8.7%); the lifetime risk of AMD was lower for individuals taking other diabetes medication (17.0%; 95% CI, 5.8%-26.8% vs 33.1%; 95% CI, 30.6%-35.6%).
Results of this cohort study suggest that, although diabetes was clearly associated with cataract, diabetes medication was not. Treatment with metformin was associated with a lower risk of OAG, and other diabetes medication was associated with a lower risk of AMD. Proof of benefit would require interventional clinical trials.
Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association ...studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.
•variants in 10q26 are the strongest contributors to genetic AMD-risk.•The genetic risk region has recently been narrowed to ARMS2.•ARMS2 and HTRA1 are both interacting with extracellular matrix components, linking AMD pathology to ECM homeostasis.•Risk associated gene-regulatory and epigenetic alterations may influence expression levels from 10q26 in diseased individuals.•targeting 10q26 gene products remains risky due to lack of functional data.
Inflammation is involved in the pathogenesis of cataract, age-related macular degeneration (AMD), and possibly open-angle glaucoma (OAG). We assessed whether the inflammatory potential of diet ...(quantified using the dietary inflammatory index; DII) affects the incidence of these common blinding age-related eye diseases. Serum inflammation markers were investigated as possible mediators.
Participants aged >45 years were selected from the prospective, population-based Rotterdam Study. From 1991 onwards, every 4–5 years, participants underwent extensive eye examinations. At baseline, blood samples and dietary data (using food frequency questionnaires) were collected. The DII was adapted based on the data available. Of the 7436 participants free of eye diseases at baseline, 4036 developed incident eye diseases during follow-up (cataract = 2895, early-intermediate AMD = 891, late AMD = 81, OAG = 169).
The adapted DII (aDII) ranged from −4.26 (i.e., anti-inflammatory) to 4.53 (i.e., pro-inflammatory). A higher aDII was significantly associated with increased inflammation. A higher neutrophil-lymphocyte ratio (NLR) was associated with an increased risk of cataract and AMD. Additionally, complement component 3c (C3c) and systemic immune-inflammation index (SII) were associated with increased risks of cataract and late AMD, respectively. Every point increase in the aDII was associated with a 9% increased risk of cataract (Odds ratio 95% confidence interval: 1.09 1.04–1.14). The NLR and C3c partly mediated this association. We also identified associations of the aDII with risk of AMD (early-intermediate AMD, OR 95% CI: 1.11 1.03–1.19; late AMD, OR 95% CI: 1.24 1.02–1.53). The NLR partly mediated these associations. The aDII was not associated with OAG.
A pro-inflammatory diet was associated with increased risks of cataract and AMD. Particularly the NLR, a marker of subclinical inflammation, appears to be implicated. These findings are relevant for patients with AMD and substantiate the current recommendations to strive for a healthy lifestyle to prevent blindness.
To investigate the impact of physical activity (PA) on the incidence or progression of age-related macular degeneration (AMD) in the general population.
Meta-analysis of longitudinal cohort studies.
...We included 14,630 adults with no or early AMD at baseline from 7 population-based studies and examined associations of PA with AMD incidence and progression using multistate models (MSM) per study and subsequent random effects meta-analysis. Age effects were assessed using meta-regression. The main outcome measure was the hazard ratio (HR) for incident early or progression to late AMD.
At baseline, mean age was 60.7 ± 6.9 to 76.4 ± 4.3 years, and prevalence of early AMD was 7.7% (range, 3.6%-16.9%) between cohorts. During follow-up, 1461 and 189 events occurred for early and late AMD, respectively. In meta-analyses, no or low to moderate PA (high PA as reference) was associated with an increased risk for incident early AMD (HR, 1.19; 95% CI, 1.01-1.40; P = .04), but not for late AMD. In subsequent meta-regression, we found no association of age with the effect of PA on incident AMD.
Our study suggests high levels of PA to be protective for the development of early AMD across several population-based cohort studies. Our results establish PA as a modifiable risk factor for AMD and inform further AMD prevention strategies to reduce its public health impact.
Looking older for one's chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing ...reflects systemic ageing of the human body.
To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age.
We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5-87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2).
We observed 5-year higher ΔPA (i.e. looking younger by 5 years for one's age) to be associated with less osteoporosis odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93, less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95), less age-related hearing loss (model 2; B = -0.76, 95% CI -1.35 to -0.17) and fewer cataracts (OR 0.84, 95% CI 0.73-0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04-0.10).
PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.
Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle factors triggering various systemic ...pathways. This study aimed to characterize metabolomic profiles for AMD and to evaluate their position in the trias with genetics and lifestyle. This study included 5923 individuals from five European studies. Blood metabolomics were assessed using a nuclear magnetic resonance platform of 146 metabolites. Associations were studied using regression analyses. A genetic risk score (GRS) was calculated using β-values of 49 AMD variants, a lifestyle risk score (LRS) using smoking and diet data, and a metabolite risk score (MRS) using metabolite values. We identified 61 metabolites associated with early-intermediate AMD, of which 94% were lipid-related, with higher levels of HDL-subparticles and apolipoprotein-A1, and lower levels of VLDL-subparticles, triglycerides, and fatty acids (false discovery rate (FDR)
-value < 1.4 × 10
). Late AMD was associated with lower levels of the amino acids histidine, leucine, valine, tyrosine, and phenylalanine, and higher levels of the ketone bodies acetoacetate and 3-hydroxybutyrate (FDR
-value < 1.5 × 10
). A favorable lifestyle characterized by a healthy diet was associated with higher levels of amino acids and lower levels of ketone bodies, while an unfavorable lifestyle, including smoking, showed opposite effects (FDR
-value < 2.7 × 10
). The MRS mediated 5% of the effect of the GRS and 20% of that of the LRS on late AMD. Our findings show that metabolomic profiles differ between AMD stages and show that blood metabolites mostly reflect lifestyle. The severity-specific profiles spur further interest into the systemic effects related to disease conversion.
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