Microcirculatory model predicts blood flow and autoregulation range in the human retina:in vivo investigation with laser speckle flowgraphy

In this study, we mathematically predict retinal vascular resistance (RVR) and retinal blood flow (RBF), we test predictions using laser speckle flowgraphy (LSFG), we estimate the range of vascular autoregulation, and we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, optical coherence tomography (OCT), and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained float 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregula tion limits (LARL/HARL), using retinal vessel calibers, fractal dimen- sion, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R-2 =0.77/P = 6.9.10(-9)) and RBF (R-2 =0.65/P = 1.0.10(-6)), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P = 4.0.10(-4)) and GCC (P = 0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies. NEW & NOTEWORTHY We describe and test a new approach to quantify retinal blood flow, based on standard clinical examinations and imaging techniques, linked together with a physiological model. We use these findings to generate individualized estimates of the autoregulation range. We provide evidence that healthy subjects are closer to the lower autoregulation limit than thought before. This suggests that some retinas are less prepared to withstand hypoperfusion, even after small intraocular pressure rises or blood pressure drops

Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo

Abnormalities in arterial versus venous endothelial cell identity and dysregulation of angiogenesis are deemed important in the pathophysiology of brain arteriovenous malformations (AVMs). The Sonic hedgehog (Shh) pathway is crucial for both angiogenesis and arterial versus venous differentiation of endothelial cells, through its dual role on the vascular endothelial growth factor/Notch signaling and the nuclear orphan receptor COUP-TFII. In this study, we show that Shh, Gli1 (the main transcription factor of the Shh pathway), and COUP-TFII (a target of the non-canonical Shh pathway) are aberrantly expressed in human brain AVMs. We also show that implantation of pellets containing Shh in the cornea of Efnb2/LacZ mice induces growth of distinct arteries and veins, interconnected by complex sets of arteriovenous shunts, without an interposed capillary bed, as seen in AVMs. We also demonstrate that injection in the rat brain of a plasmid containing the human Shh gene induces the growth of tangles of tortuous and dilated vessels, in part positive and in part negative for the arterial marker \u3b1SMA, with direct connections between \u3b1SMA-positive and -negative vessels. In summary, we show that the Shh pathway is active in human brain AVMs and that Shh-induced angiogenesis has characteristics reminiscent of those seen in AVMs in humans

What went wrong? The flawed concept of cerebrospinal venous insufficiency

In 2006, Zamboni reintroduced the concept that chronic impaired venous outflow of the central nervous system is associated with multiple sclerosis (MS), coining the term of chronic cerebrospinal venous insufficiency ('CCSVI'). The diagnosis of 'CCSVI' is based on sonographic criteria, which he found exclusively fulfilled in MS. The concept proposes that chronic venous outflow failure is associated with venous reflux and congestion and leads to iron deposition, thereby inducing neuroinflammation and degeneration. The revival of this concept has generated major interest in media and patient groups, mainly driven by the hope that endovascular treatment of 'CCSVI' could alleviate MS. Many investigators tried to replicate Zamboni's results with duplex sonography, magnetic resonance imaging, and catheter angiography. The data obtained here do generally not support the 'CCSVI' concept. Moreover, there are no methodologically adequate studies to prove or disprove beneficial effects of endovascular treatment in MS. This review not only gives a comprehensive overview of the methodological flaws and pathophysiologic implausibility of the 'CCSVI' concept, but also summarizes the multimodality diagnostic validation studies and open-label trials of endovascular treatment. In our view, there is currently no basis to diagnose or treat 'CCSVI' in the care of MS patients, outside of the setting of scientific research

Automated Systems for Calculating Arteriovenous Ratio in Retinographies : A Scoping Review

There is evidence of an association between hypertension and retinal arteriolar narrowing. Manual measurement of retinal vessels comes with additional variability, which can be eliminated using automated software. This scoping review aims to summarize research on automated retinal vessel analysis systems. Searches were performed on Medline, Scopus, and Cochrane to find studies examining automated systems for the diagnosis of retinal vascular alterations caused by hypertension using the following keywords: diagnosis; diagnostic screening programs; image processing, computer-assisted; artificial intelligence; electronic data processing; hypertensive retinopathy; hypertension; retinal vessels; arteriovenous ratio and retinal image analysis. The searches generated 433 articles. Of these, 25 articles published from 2010 to 2022 were included in the review. The retinographies analyzed were extracted from international databases and real scenarios. Automated systems to detect alterations in the retinal vasculature are being introduced into clinical practice for diagnosis in ophthalmology and other medical specialties due to the association of such changes with various diseases. These systems make the classification of hypertensive retinopathy and cardiovascular risk more reliable. They also make it possible for diagnosis to be performed in primary care, thus optimizing ophthalmological visits

Cell migration and capillary plexus formation in wounds and retinae

Cell migration is a fundamental biological phenomenon that is critical to the development and maintenance of tissues in multi-cellular organisms. This thesis presents a series of discrete mathematical models designed to study the migratory response of such cells when exposed to a variety of environmental stimuli. By applying these models to pertinent biological scenarios and benchmarking results against experimental data, novel insights are gained into the underlying cell behaviour. The process of angiogenesis is investigated first and models are developed for simulating capillary plexus expansion during both wound healing and retinal vascular development. The simulated cell migration is coupled to a detailed model of blood perfusion that allows prediction of dynamic flow-induced evolution of the nascent vascular architectures – the network topologies generated in each case are found to successfully reproduce a number of longitudinal experimental metrics. Moreover, in the case of retinal development, the resultant distributions of haematocrit and oxygen are found to be essential in generating vasculatures that resemble those observed in vivo. An alternative cell migration model is then derived that is capable of more accurately describing both individual and collective cell movement. The general model framework, which allows for biophysical cell-cell interactions and adaptive cell morphologies, is seen to have the potential for a range of applications. The value of the modelling approach is well demonstrated by benchmarking in silico cell movement against experimental data from an in vitro fibroblast scrape wound assay. The results subsequently reveal an unexplained discrepancy that provides an intriguing challenge for future studies

Nutrition and ocular disease in an older Australian cohort : the Blue Mountains Eye Study

Wolfram syndrome patients are mainly characterised by juvenile onset diabetes mellitus and optic atrophy. A synonym is the acronym DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness. Diabetes insipidus and sensorineural high-frequency hearing impairment are important additional features. This rare autosomal recessively inherited neurodegenerative syndrome is caused by mainly inactivating mutations in the WFS1 gene. It is located at chromosome 4p16 and encodes wolframin, a transmembrane protein. No function has yet been ascribed to this protein

Retinal Blood Oxygen Saturation and Angiogenic and Inflammatory Biomarkers in Type 2 Diabetes

Introduction: Diabetic retinopathy (DR) is a major source of visual loss in the world, including North America. A number of hyperglycemia-related pathways have been associated with DR onset and progression. Disturbances in the retinal vasculature appear to play a vital role in DR, resulting in biochemical and functional vascular changes. Therefore, this study investigated retinal blood oxygen saturation and angiogenic and inflammatory biomarkers in DR. Methods: Chapter 3 and 5: FD-OCT Doppler blood flow was non-invasively measured using a prototype system based on the RTVue (Optovue Inc., USA). A minimum of six separate FD-OCT Doppler measurements was acquired. Chapter 4, 5, 7: Non-invasive hyperspectral retinal (HR) imaging was acquired in participants with mild-to-moderate NPDR and age-matched controls. For each subject, six repeated HRC images were acquired at wavelengths of 586 and 605nm. Results: Chapter3: The individual COV medians for retinal blood flow were 7.5% and 9.2% for young and elderly subjects, respectively. The group mean CORs for retinal blood flow for young participants were 6.4µl/min and for elderly subjects were 10.5µl/min. Chapter 4: Retinal blood oxygen saturation in the arterioles of healthy controls was 92.97±1.6%, and in the venules was 55.90±4.8%. Retinal blood oxygen saturation for diabetic subjects with NPDR was significantly higher at 94.65±2.2% (p=0.015) in the arterioles and 64.13±4.3% (p<0.001) in the venules. Chapter 5: Total retinal blood flow was significantly lower in NPDR when compared to controls (42.66 vs 32.97; p=0.004). There was no relationship between total retinal blood flow and venular oxygen saturation (r=0.2). Chapter 6: Angiopoietin 2, IL-8, HGF was significantly higher in NPDR patients than in control patients (p=0.005, p=0.034, p=0.018, respectively) and EGF was significantly lower in NPDR patients when compared to controls (p=0.025). Chapter 7: The study demonstrated a correlation between retinal blood oxygen saturation and Ang 2, HGF and EGF but did not find any correlation for IL-8, TGF-β even though these biomarkers were significantly higher in the diabetic group. Conclusions: Chapter 3: Doppler OCT gave consistent and repeatable blood flow measurements within retinal venules in normal subjects. Chapter 4: A higher blood oxygen saturation could be the result of less oxygen consumtion due to cell death. Chapter 5: There is no correlation between retinal blood flow and retinal blood oxygen saturation. Chapter 6: Further investigation of Ang 2, HGF, IL-8, EGF, TGF-β could be used to better understand the pathophysiology of DR. Chapter 7: The result of this study revealed a relationship between the biomarkers that might result in cell death and higher retinal blood oxygen saturation.1 yea

Ocular and systemic vascular alterations in overweight and obese individuals undergoing weight-loss interventions

Obesity and its accompanying comorbidities play a crucial role in the pathogenesis of endothelial function which is a pre-cursor to atherosclerosis, subsequently leading to increases in cardiovascular risk. However, amelioration of these risk factors and improvements in endothelial function have never been fully explored in functional assessments of the retinal and peripheral microcirculations.The aim of this thesis was therefore to investigate the presence and impact of weight-loss interventions in overweight and obese individuals and also the relationships between functional measurements of different vascular beds. The principle findings of this work were:1. The relationship between retinal and peripheral vascular function in healthy individuals with low cardiovascular risk• Participants with higher peripheral vascular reactivity indices had a higher amplitude change from maximum to minimum and also showed enhanced reaction times to flicker provocation, which correlated to the degree of peripheral vascular function. 2. The effects of physical training on retinal and systemic microvascular function• Physical exercise positively influenced the retinal microcirculation through improvements in dilation and constriction reaction times to flicker provocation. 3. The long-lasting effects of fasting during the month of Ramadan on retinal and peripheral vascular function• Participants during fasting had a higher capacity to reach maximum dilation and also a greater percentage increase from baseline diameters. The retinal veins were also significantly less variable during baseline corrected measurements. 4. The effect of bariatric surgery on retinal vessels structure and systemic microvascular function• Increases were recorded for the diameter of retinal arteries but also for the veins. Peripheral vascular function was significantly improved and arterial stiffness was decreased. CVD risk was significantly decreased and also correlated with retinal vessel calibre measurements. 5. Is there an improvement in anterior ocular health after bariatric surgery?• Anterior surface health doesn’t necessarily cause ocular health problems in obese individuals nor can it be improved or ameliorated through bariatric surger

Eye as a window to the brain: investigating the clinical utility of retinal imaging derived biomarkers in the phenotyping of neurodegenerative disease.

Background Neurodegenerative diseases, like multiple sclerosis, dementia and motor neurone disease, represent one of the major public health threats of our time. There is a clear persistent need for novel, affordable, and patient‐acceptable biomarkers of these diseases, to assist with diagnosis, prognosis and impact of interventions. And these biomarkers need to be sensitive, specific and precise. The retina is an attractive site for exploring this potential, as it is easily accessible to non‐invasive imaging. Remarkable technology revolutions in retinal imaging are enabling us to see the retina in microscopic level detail, and measure neuronal and vascular integrity. Aims and objectives I therefore propose that retinal imaging could provide reliable and accurate markers of these neurological diseases. In this project, I aimed to explore the clinical utility of retinal imaging derived measures of retinal neuronal and vessel size and morphology, and determine their candidacy for being reliable biomarkers in these diseases. I also aimed to detail the methods of retinal imaging acquisition, and processing, and the principles underlying all these stages, in relation to understanding of retinal structure and function. This provides an essential foundation to the application of retinal imaging analysis, highlighting both the strengths and potential weaknesses of retinal biomarkers and how they are interpreted. Methods After performing detailed systematic reviews and meta‐analyses of the existing work on retinal biomarkers of neurodegenerative disease, I carried out a prospective, controlled, cross‐sectional study of retinal image analysis, in patients with MS, dementia, and ALS. This involved developing new software for vessel analysis, to add value and maximise the data available from patient imaging episodes. Results From the systematic reviews, I identified key unanswered questions relating to the detailed analysis and utility of neuroretinal markers, and diseases with no studies yet performed of retinal biomarkers, such as non‐AD dementias. I recruited and imaged 961 participants over a two‐year period, and found clear patterns of significance in the phenotyping of MS, dementia and ALS. Detailed analysis has provided new insights into how the retina may yield important disease information for the individual patient, and also generate new hypotheses with relation to the disease pathophysiology itself. Conclusions Overall, the results show that retinal imaging derived biomarkers have an important and specific role in the phenotyping of neurodegenerative diseases, and support the hypothesis that the eye is an important window to neurological brain disease