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The Journal of Clinical Investigation Jan 2024Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically...
Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.
Topics: Animals; Humans; Mice; Brain; CADASIL; Dementia, Vascular; Mice, Knockout; Mutation; Receptor, Notch3
PubMed: 38015629
DOI: 10.1172/JCI166134 -
Journal of Neuro-ophthalmology : the... Mar 2020Cerebrovascular disease (CeVD), including stroke, is a leading cause of death globally. The retina is an extension of the cerebrum, sharing embryological and vascular... (Review)
Review
BACKGROUND
Cerebrovascular disease (CeVD), including stroke, is a leading cause of death globally. The retina is an extension of the cerebrum, sharing embryological and vascular pathways. The association between different retinal signs and CeVD has been extensively evaluated. In this review, we summarize recent studies which have examined this association.
EVIDENCE ACQUISITION
We searched 6 databases through July 2019 for studies evaluating the link between retinal vascular signs and diseases with CeVD. CeVD was classified into 2 groups: clinical CeVD (including clinical stroke, silent cerebral infarction, cerebral hemorrhage, and stroke mortality), and sub-clinical CeVD (including MRI-defined lacunar infarct and white matter lesions [WMLs]). Retinal vascular signs were classified into 3 groups: classic hypertensive retinopathy (including retinal microaneurysms, retinal microhemorrhage, focal/generalized arteriolar narrowing, cotton-wool spots, and arteriovenous nicking), clinical retinal diseases (including diabetic retinopathy [DR], age-related macular degeneration [AMD], retinal vein occlusion, retinal artery occlusion [RAO], and retinal emboli), and retinal vascular imaging measures (including retinal vessel diameter and geometry). We also examined emerging retinal vascular imaging measures and the use of artificial intelligence (AI) deep learning (DL) techniques.
RESULTS
Hypertensive retinopathy signs were consistently associated with clinical CeVD and subclinical CeVD subtypes including subclinical cerebral large artery infarction, lacunar infarction, and WMLs. Some clinical retinal diseases such as DR, retinal arterial and venous occlusion, and transient monocular vision loss are consistently associated with clinical CeVD. There is an increased risk of recurrent stroke immediately after RAO. Less consistent associations are seen with AMD. Retinal vascular imaging using computer assisted, semi-automated software to measure retinal vascular caliber and other parameters (tortuosity, fractal dimension, and branching angle) has shown strong associations to clinical and subclinical CeVD. Other new retinal vascular imaging techniques (dynamic retinal vessel analysis, adaptive optics, and optical coherence tomography angiography) are emerging technologies in this field. Application of AI-DL is expected to detect subclinical retinal changes and discrete retinal features in predicting systemic conditions including CeVD.
CONCLUSIONS
There is extensive and increasing evidence that a range of retinal vascular signs and disease are closely linked to CeVD, including subclinical and clinical CeVD. New technology including AI-DL will allow further translation to clinical utilization.
Topics: Cerebrovascular Disorders; Humans; Magnetic Resonance Imaging; Retina; Retinal Vessels; Tomography, Optical Coherence
PubMed: 31977663
DOI: 10.1097/WNO.0000000000000888 -
Cureus Oct 2022Diabetes is a chronic progressive metabolic disorder that is caused by the body's inability to regulate blood glucose levels. If uncontrolled, it can lead to various... (Review)
Review
Diabetes is a chronic progressive metabolic disorder that is caused by the body's inability to regulate blood glucose levels. If uncontrolled, it can lead to various complications. Among its various complications, long-term diabetes leads to diabetic retinopathy (DR). It is a disease involving blood vessels and the destruction of retinal nerves. It is usually classified into two types: proliferative diabetic retinopathy (PDR) and nonproliferative diabetic retinopathy (NPDR). It progresses and causes loss of vision. The leading cause of loss of vision is diabetic macular edema (DME). The argon laser is used as a modality in the management of PDR. There are various types of laser photocoagulation, such as peripheral retinal laser photocoagulation, focal macular laser photocoagulation, and grid photocoagulation. DR results in various adverse consequences such as vitreous hemorrhage, fibrosis, traction, detachment of the retina, and glaucoma. To assess DR, a detailed fundus examination with a slit lamp biomicroscope needs to be done. Seven-standard field stereoscopic-color fundus photography needs to be done for documentation and follow-up. Patients with diabetes mellitus (DM) type 1 have a greater risk of suffering from DR. Another major complication of the condition is DME, which is characterized by an increase in the permeability of vessels and the thickening of the central part of the retina along with the accumulation of hard exudates on the macula. This article discusses various laser therapy modalities for the treatment of DR, their types, mechanisms, and aims. Clinical features of DR include abnormal dilatation of capillaries, and outpouchings in the form of microaneurysm from the capillary wall are one of the earliest and most dangerous changes; later, non-perfusion of the retina occurs, which is associated with cotton wool spots and blot hemorrhages. In patients suffering from PDR and maculopathy, peripheral retinal laser photocoagulation is used as a mode of intervention.
PubMed: 36348830
DOI: 10.7759/cureus.30024 -
Nature Communications May 2021Retinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system,... (Observational Study)
Observational Study
Retinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system, named DeepDR, that can detect early-to-late stages of diabetic retinopathy. DeepDR is trained for real-time image quality assessment, lesion detection and grading using 466,247 fundus images from 121,342 patients with diabetes. Evaluation is performed on a local dataset with 200,136 fundus images from 52,004 patients and three external datasets with a total of 209,322 images. The area under the receiver operating characteristic curves for detecting microaneurysms, cotton-wool spots, hard exudates and hemorrhages are 0.901, 0.941, 0.954 and 0.967, respectively. The grading of diabetic retinopathy as mild, moderate, severe and proliferative achieves area under the curves of 0.943, 0.955, 0.960 and 0.972, respectively. In external validations, the area under the curves for grading range from 0.916 to 0.970, which further supports the system is efficient for diabetic retinopathy grading.
Topics: Aged; Datasets as Topic; Deep Learning; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Fundus Oculi; Humans; Image Interpretation, Computer-Assisted; ROC Curve; Severity of Illness Index
PubMed: 34050158
DOI: 10.1038/s41467-021-23458-5 -
World Journal of Diabetes Oct 2023Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations... (Review)
Review
Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure. The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments, such as the vascular system and glomeruli. Glomerular alterations include thickening of the glomerular basement membrane, loss of podocytes, and segmental mesangiolysis, which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules. Beyond lesions directly related to diabetes, awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, and other primary or secondary renal disorders. Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches. However, the relationship between diabetes and the kidney is bidirectional; thus, new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases. Here, we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course, differential diagnosis, and therapeutic oppor-tunities offered by novel drugs.
PubMed: 37970131
DOI: 10.4239/wjd.v14.i10.1450 -
Advances in Experimental Medicine and... 2020At medical checkups or mass screenings, the fundus examination is effective for early detection of systemic hypertension, arteriosclerosis, diabetic retinopathy, etc. In... (Review)
Review
At medical checkups or mass screenings, the fundus examination is effective for early detection of systemic hypertension, arteriosclerosis, diabetic retinopathy, etc. In most cases, ophthalmologists and physicians grade retinal images by the condition of the blood vessels, lesions. However, human observation does not provide quantitative results, thus blood vessel analysis is an important process in determining hypertension and arteriosclerosis, quantitatively. This chapter describes the latest automated blood vessel extraction using the deep convolution neural network (DCNN). Diabetic retinopathy is a common cardiovascular disease and a major factor in blindness. Therefore, early detection of diabetic retinopathy is very important to preventing blindness. A microaneurysm is an initial sign of diabetic retinopathy, and much research has been conducted for microaneurysm detection. This chapter also describes diabetic retinopathy detection and automated microaneurysm detection using the DCNN.
Topics: Deep Learning; Diabetic Retinopathy; Early Diagnosis; Fundus Oculi; Humans; Microaneurysm
PubMed: 32030666
DOI: 10.1007/978-3-030-33128-3_7 -
Survey of Ophthalmology 2022The electroretinogram (ERG) is a noninvasive, objective technique to evaluate retinal function that has become increasingly important in the study of diabetic... (Review)
Review
The electroretinogram (ERG) is a noninvasive, objective technique to evaluate retinal function that has become increasingly important in the study of diabetic retinopathy. We summarize the principles and rationale of the ERG, present findings from recent clinical studies that have used the full-field ERG, multifocal ERG, and pattern ERG to evaluate neural dysfunction in patients with diabetes, and weigh the strengths and limitations of the technique as it applies to clinical studies and management of patients with diabetic retinopathy. Taken together, ERG studies have provided convincing evidence for dysfunction of the neural retina in patients with diabetes, including those who have no clinically-apparent retinal vascular abnormalities. Recent full-field ERG findings have pointed to the intriguing possibility that photoreceptor function is abnormal in early-stage disease. Pattern ERG data, in conjunction with recently developed photopic negative response analyses, indicate inner retina dysfunction. In addition, multifocal ERG studies have shown spatially localized neural abnormalities that can predict the location of future microaneurysms. Given the insights provided by the ERG, it is likely to play a growing role in understanding the natural history of neural dysfunction in diabetes, as well as providing an attractive outcome measure for future clinical trials that target neural preservation in diabetic retinopathy.
Topics: Color Vision; Diabetes Mellitus; Diabetic Retinopathy; Electroretinography; Humans; Retina
PubMed: 34487740
DOI: 10.1016/j.survophthal.2021.08.011 -
Medicina (Kaunas, Lithuania) May 2023Diabetic retinopathy is a form of diabetic microangiopathy, and vascular hyperpermeability in the macula leads to retinal thickening and concomitant reduction of visual... (Review)
Review
Diabetic retinopathy is a form of diabetic microangiopathy, and vascular hyperpermeability in the macula leads to retinal thickening and concomitant reduction of visual acuity in diabetic macular edema (DME). In this review, we discuss multimodal fundus imaging, comparing the pathogenesis and interventions. Clinicians diagnose DME using two major criteria, clinically significant macular edema by fundus examination and center-involving diabetic macular edema using optical coherence tomography (OCT), to determine the appropriate treatment. In addition to fundus photography, fluorescein angiography (FA) is a classical modality to evaluate morphological and functional changes in retinal capillaries, e.g., microaneurysms, capillary nonperfusion, and fluorescein leakage. Recently, optical coherence tomography angiography (OCTA) has allowed us to evaluate the three-dimensional structure of the retinal vasculature and newly demonstrated that lamellar capillary nonperfusion in the deep layer is associated with retinal edema. The clinical application of OCT has accelerated our understanding of various neuronal damages in DME. Retinal thickness measured by OCT enables us to quantitatively assess therapeutic effects. Sectional OCT images depict the deformation of neural tissues, e.g., cystoid macular edema, serous retinal detachment, and sponge-like retinal swelling. The disorganization of retinal inner layers (DRIL) and foveal photoreceptor damage, biomarkers of neurodegeneration, are associated with visual impairment. Fundus autofluorescence derives from the retinal pigment epithelium (RPE) and its qualitative and quantitative changes suggest that the RPE damage contributes to the neuronal changes in DME. These clinical findings on multimodal imaging help to elucidate the pathology in the neurovascular units and lead to the next generation of clinical and translational research in DME.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Retrospective Studies; Retina; Tomography, Optical Coherence; Multimodal Imaging; Diabetes Mellitus
PubMed: 37241128
DOI: 10.3390/medicina59050896 -
Frontiers in Medicine 2022Cones in diabetic patients are at risk due to metabolic and vascular changes. By imaging retinal vessel modeling at high magnification, we reduced its impact on cone...
PURPOSE
Cones in diabetic patients are at risk due to metabolic and vascular changes. By imaging retinal vessel modeling at high magnification, we reduced its impact on cone distribution measurements. The retinal vessel images and retinal thickness measurements provided information about cone microenvironment.
METHODS
We compared cone data in 10 diabetic subjects (28-78 yr) to our published norms from 36 younger and 10 older controls. All subjects were consented and tested in a manner approved by the Indiana University Institutional Review Board, which adhered to the Declaration of Helsinki. Custom adaptive optics scanning laser ophthalmoscopy (AOSLO) was used to image cones and retinal microcirculation. We counted cones in a montage of foveal and temporal retina, using four non-contiguous samples within 0.9-7 deg that were selected for best visibility of cones and least pathology. The data were fit with a two parameter exponential model: ln(cone density) = a microns eccentricity + b. These results were compared to retinal thickness measurements from SDOCT.
RESULTS
Diabetic cone maps were more variable than in controls and included patches, or unusually bright and dark cones, centrally and more peripherally. Model parameters and total cones within the central 14 deg of the macula differed across diabetic patients. Total cones fell into two groups: similar to normal for 5 vs. less than normal for 2 of 2 younger diabetic subjects and 3 older subjects, low but not outside the confidence limits. Diabetic subjects had all retinal vascular remodeling to varying degrees: microaneurysms; capillary thickening, thinning, or bends; and vessel elongation including capillary loops, tangles, and collaterals. Yet SD-OCT showed that no diabetic subject had a Total Retinal Thickness in any quadrant that fell outside the confidence limits for controls.
CONCLUSIONS
AOSLO images pinpointed widespread retinal vascular remodeling in all diabetic eyes, but the SDOCT showed no increased retinal thickness. Cone reflectivity changes were found in all diabetic patients, but significantly low cone density in only some. These results are consistent with early changes to neural, glial, or vascular components of the retinal without significant retinal thickening due to exudation.
PubMed: 35372411
DOI: 10.3389/fmed.2022.826643 -
Journal of Stroke and Cerebrovascular... Sep 2021Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of... (Review)
Review
Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of the CKD may be heterogeneous, affected patients may have one or more major co-morbidities that themselves can cause significant neurologic disease, and agonal events may result in significant findings that were of minimal significance earlier in a patient's life. We studied the constellation of neuropathologic abnormalities in 40 autopsy brains originating from subjects of ages 34-95 years (no children in the study). The most common pathologic change was that of ischemic infarcts (cystic, lacunar and/or microinfarcts), which were seen in over half of subjects. These were associated with both large artery atherosclerosis and arteriolosclerosis (A/S), the latter finding being present in 29/40 subjects. Charcot-Bouchard microaneurysms were present in the brains of three subjects, in one case associated with severe amyloid angiopathy. Microvascular calcinosis (medial sclerosis in the case of arterioles) was seen in the basal ganglia (n=8) and/or endplate region of the hippocampus (n=7) and occasional ischemic infarcts in one brain showed severe calcification. Sequelae of cerebrovascular disease (especially A/S or microvascular disease) are a common neuropathologic substrate for neurologic disability and brain lesions in this complex group of patients. Regulation of calcium metabolism within brain microvessel walls may be worthy of further research in both human brain specimens and animal models.
Topics: Adult; Aged; Aged, 80 and over; Animals; Arteriolosclerosis; Autopsy; Brain; Cerebral Arteries; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Vascular Calcification
PubMed: 33579545
DOI: 10.1016/j.jstrokecerebrovasdis.2021.105657