Peripapillary Optical Coherence Tomography Angiography in Alzheimer's Disease, Mild Cognitive Impairment, and Normal Cognition.

OBJECTIVE: This study aimed to identify peripapillary microvascular changes in Alzheimer's disease (AD) and mild cognitive impairment (MCI). PATIENTS AND METHODS: In this prospective study, 66 eyes of 36 subjects with AD, 119 eyes of 63 with MCI, and 513 eyes of 265 controls with normal cognition were enrolled. Peripapillary capillary perfusion density (CPD), capillary flux index (CFI), and retinal nerve fiber layer (RNFL) thickness were determined. RESULTS: Average CPD differed significantly between all three groups (P = 0.001), being significantly greater in AD vs controls (0.446 ± 0.015 vs 0.439 ± 0.017, P = 0.001) and MCI vs controls (0.443 ± 0.020 vs 0.439 ± 0.017, P = 0.007) but not AD vs MCI (P = 0.69). CFI and average RNFL thickness did not significantly differ among groups (all P > 0.05). CONCLUSION: Peripapillary CPD is increased in eyes with AD or MCI compared to controls despite similar RNFL thickness. [Ophthalmic Surg Lasers Imaging Retina 2024;55:78-84.].

GABAergic Inhibition Controls Receptive Field Size, Sensitivity, and Contrast Preference of Direction Selective Retinal Ganglion Cells Near the Threshold of Vision.

Information about motion is encoded by direction-selective retinal ganglion cells (DSGCs). These cells reliably transmit this information across a broad range of light levels, spanning moonlight to sunlight. Previous work indicates that adaptation to low light levels causes heterogeneous changes to the direction tuning of ON-OFF (oo)DSGCs and suggests that superior-preferring ON-OFF DSGCs (s-DSGCs) are biased toward detecting stimuli rather than precisely signaling direction. Using a large-scale multielectrode array, we measured the absolute sensitivity of ooDSGCs and found that s-DSGCs are 10-fold more sensitive to dim flashes of light than other ooDSGCs. We measured their receptive field (RF) sizes and found that s-DSGCs also have larger receptive fields than other ooDSGCs; however, the size difference does not fully explain the sensitivity difference. Using a conditional knock-out of gap junctions and pharmacological manipulations, we demonstrate that GABA-mediated inhibition contributes to the difference in absolute sensitivity and receptive field size at low light levels, while the connexin36-mediated gap junction coupling plays a minor role. We further show that under scotopic conditions, ooDSGCs exhibit only an ON response, but pharmacologically removing GABA-mediated inhibition unmasks an OFF response. These results reveal that GABAergic inhibition controls and differentially modulates the responses of ooDSGCs under scotopic conditions.

The Impact of Pregnancy on Diabetic Retinopathy: A Single-Site Study of Clinical Risk Factors.

INTRODUCTION: This study aimed to provide information on modifiable and non-modifiable risk factors for the progression and development of diabetic retinopathy (DR) and diabetic macular edema (DME). This retrospective chart review case-control study was designed to provide perspective on clinical variables. METHODS: Single-center study analysis was completed with chart review, identifying 50 patients (100 eyes) ultimately included in the final analysis. Included patients were women with type 1 or 2 diabetes that entered prenatal care and had a delivery from January 2010 to December 2022. The primary outcome measure was clinical variables between progression and no progression groups. Data were analyzed via χ2 analysis and independent samples t test when appropriate. Significantly different variables were further analyzed by binary logistic regression. RESULTS: The DR progression group had significantly higher prepregnancy HbA1c levels (9.9) when compared to the no progression group (8.5, p value 0.028). DR progression group also had higher rates (51.9%) of full-term births. The DME progression group had significantly higher rates of type 2 diabetics (100%) compared to the no progression group (30.9%, p value 0.029). Hypertension treatment before (81.8%; p value 0.008) pregnancy was also more common in the DME progression group. Intravitreal injections were more common in patients with visual acuity deterioration (26.7%, p value 0.046). The average number of fetal complications was significantly higher in the visual acuity non-worsening group (1.1) compared to the progression group (0.5, p value 0.04). These variables were not statistically significant after entry into multivariate analysis. DISCUSSION: Severity and treatment of retinopathy before pregnancy, type of diabetes, and blood pressure control are all significant factors affecting the progression and development of severe ocular complications in pregnancy.

Qualitative Analysis of Barriers and Facilitators to Glaucoma Medication Adherence in a Randomized Controlled Trial Intervention.

OBJECTIVE: In the Medication Adherence In Glaucoma To Improve Care trial, 200 veterans with medically-treated glaucoma were randomized to an intervention designed to improve glaucoma medication adherence or to usual care. In the 6 months after intervention, the mean proportion of doses taken on schedule was higher for participants in the intervention group compared with controls (0.85 vs. 0.62, P < 0.001). The purpose of this study was to use a mixed-methods approach to compare barriers and facilitators with adherence among participants through qualitative analysis of structured interviews. DESIGN: This is an analysis of interviews conducted from patients participating in a clinical trial. PARTICIPANTS: Participants from the intervention arm were separated into quartiles based on medication adherence according to the electronic monitor to sample from high and low responders to the intervention. We interviewed 23 participants; 11 participants with low adherence and 12 with high adherence. METHODS: Interviews were conducted over telephone and transcribed. Staff members used grounded theory to conduct content analysis and code the transcribed interviews. The iterative process produced categories of common barriers and facilitators for medication adherence. MAIN OUTCOME MEASURES: The frequency of responses addressing common barriers and facilitators were compared between participants with high and low adherence. RESULTS: In the lowest- and highest-adherence groups, a difficult schedule was the most cited barrier for regular drop usage (63.6% and 58.3%, respectively). In the lowest and highest-adherence groups, the most cited facilitator for adherence was use of the smart bottle (100% and 91.7%, respectively). In the lowest-adherence group, 72.7% of participants cited that improved ability to administer drops was a benefit from the intervention. In the highest-adherence group, 75% of participants cited increased disease knowledge and formation of habits as facilitators from the intervention. Of the 22 of 23 participants who mentioned the smart bottle, 100% cited that they had increased adherence and would continue using the smart bottle. CONCLUSIONS: Using dosing reminders and personalized patient education may be important avenues for addressing difficulties with adhering to an eye drop schedule to improve glaucoma self-management. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.

To overcome the ethical and technical limitations of in vivo human disease models, the broader scientific community frequently employs model organism-derived cell lines to investigate disease mechanisms, pathways, and therapeutic strategies. Despite the widespread use of certain in vitro models, many still lack contemporary genomic analysis supporting their use as a proxy for the affected human cells and tissues. Consequently, it is imperative to determine how accurately and effectively any proposed biological surrogate may reflect the biological processes it is assumed to model. One such cellular surrogate of human disease is the established mouse neural precursor cell line, SN4741, which has been used to elucidate mechanisms of neurotoxicity in Parkinson disease for over 25 years. Here, we are using a combination of classic and contemporary genomic techniques - karyotyping, RT-qPCR, single cell RNA-seq, bulk RNA-seq, and ATAC-seq - to characterize the transcriptional landscape, chromatin landscape, and genomic architecture of this cell line, and evaluate its suitability as a proxy for midbrain dopaminergic neurons in the study of Parkinson disease. We find that SN4741 cells possess an unstable triploidy and consistently exhibits low expression of dopaminergic neuron markers across assays, even when the cell line is shifted to the non-permissive temperature that drives differentiation. The transcriptional signatures of SN4741 cells suggest that they are maintained in an undifferentiated state at the permissive temperature and differentiate into immature neurons at the non-permissive temperature; however, they may not be dopaminergic neuron precursors, as previously suggested. Additionally, the chromatin landscapes of SN4741 cells, in both the differentiated and undifferentiated states, are not concordant with the open chromatin profiles of ex vivo, mouse E15.5 forebrain- or midbrain-derived dopaminergic neurons. Overall, our data suggest that SN4741 cells may reflect early aspects of neuronal differentiation but are likely not a suitable proxy for dopaminergic neurons as previously thought. The implications of this study extend broadly, illuminating the need for robust biological and genomic rationale underpinning the use of in vitro models of molecular processes.

Longitudinal Assessment of the Choroidal Vascularity Index in Eyes with Branch Retinal Vein Occlusion-Associated Cystoid Macular Edema.

INTRODUCTION: Cystoid macular edema (CME) is the most common cause of central vision loss in eyes with branch retinal vein occlusion (BRVO eyes). In recent literature, choroidal vascularity index (CVI) has been proposed to be an enhanced depth imaging optical coherence tomography (EDI-OCT) metric that may help characterize choroidal vascular changes in the setting of retinal ischemia, and potentially prognose visual outcomes and treatment patterns for patients with BRVO-related CME. This study sought to further characterize choroidal vascular changes in BRVO by comparing the CVI, subfoveal choroidal thickness (SFCT), and central subfield thickness (CST) in BRVO eyes with CME compared to unaffected fellow eyes. METHODS: This was a retrospective cohort study. Subjects included treatment-naïve BRVO eyes with CME diagnosed within 3 months of onset of symptoms and unaffected fellow eyes. EDI-OCT images were collected at baseline and at the 12-month follow-up visit. CVI, SFCT, and CST were measured. Demographics, treatment patterns, and best-corrected visual acuity (VA) were abstracted. Median CVI, SFCT, CST, and VA were compared between the two cohorts. Longitudinal relationships between these variables were analyzed. RESULTS: A total of 52 treatment-naïve eyes with BRVO and CME and 48 unaffected fellow eyes were identified. Baseline CVI was lower in eyes with BRVO than in fellow eyes (64.7% vs. 66.4%, P = 0.003). At 12 months, there was no difference in CVI between BRVO eyes and fellow eyes (65.7% vs 65.8%, P = 0.536). In BRVO eyes, there was a strong correlation between reduced CST and improved VA over the 12-month study period (r = 0.671, P < 0.001). CONCLUSION: There are differences in CVI in treatment-naïve BRVO eyes with CME at presentation compared to fellow eyes, but these differences resolve over time. Anatomic changes in macular thickness in BRVO eyes with CME may be correlated with VA outcomes.

Our study evaluated a novel ocular optical coherence tomography imaging metric, the choroidal vascularity index, in eyes that developed cystoid macular edema, a condition which can significantly impair acuity of central vision, after being diagnosed with branch retinal vein occlusion. In each patient, we compared the choroidal vascularity index in eyes that developed treatment-naïve, newly diagnosed branch retinal vein occlusion with cystoid macular edema to the non-diseased fellow eye. We made comparisons at the time of diagnosis (baseline) and at the 12-month follow up, and analyzed changes over time. We found that at the baseline visit, branch retinal vein occlusion eyes with cystoid macular edema had a significantly lower choroidal vascularity index than their unaffected fellow eyes, but that the differences between eyes resolved by the 12-month follow-up visit. Our findings suggest that choroidal vascularity may be compromised in the acute phase of branch retinal vein occlusion, but that this phenomenon resolves over time. Future research should further evaluate whether imaging characteristics of choroidal vascularity may be associated with changes in anatomic and visual outcomes in retinal diseases.

Cones and cone pathways remain functional in advanced retinal degeneration.

Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating cones and retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment. Light responses of second-order horizontal and bipolar cells are less sensitive but otherwise resemble those of normal retina. Furthermore, retinal output as reflected in responses of ganglion cells is less sensitive but maintains spatiotemporal receptive fields at cone-mediated light levels. Together, these findings show that cones and their retinal pathways can remain functional even as degeneration is progressing, an encouraging result for future research aimed at enhancing the light sensitivity of residual cones to restore vision in patients with genetically inherited retinal degeneration.

Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.

To overcome the ethical and technical limitations of in vivo human disease models, the broader scientific community frequently employs model organism-derived cell lines to investigate of disease mechanisms, pathways, and therapeutic strategies. Despite the widespread use of certain in vitro models, many still lack contemporary genomic analysis supporting their use as a proxy for the affected human cells and tissues. Consequently, it is imperative to determine how accurately and effectively any proposed biological surrogate may reflect the biological processes it is assumed to model. One such cellular surrogate of human disease is the established mouse neural precursor cell line, SN4741, which has been used to elucidate mechanisms of neurotoxicity in Parkinson disease for over 25 years. Here, we are using a combination of classic and contemporary genomic techniques - karyotyping, RT-qPCR, single cell RNA-seq, bulk RNA-seq, and ATAC-seq - to characterize the transcriptional landscape, chromatin landscape, and genomic architecture of this cell line, and evaluate its suitability as a proxy for midbrain dopaminergic neurons in the study of Parkinson disease. We find that SN4741 cells possess an unstable triploidy and consistently exhibits low expression of dopaminergic neuron markers across assays, even when the cell line is shifted to the non-permissive temperature that drives differentiation. The transcriptional signatures of SN4741 cells suggest that they are maintained in an undifferentiated state at the permissive temperature and differentiate into immature neurons at the non-permissive temperature; however, they may not be dopaminergic neuron precursors, as previously suggested. Additionally, the chromatin landscapes of SN4741 cells, in both the differentiated and undifferentiated states, are not concordant with the open chromatin profiles of ex vivo , mouse E15.5 forebrain- or midbrain-derived dopaminergic neurons. Overall, our data suggest that SN4741 cells may reflect early aspects of neuronal differentiation but are likely not a suitable a proxy for dopaminergic neurons as previously thought. The implications of this study extend broadly, illuminating the need for robust biological and genomic rationale underpinning the use of in vitro models of molecular processes.

Younger Age and Longer Case Times Associated With Emergency Department Visits After Cataract Surgery.

PURPOSE: To characterize the frequency, reasons, hospital costs, and risk factors for emergency department (ED) visits within 30 days of cataract surgery. DESIGN: Retrospective cohort study. METHODS: A retrospective review of all cataract surgeries at Duke Health between 2013 and 2021 was conducted. Demographics, case characteristics (length, complexity by billing codes, anesthesia type), ED visit findings, and hospital costs were collected. Logistic regression models were used to determine the odds of ED visits based on several risk factors. RESULTS: Of 34 246 patients (57 656 eyes) undergoing cataract surgery at Duke Health from 2013 to 2021, a total of 607 patients (1.77%) had 680 ED visits within 30 days of surgery. The most common ED diagnosis was cardiovascular (24.4%), whereas ocular complaints constituted 15.4% of visits. The most common ocular diagnoses were high intraocular pressure, rebound iritis, and posterior vitreous detachment. Hospital costs were lowest for ocular diagnoses (mean $467.72) and highest for trauma diagnoses (mean $4660.55). Risk factors for ED visits included case lengths greater than 30 minutes (OR 2.1, 95% CI 1.56-2.83, P < .001), the combination of Monitored Anesthesia Care (MAC) and retrobulbar anesthesia or general anesthesia (OR 2.98, 95% CI 1.73-5.12, P < .001), and age less than 70 years (OR 1.39, 95% CI 1.16-1.65, P < .001). CONCLUSIONS: ED visits within 30 days of cataract surgery are uncommon. Longer case lengths, anesthesia other than MAC alone, and younger age are associated with higher odds of ED visits.

Risk factors for the development or progression of diabetic retinopathy in pregnancy: Meta-analysis and systematic review.

BACKGROUND: Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population, and it increases in severity during pregnancy. METHODS: Systematic review of literature from PubMed, Cochrane Library and Web of Science using keywords 'diabetic retinopathy' and 'pregnancy' and 'progression' from inception to 2021 was completed. Included studies were (1) peer-reviewed observational studies addressing progression/development of DR in pregnancy, (2) provided the number of diabetic patients that developed/progressed in DR during pregnancy, and (3) included differential data on variables between progression and non-progression groups. This was applied by two independent researchers and referred to a third researcher as necessary. Twenty-seven of the original 138 studies met this criterion. Data were pooled and analysed using fixed-effects in meta-analysis. RESULTS: From 27 studies, 2537 patients were included. Pre-eclampsia [Risk Ratio (RR) 2.62 (95% CI = 1.72, 4.00)] and hypertension treatment during pregnancy [RR 2.74 (95% CI = 1.72, 4.00)] were significantly associated with the development/progression of DR. HbA1c at baseline [MD 0.82 (95% CI = 0.59, 1.06)], duration of diabetes [mean difference (MD) 5.97 (95% CI = 5.38, 6.57)], and diastolic blood pressure at baseline [MD 3.29 (95% CI = 0.46, 6.12)] were all significantly higher in the progression group while only mean birth weight [MD -0.17 (95% CI = -0.31, -0.03)] was significantly higher in the non-progression group. CONCLUSIONS: This study fills a gap in the literature and provide physicians with more information on the risk factors associated with the progression of DR in pregnancy and how to counsel this vulnerable patient population appropriately.