bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morpho‐functional alterations and mirnome dysregulation in the retina of a mouse model of Alzheimer's disease: Paving the way for new strategies of gene therapy
Authors: Guidotti Lorenzo , Amato Rosario , Lucchesi Martina , Borello Ugo , Cammalleri Maurizio , Monte Massimo Dal 
Published: January 2025

Aims/Purpose: To investigate if the retina might be considered a reliable tool to monitor Alzheimer's disease (AD) progression and a benchmark for testing novel gene therapy strategies.Methods: The morpho‐functional and molecular features of 5xFAD and wild‐type (WT) mice have been evaluated at different time points: 3, 6, and 9 months of age. To assess retinal function we used scotopic, photopic, and pattern electroretinogram. Retinal structure was evaluated through optical coherence tomography. Retinal sections were immunostained with rhodopsin, cone‐arrestin, and RNA binding protein mRNA processing factor in order to identify rods, cones, and retinal ganglion cells, respectively. Further retinal sections were immunostained with amyloid beta (Aβ) to visualize the presence of plaques. Western blot experiments were conducted to evaluate retinal levels of Aβ and Tau. Markers of neuroinflammation (NFκB and IL‐6) and oxidative stress (NRF2, HO‐1, and NQO1) were also assessed by Western blot. The retinal miRNome was analyzed to highlight the potentially dysregulated miRNAs between 5xFAD and WT.Results: We observed a progressive loss of visual function followed by retinal thinning starting at 6 months of age. Moreover, photoreceptor and ganglion cell degeneration were reported from 6 months of age. Concurrently, molecular analyses demonstrated retinal Aβ and phospho‐Tau accumulation, which correlated with the progressive increment in oxidative and inflammatory markers. The miRNome analyses revealed several dysregulated miRNAs at 6 months of age in 5xFAD mice, which return to control levels at 9 months of age.Conclusions: These data might pave the way for a possible novel gene therapy strategy based on reinstating miRNA homeostasis, to be preliminary tested in the easily accessible retina and then, if successful, in the brain.
Upregulation of rod ribbon synapse components implies homeostatic presynaptic scaling in early‐stage retinitis pigmentosa
Authors: Roihuvuo Elias , Tabaka Marcin , Montaser Ahmed , Choi Elliot , Palczewski Krzysztof , Vinberg Frans , Leinonen Henri 
Published: January 2025

Aims/Purpose: Photoreceptor death triggers retinal rewiring and remodeling that are generally thought to be detrimental for vision. Some recent research results challenge this dogma. It was recently shown that in early‐stage retinitis pigmentosa (RP), the retina compensates for the reduced rod population activity by upscaling synaptic transmission between the remaining rods and rod bipolar cells. The purpose of the current project is to study the molecular mechanism behind this phenomenon.Methods: To model the primary pathology, P23H mouse model of autosomal dominant RP was used. Notably, wild‐type mice were not used as controls, instead, cone‐transducin (GNAT2) knockout mice that lack cone photoreceptor functionality were used. To produce “rod‐function‐only” RP mice, P23H and Gnat2‐/‐ mice were cross‐bred. Single cell RNA‐sequencing (scRNA‐seq; Gnat2‐/‐, n = 4; P23H/Gnat2‐/‐, n = 4) and retinal global proteomics (Gnat2‐/‐, n = 5; P23H/Gnat2‐/‐, n = 10) analyses were performed at P30. Statistical significance was set at q < 0.05. Additional protein expression analyses for synaptic proteins were performed using immunohistochemistry and immunoblotting.Results: ScRNA‐seq analysis revealed upregulation of several major ribbon synapse genes exclusively in P23H/Gnat2‐/‐ mouse rods. These included genes that are crucial in presynaptic structure and neurotransmitter release, such as the Ca2+ sensor Syt1, snare protein complex component Snap25, ribbon protein Ctbp2, and the synaptic vesicle protein Sv2b. In addition, upregulation of the glutamate transporter Slc1a2 was found. Based on proteomics data, STX1B and SYT7 were overexpressed in whole P23H/Gnat2‐/‐ mouse retinas as compared to controls.Conclusions: Early‐stage RP in mice associates with increased expression of several rod ribbon synapse components that play a role in glutamate release. These results imply that regulation of presynaptic glutamate release may play a role in improving retinal synaptic transmission during RP.
Evaluation of macular ganglion cell layer‐inner plexiform layer (GCL‐IPL) thickness in patients treated with ozurdex: A retrospective study from a Swiss cohort of patients
Authors: Rizzato Angelica , Kochkorov Asan , Katamay Robert , Katja Hatz 
Published: January 2025

Aims/Purpose: To investigate the effect of Dexamethasone intravitreal implants (Ozurdex®) on macular GCL‐IPL thickness in patients treated for diabetic macular edema (DME), retinal vein occlusion (RVO), and non‐infectious uveitic macular edema (UME).Methods: All eyes receiving Ozurdex® between 2013 and 2021 were included and assigned to group 1 (≤5 implants) or group 2 ( > 5 implants). Clinical records were reviewed, and SD‐OCT images manually segmented. Data were evaluated at baseline and at 3 years ± 4 months. Exclusion criteria were poor imaging quality, lack of adequate follow‐up, and absence of dry SD‐OCT at the timepoints. Primary outcome is change in macular GCL‐IPL thickness between baseline and 3‐year follow‐up, compared using paired t‐test. Secondary outcome: incidence of ocular hypertension (IOP > 25mmHg) at three years, compared using Fisher's exact test.Results: 82 eyes of 73 patients were included (mean age 67.5 years). 30 eyes with DME, 26 with RVO, and 26 with UME. Group 1 (40 eyes) received a mean of 3.0 injections (SD = 1.5; range = 1‐5), while group 2 (42 eyes) received a mean of 7.9 injections (SD = 1.7; range = 6‐14). Macular GCL‐IPL thickness in group 1 was not significantly reduced after 3 years (mean difference: ‐1.8μm, 95% CI: ‐4.4; 0.8, p = 0.18), while group 2 showed significant reduction (mean difference: ‐5.9μm, 95% CI: ‐10.5; ‐1.3, p < 0.05). However, no significant difference in new ocular hypertension cases between group 1 (42.5%) and group 2 (38.0%), p = 0.82 was found.Conclusions: The study shows that repeated Ozurdex® injections are associated with significant reduction in macular GCL‐IPL thickness over 3 years, however, despite increased ocular hypertension in both groups, no significant differences between groups were found. These findings highlight the need for long‐term monitoring of macular GCL‐IPL thickness and intraocular pressure in patients receiving multiple Ozurdex® injections for DME, RVO, and UME.
Is intravitreal faricimab an effective treatment for diabetic macular oedema not‐responsive to aflibercept? An audit of treated patients at the Princess Alexandra eye pavilion
Authors: Lowe Cameron , Das Meghomala 
Published: January 2025

Aims/Purpose: We aim to evaluate both functional and anatomical outcomes of patients switched from aflibercept to faricimab for management of treatment‐resistant diabetic macular oedema (DMO) in a real‐world environment, and the proportion of patients who achieved improvement, stability or deterioration.Methods: Casenotes of 20 eyes not responding to aflibercept, then switched to faricimab were reviewed. Patient demographics, best‐corrected visual acuity (BCVA) and presence of macular oedema on OCT pre‐switch and at post‐treatment clinic review, and injection intervals were recorded. We then categorised whether there was an improvement, stability or deterioration in both BCVA and presence of macular oedema on OCT.Results: Of 16 eyes where analysis was complete for BCVA, there was improvement in 31% (n = 5), stability in 19% (n = 3) and deterioration in 50% (n = 8). Of the eyes where there was deterioration, 4 had other co‐morbidity which affected BCVA. Of 17 eyes with pre‐ and post‐switch macular OCT, there was improvement in macular oedema in 71% (n = 12), stability in 24% (n = 4) and deterioration in 6% (n = 1). The mean injection interval where prescribed 4x 1 monthly (n = 13) was 61 days, with a range from 35 ‐ 138 days.Conclusions: In this real‐world setting with challenges providing patients with regular monthly treatment, faricimab demonstrates the ability to improve DMO in chronic disease with sub‐optimal dosing regimens. A majority of patients demonstrated anatomical improvements, and functional stability or improvement was seen in half of treated eyes. Though the anatomical outcomes were more positive than the functional outcomes on BCVA, this likely reflects the chronicity of DMO in affected eyes, and notably in half of the eyes treated where BCVA deteriorated, there was an alternative cause for this. Given the poorer prognosis of treatment non‐responsive DMO, faricimab is promising as a further option for these harder to treat patients. Overall, there would appear to be a role for faricimab to be a treatment option in chronic‐DMO, and its increased durability is beneficial in busy centres where it is challenging to provide patients with 1‐monthly dosing. This could be further supported by investigating outcomes in patients with treatment‐naive disease.
Comparative retinal study by OCT in Alzheimer's disease: Insights from the app NL‐F/NL‐F model
Authors: Sanchez‐Puebla Lidia , López‐Cuenca Inés , Vázquez Alberto Arias , Salobrar‐Garcia Elena , Matamoros José A. , Lozano María Pilar Rojas , Fernández‐Albarral José A. , Elvira‐Hurtado Lorena , Ramirez Ana Isabel , Salazar Juan Jose , Saido Takaomi , Saito Takashi , Nieto‐Vaquero Carmen , Cuartero María Isabel , Moro María Ángeles , de Hoz Rosa , Ramirez Jose Manuel 
Published: January 2025

Aims/Purpose: Transgenic mouse models of Alzheimer's disease (AD) have shown a correlation between retinal abnormalities and brain pathology. The APPNL‐F/NL‐F murine humanized AD model accurately replicates many pathological features seen in AD patients. This study aims to analyze, using manual retinal segmentation by optical coherence tomography (OCT), the changes occurring in several retinal layers in the APPNL‐F/NL‐F AD model at 6, 9, 12, 15, 17, and 20 months of age, in comparison to C57BL/6J mice (WT).Methods: A diachronic study was conducted using OCT for manual retinal segmentation to evaluate changes in retinal layers. The analysis focused on retinal thickness in the retinal nerve fiber layer (RNFL)‐ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) based on Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. The study included both the APPNL‐F/NL‐F AD model and age‐matched WT controls, with measurements taken at 6, 9, 12, 15, 17, and 20 months.Results: Both the APPNL‐F/NL‐F model and WT animals exhibited changes in retinal thickness at various study time points. WT mice showed significant changes in the INL, OPL, and ONL. In contrast, the AD model exhibited significant changes in all analyzed retinal layers except for the IPL. The APPNL‐F/NL‐F model displayed significant thickness variations in the retinal layers analyzed, which closely resemble those found in humans during pre‐clinical, as well as mild and moderate stages of AD.Conclusions: The study identifies early retinal vascular and structural changes in the APPNL‐F/NL‐F model that precede cognitive changes observed at later stages. These findings suggest that the retinal changes in this model more closely resemble those in human AD compared to other transgenic models, highlighting the potential of retinal assessments in early AD diagnosis.
Association between atherosclerotic cardiovascular disease risk and diabetic retinopathy in patients with type 2 diabetes mellitus
Authors: Agapitou Chrysa , Lampsas Stamatios , Risi‐Koziona Alexia , Kyratzidis Fotis , Pappelis Konstantinos , Theodossiadis Panagiotis , Chatziralli Irini 
Published: January 2025

Aims/Purpose: The purpose of this study is to examine the association between diabetic retinopathy (DR) and the atherosclerotic cardiovascular disease (ASCVD) risk in patients with type 2 diabetes mellitus (DM) and to assess risk factors potentially associated with DR.Methods: Participants in the study were 215 patients with type 2 DM, who underwent a thorough ophthalmic examination, including best‐corrected visual acuity (BCVA) measurement, dilated fundoscopy, fundus photography, optical coherence tomography (OCT) and OCT angiography (OCTA). DR was graded as no apparent retinopathy (NDR), mild non‐proliferative (NPDR), moderate NPDR, severe NPDR and proliferative DR (PDR). In addition, a detailed medical history of patients was recorded, while the ASCVD risk estimator plus by the American College of Cardiology was used to calculate the ASCVD risk.Results: Multivariate logistic regression analysis showed that factors associated with DR independently were: DM duration (multivariate OR = 3.16, 95%CI: 1.55‐6.44, p = 0.002), HbA1c levels (multivariate OR = 2.94, 95%CI: 1.37‐6.32, p = 0.006) and presence of neuropathy (multivariate OR = 3.59, 95%CI:1.43‐9.05, p = 0.007). At the multivariate multinomial logistic regression analysis, NPDR development was associated with duration of DM (multivariate RR = 3.31, 95%CI: 1.57‐6.97, p = 0.002), HbA1c levels (multivariate RR = 2.24, 95%CI: 1.00‐5.02, p = 0.050) and neuropathy (multivariate RR: 3.94, 95%CI: 1.54‐10.11, p = 0.004), while PDR development was only associated with HbA1c levels (multivariate RR = 6.88, 95%CI: 2.19‐21.63, p = 0.001). The ASCVD score was not found to be significantly correlated with DR (p = 0.191).Conclusions: Factors associated with DR were DM duration, HbA1c levels and presence of neuropathy, while the ASCVD score was not found to be significantly associated with DR.
Pilot outcomes of algorithmic decision support software for intravitreal treatment intervals
Authors: Zakri Rosina , Davies Nigel 
Published: January 2025

Aims/Purpose: Timely intravitreal therapy to ensure best outcomes can be difficult to achieve owing to large numbers of patients needing treatment. A protocol‐driven approach to assessment would help train non‐medical staff make accurate decisions regarding treatment and treatment intervals. We develop algorithmic decision support software and present initial analysis comparing software decision with ophthalmologist for treatment interval in wAMD, DMO and RVO patients.Methods: Ethical approval was obtained. Wet AMD, DMO and RVO patients with more than one year of treatment were recruited, seen as usual by an ophthalmologist. Visual acuity and OCT values were used to calculate two parameters: treatment response and comparison with normality. The algorithm outputs the number of weeks recommended before next treatment. This was compared with ophthalmologist decision.Results: There was excellent agreement of algorithm recommendation in comparison with ophthalmologist decision. Overall there was exact agreement in 118/225 (52%) of cases and 201/225 (89%) were within 2 weeks of each other. When assessed prospectively in cross sectional single visit, 15/26 wAMD showed exact agreement, 23/26 within 2 weeks. For DMO 14/26 were in exact agreement, 25/26 within 2 weeks and RVO 18/26 exact agreement, 25/26 within 2 weeks. Longitudinal visits over 3 appointments 27/30 wAMD, 25/30 DMO, and 28/30 RVOs are within 2 weeks of each other. Algorithm decision recommendations outside 2 weeks were shorter treatment intervals than ophthalmologist decision.Conclusions: The decision support algorithm shows excellent agreement with ophthalmologist treatment decisions for wAMD, DMO and RVO. The tool may be a useful aid for trained non‐medical staff working in injection clinics. We are working on further improvement in agreement by programming trend‐based outcomes.
Optical coherence tomography findings in persistent hyaloid artery: A prospective study
Authors: Sakji Fatma , Aoun Safa Ben , Maamouri Rym , Ferchichi Molka , Fendouli Ines , Cheour Monia 
Published: January 2025

Aims/Purpose: To describe the features of peripapillary persistent hyaloid artery and its effects on disc parameters using Swept‐source optical coherence tomography (SS‐OCT) and SS‐OCT angiography (SS‐OCT A).Methods: Seven eyes of 7 patients diagnosed with Persistent hyaloid artery were prospectively reviewed at the department of Ophthalmology in the Habib Thameur Hospital, Tunisia, between January 2024 and June 2024. All patients were assessed for peripapillary retinal nerve fibers layer (pRNFL) thickness by SS‐OCT, and blood flow by papillary OCT‐A, 4.5 mm*4.5 mm cubes.Results: Mean age was 36.33 years, with 4 women and 3 men. SS‐OCT showed peripapillary hyperreflective tubular material of the persistent hyaloid artery in the right eye of 3 patients and in the left eye of 4 patients. On analysis of the pRNFL thickness, the mean average thickness was 110.8, Inferior quadrant (150.8), superior quadrant (134), nasal quadrant (83.4) and temporal quadrant (74.8). pRNFL were thickened in one eye, altered in one eye in the superior quadrant, and preserved in five eyes. SS‐OCT A revealed no blood flow at the lesion in all eyes.Conclusions: A persistent hyaloid artery is an uncommon lesion whose diagnosis, evaluation and monitoring have become easily possible using SS‐OCT and SS‐OCT A. Evaluating the vascular flow at the level of the optic nerve head would be of great importance in order to prevent certain complications, notably vitreous hemorrhage and retinal detachment.References
Jeon, H., Kim, J., & Kwon, S. OCT angiography of persistent hyaloid artery: a case report. BMC Ophthalmol. 2019 Jul 4;19(1):141.
Gamidov AA, Durzhinskaya MH, Makashova NV, Sakalova ED, Velieva IA. Persistent hyaloid artery in an adult (a case report). Vestn Oftalmol. 2020;136(4):214.
Exploratory and comprehensive description of an Italian cohort of patients affected by leber hereditary optic neuropathy carrying the pathogenic variants m.11778G > A/MT‐ND4 and m.3460G > A/MT‐ND1
Authors: Romagnoli Martina , Carbonelli Michele , Amore Giulia , Fiorini Claudio , Zenesini Corrado , D'Agati Pietro , Tropeano Concetta Valentina , Cascavilla Maria Lucia , Barboni Piero , Caporali Leonardo , Carelli Valerio , La Morgia Chiara 
Published: January 2025

Aims/Purpose: This is an observational study to track the disease course of patients affected by Leber Hereditary Optic Neuropathy (LHON), regularly attending the neurophthalmological clinic of the IRCCS ISNB (Bologna).Methods: To satisfy inclusion criteria, subjects needed a confirmed genetic diagnosis for 2 of the 3 primary LHON mutations (m.11778G > A/MT‐ND4; m.3460G > A/MT‐ND1). There was no restriction on age, and patients could have received idebenone or any other treatment.Results: 397 subjects from 137 families were enrolled, 196 symptomatic (49%; male: 79%), 201 asymptomatic (51%; male: 40%). Of these, 66 (17%; symptomatic: 55%) carried the m.3460G > A/MT‐ND1 variant, 331 (83%; symptomatic: 48%) the m.11778G > A/MT‐ND4, with a ratio of affected male:female of 2:1 for the first, and 4:1 for the m.11778G > A/MT‐ND4 carriers.Of the 196 symptomatic patients, 37 had LHON childhood onset and 3 had unilateral LHON.106 patients (54%) were treated with idebenone and/or lenadogene nolparvovec.For both mutations the distribution of age at onset is multimodal, and different between males and females. LHON females showed later age at onset (post‐menopausal peak) in the m.11778G > A/MT‐ND4 subgroup, while the m.3460G > A/MT‐ND1 density plot showed a peak in the fertile young age.Then, visual acuities of both eyes were collected from 1252 outpatient visits. The resulted best‐fitted LOWESS curve depicting the evolution of BCVA over time did not show a difference between m.11778G > A/MT‐ND4 and m.3460G > A/MT‐ND1 symptomatic patients.Conclusions: We highlight the highest penetrance in females of the m.3460G > A/MT‐ND1 variant, for which females had an age of onset more similar to males at difference with the m.11778G > A/MT‐ND4 for which females had a delayed peak of onset, after menopause. Clinically, the two variants seem to behave similarly. This “real world” study is a precious tool to define genotype/phenotype relationships and highlight the most appropriate subpopulations for clinical trials.
Gut microbial dysbiosis in age‐related macular degeneration
Authors: Vergroesen Joëlle , Vermeulen Jeroen , Thee Eric , Liefers Bart , Klaver Caroline 
Published: January 2025

Purpose: The gut microbiome is highly influential in diseases with inflammatory components. Multiple studies showed a link between the gut microbiome and age‐related macular degeneration (AMD). However, no consistent taxa have been reported.Methods: We included 1372 participants from the Rotterdam Study (RS). AMD features (e.g. [reticular pseudo‐]drusen, retinal pigment epithelium degeneration, and hyperpigmentation) were graded by human graders on color fundus photographs. Next, areas of these features were automatically quantified by a deep learning segmentation model. Stages were determined according to the RS classification (preliminary = 239, early‐intermediate = 75, late = 6). Propensity score matching was performed on age, sex and BMI. Multivariable associations with taxonomic and functional profiles were assessed using zero‐adjusted models (MaAsLin2; Compound Poisson). p‐values were false discovery rate‐adjusted (q‐values). Taxa associated (q < 0.25) with at least two out of seven AMD(‐related) outcomes are reported.Results: We observed no associations with alpha‐ or beta‐diversity. Nineteen taxa were associated with AMD, of which 7 persisted after additional adjustment for dietary data. Eubacterium xylanophilum group, Lachnoclostridium, Faecalibacterium, Odoribacter splanchnicus and Parabacteroides distasonis were associated with an AMD phenotype. Parabacteroides and Akkermansia were inversely associated with an AMD phenotype. Moreover, 46 MetaCyc pathways were associated with AMD, of which 15 persisted after additional adjustment for dietary data. GLUCARDEG.PWY, PWY.5028, PWY.5347, PWY.5415, PWY.5532, PWY.5971, PWY.6969 and TCA were associated with an AMD phenotype. FOLSYN.PWY, LEU.DEG2.PWY, PANTO.PWY, PANTOSYN.PWY, PWY.6612, PWY0.1586 and PYRIDNUCSYN.PWY were inversely associated with an AMD phenotype.Conclusions: Several gut microbiota were associated with an AMD phenotype. AMD pathophysiology might be linked to changes in gut‐related metabolic pathways.