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American Journal of Ophthalmology Jun 2024To investigate the clinical, functional, and imaging characteristics in patients affected by inherited retinal diseases associated with RDH5 and RLBP1 gene variants, and...
PURPOSE
To investigate the clinical, functional, and imaging characteristics in patients affected by inherited retinal diseases associated with RDH5 and RLBP1 gene variants, and to report novel genotype-phenotype correlations.
DESIGN
Retrospective single-center cohort study.
METHODS
Twenty-two patients with molecularly confirmed RLBP1-associated retinopathy and 5 with RDH5-associated retinopathy. Medical records were reviewed to obtain data on family history and ophthalmologic examinations, including retinal imaging and full-field electroretinography (ffERG). Genotype was determined by targeted next-generation sequencing followed by confirmation and familial segregation by Sanger sequencing.
RESULTS
The median (IQR) age at baseline for the RDH5 and RLBP1 cohort was 44.6 (38.2-67.9) years and 36.9 (23.1-45.2) years, respectively. Macular atrophy was found in approximately 80% of eyes from both cohorts. The RLBP1 genotype was associated with a lower macular volume by 0.28 mm (95% CI, -0.46 to -0.11; P = .005) compared to the RDH5 genotype. In both genotypic cohorts, we found a significant annual rate of macular volume loss, estimated at -0.007 mm/y (95% CI, -0.012 to -0.001; P = .02), without any significant difference the two genotypes. Three unrelated patients homozygous for the c.361C>T p.(Arg121Trp) RLBP1 variant showed minimal impairment of both the rod and cone systems function on ffERG and absence of macular atrophy.
CONCLUSIONS
Progressive macular atrophy in addition to congenital night blindness can be identified in adult patients with RDH5-associated retinopathy. Vice versa, hypomorphic RLBP1 variants may cause milder retinal phenotypes rather than the typical severe rod-cone dystrophy with macular atrophy. These findings could prove beneficial to improve the prognostication of patients and help in designing future interventional trials.
PubMed: 38945349
DOI: 10.1016/j.ajo.2024.06.016 -
International Journal of Biological... Jun 2024Hyaluronic acid (HA) serves as a vitreous substitute owing to its ability to mimic the physical functions of native vitreous humor. However, pure HA hydrogels alone do...
Hyaluronic acid (HA) serves as a vitreous substitute owing to its ability to mimic the physical functions of native vitreous humor. However, pure HA hydrogels alone do not provide sufficient protection against potential inflammatory risks following vitrectomy. In this study, HA was crosslinked with 1,4-butanediol diglycidyl ether (BDDE) to form HA hydrogels (HB). Subsequently, the anti-inflammatory agent epigallocatechin gallate (EGCG) was added to the hydrogel (HBE) for ophthalmic applications as a vitreous substitute. The characterization results indicated the successful preparation of HB with transparency, refractive index, and osmolality similar to those of native vitreous humor, and with good injectability. The anti-inflammatory ability of HBE was also confirmed by the reduced expression of inflammatory genes in retinal pigment epithelial cells treated with HBE compared with those treated with HB. In a New Zealand white rabbit model undergoing vitreous substitution treatment, HBE 50 (EGCG 50 mM addition) exhibited positive results at 28 days post-surgery. These outcomes included restored intraocular pressure, improved electroretinogram responses, minimal increase in corneal thickness, and no inflammation during histological examination. This study demonstrated the potential of an injectable HA-BDDE cross-linked hydrogel containing EGCG as a vitreous substitute for vitrectomy applications, offering prolonged degradation time and anti-inflammatory effects postoperatively.
PubMed: 38945319
DOI: 10.1016/j.ijbiomac.2024.133467 -
Multiple Sclerosis and Related Disorders Jun 2024Optical coherence tomography (OCT) investigations have revealed that the thickness of inner retinal layers becomes decreased in multiple sclerosis (MS) patients,...
OBJECTIVE
Optical coherence tomography (OCT) investigations have revealed that the thickness of inner retinal layers becomes decreased in multiple sclerosis (MS) patients, compared to healthy control (HC) individuals. To date, a number of studies have applied machine learning to OCT thickness measurements, aiming to enable accurate and automated diagnosis of the disease. However, there have much less emphasis on other less common retinal imaging modalities, like infrared scanning laser ophthalmoscopy (IR-SLO), for classifying MS. IR-SLO uses laser light to capture high-resolution fundus images, often performed in conjunction with OCT to lock B-scans at a fixed position.
METHODS
We incorporated two independent datasets of IR-SLO images from the Isfahan and Johns Hopkins centers, consisting of 164 MS and 150 HC images. A subject-wise data splitting approach was employed to ensure that there was no leakage between training and test datasets. Several state-of-the-art convolutional neural networks (CNNs), including VGG-16, VGG-19, ResNet-50, and InceptionV3, and a CNN with a custom architecture were employed. In the next step, we designed a convolutional autoencoder (CAE) to extract semantic features subsequently given as inputs to four conventional ML classifiers, including support vector machine (SVM), k-nearest neighbor (K-NN), random forest (RF), and multi-layer perceptron (MLP).
RESULTS
The custom CNN (85 % accuracy, 85 % sensitivity, 87 % specificity, 93 % area under the receiver operating characteristics [AUROC], and 94 % area under the precision-recall curve [AUPRC]) outperformed state-of-the-art models (84 % accuracy, 83 % sensitivity, 87 % specificity, 92 % AUROC, and 94 % AUPRC); however, utilizing a combination of the CAE and MLP yields even superior results (88 % accuracy, 86 % sensitivity, 91 % specificity, 94 % AUROC, and 95 % AUPRC).
CONCLUSIONS
We utilized IR-SLO images to differentiate between MS and HC eyes, with promising results achieved using a combination of CAE and MLP. Future multi-center studies involving more heterogenous data are necessary to assess the feasibility of integrating IR-SLO images into routine clinical practice.
PubMed: 38945032
DOI: 10.1016/j.msard.2024.105743 -
Biochimica Et Biophysica Acta.... Jun 2024
PubMed: 38944555
DOI: 10.1016/j.bbamcr.2024.119790 -
Photodiagnosis and Photodynamic Therapy Jun 2024Diabetes, characterized by heightened blood sugar levels, can lead to a condition called Diabetic Retinopathy (DR), which adversely impacts the eyes due to elevated...
Diabetes, characterized by heightened blood sugar levels, can lead to a condition called Diabetic Retinopathy (DR), which adversely impacts the eyes due to elevated blood sugar affecting the retinal blood vessels. The most common cause of blindness in diabetics is thought to be Diabetic Retinopathy (DR), particularly in working-age individuals living in poor nations. People with type 1 or type 2 diabetes may develop this illness, and the risk rises with the length of diabetes and inadequate blood sugar management. There are limits to traditional approaches for the early identification of diabetic retinopathy (DR). In order to diagnose diabetic retinopathy, a model based on Convolutional neural network (CNN) is used in a unique way in this research. The suggested model uses a number of deep learning (DL) models, such as VGG19, Resnet50, and InceptionV3, to extract features. After concatenation, these characteristics are sent through the CNN algorithm for classification. By combining the advantages of several models, ensemble approaches can be effective tools for detecting diabetic retinopathy and increase overall performance and resilience. Classification and image recognition are just a few of the tasks that may be accomplished with ensemble approaches like combination of VGG19,Inception V3 and Resnet 50 to achieve high accuracy. The proposed model is evaluated using a publicly accessible collection of fundus images.VGG19, ResNet50, and InceptionV3 differ in their neural network architectures, feature extraction capabilities, object detection methods, and approaches to retinal delineation. VGG19 may excel in capturing fine details, ResNet50 in recognizing complex patterns, and InceptionV3 in efficiently capturing multi-scale features. Their combined use in an ensemble approach can provide a comprehensive analysis of retinal images, aiding in the delineation of retinal regions and identification of abnormalities associated with diabetic retinopathy. For instance, micro aneurysms, the earliest signs of DR, often require precise detection of subtle vascular abnormalities. VGG19's proficiency in capturing fine details allows for the identification of these minute changes in retinal morphology. On the other hand, ResNet50's strength lies in recognizing intricate patterns, making it effective in detecting neo neo-vascularization and complex hemorrhagic lesions. Meanwhile, InceptionV3's multi-scale feature extraction enables comprehensive analysis, crucial for assessing macular edema and ischemic changes across different retinal layers.
PubMed: 38944405
DOI: 10.1016/j.pdpdt.2024.104259 -
Mitochondrion Jun 2024In diabetic retinopathy, mitochondrial DNA (mtDNA) is damaged and mtDNA-encoded genes and long noncoding RNA cytochrome B (LncCytB) are downregulated. LncRNAs lack an...
In diabetic retinopathy, mitochondrial DNA (mtDNA) is damaged and mtDNA-encoded genes and long noncoding RNA cytochrome B (LncCytB) are downregulated. LncRNAs lack an open reading frame, but they can regulate gene expression by associating with DNA/RNA/protein. Double stranded mtDNA has promoters on both heavy (HSP) and light (LSP) strands with binding sites for mitochondrial transcription factor A (TFAM) between them. The aim was to investigate the role of LncCytB in mtDNA transcription in diabetic retinopathy. Using human retinal endothelial cells incubated in high glucose, the effect of regulation of LncCytB on TFAM binding at mtDNA promoters was investigated by Chromatin immunoprecipitation, and binding of LncCytB at TFAM by RNA immunoprecipitation and RNA fluorescence in situ hybridization. High glucose decreased TFAM binding at both HSP and LSP, and binding of LncCytB at TFAM. While LncCytB overexpression ameliorated decrease in TFAM binding and transcription of genes encoded by both H- and L- strands, LncCytB-siRNA further downregulated them. Maintenance of mitochondrial homeostasis by overexpressing mitochondrial superoxide dismutase or Sirtuin-1 protected diabetes-induced decrease in TFAM binding at mtDNA and LncCytB binding at TFAM, and mtDNA transcription. Similar results were obtained from mouse retinal microvessels from streptozotocin-induced diabetic mice. Thus, LncCytB facilitates recruitment of TFAM at HSP and LSP, and its downregulation in diabetes compromises the binding, resulting in the downregulation of polypeptides encoded by mtDNA. Regulation of LncCytB, in addition to protecting mitochondrial genomic stability, should also help in maintaining the transcription of mtDNA encoded genes and electron transport chain integrity in diabetic retinopathy.
PubMed: 38944370
DOI: 10.1016/j.mito.2024.101925 -
Experimental Neurology Jun 2024In an attempt to repair injured central nervous system (CNS) nerves/tracts, immune cells are recruited into the injury site, but endogenous response in adult mammals is...
In an attempt to repair injured central nervous system (CNS) nerves/tracts, immune cells are recruited into the injury site, but endogenous response in adult mammals is insufficient for promoting regeneration of severed axons. Here, we found that a portion of retinal ganglion cell (RGC) CNS projection neurons that survive after optic nerve crush (ONC) injury are enriched for and upregulate fibronectin (Fn)-interacting integrins Itga5 and ItgaV, and that Fn promotes long-term survival and long-distance axon regeneration of a portion of axotomized adult RGCs in culture. We then show that, Fn is developmentally downregulated in the axonal tracts of optic nerve and spinal cord, but injury-activated macrophages/microglia upregulate Fn while axon regeneration-promoting zymosan augments their recruitment (and thereby increases Fn levels) in the injured optic nerve. Finally, we found that Fn's RGD motif, established to interact with Itga5 and ItgaV, promotes long-term survival and long-distance axon regeneration of adult RGCs after ONC in vivo, with some axons reaching the optic chiasm when co-treated with Rpl7a gene therapy. Thus, experimentally augmenting Fn levels in the injured CNS is a promising approach for therapeutic neuroprotection and axon regeneration of at least a portion of neurons.
PubMed: 38944331
DOI: 10.1016/j.expneurol.2024.114877 -
American Journal of Ophthalmology Jun 2024The association between the total macular burden of hyperreflective foci (HRF) in eyes with intermediate AMD (iAMD) and the onset of persistent choroidal...
PURPOSE
The association between the total macular burden of hyperreflective foci (HRF) in eyes with intermediate AMD (iAMD) and the onset of persistent choroidal hypertransmission defects (hyperTDs) was studied using swept-source optical coherence tomography (SS-OCT).
DESIGN
Post hoc subgroup analysis of a prospective study.
METHODS
A retrospective review of iAMD eyes from subjects enrolled in a prospective SS-OCT study was performed. All eyes underwent 6×6 mm SS-OCT angiography (SS-OCTA) imaging at baseline and follow-up visits. En face sub-retinal pigment epithelium (subRPE) slabs with segmentation boundaries positioned 64-400 µm beneath Bruch's membrane (BM) were used to identify persistent choroidal hyperTDs. None of the eyes had persistent hyperTDs at baseline. The same subRPE slab was used to identify choroidal hypotransmission defects (hypoTDs) attributable to HRF located either intraretinally (iHRF) or along the RPE (rpeHRF) based on corresponding B-scans. A semiautomated algorithm was used by two independent graders to validate and refine the HRF outlines. The HRF area and the drusen volume within a 5mm fovea-centered circle were measured at each visit.
RESULTS
The median follow-up time for the 171 eyes from 121 patients included in this study was 59.1 months (95%CI: 52.0-67.8 months). Of these, 149 eyes (87%) had HRF, and 82 (48%) developed at least one persistent hyperTD during the follow-up. Although univariable Cox regression analyses showed that both drusen volume and total HRF area were associated with the onset of the first persistent hyperTD, multivariable analysis showed that the area of total HRF was the sole significant predictor for the onset of hyperTDs (P<0.001). ROC analysis identified an HRF area ≥ 0.07 mm² to predict the onset of persistent hyperTDs within one year with an area under the curve (AUC) of 0.661 (0.570-0.753), corresponding to a sensitivity of 55% and a specificity of 74% (P<0.001).
CONCLUSIONS
The total macular burden of HRF, which includes both the HRF along the RPE and within the retina, is an important predictor of disease progression from iAMD to the onset of persistent hyperTDs and should serve as a key OCT biomarker to select iAMD patients at high-risk for disease progression in future clinical trials.
PubMed: 38944135
DOI: 10.1016/j.ajo.2024.06.023 -
Clinical Hemorheology and... Jun 2024Diabetic retinopathy (DR) is a serious retinal vascular disease that affects many individuals in their prime working years. The present research aimed at whether and how...
PURPOSE
Diabetic retinopathy (DR) is a serious retinal vascular disease that affects many individuals in their prime working years. The present research aimed at whether and how LOC681216 (LNC-216) is involved in retinal vascular dysfunction under diabetic conditions.
METHODS
Rat retinal microvascular endothelial cells (RRMECs) treated with high glucose (HG) were used for functional analysis. Gene expression analysis was conducted using the Clariom D Affymetrix platform. The wound healing, transwell, and vascular tube formation assays were used to identify the migration, invasion, and tube formation capability of RRMECs. The dual-luciferase reporter confirmed the binding interaction between miR-143-5p and LNC-216 or matrix metallopeptidase 2 (MMP2).
RESULTS
Lnc-216 was upregulated in RRMECs treated with HG. Lnc-216 knockdown markedly suppressed the tube formation, cell migration, and wound healing of cultured RRMECs under HG conditions. Mechanistically, Lnc-216 acted as a miR-143-5p sponge to affect the biological activity of miR-143-5p, which led to increased expression of matrix metallopeptidase 2 (MMP2).
CONCLUSIONS
Lnc-216 attenuates diabetic retinal vascular dysfunction through the miR-143-5p/MMP2 axis, providing a potential therapeutic strategy for DR.
PubMed: 38943385
DOI: 10.3233/CH-242163 -
Acta Neuropathologica Communications Jun 2024The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a...
The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.
Topics: Humans; Male; Female; Aged; Cognitive Dysfunction; Hippocampus; Atrophy; Amyloidosis; Aged, 80 and over; Retrospective Studies; Middle Aged; Plaque, Amyloid; Retinal Diseases; Retinal Vessels; Ophthalmoscopy
PubMed: 38943220
DOI: 10.1186/s40478-024-01810-2