RESUMO
BACKGROUND: Intra-arterial chemotherapy (IA) as a treatment to salvage the eye with advanced retinoblastoma is increasingly utilized based on successes reported by institutions around the world mainly through retrospective studies. OBJECTIVE: To study the feasibility of delivering melphalan directly into the ophthalmic artery in a multi-institutional prospective study in children with newly diagnosed unilateral group D retinoblastoma. METHODS: The Children's Oncology Group (COG) initiated study ARET12P1 in 2014 and was open to nine institutions. Eligible patients older than six months of age were enrolled. The feasibility of delivering three injections of melphalan into the ophthalmic artery every 28 days was assessed. RESULTS: Nine institutions participated in this trial. Fourteen patients were enrolled, two of whom were unevaluable for feasibility. Four patients experienced a feasibility failure. In two patients, the ophthalmic artery could not be accessed for the second IA injection, in one the artery could not be accessed for the first injection, and one patient experienced grade 4 hypotension during the procedure. CONCLUSION: Delivery of prescribed therapy within the context of this study did not meet the feasibility goals of the study with only a 67% feasibility success rate. These results should caution centers that plan to initiate this treatment and suggest investment in training to achieve technical expertise or referral to centers with expertise.
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Neoplasias da Retina , Retinoblastoma , Humanos , Criança , Lactente , Retinoblastoma/tratamento farmacológico , Retinoblastoma/diagnóstico , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/diagnóstico , Melfalan , Estudos de Viabilidade , Estudos Retrospectivos , Estudos Prospectivos , Resultado do Tratamento , Seguimentos , Infusões Intra-Arteriais , Artéria OftálmicaRESUMO
Glaucoma is the leading cause of irreversible blindness, and its pathophysiology includes neuroinflammatory changes. The present therapies for glaucoma target pressure-lowering mechanisms with limited success, making neuroinflammation a target for future interventions. This review summarizes the neuroinflammatory pathways seen in glaucoma and their interplay with stress. Glucocorticoids have been shown to activate proinflammatory glial cells, contributing to the neuroinflammation in glaucoma. Glucocorticoids have also been shown to increase the IOP directly. Stress-associated autonomic dysfunction can affect the vascular homeostasis in the retina and create oxidative stress. Diabetes, hyperglycemic-mediated endothelial damage, and vascular inflammation also play important roles in the neuroinflammation in glaucoma and diabetic retinopathy. Psychosocial stress has been implicated in an increased IOP and glaucoma outcomes. People who experience maladaptive chronic stress suffer from a condition known as allostatic load, which describes pathologic neuroendocrine dysregulation. The effects of allostatic load and chronic stress have been studied in patients affected by a lower socioeconomic status (SES) and marginalized racial identities. A lower SES is associated with higher rates of glaucoma and also affects the access to care and screening. Additionally, people of African ancestry are disproportionately affected by glaucoma for reasons that are multifactorial. In conclusion, this review explores neuroinflammation in glaucoma, highlighting opportunities for future investigation.
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Alostase , Glaucoma , Humanos , Alostase/fisiologia , Doenças Neuroinflamatórias , Estresse Psicológico/complicações , Classe Social , Desigualdades de SaúdeRESUMO
The underrepresentation of African American (AA) participants in medical research perpetuates racial health disparities in the United States. Open-ended phone interviews were conducted with 50 AA adults from Philadelphia who had previously participated in a genetic study of glaucoma that included complimentary ophthalmic screenings. Recruitment for the genetic study was done in partnership with a Black-owned radio station. Thematic analysis of interview transcripts, guided by the integrated behavior model (IBM), identified self-reported motivations for participating in this care-focused and community-promoted research program. Findings revealed that decisions to enroll were influenced by strong instrumental attitudes regarding learning more about personal health and contributing to future care options for others. Notable normative influences that factored into participants' decisions to enroll in the study included hearing about the study from a respected community media outlet, friends, and family. About one-third of respondents discussed past and current racial discrimination in medical research as an important sociocultural frame within which they thought about participation, suggesting that experiential attitudes play a continuing role in AA's decisions to enroll in medical research studies. Medical researchers seeking to recruit AA participants should collaborate with community partners, combine enrollment opportunities with access to health services, and emphasize the potential for new research to mitigate racial inequalities.
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Pesquisa Biomédica , Glaucoma , Adulto , Negro ou Afro-Americano , Glaucoma/genética , Humanos , Philadelphia , Estados UnidosRESUMO
TOPIC: Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship. CLINICAL RELEVANCE: Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people. METHODS: PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity. RESULTS: Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84-3.07]; longitudinal: OR, 1.66 [95% CI, 1.46-1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48-4.01]; longitudinal: OR, 2.09 [95% CI, 1.37-3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data. DISCUSSION: Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences.
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Cognição/fisiologia , Disfunção Cognitiva/epidemiologia , Saúde Pública , Transtornos da Visão/epidemiologia , Disfunção Cognitiva/fisiopatologia , Saúde Global , Humanos , Morbidade/tendências , Testes Neuropsicológicos , Fatores de Risco , Transtornos da Visão/fisiopatologiaRESUMO
BACKGROUND: Eyes with Group D intraocular retinoblastoma have low salvage rates. A pilot study showed safety and efficacy of sub-Tenon's fascia carboplatin with systemic chemotherapy supporting further study. METHODS: Children with newly diagnosed bilateral intraocular retinoblastoma with at least one remaining Group C or D eye were treated with six courses of carboplatin/etoposide/vincristine (CEV) with sub-Tenon's fascia carboplatin for Group C/D eyes during courses 2-4. Local ophthalmic therapy started at course 3. The primary study objective was to determine the 1-year failure rate of Group D eyes. RESULTS: The study closed prematurely due to poor accrual and 22 of 30 patients were evaluable for failure rate, contributing 25 Group D and four Group C eyes. Among the 25 Group D eyes, there were 13 failures within the first year of study enrollment including eight needing external beam radiotherapy (EBR) and five needing enucleation, resulting in 1-year failure rate of 52%. The failure rate was significantly lower than the historical rate of 70% (P = .039). The 1-year eye preservation rate for Group D eyes was 80% (20/25). One-year failure rate for Group C eyes was 25% (1/4); 1-year preservation rate was 100% without need for EBR. Systemic toxicity included Grade 3 hearing loss in two subjects, infections, neutropenia, and thrombocytopenia. Ocular toxicities included periorbital fat atrophy (13/29 = 45% eyes), optic nerve atrophy (1/29 = 3% eyes), and restrictive fibrosis (1/29 = 3% eyes). CONCLUSIONS: Sub-Tenon's fascia carboplatin plus CEV was partially effective in Group D intraocular retinoblastoma but had unacceptable ocular toxicities.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Cápsula de Tenon , Adolescente , Adulto , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Masculino , Prognóstico , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Vincristina/administração & dosagem , Adulto JovemRESUMO
Mitochondrial dysfunction has been implicated in the pathogenesis of primary open-angle glaucoma (POAG). However, the potential significance of mitochondrial DNA (mtDNA) haplogroups to POAG has not been evaluated in the overaffected African American population. To investigate the association of mtDNA haplogroups with POAG and its phenotypic characteristics, genotyping data from 4081 African American subjects (1919 cases and 2162 controls) was analyzed using 1293 positions on mtDNA. The overall frequency of mtDNA haplogroups in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort was 37% L3, 29% L2, 21% L1, 4% L0, and 10% non-African haplogroups (non-L). When all haplogroups (L0, L1, L2, and non-L) were compared against theL3 reference group, after adjusting by age and principal component of ancestry, the non-L3 haplogroups showed higher risk of POAG (OR-1.19, pâ¯=â¯0.02), with a particularly strong association among males (ORâ¯=â¯1.41, pâ¯=â¯0.003). More specifically the non-L group was associated with higher POAG risk than the L3 haplogroup (ORâ¯=â¯1.77, pâ¯=â¯0.007, Bonferroni adjusted pâ¯=â¯0.027) and to the L3e (nâ¯=â¯256, ORâ¯=â¯1.92, pâ¯=â¯0.007, Bonferroni adjusted pâ¯=â¯0.029). No significant association was found when genders were analyzed together or in female only analysis. There were no significant differences in various POAG endophenotypes across mtDNA haplogroups. This study expands our knowledge of mitochondrial genetics and mtDNA haplogroup associations in African American POAG. Further work is needed to better understand the functional role of mtDNA polymorphisms and their interactions with nuclear genes that affect POAG.
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DNA Mitocondrial/genética , Glaucoma de Ângulo Aberto/genética , Haplótipos/genética , Adulto , Negro ou Afro-Americano , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
Objective: African Americans have been historically underrepresented in research studies. Our aim was to evaluate factors influencing enrollment in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Design: Patients approached to enroll in the POAAGG study were asked to complete a 15-item survey addressing demographic characteristics, knowledge of genetics and glaucoma, and opinions on human research. Survey responses were compared between subjects who enrolled (Enrollers) and did not enroll (Decliners) in the POAAGG study. Results: Enrollers (N = 190) were 3.7 years younger (P = 0.007) and had similar gender, education, and income level to Decliners (N = 117). Knowledge about genetics and glaucoma was similar between groups. Enrollers were more comfortable providing DNA for research studies (93.1% vs 54.1%; P < 0.001) and more likely to have participated in prior studies (P = 0.003) and consider participating in future studies (P < 0.001). Among Decliners, lack of time was the primary reason given for not enrolling. Conclusion: To increase participation of African Americans in genetic research studies, efforts should be made to raise comfort with DNA donation.
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Pesquisa Biomédica , Negro ou Afro-Americano , Glaucoma de Ângulo Aberto/genética , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Participação do Paciente , Negro ou Afro-Americano/psicologia , Idoso , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Inquéritos e Questionários , Fatores de TempoRESUMO
BACKGROUND: African Americans have been historically under-represented in genetic studies. More research is needed on effective recruitment strategies for this population, especially on approaches that supplement traditional clinic enrollment. This study evaluates the cost and efficacy of four supplemental recruitment methods employed by the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. METHODS: After enrolling 2304 patients from University of Pennsylvania ophthalmology clinics, the POAAGG study implemented four new recruitment methods to supplement clinic enrollment. These methods included: 1) outreach in the local community, 2) in-house screening of community members ("in-reach"), 3) expansion to two external sites, and 4) sampling of the Penn Medicine Biobank. The cost per subject was calculated for each method and enrollment among cases, controls, and suspects was reported. RESULTS: The biobank offered the lowest cost ($5/subject) and highest enrollment yield (n = 2073) of the four methods, but provided very few glaucoma cases (n = 31). External sites provided 88% of cases recruited from the four methods (n = 388; $85/subject), but case enrollment at these sites declined over the next 9 months as the pool of eligible subjects was depleted. Outreach and in-reach screenings of community members were very high cost for low return on enrollment ($569/subject for 102 subjects and $606/subject for 45 subjects, respectively). CONCLUSIONS: The biobank offered the most cost-effective method for control enrollment, while expansion to external sites was necessary to recruit richly phenotyped cases. These recruitment methods helped the POAAGG study to exceed enrollment of the discovery cohort (n = 5500) 6 months in advance of the predicated deadline and could be adopted by other large genetic studies seeking to supplement clinic enrollment.
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Negro ou Afro-Americano/genética , Testes Genéticos/métodos , Glaucoma de Ângulo Aberto/genética , Seleção de Pacientes , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Análise Custo-Benefício , Testes Genéticos/economia , Glaucoma de Ângulo Aberto/diagnóstico , Humanos , Pessoa de Meia-Idade , Philadelphia , Reprodutibilidade dos TestesRESUMO
PURPOSE: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. PATIENTS AND METHODS: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. RESULTS: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. CONCLUSIONS: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Terapia Neoadjuvante/métodos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Carboplatina/administração & dosagem , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Vincristina/administração & dosagemRESUMO
PURPOSE: To estimate the population frequencies of all common mitochondrial variants and ancestral haplogroups among 1,999 subjects recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study, including 1,217 primary open-angle glaucoma (POAG) cases and 782 controls, and to identify ancestral subpopulations and mitochondrial mutations as potential risk factors for POAG susceptibility. METHODS: Subject classification by characteristic glaucomatous optic nerve findings and corresponding visual field defects, as defined by enrolling glaucoma specialists, stereo disc photography, phlebotomy, extraction of total DNA from peripheral blood or saliva, DNA quantification and normalization, PCR amplification of whole mitochondrial genomes, Ion Torrent deep semiconductor DNA sequencing on DNA pools ("Pool-seq"), Sanger sequencing of 3,479 individual mitochondrial DNAs, and bioinformatic analysis. RESULTS: The distribution of common African haplogroups within the POAAGG study population was broadly similar to prior surveys of African Americans. However, the POAG case population was found to be enriched in L1c2 haplogroups, which are defined in part by missense mutations m.6150G>A (Val83Ile, odds ratio [OR] 1.8, p=0.01), m.6253C>T (Met117Thr, rs200165736, OR 1.6, p=0.04), and m.6480G>A (Val193Ile, rs199476128, OR 4.6, p=0.04) in the cytochrome c oxidase subunit 1 (MT-CO1) gene and by a variant, m.2220A>G (OR 2.0, p=0.01), in MT-RNR2, which encodes the mitochondrial ribosomal 16s RNA gene. L2 haplogroups were predicted to be overrepresented in the POAG case population by Pool-seq, and the difference was confirmed to be significant with Sanger sequencing, that targeted the L2-associated variants m.2416T>C (rs28358580, OR 1.2, p=0.02) and m.2332C>T (OR 1.2, p=.02) in MT-RNR2. Another variant within MT-RNR2, m.3010G>A (rs3928306), previously implicated in sensitivity to the optic neuropathy-associated antibiotic linezolid, and arising on D4 and J1 lineages, associated with Leber hereditary optic neuropathy (LHON) severity, was confirmed to be common (>5%) but was not significantly enriched in the POAG cases. Two variants linked to the composition of the gut microbiome, m.15784T>C (rs527236194, haplogroup L2a1) and m.16390G>A (rs41378955, L2 haplogroups), were also enriched in the case DNA pools. CONCLUSIONS: These results implicate African mtDNA haplogroups L1c2, L1c2b, and L2 as risk factors for POAG. Approximately one in four African Americans have these mitochondrial ancestries, which may contribute to their elevated glaucoma risk. These haplogroups are defined in part by ancestral variants in the MT-RNR2 and/or MT-CO1 genes, several of which have prior disease associations, such as MT-CO1 missense variants that have been implicated in prostate cancer.
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Negro ou Afro-Americano/genética , DNA Mitocondrial/genética , Genes Mitocondriais , Glaucoma de Ângulo Aberto/genética , Mitocôndrias/genética , Mutação de Sentido Incorreto , Idoso , Idoso de 80 Anos ou mais , Feminino , Amplificação de Genes , Glaucoma de Ângulo Aberto/diagnóstico , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Análise de Sequência de DNARESUMO
PURPOSE: To describe the baseline characteristics of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort, the largest African American population with primary open-angle glaucoma (POAG) recruited at a single institution (University of Pennsylvania [UPenn], Department of Ophthalmology, Scheie Eye Institute) to date. DESIGN: Population-based, cross-sectional, case-control study. PARTICIPANTS: A total of 2520 African American subjects aged 35 years or more who were recruited from the greater Philadelphia, Pennsylvania area. METHODS: Each subject underwent a detailed interview and eye examination. The interview assessed demographic, behavioral, medical, and ocular risk factors. Current ZIP codes surrounding UPenn were recorded and US census data were queried to infer socioeconomic status. The eye examination included measurement of visual acuity (VA) and intraocular pressure, and a detailed anterior and posterior segment examination, including gonioscopy, dilated fundus and optic disc examination, visual fields, stereo disc photography, optical coherence tomography, and measurement of central corneal thickness. MAIN OUTCOME MEASURES: The baseline characteristics of gender, age, and glaucoma diagnosis were collected. Body mass index (BMI), hypertension, diabetes, alcohol and tobacco use, ocular conditions (including blindness, cataract, nonproliferative diabetic retinopathy, and age-related macular degeneration), and use of ocular medication and surgery were examined. Median population density, income, education level, and other socioeconomic measures were determined for the study cohort. RESULTS: Of the 2520 African Americans recruited to the POAAGG study to date, 2067 (82.0%), including 807 controls and 1260 POAG cases, met all inclusion criteria and completed the detailed clinical ocular examination. Cases were more likely to have a lower BMI (P < 0.01) and report a history of blindness (VA of ≤20/200; P < 0.001), whereas controls were more likely to have diabetes (P < 0.001), have nonproliferative diabetic retinopathy (P = 0.02), and be female (P < 0.001). Study participants were drawn largely from predominantly African American neighborhoods of low income, high unemployment, and lower education surrounding UPenn. CONCLUSIONS: The POAAGG study has currently recruited more than 2000 African Americans eligible for a POAG genetics study. Blindness and low BMI were significantly associated with POAG. This population was predominantly recruited from neighborhoods whose population income exists at or near the federal poverty level.
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Negro ou Afro-Americano/genética , Interação Gene-Ambiente , Glaucoma de Ângulo Aberto/genética , Negro ou Afro-Americano/etnologia , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Paquimetria Corneana , Estudos Transversais , Feminino , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/etnologia , Gonioscopia , Humanos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Classe Social , Inquéritos e Questionários , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which the equivalent oncogenic events are currently unknown. Here we report frequent somatic mutations in the heterotrimeric G protein alpha-subunit, GNAQ, in blue naevi (83%) and ocular melanoma of the uvea (46%). The mutations occur exclusively in codon 209 in the Ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting oncogene. Our results demonstrate an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention.
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Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Mutação/genética , Nevo Azul/genética , Neoplasias Cutâneas/genética , Neoplasias Uveais/genética , Apoptose , Biópsia , Proliferação de Células , Transformação Celular Neoplásica , Células Cultivadas , Códon/genética , Análise Mutacional de DNA , Ativação Enzimática , Subunidades alfa de Proteínas de Ligação ao GTP/química , Subunidades alfa de Proteínas de Ligação ao GTP/deficiência , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Genes Dominantes/genética , Humanos , Sistema de Sinalização das MAP Quinases , Melanócitos/enzimologia , Melanócitos/patologia , Melanoma/enzimologia , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nevo Azul/enzimologia , Nevo Azul/patologia , Oncogenes/genética , Estrutura Terciária de Proteína , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Neoplasias Uveais/enzimologia , Neoplasias Uveais/patologia , Proteínas ras/químicaRESUMO
Glaucoma, the leading cause of irreversible blindness worldwide, comprises a group of progressive optic neuropathies requiring early detection and lifelong treatment to preserve vision. Artificial intelligence (AI) technologies are now demonstrating transformative potential across the spectrum of clinical glaucoma care. This review summarizes current capabilities, future outlooks, and practical translation considerations. For enhanced screening, algorithms analyzing retinal photographs and machine learning models synthesizing risk factors can identify high-risk patients needing diagnostic workup and close follow-up. To augment definitive diagnosis, deep learning techniques detect characteristic glaucomatous patterns by interpreting results from optical coherence tomography, visual field testing, fundus photography, and other ocular imaging. AI-powered platforms also enable continuous monitoring, with algorithms that analyze longitudinal data alerting physicians about rapid disease progression. By integrating predictive analytics with patient-specific parameters, AI can also guide precision medicine for individualized glaucoma treatment selections. Advances in robotic surgery and computer-based guidance demonstrate AI's potential to improve surgical outcomes and surgical training. Beyond the clinic, AI chatbots and reminder systems could provide patient education and counseling to promote medication adherence. However, thoughtful approaches to clinical integration, usability, diversity, and ethical implications remain critical to successfully implementing these emerging technologies. This review highlights AI's vast capabilities to transform glaucoma care while summarizing key achievements, future prospects, and practical considerations to progress from bench to bedside.
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Background: Over the last decade, studies have suggested that primary open-angle glaucoma (POAG) may be associated with cognitive impairment and dementia, as both pathologies are age-related neurodegenerative processes. It remains unclear to what extent neurodegeneration in POAG extends to other neurological functions beyond vision, such as cognition. This follow-up study examined the potential association between POAG and cognitive decline in an African ancestry population. Methods: The Telephone-Montreal Cognitive Assessment (T-MoCA) was administered to POAG cases and controls previously enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Cases were assessed for retinal nerve fiber layer (RNFL) thickness and for the presence of dementia via chart review. Comparisons between POAG cases and controls were performed using two-sample t-tests for the T-MoCA total score and five subsection scores, and using chi-squared tests for incidence of dementia. Current scores were compared to scores from this same cohort from 7 years prior. Results: The T-MoCA was administered to 13 cases and 20 controls. The mean ± standard deviation (SD) T-MoCA total score was 15.5 ± 4.0 in cases and 16.7 ± 3.5 in controls (p = 0.36). However, there was a borderline significant difference in the delayed recall sub-score (2.3 ± 1.6 for cases vs. 3.4 ± 1.5 for controls, p = 0.052) and a significant difference in its sub-domain, the memory index score (MIS, 9.1 ± 4.3 for cases vs. 12.1 ± 3.0 for controls, p = 0.02). There were no significant differences between cases and controls for the remaining subsections. During 7 years of follow-up, a higher incidence of dementia was noted in POAG cases (7.1% for cases vs. 0% for controls, p = 0.058). Over 7 years, there was no significant deterioration in the cognitive performance of cases versus controls, and no association was seen between RNFL thinning and cognitive impairment. Conclusions: In this small-sample follow-up study of African ancestry individuals, POAG cases demonstrated worse short-term memory and higher incidence of dementia compared to controls. Future larger studies are needed to further investigate the presence and impact of neurodegeneration in POAG.
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The retina, an anatomical extension of the brain, forms physiological connections with the visual cortex of the brain. Although retinal structures offer a unique opportunity to assess brain disorders, their relationship to brain structure and function is not well understood. In this study, we conducted a systematic cross-organ genetic architecture analysis of eye-brain connections using retinal and brain imaging endophenotypes. We identified novel phenotypic and genetic links between retinal imaging biomarkers and brain structure and function measures from multimodal magnetic resonance imaging (MRI), with many associations involving the primary visual cortex and visual pathways. Retinal imaging biomarkers shared genetic influences with brain diseases and complex traits in 65 genomic regions, with 18 showing genetic overlap with brain MRI traits. Mendelian randomization suggests bidirectional genetic causal links between retinal structures and neurological and neuropsychiatric disorders, such as Alzheimer's disease. Overall, our findings reveal the genetic basis for eye-brain connections, suggesting that retinal images can help uncover genetic risk factors for brain disorders and disease-related changes in intracranial structure and function.
Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Retina , Humanos , Imageamento por Ressonância Magnética/métodos , Retina/diagnóstico por imagem , Masculino , Encéfalo/diagnóstico por imagem , Feminino , Córtex Visual/diagnóstico por imagem , Imagem Multimodal/métodos , Adulto , Vias Visuais/diagnóstico por imagem , Pessoa de Meia-Idade , Análise da Randomização Mendeliana , Endofenótipos , IdosoRESUMO
There are scarce data regarding the rate of the occurrence of primary open-angle glaucoma (POAG) and visible lamina cribrosa pores (LCPs) in the eyes of individuals with African ancestry; the potential impact of these features on disease burden remains unknown. We recruited subjects with POAG to the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Through regression models, we evaluated the association between the presence of LCPs and various phenotypic features. In a multivariable analysis of 1187 glaucomatous eyes, LCPs were found to be more likely to be present in eyes with cup-to-disc ratios (CDR) of ≥0.9 (adjusted risk ratio (aRR) 1.11, 95%CI: 1.04-1.19, p = 0.005), eyes with cylindrical-shaped (aRR 1.22, 95%CI: 1.11-1.33) and bean pot (aRR 1.24, 95%CI: 1.13-1.36) cups versus conical cups (p < 0.0001), moderate cup depth (aRR 1.24, 95%CI: 1.06-1.46) and deep cups (aRR 1.27, 95%CI: 1.07-1.50) compared to shallow cups (p = 0.01), and the nasalization of central retinal vessels (aRR 1.33, 95%CI: 1.23-1.44), p < 0.0001). Eyes with LCPs were more likely to have a higher degree of African ancestry (q0), determined by means of SNP analysis (aRR 0.96, 95%CI: 0.93-0.99, p = 0.005 for per 0.1 increase in q0). Our large cohort of POAG cases of people with African ancestry showed that LCPs may be an important risk factor in identifying severe disease, potentially warranting closer monitoring by physicians.
RESUMO
Piezo channels are associated with neuropathology in diseases like traumatic brain injury and glaucoma, but pathways linking tissue stretch to aberrant neural signaling remain unclear. The present study demonstrates that Piezo1 activation increases action potential frequency in response to light and the spontaneous dark signal from mouse retinal explants. Piezo1 stimulation was sufficient to increase cytoplasmic Ca 2+ in soma and neurites, while stretch increased spiking activity in current clamp recordings from of isolated retinal ganglion cells (RGCs). Axon-marker beta-tubulin III colocalized with both Piezo1 and Piezo2 protein in the mouse optic nerve head, while RGC nuclear marker BRN3A colocalized with Piezo channels in the soma. Piezo1 was also present on GFAP-positive regions in the optic nerve head and colocalized with glutamine synthetase in the nerve fiber layer, suggesting expression in optic nerve head astrocytes and Müller glia end feet, respectively. Human RGCs from induced pluripotent stem cells also expressed Piezo1 and Piezo2 in soma and axons, while staining patterns in rats resembled those in mice. mRNA message for Piezo1 was greatest in the RPE/choroid tissue, while Piezo2 levels were highest in the optic nerve, with both channels also expressed in the retina. Increased expression of Piezo1 and Piezo2 occurred both 1 and 10 days after a single stretch in vivo; this increase suggests a potential role in rising sensitivity to repeated nerve stretch. In summary, Piezo1 and Piezo2 were detected in the soma and axons of RGCs, and stimulation affected the light-dependent output of RGCs. The rise in RGCs excitability induced by Piezo stimulation may have parallels to the early disease progression in models of glaucoma and other retinal degenerations. Highlights: Activation of Piezo1 excites retinal ganglion cells, paralleling the early neurodegenerative progression in glaucoma mouse models and retinal degeneration.Piezo1 and Piezo2 were expressed in axons and soma of retinal ganglion cells in mice, rats, and human iPSC-RGCs.Functional assays confirmed Piezo1 in soma and neurites of neurons. Sustained elevation of Piezo1 and Piezo2 occurred after a single transient stretch may enhance damage from repeated traumatic nerve injury.
RESUMO
Recent genome-wide association studies (GWAS) have revealed shared genetic components among alcohol, opioid, tobacco and cannabis use disorders. However, the extent of the underlying shared causal variants and effector genes, along with their cellular context, remain unclear. We leveraged our existing 3D genomic datasets comprising high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq and RNA-seq across >50 diverse human cell types to focus on genomic regions that coincide with GWAS loci. Using stratified LD regression, we determined the proportion of genomewide SNP heritability attributable to the features assayed across our cell types by integrating recent GWAS summary statistics for the relevant traits: alcohol use disorder (AUD), tobacco use disorder (TUD), opioid use disorder (OUD) and cannabis use disorder (CanUD). Statistically significant enrichments (P<0.05) were observed in 14 specific cell types, with heritability reaching 9.2-fold for iPSC-derived cortical neurons and neural progenitors, confirming that they are crucial cell types for further functional exploration. Additionally, several pancreatic cell types, notably pancreatic beta cells, showed enrichment for TUD, with heritability enrichments up to 4.8-fold, suggesting genomic overlap with metabolic processes. Further investigation revealed significant positive genetic correlations between T2D with both TUD and CanUD (FDR<0.05) and a significant negative genetic correlation with AUD. Interestingly, after partitioning the heritability for each cell type's cis-regulatory elements, the correlation between T2D and TUD for pancreatic beta cells was greater (r=0.2) than the global genetic correlation value. Our study provides new genomic insights into substance use disorders and implicates cell types where functional follow-up studies could reveal causal variant-gene mechanisms underpinning these disorders.
RESUMO
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.