Deep learning for automatic prediction of early activation of treatment naïve non-exudative MNVs in AMD.

BACKGROUND: Around 30% of non-exudative macular neovascularizations(NE-MNVs) exudate within 2 years from diagnosis in patients with age-related macular degeneration(AMD).The aim of the study is to develop a deep learning classifier based on optical coherence tomography(OCT) and OCT angiography(OCTA) to identify NE-MNVs at risk of exudation. METHODS: AMD patients showing OCTA and fluorescein angiography (FA) documented NE-MNV with a 2-years minimum imaging follow-up were retrospectively selected. Patients showing OCT B-scan-documented MNV exudation within the first 2 years formed the EX-GROUP while the others formed QU-GROUP.ResNet-101, Inception-ResNet-v2 and DenseNet-201 were independently trained on OCTA and OCT B-scan images. Combinations of the 6 models were evaluated with major and soft voting techniques. RESULTS: Eighty-nine (89) eyes of 89 patients with a follow-up of 5.7 ± 1.5 years were recruited(35 EX GROUP and 54 QU GROUP). Inception-ResNet-v2 was the best performing among the 3 single convolutional neural networks(CNNs).The major voting model resulting from the association of the 3 different CNNs resulted in improvement of performance both for OCTA and OCT B-scan (both significantly higher than human graders' performance). Soft voting model resulting from the combination of OCTA and OCT B-scan based major voting models showed a testing accuracy of 94.4%. Peripheral arcades and large vessels on OCTA enface imaging were more prevalent in QU GROUP. CONCLUSIONS: Artificial intelligence shows high performances in identifications of NE-MNVs at risk for exudation within the first 2 years of follow up, allowing better customization of follow up timing and avoiding treatment delay. Better results are obtained with the combination of OCTA and OCT B-scan image analysis.

Macular Neovascularization Secondary to Subclinical Angioid Streaks in Age-Related Macular Degeneration: Treatment Response to Anti-VEGF at 2-Year Follow-up.

INTRODUCTION: To characterize the response to antivascular endothelial growth factor (VEGF) treatment of macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) with subclinical angioid streaks (AS) during a 2-year follow-up. METHODS: Retrospective, longitudinal, case-control, and multicentric study. Among a cohort of neovascular AMD population, we selected patients with subclinical AS and treatment-naïve MNV treated with anti-VEGF for a 2-year follow-up. An age- and sex-matched control group with treatment-naïve MNV secondary to AMD without subclinical AS was selected. Demographics and differences in treatment response (i.e., number of injections needed, anatomical and functional outcomes) between the two groups were analyzed. RESULTS: Among 102 eyes of 102 patients with neovascular AMD, 34 eyes of 34 patients (82 ± 6 years old) were included in the subclinical AS group, whereas 68 eyes of 68 patients (81 ± 6 years old, p = 0.342) in the control group. All eyes with subclinical AS presented RPD compared to 56% of eyes without subclinical AS (p < 0.001). During the 2-year follow-up, eyes with subclinical AS needed more injections (10.6 ± 3.2 vs 8.3 ± 3.1 injections for eyes with and without subclinical AS, respectively, p < 0.001). Visual acuity (VA) decreased during the treatment (from 0.53 ± 0.37 at the baseline to 0.69 ± 0.45 LogMAR at 2-year follow-up, p = 0.044) in eyes with subclinical AS; no VA changes were observed in the control group (p = 0.798). RPE atrophy at the end of the 2-year follow-up affected 74% of cases with subclinical AS and 29% of cases of the control group (p < 0.001). CONCLUSIONS: MNVs secondary to AMD with subclinical AS are characterized by worse functional and anatomical outcomes after 2-year anti-VEGF treatment compared to MNV secondary to AMD without subclinical AS, supporting the different pathophysiological mechanisms involved in this recently described AMD phenotype.

Phenotypic characterization of predictors for development and progression of geographic atrophy using optical coherence tomography.

PURPOSE: To evaluate the impact of optical coherence tomography (OCT) phenotypes preceding atrophy related to age-related macular degeneration (AMD) on the progression of atrophic lesions. METHODS: In this observational retrospective cohort study, a total of 70 eyes of 60 consecutive patients with intermediate AMD with a minimum follow-up of 24 months were included. The atrophy was quantified using fundus autofluorescence, also considering the directionality of atrophy as centrifugal and centripetal progression rates.Main outcome measures were geographic atrophy (GA) progression rate (mm2/year) and square root-transformation GA (mm2/year). RESULTS: The best-fit model for GA (OR: 1.81, p<0.001) and square root-transformation GA (OR: 1.36, p<0.001) areas revealed that the main baseline predictor was the presence of an RPE-basal lamina-(BL)-Bruch's membrane (BrM) splitting. Large drusen at baseline appeared protective for the GA area lesion expansion over time (OR: 0.52, p<0.001) when considered with other confounders. CONCLUSION: A thin RPE-BL-BrM splitting without evidence of neovascularization on OCT angiography likely represents an OCT signature for late basal laminar deposits. Identifying this phenotype can help identify individuals with a higher risk of rapid progression and atrophy expansion.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

NONEXUDATIVE INTRARETINAL FLUID IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

BACKGROUND: To describe the occurrence of nonexudative intraretinal fluid (IRF) in intermediate age-related macular degeneration. METHODS: A retrospective study was designed to include consecutive cases with intermediate age-related macular degeneration associated with IRF. A multimodal imaging approach was used to confirm diagnosis of IRF in intermediate age-related macular degeneration. Multimodal imaging included color fundus photograph, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography, and optical coherence tomography angiography. RESULTS: Ten eyes of 10 patients (2 male and 8 female patients, ages 68-80 years) showing IRF in intermediate age-related macular degeneration were included in the study. The mean best-corrected visual acuity was 20/40 Snellen equivalent. Multimodal imaging including fluorescein angiography/indocyanine green angiography and optical coherence tomography demonstrated the absence of macular neovascularization in all cases; optical coherence tomography-angiography did not detect any abnormal flow signal associated with IRF. Seven of 10 patients developed IRF in correspondence of pigment epithelium detachment. Three of 10 patients presented IRF in correspondence of an area of nascent geographic atrophy. CONCLUSION: Nonexudative intraretinal fluid in intermediate age-related macular degeneration is a novel, distinctive feature that is characterized by the presence of IRF with no evidence of macular neovascular lesions. The authors described different phenotypes of IRF in intermediate age-related macular degeneration. The definite diagnosis of this condition requires further studies with thorough application of multimodal imaging.

Use of the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) questionnaires for clinical decision-making and psychological referral in ophthalmic care: a multicentre observational study.

OBJECTIVES: The aim of this study was to evaluate the influence of anxiety and depression on clinician decision-making in patients suffering from chronic eye disease in ophthalmological clinical practice. DESIGN AND SETTING: This multicentre observational study, in collaboration with the WHO, included ophthalmologists and their patients affected by chronic eye disease. States of anxiety and depression were screened with specific questionnaires, the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), self-administered by patients before the visit. In the present analysis, we report data from three major eye care centres in Italy between 2021 and 2022. PRIMARY AND SECONDARY OUTCOMES: To assess self-reported changes in ophthalmologists' clinical approach (communication style and their clinical-therapeutic strategies) and decisions after knowing questionnaire scores (primary aim), and to analyse the PHQ-9 and GAD-7 scores in patients with chronic eye diseases (secondary aim). RESULTS: 41 ophthalmologists and 359 patients were included. The results from PHQ-9 and GAD-7 scores showed critical depression and anxiety status scores (PHQ-9 ≥5 and GAD-7 ≥10) in 258 patients. In 74% of cases, no actions were taken by the ophthalmologists based on these scores; in 26% of cases, they changed their clinical approach; and in 14% of cases, they referred the patients for psychological/psychiatric evaluation. CONCLUSIONS: States of anxiety and depression affect many patients with chronic eye conditions and need to be detected and managed early to improve patients' well-being. Providing ophthalmologists with knowledge of their patients' psychological conditions can change the clinical management and attitude towards referral for a psychological evaluation. Further studies are needed to expand our knowledge of how to raise awareness among ophthalmologists regarding multimorbidity of patients suffering from chronic eye diseases in order to achieve better clinical outcomes.

The Insulin-Degrading Enzyme from Structure to Allosteric Modulation: New Perspectives for Drug Design.

The insulin-degrading enzyme (IDE) is a Zn2+ peptidase originally discovered as the main enzyme involved in the degradation of insulin and other amyloidogenic peptides, such as the ß-amyloid (Aß) peptide. Therefore, a role for the IDE in the cure of diabetes and Alzheimer's disease (AD) has been long envisaged. Anyway, its role in degrading amyloidogenic proteins remains not clearly defined and, more recently, novel non-proteolytic functions of the IDE have been proposed. From a structural point of view, the IDE presents an atypical clamshell structure, underscoring unique enigmatic enzymological properties. A better understanding of the structure-function relationship may contribute to solving some existing paradoxes of IDE biology and, in light of its multifunctional activity, might lead to novel therapeutic approaches.

Use of electronic devices by people attending vision rehabilitation services in Italy: A study based on the device and aids registry (D.A.Re).

PURPOSE: To investigate the characteristics of electronic device users, specifically smartphones and tablets, in the Device & Aids Register (D.A.Re), from several low-vision rehabilitation services in Italy. METHODS: We collected general and clinical information about ocular and systemic diseases, visual function, reading speed and Instrumental Activities of Daily Living (IADL) questionnaire score. Technological details of each optical and electronic device, (including screen size, touch-screen and OCR functions, text-to-speech function) were also collected. RESULTS: 1218 patients (752 females and 466 males) were included in our analysis, mean age 71.5 (±18.8) years. Users of electronic aids (n.237) were slightly younger (67 vs 72 years, p < 0.001) than non-users (n.981), had a worse reading speed (38 vs 65 words/minute), critical print size (43 vs 28 print size, p < 0.001), poorer visual acuity (VA)(1.0 logMAR or less: 30% non-users vs 73% users, p < 0.001) and more commonly visual field restriction within 10° (23% vs 14%, p = 0.001). A similar proportion of users and non-users were retired (about 70%) and about 16-17% were employed. The use of portable electronic devices (5″or less, p < 0.001; 6″ to 18″ screen size, p = 0.017) was associated with better IADL scores, and the use of stand devices with worse IADL score (p < 0.001); Furthermore, using smartphones and tablets (193 subjects) was strongly associated with better IADL scores. CONCLUSION: We found that using electronic devices, and especially smartphone and tablets, were associated with better vision-related quality of life in low-vision people attending rehabilitation services. While this association does not mean causality, these findings seemed robust to confounder adjustment.

ARTIFICIAL INTELLIGENCE'S ROLE IN DIFFERENTIATING THE ORIGIN FOR SUBRETINAL BLEEDING IN PATHOLOGIC MYOPIA.

PURPOSE: To identify salient imaging features to support human-based differential diagnosis between subretinal hemorrhage (SH) due to choroidal neovascularization (CNV) onset and SH without CNV (simple bleeding [SB]) in pathologic myopia eyes using a machine learning (ML)-based step-wise approach. METHODS: Four different methods for feature extraction were applied: GradCAM visualization, reverse engineering, image processing, and human graders' measurements. GradCAM was performed on a deep learning model derived from Inception-ResNet-v2 trained with OCT B-scan images. Reverse engineering consisted of merging U-Net architecture with a deconvolutional network. Image processing consisted of the application of a local adaptive threshold. Available OCT B-scan images were divided in two groups: the first group was classified by graders before knowing the results of feature extraction and the second (different images) was classified after familiarization with the results of feature extraction. RESULTS: Forty-seven and 37 eyes were included in the CNV group and the simple bleeding group, respectively. Choroidal neovascularization eyes showed higher baseline central macular thickness ( P = 0.036). Image processing evidenced in CNV eyes an inhomogeneity of the subretinal material and an interruption of the Bruch membrane at the margins of the SH area. Graders' classification performance improved from an accuracy of 76.9% without guidance to 83.3% with the guidance of the three methods ( P  = 0.02). Deep learning accuracy in the task was 86.0%. CONCLUSION: Artificial intelligence helps identifying imaging biomarkers suggestive of CNV in the context of SH in myopia, improving human ability to perform differential diagnosis on unprocessed baseline OCT B-scan images. Deep learning can accurately distinguish between the two causes of SH.

Polytherapy and Multimorbidity Pattern of Users of Anti-VEGF Drugs and Dexamethasone for the Treatment of Age-Related Macular Degeneration and other Vascular Retinopathies in Clinical Practice.

Introduction: Our aim was to describe the polytherapy and multimorbidity pattern of users of anti-VEGF and dexamethasone drugs for the treatment of these conditions, and to investigate their polytherapy and multimorbidity profiles, together with adherence and the burden of care. Methods: Descriptive, population-based, pharmacoepidemiology study on the users of anti-VEGF drugs, and secondarily intravitreal dexamethasone, for the treatment of age-related macular degeneration and other vascular retinopathies in clinical practice, using administrative databases of Lazio region, Italy. We used a cohort of 50,000 residents in Lazio in 2019 with same age as comparison. Polytherapy was assessed using databases of prescribed drugs intended for outpatient use. Multimorbidity was investigated with additional sources, such as hospital discharge records, outpatient care records, and disease-specific exemptions from co-payment. Each patient was followed for 1 to 3 years from the first intravitreal injection received. Results: 16,266 residents in Lazio who received the first IVI from 1 January 2011 to 31 December 2019, with at least 1 year of observation before index date, were included. The proportion of patients with at least one comorbidity was 54.0%. Patients used an average 8.6 (SD 5.3) concomitant drugs other than anti-VEGF used for injections. A large percentage of patients (39.0%) used 10 or more concomitant drugs, including antibacterials (62.9%), drugs for peptic ulcers (56.8%), anti-thrombotics (52.3%), NSAIDs (44.0%), and anti-dyslipidaemics (42.3%). The same proportions were found across patients of all ages, probably due to high prevalence of diabetes (34.3%), especially in younger age groups. When stratified by diabetes, a comparison of multimorbidity and polytherapy with a sample of 50,000 residents of the same age found that patients receiving IVIs used more drugs and had more comorbidities, particularly in non-diabetics. Lapses of care, whether short (absence of any type of contact for at least 60 days in the first year of follow-up and 90 in the second year) or long (90 days in the first and 180 days in the second year) were common: 66% and 51.7%, respectively. Conclusions: Patients receiving intravitreal drugs for retinal conditions have high multimorbidity and polytherapy rates. Their burden of care is aggravated by the large number of contacts with the eye care system for examinations and injections. Pursuing Minimally Disruptive Medicine to optimise patient care is a difficult goal for health systems, and more research on clinical pathways and their implementation is warranted.

Progression Biomarkers of Microvascular and Photoreceptor Changes Upon Long-Term Evaluation in Type 1 Diabetes.

Purpose: To assess demographic, metabolic, and imaging predictors influencing microvasculature and photoreceptors changes over a 4-year follow-up in type 1 diabetes mellitus (DM1). Methods: This prospective cohort study enrolled patients with DM1 with mild non-proliferative diabetic retinopathy. Complete medical records, glycosylated hemoglobin (HbA1c), optical coherence tomography angiography, and adaptive optics were collected for the 4 years of follow-up. The main outcome measures included perfusion density at the superficial capillary plexus (SCP) and deep capillary plexus (DCP), choriocapillaris (CC) flow deficits (FDs, %), cone density, linear dispersion index (LDi), and heterogeneity packing index (HPi). Results: The SCP presented a dichotomic perfusion trend, with increasing PD at 1 and 2 years and a subsequent decline (P < 0.001). DCP presented a similar trend in the first 2 years (P < 0.01) but not at the following time points, whereas CC FDs constantly increased over time (P < 0.01). The best-fitted model for the microvascular parameters demonstrated that the main factors affecting SCP included time (P < 0.001), duration of diabetes (P = 0.007), and HbA1c (P = 0.03), whereas the DCP was influenced by LDi modifications (P = 0.006). The LDi and HPi were mainly influenced by SCP and CC perfusion in the parafovea (P = 0.02). Conclusions: This study demonstrated an initial vasodilatory phenomenon resulting from a compensatory mechanism from the superficial vasculature, followed by capillary dropout. Initially, it would seem that there was an adaptive response by the DCP to the needs of the photoreceptors. Although the SCP may initially support the DCP, when the microvascular damage becomes diffuse and involves the SCP and CC it directly affects photoreceptor integrity.

Nascent Geographic Atrophy as a Predictor of Type 3 Macular Neovascularization Development.

PURPOSE: To investigate the association of nascent geographic atrophy (GA) preceding the development of exudative type 3 macular neovascularization (MNV) in patients with age-related macular degeneration (AMD). DESIGN: Retrospective longitudinal study. PARTICIPANTS: Patients with AMD diagnosed with treatment-naive exudative type 3 MNV in 1 or both eyes were evaluated. Inclusion criteria included serial tracked structural OCT examinations for ≥ 2 years before the detection of exudative type 3 MNV. METHODS: Clinical characteristics and retinal imaging, including structural OCT at baseline and at each follow-up examination, were analyzed. Eyes showing the presence of nascent GA during the follow-up were selected for analysis of prevalence, and clinical characteristics at the site of subsequent type 3 MNV development. MAIN OUTCOME MEASURES: Description of the prevalence and clinical characteristics of nascent GA at the site of subsequent type 3 MNV development. RESULTS: Overall, 97 eyes affected by type 3 MNV meeting inclusion criteria were analyzed. Of 97 eyes (71 patients), 22 eyes of 21 patients (mean age 82 ± 9 years) showed nascent GA preceding exudative type 3 MNV. The observed prevalence of nascent GA preceding exudative type 3 MNV was 22.7% (95% confidence interval, 14.4%-31.0%). Exudative type 3 MNV developed a mean of 9 ± 6 months after detection of nascent GA. The presence of reticular pseudodrusen in the study eye did not significantly influence the timing of exudative type 3 MNV development after the observation of nascent GA (P > 0.1 in all analyses). Reduced best-corrected visual acuity was recorded at the exudative type 3 stage in comparison with the nascent GA stage (P = 0.003). CONCLUSIONS: As nascent GA may precede the development of exudative type 3 MNV, the detection of nascent GA in eyes with AMD may warrant closer surveillance to identify early exudative type 3 MNV warranting treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

SUBRETINAL LIPID GLOBULES AN EARLY BIOMARKER OF MACULAR NEOVASCULARIZATION IN EYES WITH INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To explore the association between subretinal lipid globules (SLGs) detected in eyes with intermediate age-related macular degeneration with the presence of nonexudative macular neovascularization. METHODS: This was a retrospective analysis of 113 consecutive patients with bilateral intermediate age-related macular degeneration (226 eyes) followed for a least 6 months. All eyes underwent multimodal imaging with fundus autofluorescence, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Subretinal lipid globules were identified on spectral-domain optical coherence tomography as round hyporeflective lesions measuring 31 to 157 µ m located between the ellipsoid zone and the retinal pigment epithelium/Bruch membrane complex. Nonexudative macular neovascularization was detected with optical coherence tomography angiography. The features of NE-MNV lesions detected in eyes with SLGs were compared with those in eyes without SLGs. RESULTS: Subretinal lipid globules were identified in 15 eyes of which 14 eyes (93.3%) demonstrated NE-MNV on optical coherence tomography angiography. In the remaining 98 eyes without SLGs, 18 (18.4%) displayed NE-AMD on optical coherence tomography angiography. The macular neovascularization area was larger in the SLG subgroup (+0.38 vs. +0.21 mm 2 , P = 0.008) and showed faster horizontal growth (+727 µ m, CI 95% 250.4, 1,205.4) than MNV in eyes without SLGs (+64.9 µ m, CI 95%, 24.3, 154) on optical coherence tomography B-scans. After a mean of 11.6 months, the conversion rate to exudative MNV was similar between eyes with SLGs and those without SLGs [8/26 (38.5%) versus 3/13 (27.3%), P = 0.56)]. CONCLUSION: The detection of SLGs in eyes with intermediate age-related macular degeneration was strongly correlated with the presence of NE-MNV. Although these MNV lesions were larger and grew faster than NE-MNV detected in eyes lacking SLGs, the rates of conversion to exudative MNV appeared similar.

Practical guidance for imaging biomarkers in exudative age-related macular degeneration.

We provide an overview of current macular imaging techniques and identify and describe biomarkers that may be of use in the routine management of macular diseases, particularly exudative age-related macular degeneration (AMD). This perspective includes sections on macular imaging techniques including optical coherence tomography (OCT) and OCT angiography (OCTA), classification of exudative AMD, and biomarkers in structural OCT and OCTA. Fluorescein angiography remains a vital tool for assessing the activity of neovascular lesions, while indocyanine green angiography is the preferred option for choroidal vessel imaging in neovascular AMD. OCT provides a non-invasive three-dimensional visualization of retinal architecture in vivo and is useful in the diagnosis of many imaging biomarkers of AMD-related neovascular lesions, including lesion activity. OCTA is a recent advance in OCT technology that allows accurate visualization of retinal and choroidal vascular flow. OCT and OCTA have led to an updated classification of exudative AMD lesions and provide several biomarkers that help to establish a diagnosis and the disease activity status of neovascular lesions. Individualization of therapy guided by OCT and OCTA biomarkers has the potential to further improve visual outcomes in exudative AMD. Moving forwards, integration of technologically-advanced imaging equipment with AI software will help ophthalmologists to provide patients with the best possible care.

Prognostic Imaging Biomarkers in Diabetic Macular Edema Eyes Treated with Intravitreal Dexamethasone Implant.

BACKGROUND: The aim was to evaluate predictive value of baseline optical coherence tomography (OCT) and OCT angiography (OCTA) parameters in diabetic macular edema (DME) treated with dexamethasone implant (DEXi). METHODS: OCT and OCTA parameters were collected: central macular thickness (CMT), vitreomacular abnormalities (VMIAs), intraretinal and subretinal fluid (mixed DME pattern), hyper-reflective foci (HRF), microaneurysms (MAs) reflectivity, ellipsoid zone disruption, suspended scattering particles in motion (SSPiM), perfusion density (PD), vessel length density, and foveal avascular zone. Responders' (RES) and non-responders' (n-RES) eyes were classified considering morphological (CMT reduction ≥ 10%) and functional (BCVA change ≥ 5 ETDRS letters) changes after DEXi. Binary logistic regression OCT, OCTA, and OCT/OCTA-based models were developed. RESULTS: Thirty-four DME eyes were enrolled (18 treatment-naïve). OCT-based model combining DME mixed pattern + MAs + HRF and OCTA-based model combining SSPiM and PD showed the best performance to correctly classify the morphological RES eyes. In the treatment-naïve eyes, VMIAs were included with a perfect fit for n-RES eyes. CONCLUSION: The presence of DME mixed pattern, a high number of parafoveal HRF, hyper-reflective MAs, SSPiM in the outer nuclear layers, and high PD represent baseline predictive biomarkers for DEXi treatment responsiveness. The application of these models to treatment-naïve patients allowed a good identification of n-RES eyes.

Targeting immunoproteasome in neurodegeneration: A glance to the future.

The immunoproteasome is a specialized form of proteasome equipped with modified catalytic subunits that was initially discovered to play a pivotal role in MHC class I antigen processing and immune system modulation. However, over the last years, this proteolytic complex has been uncovered to serve additional functions unrelated to antigen presentation. Accordingly, it has been proposed that immunoproteasome synergizes with canonical proteasome in different cell types of the nervous system, regulating neurotransmission, metabolic pathways and adaptation of the cells to redox or inflammatory insults. Hence, studying the alterations of immunoproteasome expression and activity is gaining research interest to define the dynamics of neuroinflammation as well as the early and late molecular events that are likely involved in the pathogenesis of a variety of neurological disorders. Furthermore, these novel functions foster the perspective of immunoproteasome as a potential therapeutic target for neurodegeneration. In this review, we provide a brain and retina-wide overview, trying to correlate present knowledge on structure-function relationships of immunoproteasome with the variety of observed neuro-modulatory functions.

Ocular Biomarkers for Alzheimer Disease Dementia: An Umbrella Review of Systematic Reviews and Meta-analyses.

Importance: Several ocular biomarkers have been proposed for the early detection of Alzheimer disease (AD) and mild cognitive impairment (MCI), particularly fundus photography, optical coherence tomography (OCT), and OCT angiography (OCTA). Objective: To perform an umbrella review of systematic reviews to assess the diagnostic accuracy of ocular biomarkers for early diagnosis of Alzheimer disease. Data Sources: MEDLINE, Embase, and PsycINFO were searched from January 2000 to November 2021. The references of included reviews were also searched. Study Selection: Systematic reviews investigating the diagnostic accuracy of ocular biomarkers to detect AD and MCI, in secondary care or memory clinics, against established clinical criteria or clinical judgment. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline checklist was followed and the Risk Of Bias in Systematic reviews tool was used to assess review quality. Main Outcomes and Measures: The prespecified outcome was the accuracy of ocular biomarkers for diagnosing AD and MCI. The area under the curve (AUC) was derived from standardized mean difference. Results: From the 591 titles, 14 systematic reviews were included (median [range] number of studies in each review, 14 [5-126]). Only 4 reviews were at low risk of bias on all Risk of Bias in Systematic Reviews domains. The imaging-derived parameters with the most evidence for detecting AD compared with healthy controls were OCT peripapillary retinal nerve fiber layer thickness (38 studies including 1883 patients with AD and 2510 controls; AUC = 0.70; 95% CI, 0.53-0.79); OCTA foveal avascular zone (5 studies including 177 patients with AD and 371 controls; AUC = 0.73; 95% CI, 0.50-0.89); and saccadic eye movements prosaccade latency (30 studies including 651 patients with AD/MCI and 771 controls; AUC = 0.64; 95% CI, 0.58-0.69). Antisaccade error was investigated in fewer studies (12 studies including 424 patients with AD/MCI and 382 controls) and yielded the best accuracy (AUC = 0.79; 95% CI, 0.70-0.88). Conclusions and Relevance: This umbrella review has highlighted limitations in design and reporting of the existing research on ocular biomarkers for diagnosing AD. Parameters with the best evidence showed poor to moderate diagnostic accuracy in cross-sectional studies. Future longitudinal studies should investigate whether changes in OCT and OCTA measurements over time can yield accurate predictions of AD onset.

The state-of-the-art pharmacotherapeutic management of neovascular age-related macular degeneration.

INTRODUCTION: Age-related macular degeneration (AMD) is a major cause of central visual loss in the developed world. Although the pathogenesis is not fully understood, vascular endothelial growth factor (VEGF) is considered the most important growth factor involved in angiogenesis and exudation in neovascular AMD eyes. Advances in anti-VEGF agents have changed the treatment approach for wet AMD, allowing better outcomes in visual acuity and retinal anatomy. AREAS COVERED: The present review describes the main pharmacological and clinical characteristics of anti-VEGF drugs, focusing firstly on the molecules commonly in use and then on the new candidate therapies. We performed a comprehensive literature search using the PubMed database from 1 January 1993 to 1 June 2022, with search terms including anti-VEGF, biosimilar, neovascular macular degeneration, AMD, and safety. EXPERT OPINION: The management of AMD is still onerous for both the physician and patient due to the great number of required injections. Current research is underway to resolve not only the economic burden but also the discomfort of patients, aiming to develop a drug with a different or a multiple target, increasing the potency whilst maintaining a good safety profile. Furthermore, clinical research is currently investigating different forms of drug administration.

Towards a better understanding of non-exudative choroidal and macular neovascularization.

Non-exudative macular and choroidal neovascularization (MNV and CNV) usually refers to the entity of treatment-naïve type 1 neovascularization in the absence of associated signs of exudation. Histopathological studies, dating back in the early 70s, identified the presence of non-exudative MNV, but the first clinical report of this finding was in the late 90s using indocyanine green angiography in eyes with age-related macular degeneration (AMD). With more advanced retinal imaging, there has been an ever increasing appreciation of non-exudative MNV associated with AMD and CNV with other macular disorders. However, consensus regarding the exact definition and the clinical management of this entity is lacking. Furthermore, there may be variation in the imaging features and clinical course suggesting that a spectrum of disease may exist. Herein, we review the large body of published work that has provided a better understanding of non-exudative MNV and CNV in the last decade. The prevalence, multimodal imaging features, clinical course, and response to treatment are discussed to elucidate further key insights about this entity. Based on these observations, this review also proposes a new theory about the origin and course of different sub-types of non-exudative MNV/CNV which can have different etiologies and pathways according to the clinical context of disease.