Progressive Choriocapillaris Changes on Optical Coherence Tomography Angiography Correlate With Stage Progression in AMD.

Purpose: We investigated the association between inner choroid flow deficit percentage (IC-FD%) using swept-source optical coherence tomography angiography (SS-OCTA) and progression of AMD. Methods: Retrospective, observational study including 64 eyes (42 participants) with early or intermediate AMD at baseline. Participants had two or more consecutive swept-source optical coherence tomography angiography covering a period of at least 18 months. Demographics, visual acuity, and AMD staging based on Beckman classification were reviewed. OCT was analyzed for hyperreflective foci, subretinal drusenoid deposits, hyporeflective drusen cores, and subfoveal choroidal thickness. IC-FD% was measured within the central 3- and 6-mm using a 16-µm slab, after compensation and binarization (Phansalkar method). Mixed-effects Cox regression models assessed the association between imaging biomarkers and AMD progression. Results: During follow-up (37 ± 9 months), 4 eyes with early AMD (31%) progressed to intermediate AMD and 30 (59%) eyes with intermediate AMD developed late AMD (19 geographic atrophy; 11 wet AMD). Baseline hyporeflective drusen core was associated with geographic atrophy development (P < 0.01), whereas greater IC-FD% (3-mm) was associated with wet AMD (P = 0.03). Time-varying analysis showed that faster subfoveal choroidal thickness reduction and IC-FD% (6-mm) increase were associated with geographic atrophy onset (P < 0.05), whereas IC-FD% (3-mm) increase was associated with wet AMD (P = 0.03). Notably, greater IC-FD% increases in the 3 mm (area under the curve = 0.72) and 6 mm (area under the curve = 0.89) were better predictive of wet AMD and geographic atrophy development, respectively. Conclusions: Our longitudinal IC-FD% assessment emphasizes the role of progressive choriocapillaris changes as a biomarker for AMD progression. Our findings support that widespread choriocapillaris alterations (6 mm) may precede progression to geographic atrophy, whereas more central choriocapillaris loss (3 mm) may provide an ischemic stimulus for wet AMD.

Visual restoration with KPro after face allotransplantation with a grade III phthisical eye.

The Boston Keratoprosthesis type I (KPro-I) has been shown to be successful in restoring vision after severe ocular burns; however, its long-term outcomes in phthisical eyes have rarely been reported. A monocular woman with a history of severe alkali chemical injury necessitating facial transplantation presented with a light perception left eye after a complicated course, including failed KPro-I, therapeutic penetrating keratoplasty, endophthalmitis, hypotony, total retinal detachment, and structural changes, including a shrunken 18 mm axial length and eye wall thickening. The patient underwent a combined vitrectomy with silicone oil and KPro-I implantation, resulting in her regaining ambulatory visual acuity (20/250) at 3 years' follow-up.

Contrast Sensitivity Better Reflects Wide-Field Swept-Source Optical Coherence Tomography Angiography Vascular Metrics Among Healthy Eyes Compared to Visual Acuity.

BACKGROUND AND OBJECTIVE: To evaluate the association between widefield swept-source optical coherence tomography angiography (WF SS-OCTA) and visual function in healthy eyes. PATIENTS AND METHODS: Fifty-seven eyes of 45 patients were evaluated with visual acuity (VA), contrast sensitivity (CS), and WF SS-OCTA (3 × 3, 6 × 6, and 12 × 12 mm images) on the same day. Mixed-effects multivariable regression analyses were performed. RESULTS: Contrast sensitivity metrics, including CS between 6 to 18 cycles per degree (cpd) and area under the logarithm CS function, were significantly associated with vessel density (VD) and vessel skeletonized density (VSD), whereas VA was not. The largest effect size was between CS at 18 cpd and VD (ß = 0.41, P = 0.007) and VSD (ß = 0.42, P = 0.006) on 12 × 12 mm images. CONCLUSIONS: Reduced VSD and VD on WF SSOCTA was significantly associated with decreased CS, whereas VA was not. These results suggest CS could serve as a screening tool for early stage retinal and neurologic disorders. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Decreased Macular Choriocapillaris Perfusion Correlates with Contrast Sensitivity Function in Dry Age-related Macular Degeneration.

PURPOSE: To investigate the relationships between contrast sensitivity (CS), choriocapillaris perfusion and other structural optical coherence tomography (OCT) biomarkers in dry age-related macular degeneration (AMD). DESIGN: Cross-sectional, observational study. PARTICIPANTS: One hundred AMD eyes (22 early, 52 intermediate and 26 late) from 74 patients and 45 control eyes from 37 age-similar subjects. METHODS: All participants had visual acuity (VA) assessment, quantitative contrast sensitivity function (qCSF) testing, macular OCT, and 6x6-mm swept-source OCT angiography (OCTA) scans on the same day. OCT volumes were analyzed for subretinal drusenoid deposits and hyporeflective drusen cores, and to measure thickness of the outer nuclear layer (ONL). OCTA scans were utilized to calculate drusen volume, inner choroid flow deficit percentage (IC-FD%), and to measure the area of choroidal hypertransmission defects (HTD). IC-FD% was measured from a 16 µm-thick choriocapillaris slab after compensation and binarization with Phansalkar's method. Generalized linear mixed-effects models were used to evaluate the associations between functional and structural variables. MAIN OUTCOME MEASURES: To explore the associations between qCSF-measured CS, ICFD% and various AMD imaging biomarkers. RESULTS: AMD exhibited significantly reduced qCSF metrics eyes across all stages compared to controls. Univariate analysis revealed significant associations between various imaging biomarkers, reduced qCSF metrics and VA in both groups. Multivariate analysis confirmed that higher IC-FD% in the central 5 mm was significantly associated with decreases in all qCSF metrics in AMD eyes (ß= -0.74 to -0.25, all p<0.05), but not with VA (p>0.05). ONL thickness in the central 3 mm correlated with both VA (ß= 2.85, p<0.001) and several qCSF metrics (ß= 0.01-0.90, all p<0.05), especially in AMD eyes. Further, larger HTD areas were associated with decreased VA (ß=-0.89, p<0.001) and reduced CS at low-intermediate frequencies across AMD stages (ß= -0.30 to -0.29, p<0.001). CONCLUSIONS: The significant association between IC-FD% in the central 5 mm and qCSF-measured CS reinforces the hypothesis that decreased macular choriocapillaris perfusion contributes to visual function changes in AMD, which are more pronounced in CS than in VA.

Correction: AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.

[This corrects the article DOI: 10.1371/journal.pone.0147279.].

Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease.

Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.

Associations of quantitative contrast sensitivity with vascular metrics on widefield swept-source OCT angiography across stages of diabetic retinopathy.

PURPOSE: To investigate structure-function associations between contrast sensitivity (CS) and widefield swept-source optical coherence tomography angiography (WF SS-OCTA) vascular metrics across stages of non-proliferative (NPDR) and proliferative diabetic retinopathy (PDR), without diabetic macular oedema. METHODS: Prospective cross-sectional study in 140 eyes of 99 patients: 33 mild NPDR, 24 moderate/severe NPDR, 15 PDR, 33 diabetic without DR (DMnoDR) and 46 control eyes. Mixed-effects multivariable regression models to evaluate associations between quantitative contrast sensitivity function (Adaptive Sensory Technology) and vessel density (VD) and vessel skeletonised density (VSD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) on same-day imaging with WF SS-OCTA (Plex Elite 9000, Carl Zeiss Meditec). RESULTS: Standardised ß coefficients for area under the logarithm of contrast sensitivity function curve (AULCSF) versus visual acuity (VA) at 3×3 mm scans: SCP VSD (ß=0.32, p<0.001 vs -0.18, p=0.044), DCP VSD (ß=0.30, p<0.001 vs -0.21, p=0.02), SCP VD (ß=0.25, p=0.004 vs -0.13, p=0.129), DCP VD (ß=0.26, p=0.003 vs -0.19, p=0.034). AULCSF was significantly reduced in mild NPDR (ß=-0.28, p<0.001) and DMnoDR (ß=-0.19, p=0.005) versus controls, while VA was not significantly different. AULCSF performed better than VA in differentiating between controls and DMnoDR (0.69 vs 0.50), controls and mild NPDR (0.76 vs 0.61) and controls and moderate/severe NPDR (0.89 vs 0.73). CONCLUSIONS: DR-induced microvascular changes on OCTA are associated with larger changes on CS than in VA. CS is affected earlier than VA in the course of DR and performed better in discriminating between controls, DMnoDR and across DR stages.

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

Widefield, Swept-Source Optical Coherence Tomography Angiography Metrics as Predictors of Anti-VEGF Treatment in Retinal Vein Occlusions.

BACKGROUND AND OBJECTIVE: Our objective was to assess baseline widefield swept-source optical coherence tomography angiography (WF SSOCTA) microvascular metrics as predictors for the number of anti-vascular endothelial growth factor (VEGF) injections and visual acuity (VA) at 12-months follow-up in patients with retinal vein occlusion (RVO). PATIENTS AND METHODS: This was a prospective study including 49 RVO eyes from 49 patients who had not received an anti-VEGF injection for at least 3 months prior to imaging. Microvascular metrics from 6×6-mm and 12×12-mm angiograms were assessed using linear regression models, adjusting for age. RESULTS: Reductions in the vessel density (VD) and vessel skeletonized density (VSD) vascular metrics were associated both with a higher number of anti-VEGF injections at all follow-up time points and reduced VA 12 months after imaging in all RVO eyes. CONCLUSIONS: WF SS-OCTA VD and VSD micro-vascular metrics at baseline can prognosticate VA and number of anti-VEGF injections required at 3, 6, and 12 months in RVO eyes. [Ophthalmic Surg Lasers Imaging Retina 2024;55:374-382.].

Quantitative Contrast Sensitivity Function and the Effect of Aging in Healthy Adult Eyes: A Normative Database.

BACKGROUND AND OBJECTIVE: We sought to establish normative quantitative contrast sensitivity function (qCSF) values in healthy adult eyes and investigate the effect of age on qCSF. PATIENTS AND METHODS: Healthy eyes underwent qCSF testing (adaptive sensory technology) and Snellen's visual acuity (VA). Descriptive statistics and mixed-effects multivariable linear regressions were evaluated. RESULTS: A total of 334 eyes (290 patients) with median age 61 years (range 21 to 88) had qCSF values as follows: area under the log contrast sensitivity function curve: 1.18; contrast acuity: 1.32; contrast sensitivity (CS) at 1 cycle per degree (cpd): 1.32; CS at 1.5 cpd: 1.37; CS at 3 cpd: 1.38; CS at 6 cpd: 1.20; CS at 12 cpd: 0.69; CS at 18 cpd: 0.22. Linear reductions in qCSF values per decade of age ranged from -0.02 to -0.07 vs 0.01 for visual acuity (VA). Age had a greater effect on the majority of qCSF values than VA (beta standardized regression coefficient ranged from -0.309 to -0.141 for qCSF values vs 0.177 for VA). CONCLUSIONS: We herein establish a normative database for qCSF and quantify the effect of age on qCSF values, adding evidence towards the validation of qCSF as a clinical endpoint. [Ophthalmic Surg Lasers Imaging Retina 2024;55:212-219.].

Early recurrence of macular schisis in X-linked retinoschisis treated with vitrectomy for rhegmatogenous retinal detachment under silicone oil: case report and brief literature review.

X-linked retinoschisis (XLRS) is an inherited retinal degeneration affecting males, characterized by splitting of the retinal layers. We herein present the outcomes of surgical treatment in a case of XLRS complicated by rhegmatogenous retinal detachment (RRD). A 22-year-old male presented to the emergency department due to decreased visual acuity and visual field defect in his left eye Oculus Sinister (OS) of 1 week duration. The patient reported an early onset retinal degeneration and decreased visual acuity in both eyes since childhood in his past ocular history. Upon presentation, best corrected visual acuity (BCVA) was 6/30 on the right eye Oculus Dexter (OD) and 6/120 OS. Fundus examination revealed areas of peripheral retinal schisis, and the characteristic spoke wheel pattern on the macula of both eyes. In OS, a temporal RRD involving the macula was identified. The patient underwent surgical treatment with pars plana vitrectomy with internal limiting membrane (ILM) peeling, endolaser, and silicone oil (SO) tamponade. BCVA in OS improved to 6/60 and schistic cavities resolution was observed in the immediate postoperative period. The patient's BCVA further improved to 6/19 at 1 month, as foveal anatomy showed relative improvement. However, there was a rapid reappearance of schisis spaces in the macular area at this point, which was also followed by progressive deterioration of foveal schisis by 3 months post-operatively. The resorption and recurrence of lamellar macular schisis changes after ILM peel and presence of SO, highlights that although XLRS findings can temporarily improve upon surgical intervention, the pathogenetic mechanisms contributing to disease phenotype remain to be elucidated.

Feasibility demonstration of a device for vitreous liquid biopsy incidental to intravitreal injection.

PURPOSE: VitreoDx is an experimental device enabling push-button collection of a neat vitreous liquid biopsy incidental to an intravitreal injection. We explored the ability of the device to collect a sample usable for proteomic biomarker discovery and testing. DESIGN: Pilot study using ex vivo human eyes. METHODS: Non-vitrectomized, human eyes from nine donors 75-91 years of age were refrigerated in BSS and used within 5 days of death. Four VitreoDx devices fitted with 25G needles, and four staked needle insulin syringes with 30G needles, were inserted at equal intervals through the pars plana of each eye and held in place by a fixture. The sampling mode of each VitreoDx device was triggered to attempt to acquire a liquid biopsy up to 70 µL. The plunger of each insulin syringe was retracted to attempt to obtain a liquid biopsy with a maximum volume of 50 µL. Samples acquired with the VitreoDx were extracted to polypropylene cryovials, refrigerated to -80 ºC, and sent for offsite proteomic analysis by proximity extension assay with a focus on panels containing approved and pipelined drug targets for neovascular disease and inflammatory factors. RESULTS: Of the attempted liquid biopsies with the novel 25G VitreoDx, 92% (66 of 72) resulted in successful acquisition (>25 µL) while 89% (64 of 72) attempted by a traditional 30G needle resulted in a successful acquisition. Sample volume sufficient for proteomics array analysis was acquired by the VitreoDx for every eye. Detectable protein was found for 151 of 166 unique proteins assayed in at least 25% of eyes sampled by VitreoDx. CONCLUSIONS: The high acquisition rate achieved by the prototype was similar to that achieved in previous clinical studies where a standard syringe was used with a 25G needle to biopsy vitreous fluid directly prior to standard intravitreal injection. Successful aspiration rates were likewise high for 30G needles. Together, these suggest that it is possible to routinely acquire liquid vitreous biopsies from patients who typically receive intravitreal injections with an injection device using a standard size needle without a vitreous cutter. Protein analysis shows that proteins of interest survive the sampling mechanism and may have potential to direct care in the future.

Associations of quantitative contrast sensitivity with wide-field swept-source optical coherence tomography angiography in retinal vein occlusion.

PURPOSE: To investigate associations between contrast sensitivity (CS) and vascular metrics on wide-field swept-source optical coherence tomography angiography (WF-SS-OCTA) in patients with retinal vein occlusion (RVO). METHODS: This prospectively recruited, cross-sectional observational study included RVO patients who underwent quantitative CS function (qCSF) testing and WF-SS-OCTA using 3 × 3, 6 × 6, and 12 × 12 mm angiograms on the same day. The study measured several qCSF outcomes and WF-SS-OCTA vascular metrics, including vessel density (VD), vessel skeletonized density (VSD), and foveal avascular zone (FAZ). The data were analyzed using multivariable regression analysis controlling for age and central subfield thickness (CST). RESULTS: A total of 43 RVO eyes of 43 patients and 30 fellow eyes were included. In RVO eyes, multiple vascular metrics were associated with CS outcomes but not visual acuity (VA). On 12 × 12 images, CS thresholds at 1 cpd, 1.5 cpd, and 3 cpd were significantly associated with VD and VSD, but VA was not. When comparing standardized regression coefficients, we found that vascular metrics had a larger effect size on CS than on VA. For instance, the standardized beta coefficient for FAZ area and CS at 6 cpd (ß* = - 0.46, p = 0.007) was larger than logMAR VA (ß* = 0.40, p = 0.011). CONCLUSION: Microvascular changes on WF-SS-OCTA in RVO had a larger effect size on CS than VA. This suggests CS may better reflect the microvascular changes of RVO compared to VA. qCSF-measured CS might be a valuable adjunct functional metric in evaluating RVO patients.

Effects of newer-generation anti-diabetics on diabetic retinopathy: a critical review.

Diabetic retinopathy (DR) is the leading etiology of blindness in the working population of the USA. Its long-term management relies on effective glycemic control. Seven anti-diabetic classes have been introduced for patients with type 2 diabetes (T2D) in the past two decades, with different glucose-lowering and cardiovascular benefits. Yet, their effects specifically on DR have not been studied in detail. A systematic review of the literature was conducted to investigate this topic, focusing on the available clinical data for T2D. Published studies were evaluated based on their level of statistical evidence, as long as they incorporated at least one endpoint or adverse event pertaining to retinal health. Fifty nine articles met our inclusion criteria and were grouped per anti-diabetic class as follows: alpha-glucosidase inhibitors (1), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (8), amylin analogs (1), glucagon-like peptide-1 (GLP-1) receptor agonists (28), dipeptidyl peptidase 4 (DPP-4) inhibitors (9), and sodium glucose co-transporter-2 (SGLT-2) inhibitors (9), plus one retrospective study and two meta-analyses evaluating more than one of the aforementioned anti-diabetic categories. We also reviewed publicly-announced results of trials for the recently-introduced class of twincretins. The available data indicates that most drugs in the newer anti-diabetic classes are neutral to DR progression; however, there are subclasses differences in specific drugs and T2D populations. In particular, there is evidence suggesting there may be worse diabetic macular edema with PPAR-gamma agonists, potential slight DR worsening with semaglutide (GLP-1 receptor agonist), and potential slight increase in the incidence of retinal vein occlusion in elderly and patients with advanced kidney disease receiving SGLT-2 inhibitors. All these warrant further investigation. Longer follow-up and systematic assessment of at least one DR-related endpoint are highly recommended for all future trials in the T2D field, to ultimately address this topic.