RAGE and its ligand amyloid beta promote retinal ganglion cell loss following ischemia-reperfusion injury

IntroductionGlaucoma is a progressive neurodegenerative disease associated with age. Accumulation of amyloid-beta (Aß) proteins in the ganglion cell layer (GCL) and subsequent retinal ganglion cell (RGC) loss is an established pathological hallmark of the disease. The mechanism through which Aß provokes RGC loss remains unclear. The receptor for the advanced glycation end product (RAGE), and its ligand Aß, have been shown to mediate neuronal loss via internalizing Aß within the neurons. In this study, we investigated whether the RAGE–Aß axis plays a role in RGC loss in experimental glaucoma.MethodsRetinal ischemia was induced by an acute elevation of intraocular pressure in RAGE–/– and wild-type (WT) control mice. In a subset of animals, oligomeric Aß was injected directly into the vitreous of both strains. RGC loss was assessed using histology and biochemical assays. Baseline and terminal positive scotopic threshold (pSTR) were also recorded.ResultsRetinal ischemia resulted in 1.9-fold higher RGC loss in WT mice compared to RAGE–/– mice (36 ± 3% p < 0.0001 vs. 19 ± 2%, p = 0.004). Intravitreal injection of oligomeric Aß resulted in 2.3-fold greater RGC loss in WT mice compared to RAGE–/– mice, 7-days post-injection (55 ± 4% p = 0.008 vs. 24 ± 2%, p = 0.02). We also found a significant decline in the positive scotopic threshold response (pSTR) amplitude of WT mice compared to RAGE–/– (36 ± 3% vs. 16 ± 6%).DiscussionRAGE–/– mice are protected against RGC loss following retinal ischemia. Intravitreal injection of oligomeric Aß accelerated RGC loss in WT mice but not RAGE–/–. A co-localization of RAGE and Aß, suggests that RAGE–Aß binding may contribute to RGC loss

Amplitude of retinal venous pulsations are associated with retinal nerve fibre layer thickness in glaucoma

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Non-invasive estimation of intracranial pressure by means of retinal venous pulsatility

Current techniques used to measure intracranial pressure (ICP) are invasive and require surgical procedures in order to implant pressure catheters in brain ventricles. The amplitude of central retinal vein pulsations (RVPa) has been shown to be associated with the pressure gradient between intraocular pressure (IOP) and ICP. When IOP approaches ICP, the pressure gradient drops, leading to cessation of RVPa. In this study we aim to investigate this relationship and define a new method to estimate ICP non-invasively. 10 healthy subjects (mean age 35±10) with clear medical history were included in this study. Baseline IOP was measured (Goldman tonometers) and RVP recorded using Dynamic Vessel Analyser.IOP was decreased actively using 0.5% Iopidine and RVP recorded simultaneously every 15 minutes. Digital signal processing techniques were used to measure mean RVP peak-to-peak amplitude in each cardiac cycle at different IOP levels. Linear regression equations were used to extract a relation between IOP and RVPa and to estimate the pressure at which RVPa cease (i.e. RVPa=0). At this point ICP equals IOP. IOP and ICP pressure waveforms were simulated in order to estimate ICP continuously. Results show a linear relationship between RVPa and IOP such that RVP decreases with IOP reduction. Estimated ICP ranged between 2-13.7 mmHg, all falling in the normal physiological range (i.e. 0-15 mmHg). Analysis of retinal venous pulsation in accordance with IOP may introduce a novel approach for estimation of ICP non-invasively.4 page(s

Non-invasive intracranial pressure measurement using transcranial doppler sonography and support vector machines

Current techniques used for intracranial pressure (ICP) measurement are invasive. All require a surgical procedure for placement of a pressure catheter in the central nervous system (CNS) and therefore are associated with risk and morbidity. In this study we propose a noninvasive method for ICP measurement based on signal processing techniques.. In this method a non-linear relationship is used to determine ICP based on two more accessible parameters, namely arterial blood pressure (ABP) and the blood velocity of the middle cerebral artery (MCA) measured using the transcranial doppler (TCD) device. The clinical investigation of the proposed method shows high similarity between the invasively recorded intracranial pressure (ICP) and the predicted ICP using our proposed method under intensive care unit (ICU) conditions. A correlation of r=0.976 was achieved between the predicted ICP and the invasively ICP measurements, which shows a highly sensitive procedure in noninvasive ICP measurement.4 page(s

Autonomous assessment of spontaneous retinal venous pulsations in fundus videos using a deep learning framework

Abstract The presence or absence of spontaneous retinal venous pulsations (SVP) provides clinically significant insight into the hemodynamic status of the optic nerve head. Reduced SVP amplitudes have been linked to increased intracranial pressure and glaucoma progression. Currently, monitoring for the presence or absence of SVPs is performed subjectively and is highly dependent on trained clinicians. In this study, we developed a novel end-to-end deep model, called U3D-Net, to objectively classify SVPs as present or absent based on retinal fundus videos. The U3D-Net architecture consists of two distinct modules: an optic disc localizer and a classifier. First, a fast attention recurrent residual U-Net model is applied as the optic disc localizer. Then, the localized optic discs are passed on to a deep convolutional network for SVP classification. We trained and tested various time-series classifiers including 3D Inception, 3D Dense-ResNet, 3D ResNet, Long-term Recurrent Convolutional Network, and ConvLSTM. The optic disc localizer achieved a dice score of 95% for locating the optic disc in 30 milliseconds. Amongst the different tested models, the 3D Inception model achieved an accuracy, sensitivity, and F1-Score of 84 ± 5%, 90 ± 8%, and 81 ± 6% respectively, outperforming the other tested models in classifying SVPs. To the best of our knowledge, this research is the first study that utilizes a deep neural network for an autonomous and objective classification of SVPs using retinal fundus videos

Spontaneous retinal venous pulsatility in patients with cyanotic congenital heart disease

Spontaneous retinal venous pulsations (SRVP) are assessed as a clinical marker for patients with ophthalmic or neurological disorders. The pulsations are influenced by intraocular pressure (IOP), cerebrospinal fluid pressure (CSFp), and retinal venous pressure (RVP). However, little is known about the effect of cyanosis with polycythemia, a common finding in adults with complex congenital heart disease (CHD), on SRVP. This study investigated 11 subjects with long-standing cyanosis secondary to CHD and 11 control subjects to determine if there were measurable differences in resting pulsatility for a given IOP level. Intraocular pressure was measured using Goldman tonometry, and dynamic SRVP was recorded noninvasively using a retinal vessel imaging system. Peak amplitude of SRVP at each cardiac cycle was measured and compared with IOP. Heart rate was also monitored during the tests. Results show that for a similar baseline IOP, SRVP amplitudes are significantly lower in cyanotic patients compared with normal subjects (P < 0.0001). This may be explained by an increased RVP or high CSFp in these patients. Mean venous diameter is also significantly higher in cyanotic patients (P < 0.01), but no significant relationship was found between SRVP or diameter with blood parameters. © 2011 Springer

Cognitive Performance on the Montreal Cognitive Assessment Test and Retinal Structural and Functional Measures in Glaucoma

Background: Glaucoma, the leading cause of irreversible blindness, is classified as a neurodegenerative disease, and its incidence increases with age. Pathophysiological changes, such as the deposition of amyloid-beta plaques in the retinal ganglion cell layer, as well as neuropsychological changes, including cognitive decline, have been reported in glaucoma. However, the association between cognitive ability and retinal functional and structural measures in glaucoma, particularly glaucoma subtypes, has not been studied. We studied the association between cognitive ability and the visual field reliability indices as well as the retinal ganglion cell (RGC) count estimates in a cohort of glaucoma patients. Methods: A total of 95 eyes from 61 glaucoma patients were included. From these, 20 were normal-tension glaucoma (NTG), 25 were primary open-angle glaucoma (POAG), and 16 were glaucoma suspects. All the participants had a computerised Humphrey visual field (HVF) assessment and optical coherence tomography (OCT) scan and were administered the written Montreal Cognitive Assessment (MoCA) test. RGC count estimates were derived based on established formulas using the HVF and OCT results. A MoCA cut-off score of 25 and less was designated as cognitive impairment. Student&rsquo;s t-test was used to assess differences between the groups. The Pearson correlation coefficient was used to assess the association between MoCA scores and retinal structural and functional measures. Results: Significant associations were found between MoCA scores and the false-negative and pattern standard deviation indices recorded on the HVF (r = &minus;0.19, r = &minus;0.22, p &lt; 0.05). The mean IOP was significantly lower in the cognitively impaired group (i.e., MOCA &le; 25) (13.7 &plusmn; 3.6 vs. 15.7 &plusmn; 4.5, p &lt; 0.05). No significant association was found between RGC count estimates and MoCA scores. Analysis of these parameters in individual glaucoma subtypes did not reveal any group-specific significant associations either

Ophthalmological consequences of cyanotic congenital heart disease : vascular parameters and nerve fibre layer

Background: This study investigated the long-term ophthalmological consequences of cyanotic congenital heart disease (CHD). Design: Cross-sectional study, tertiary referral setting. Participants: Thirteen adults with cyanotic CHD (40 ± 4 years). Age- and sex-matched healthy controls underwent aspects of the protocol. Methods: Cyanosed subjects had a full ophthalmic examination, visual fields, scanning laser ophthalmoscopy and optical coherence tomography to assess retinal nerve fibre layer (RNFL), retinal photography and cerebral magnetic resonance imaging (MRI). Main Outcome Measures: RNFL thickness and quantitative analysis of retinal vessels with fractal dimension, branching and central retinal arterial equivalent (CRAE) and central retinal venous equivalent (CRVE). Results: No abnormalities of anatomy, motility, intraocular pressure or anterior segments were detected apart from one subject who had bilateral cataracts. Corrected visual acuity was normal in all but one cyanosed subject. Clinical examination revealed dilated retinal vasculature in 12/13 cyanosed subjects and increased tortuosity in 8/13. In the setting of cyanosis, skeletonized retinal arterial and venous beds had higher fractal dimension and increased branching (P ≤ 0.01, n = 11 for all); retinal vessels were dilated (CRAE: 227 vs. 183, n = 11, P < 0.0001; CRVE: 254 vs. 221, n = 11, P = 0.01). Visual fields showed scotomas in two subjects associated with RNFL thinning. No disc oedema was detected. 6/13 subjects' RNFL thickness fell below the normal 95% confidence interval in at least one sector without explanatory cerebral pathology (P < 0.0001, n = 13). Mean RNFL thickness correlated with MRI cerebral white matter volume (R = 0.67, P = 0.035). Conclusions: Cyanosed subjects had vessel dilatation, increased branching and tortuosity. RNFL and visual field thresholds were reduced suggesting impaired neuro-ophthalmological functioning.9 page(s

Non-invasive estimation of cerebrospinal fluid pressure waveforms by means of retinal venous pulsatility and central aortic blood pressure

Current techniques used for cerebrospinal fluid pressure (CSFp) measurements are invasive. They require a surgical procedure for placement of a pressure catheter in the brain ventricles or in the brain tissue. The human eye provides direct visualisation of its physiological structures and due to its anatomical connection with CSF via the retrolaminar optic nerve it may provide accessible information about CSFp. A total of 25 subjects were included in this study. 15 subjects were used to characterise the relationship between intraocular pressure (IOP), spontaneous retinal venous pulsatility (SRVP), and CSFp. IOP was manipulated and SRVP amplitudes recorded dynamically using the dynamic vessel analyzer (DVA). The relationship between IOP and SRVP amplitude was established to estimate CSFp. Additionally Doppler blood flow velocity of the middle cerebral artery and arterial blood pressure (ABP) were acquired for all subjects. This was to compare and validate our findings with an alternative approach (ICM+) which uses these values to estimate CSFp. A CSFp waveform was extracted from central blood pressure (CBP) waveform by removing its cardiac component frequency. Furthermore to calibrate the CSFp to CBP waveform ratio, invasive CSFp, and ABP was measured from 10 subjects with brain tumours who had a range of normal to elevated CSFp (i.e., 0-30 mmHg). Results show good agreement between the two methods (correlation r (2) = 0.55) Mean estimated CSFp for the two techniques did not show any significant difference (p > 0.05). A significant correlation between CBP pulse (CBPp) and invasive CSFp pulse (CSFpp) was observed (i.e., CSFpp = 0.0654CBBp + 3.91, p < 0.01). Estimated CSFpp was calibrated to CBPp according to this relation. In conclusion, the study demonstrated a good correlation between two different methods of estimating CSFp non-invasively and may provide a novel method to estimate CSF waveforms non-invasively.9 page(s

Average SRVP and RNFL measurements at 4 sectors of the retina in all glaucoma and normal subjects (correlation coefficient (r) and its p-value for each sector within each group).

<p>Average SRVP and RNFL measurements at 4 sectors of the retina in all glaucoma and normal subjects (correlation coefficient (r) and its p-value for each sector within each group).</p