Senile plaques in Alzheimer's disease arise from Aß- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

Senile plaques are a pathological hallmark of Alzheimer's disease (AD), yet the mechanism underlying their generation remains unknown. Beta-amyloid peptide (Aß) is a major component of senile plaques. We analysed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging to examine the neural, vascular or blood Aß contribution to senile plaque development. We found little neural marker co-expression with plaque Aß, while co-expression of blood markers, such as Haemin and ApoE, was abundant. The plaque cores were structured with vascular and glial proteins outside and blood metabolites inside, co-localizing with a characteristic of Hoechst staining-independent blue autofluorescence. Erythrocyte-interacting Aß is linked to coagulation, elevated calcium and blue autofluorescence, and it is associated with intravascular haemolysis, atherosclerosis, cerebral amyloid angiopathy, microaneurysm, and often with Cathepsin D co-expression. We identified microaneurysms as major sites of amyloid formation. Our data suggest that senile plaques arise from Aß- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

Differentiating Microaneurysm Pathophysiology in Diabetic Retinopathy Through Objective Analysis of Capillary Nonperfusion, Inflammation, and Pericytes.

Microaneurysms are biomarkers of microvascular injury in diabetic retinopathy (DR). Impaired retinal capillary perfusion is a critical pathogenic mechanism in the development of microvascular abnormalities. Targeting fundamental molecular disturbances resulting from capillary nonperfusion, such as increased vascular endothelial growth factor expression, does not always reverse the anatomic complications of DR, suggesting that other pathogenic mechanisms independent of perfusion also play a role. We stratify the effects of capillary nonperfusion, inflammation, and pericyte loss on microaneurysm size and leakage in DR through three-dimensional analysis of 636 microaneurysms using high-resolution confocal scanning laser microscopy. Capillary nonperfusion, pericyte loss, and inflammatory cells were found to be independent predictors of microaneurysm size. Nonperfusion alone without pericyte loss or inflammation was not a significant predictor of microaneurysm leakage. Microaneurysms found in regions without nonperfusion were significantly smaller than those found in regions with nonperfusion, and their size was not associated with pericyte loss or inflammation. In addition, microaneurysm size was a significant predictor of leakage in regions with nonperfusion only. This report refines our understanding of the disparate pathophysiologic mechanisms in DR and provides a histologic rationale for understanding treatment failure for microvascular complications in DR.

Seven Microaneurysms: Description of an Experimental Rodent Model for Neurovascular Training.

AIM: To demonstrate the microsurgical procedures, and to evaluate the feasibility of living models of experimental neurovascular training by developing new complex vascular exercises mimicking the most common intracranial aneurysms. MATERIAL AND METHODS: The procedures were performed under a Zeiss (OPMI pico f170) microscope using basic microsurgery instruments, 10/0 Nylon and blue Polypropylene micro-sutures. We selected adult albino Wistar rats weighing between 258 and 471g each. Seven different aneurysm types were created using carotid, jugular, cava, aorta and femoral vessels. RESULTS: Seven types of aneurysm were designed and created in the rat with a high-medium successful rate. There are differences in terms of realism and the difficulty of performance, according to the different types: lateral wall, bifurcation, top of the basilar, fusiform, fusiform + involved branch, Anterior Communicating Artery (ACoA) and giant. The steps and technical issues to produce these exercises are described. CONCLUSION: We show the feasibility of creating several types of aneurysm using different vessels in a rodent model. Training on these models help to improve microsurgical skills, allowing safe practice for neurosurgeons in all stages of their career.

Dynamic Changes of Retinal Microaneurysms in Diabetes Imaged With In Vivo Adaptive Optics Optical Coherence Tomography.

Purpose: To prospectively monitor microaneurysms (MAs) in three dimensions using adaptive optics optical coherence tomography (AOOCT). Methods: Patients with diabetes mellitus and parafoveal MAs were included in this longitudinal study. At baseline, MAs were identified in standard fluorescein angiography (FA) and subsequently imaged with an AOOCT prototype, incorporated into an AO fundus camera (RTX1, Imagine Eyes) device. Imaging was repeated every 3 months in each patient to explore the potential structural change of MAs over time including size, shape, intraretinal position, (intra-) luminal reflectivity, and other qualitative morphologic characteristics. Results: We imaged 18 MAs in seven eyes (two left eyes) of five patients (mean age: 69 ± 7 years) over 18 months. All MAs appeared as saccular in the en face imaging plane at baseline, and no change in shape was observed in any of the MAs during follow-up. Evaluation of the AOOCT volumes revealed dynamic changes of MAs during follow-up including intermittent growth (n = 2), progressive involution (n = 3), total disappearance (n = 2), and MA division (n = 1). Intraluminal hyperreflective material was visualized in 11 out of 18 MAs, which remained stable (n = 3), increased (n = 2), regressed (n = 1), or fluctuated (n = 5). Three MAs without intraluminal spots at baseline progressively developed distinct hyperreflectivities. Conclusions: AOOCT illustrates the structurally dynamic evolution of MAs in vivo in three dimensions. Despite a consistent saccular shape in the en face view, AOOCT volumes revealed a heterogeneous behavior in regard to size and reflective status of MAs over time.

Algorithms for red lesion detection in Diabetic Retinopathy: A review.

Diabetic Retinopathy (DR) is an outcome of prolonged diabetes which directly or indirectly affect the human vision. DR is asymptomatic in its early stages and the late diagnosis lead to undeviating loss of vision. The computer aided diagnosis with the assistance of medical images helps in timely and accurate treatment. Microaneurysms (MA) mark the onset of DR, thus a vital point in screening of this disease. This review discuses various state of the art methods available till date for automated computer aided analysis of microaneurysms and haemorrhages. The paper also highlights qualitative and quantitative comparison of the existing literature with limitations for analysis of microaneurysms and haemorrhages. It is an attempt to systematize the available algorithms for an easy gathering and guidance to researchers working in this domain for future research.

Neurofibromatosis 1 and massive hemothorax: a fatal combination.

Type 1 neurofibromatosis (NF 1), a rare genetic disease with autosomal dominant transmission, has typical dermatologic manifestations with pathognomonic Lisch nodules, and is rarely known for vascular alterations. Among these, aneurysmal dilatation is the most common form. We report a fatal case of massive hemothorax due to a spontaneous rupture of the left pulmonary artery branch micro-aneurysm in a NF 1 patient. Indeed, spontaneous rupture of these pathologic vessels is very rare in clinical practice and the literature, but, for its potentially life-threatening complications, there is the need for it to be taken into account in differential diagnosis. The origin of bleeding was first confirmed by computed tomography angiography (CTA). The patient's condition worsened suddenly leading to pulmonary hemorrhage and death. A clinical autopsy was required to assess the definitive cause of death.

A Pathogenetic Classification of Diabetic Macular Edema.

PURPOSE: The aim of this study was to define a new pathogenetic classification of diabetic macular edema (DME) and to present the results of its application in common clinical practice. METHODS: One hundred and seventy-seven consecutive patients with center-involving DME, central retinal thickness (CRT) ≥250 µm, were prospectively enrolled. A complete ophthalmological examination included best-corrected visual acuity (BCVA) assessment, fundus photography, and spectral-domain optical coherence tomography (OCT). The DME classification was broken down into 4 categories, combining the presence of retinal thickening with the presence/absence of visible vascular dilations and OCT-detectable macular traction. The OCT parameters included were as follows: CRT, subretinal fluid, intraretinal cysts, and hyper- reflective foci (HF). RESULTS: Four subtypes of DME were identified: vasogenic (131 eyes, DME with vascular dilation), nonvasogenic (46 eyes, DME without vascular dilation), tractional (11 eyes), and mixed DME (13 eyes). Vasogenic DME was the pattern mainly represented in each subclass of CRT (< 300, 300-400, and > 400 µm), with tractional DME observed especially with CRT > 400 µm. Internal and external cysts and a greater presence of hard exudates were predominantly found in vasogenic DME, whereas HF was equally distributed in the 4 DME subgroups. CONCLUSION: The study offers a new pathogenetic classification able to detect significant differences among DME subtypes. A tailored therapeutic approach could take into consideration specific changes associated with the different DME subtypes.

Cellular Senescence Is Associated With Human Retinal Microaneurysm Formation During Aging.

Purpose: Microaneurysms are present in healthy old-age human retinas. However, to date, no age-related pathogenic mechanism has been implicated in their formation. Here, cellular senescence, a hallmark of aging and several age-related diseases, has been analyzed in the old-age human retina and in the retina of a progeric mouse. Methods: Retinas were obtained from 17 nondiabetic donors and from mice deficient in Bmi1. Cellular senescence was analyzed by immunohistochemistry, senescent-associated ß-galactosidase activity assay, Sudan black B staining, conventional transmission electron microscopy, and immunoelectronmicroscopy. Results: Neurons, but not neuroglia, and blood vessels undergo cellular senescence in the old-age human retina. The canonical senescence markers p16, p53, and p21 were up-regulated and coexisted with apoptosis in old-age human microaneurysms. Senescent endothelial cells were discontinuously covered by fibronectin, and p16 colocalized with the ß1 subunit of fibronectin receptor α5ß1 integrin under the endothelial cellular membrane, suggesting anoikis as a mechanism involved in endothelial cell apoptosis. In a progeric mouse model deficient in Bmi1, where p21 was overexpressed, the retinal blood vessels displayed an aging phenotype characterized by enlarged caveolae and lipofuscin accumulation. Although mouse retina is not prone to develop microaneurysms, Bmi1-deficient mice presented abundant retinal microaneurysms. Conclusions: Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas.

Ventricular Microaneurysms in Moyamoya Angiopathy Visualized with 7T MR Angiography.

The pathophysiologic role of hemodynamic alteration to peripheral vessels in Moyamoya angiopathy and the formation of microaneurysms remains unclear. The purpose of this study was to investigate microaneurysms in collateral Moyamoya vessels by using 7T ultra-high-field MR imaging. Ten patients with Moyamoya disease were evaluated with TOF-MRA at 7T acquired with 0.22 × 0.22 × 0.41 mm(3) resolution. In 10 patients, 4 microaneuryms located in the ventricles were delineated. The mean diameters of collateral vessels and microaneurysms arising from those vessels were 0.87 mm (range, 0.79-1.07 mm) and 0.80 mm (range, 0.56-0.96 mm), respectively. In 1 case with follow-up scans 6 months after a direct extracranial-intracranial bypass operation, the microaneurysm disappeared. Ventricular microaneurysms in Moyamoya angiopathy collateral vessels, inaccessible by conventional imaging techniques, can be detected by 7T TOF-MRA.

Microaneurysms in renal angiomyolipomas: Can clinical and computed tomography features predict their presence and size?

PURPOSE: To evaluate clinical and multidetector computed tomography (MDCT) features associated with the presence and size of microaneurysms in renal angiomyolipomas (AMLs). MATERIALS AND METHODS: The MDCTs and digital subtraction angiographies (DSAs) of 31 patients who had further percutaneous arterial embolization of AMLs were retrospectively reviewed. They were 22 women and 9 men (mean age, 47.7±27.7 years). The medical files of the included patients were reviewed for age, gender and clinical features. MDCT and DSA images were analyzed by two readers working in consensus. RESULTS: Of the 31 patients, 15 had tuberous sclerosis complex (TSC) or lymphangioleiomyomatosis (LAM). In total, the 31 patients had 54 AMLs (5 ruptured). On DSA, 28 clusters of microaneurysms were found in 17 patients (21 AMLs). Four of the five ruptured AMLs had microaneurysms. None of the 12 AMLs≤40mm and 21 of the 42 AMLs>40mm had microaneurysms. Among AMLs>40mm, history of TSC/LAM (P=0.5), RENAL score (P=0.7) and relative volume of fat (P=0.11) did not significantly predict the presence of microaneurysms. Microaneurysms were significantly larger in ruptured (9.5±5.7mm) than non-ruptured (3.9±1.9mm, P=0.02) AMLs. No associations were found between the size of microaneurysms and the size of AMLs. CONCLUSION: Microaneurysms were found in no AML ≤40mm and in 50%of AMLs>40mm. In AMLs >40mm, history of TSC/LAM, RENAL score and relative volume of fat did not significantly predict the presence of microaneurysms.