Retinal vascular biomarkers for early detection and monitoring of Alzheimer's disease

The earliest detectable change in Alzheimer''s disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes and degeneration have previously been reported in AD using optical coherence tomography and laser Doppler techniques. This report presents results from analysis of retinal photographs from AD and healthy control participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain. We demonstrate relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD. A number of RVPs were found to be different in AD. Two of these RVPs, venular branching asymmetry factor and arteriolar length-to-diameter ratio, were also higher in healthy individuals with high plaque burden (P=0.01 and P=0.02 respectively, after false discovery rate adjustment). Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments.     

Inhibition of inflammatory cells delays retinal degeneration in experimental retinal vein occlusion in mice

The role of microglia in retinal inflammation is still ambiguous. Branch retinal vein occlusion initiates an inflammatory response whereby resident microglia cells are activated. They trigger infiltration of neutrophils that exacerbate blood–retina barrier damage, regulate postischemic inflammation and irreversible loss of neuroretina. Suppression of microglia-mediated inflammation might bear potential for mitigating functional impairment after retinal vein occlusion (RVO). To test this hypothesis, we depleted microglia by PLX5622 (a selective tyrosine kinase inhibitor that targets the colony-stimulating factor-1 receptor) in fractalkine receptor reporter mice (Cx3cr1^gfp/+) subjected to various regimens of PLX5622 treatment and experimental RVO. Effectiveness of microglia suppression and retinal outcomes including retinal thickness as well as ganglion cell survival were compared to a control group of mice with experimental vein occlusion only. PLX5622 caused dramatic suppression of microglia. Despite vein occlusion, reappearance of green fluorescent protein positive cells was strongly impeded with continuous PLX5622 treatment and significantly delayed after its cessation. In depleted mice, retinal proinflammatory cytokine signaling was diminished and retinal ganglion cell survival improved by almost 50% compared to nondepleted animals 3 weeks after vein occlusion. Optical coherence tomography suggested delayed retinal degeneration in depleted mice. In summary, findings indicate that suppression of cells bearing the colony-stimulating factor-1 receptor, mainly microglia and monocytes, mitigates ischemic damage and salvages retinal ganglion cells. Blood–retina barrier breakdown seems central in the disease mechanism, and complex interactions between different cell types composing the blood–retina barrier as well as sustained hypoxia might explain why the protective effect was only partial.     

Systematic spatiotemporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

Calcium (Ca²⁺) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca²⁺ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca²⁺ in photoreceptor degeneration, assessing the activation pattern of Ca²⁺-dependent calpain proteases, generating spatiotemporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the rd1 and rd10 models, spatiotemporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor, although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggest a causal link between Ca²⁺ dysregulation and primary, nonapoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.     

Optical coherence tomography (OCT) study in Argentinean Huntington’s disease patients

Abstract

Background: Huntington’s disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical coherence tomography (OCT) is a non-invasive methodology that analyses the retinal nerve fibre layers (RNFL) and could reflect processes of neurodegeneration.

Methods: A cross-sectional study with 14?HD patients who underwent a spectral domain OCT. Results were compared with a control group. Demographic data were also obtained.

Results: Temporal and superior RNFL sectors in HD showed a significant RNFL thinning compared with a control group. However, no differences were identified in mean total RNFL thickness between HD patients and controls.

Conclusions: OCT is a rapid and non-invasive technique that can be investigated in larger cohorts of patients to assess its potential role as a biomarker in HD patients.     

橙皮苷在低压低氧所致大鼠视网膜抗氧化能力和炎症介质调控改变中的作用

目的　探讨橙皮苷（HSD）在低压低氧所致大鼠视网膜抗氧化应激能力及炎性介质调控改变中的干预作用。方法　取健康雄性清洁级成年SD大鼠72只（144眼），随机分为对照组、低压低氧组及HSD干预组，每组24只（48眼）。对照组大鼠饲养于常氧环境，低压低氧组及HSD干预组大鼠放置于模拟海拔5000 m高度的低压氧舱内喂养。HSD干预组大鼠给予HSD灌胃，对照组和低压低氧组大鼠给予生理盐水，各组大鼠每天等量灌胃一次，连续7 d。通过HE染色光镜下观察大鼠视网膜组织形态变化；采用酶联免疫吸附(ELISA)法检测大鼠视网膜谷胱甘肽(GSH)和半胱氨酸(Cys)蛋白浓度、丙二醛（MDA）含量以及肿瘤坏死因子-α（TNF-α）活性；Western-blot检测大鼠视网膜核因子-κB p65（NF-κB p65）和细胞色素C（Cyto-C)蛋白表达水平。结果　光镜下观察可见，与对照组相比，低压低氧组大鼠出现视网膜水肿，HSD干预组较低压低氧组大鼠视网膜水肿程度减轻。与对照组相比，低压低氧组大鼠视网膜中GSH蛋白浓度和Cys蛋白浓度降低，MDA含量升高，差异均有统计学意义（均为P<0.001）；与低压低氧组相比，HSD干预组提高了GSH蛋白浓度和Cys蛋白浓度，降低了MDA含量，GSH蛋白浓度和MDA含量两组相比差异均有统计学意义（均为P<0.001），Cys蛋白浓度两组相比差异无统计学意义（P>0.05）。与对照组相比，低压低氧组大鼠视网膜中NF-κB p65蛋白表达水平和TNF-α活性升高，差异均有统计学意义（P<0.01、 P<0.001）；与低压低氧组相比，HSD干预组大鼠视网膜中NF-κB p65蛋白表达水平和TNF-α活性降低，差异均有统计学意义（P<0.05、P<0.001）。与对照组相比，低压低氧组大鼠视网膜Cyto-C蛋白表达水平明显升高，差异有统计学意义（P<0.01）；与低压低氧组相比，HSD干预组大鼠视网膜中Cyto-C蛋白表达水平降低，差异有统计学意义（P<0.05）。结论　HSD能够通过提高大鼠视网膜抗氧化应激能力、抑制炎症介质释放以及减少线粒体损伤而发挥保护视网膜功能的作用。     

Physiological concentrations of melatonin inhibit the nitridergic pathway in the Syrian hamster retina

In the present work, the effect of melatonin on the hamster retinal nitridergic pathway was examined. When the retinas were incubated in the presence of low concentrations (1 pM-10 nM) of melatonin for 15 min, a significant decrease of nitric oxide synthase (NOS) activity was observed. However, when crude retinal homogenates were preincubated with melatonin for 15 min, no changes in NOS activity were detected, despite the fact that under the same conditions trifluoperazine, a calmodulin inhibitor, significantly decreased enzymatic activity. Kinetic analysis showed that melatonin decreased the V(max) of retinal NOS without changes in the K(m). On the other hand, low concentrations (100 pM) of melatonin significantly reduced retinal L-arginine influx. A decrease in the V(max) of L-arginine uptake was observed in the presence of melatonin, whereas the K(m) remained unchanged. Melatonin significantly inhibited the accumulation of cyclic guanosine monophosphate (cGMP) levels induced by both L-arginine and sodium nitroprusside (SNP). In summary, the present results indicate that melatonin could be a potent inhibitor of the retinal nitridergic pathway.     

Recurrent monocular exudative retinal detachment as the first manifestation of squamous cell lung cancer: A case report

Rationale:In this report, we present an extremely rare case of recurrent monocular exudative retinal detachment without concomitant ocular metastases. This turned out to be the first symptom of squamous cell lung cancer.Patient concerns:A 63-year-old woman was referred to our ophthalmology clinic by her primary care physician with a complaint of deteriorating vision in her right eye that had started four months prior, without concomitant pain.Diagnoses:We observed a detachment in the lower part of the retina during her ophthalmoscopy. We did not find any tears, holes, or degenerative changes in the periphery of the retina of the right eye during the surgery. In addition, plaques, tumor masses, and metastases were absent. Therefore, we diagnosed her with unilateral paraneoplastic exudative retinal detachment. Imaging tests performed before surgery revealed perihilar density with a visible air bronchogram in the middle field of the left lung. This turned out to be squamous cell carcinoma.Interventions:Patient underwent pars plana vitrectomy and routine laboratory and imaging tests before the procedure that utilized 20-gauge instrumentation. The subretinal fluid and was drained and a tamponade using Densiron (Fluoron Co, Neu-Ulm, Germany) was applied. After ophthalmic treatment, patient underwent complex oncological treatment based on chemotherapy and radiotherapy.Outcomes:Despite the application of heavy silicone oil (Densiron) into the vitreous chamber, we observed a recurrence of retinal detachment in the right eye during the follow-up visit, 13 months after the first ophthalmic surgery. Following subsequent pars plana vitrectomy, the Densiron and subretinal membranes were removed. Despite oncological treatment, the patient died, twenty months after the appearance of the first ocular symptoms.Lessons:Exudative retinal detachment without tumor metastasis to the eyeball can be one of the first signs of lung cancer in rare cases. Multidisciplinary care and imaging methods with greater accuracy will provide comprehensive care to the patients. It will not only facilitate timely detection and treatment of lung tumors but also for a plethora of oncological diseases.     

脑红蛋白在绵羊视网膜中的分布

目的:探讨脑红蛋白在绵羊视网膜的分布特征。方法:利用免疫组织化学显色SP法,观察脑红蛋白在健康成年绵羊视网膜中的分布情况。结果:脑红蛋白在绵羊视网膜的视神经纤维层、内网状层、外网状层和光感受器内节段中有强阳性表达,在视网膜的内核层和节细胞层有弱阳性表达,在视网膜外核层、光感受器外节段和色素上皮层中未见有阳性表达,内界膜、外界膜和视神经中亦有脑红蛋白阳性表达。绵羊视网膜脑红蛋白阳性表达的细胞类型主要有节细胞、双极细胞和光感受器细胞,其中节细胞的阳性表达定位于细胞质,胞核中未见表达。结论;除外核层、光感受器外节段和色素上皮层外,脑红蛋白在绵羊视网膜其他各层中均有表达,提示脑红蛋白在维持视网膜中氧平衡状态时发挥重要作用。