Anatomy of the Human Optic Nerve: Structure and Function

The optic nerve (ON) is constituted by the axons of the retinal ganglion cells (RGCs). These axons are distributed in an organized pattern from the soma of the RGC to the lateral geniculated nucleus (where most of the neurons synapse). The key points of the ON are the optic nerve head and chiasm. This chapter will include a detailed and updated review of the ON different parts: RGC axons, glial cells, connective tissue of the lamina cribrosa and the septum and the blood vessels derivate from the central retina artery and from the ciliary system. There will be an up-to-date description about the superficial nerve fibre layer, including their organization, and about prelaminar, laminar and retrolaminar regions, emphasizing the axoplasmic flow, glial barriers, biomechanics of the lamina cribrosa and the role of the macro- and microglia in their working

Foveal avascular zone and choroidal thickness are decreased in subjects with hard drusen and without high genetic risk of developing Alzheimer’s disease

A family history (FH+) of Alzheimer’s disease (AD) and ɛ4 allele of the ApoE gene are the main genetic risk factors for developing AD, whereas ɛ4 allele plays a protective role in age-related macular degeneration. Ocular vascular changes have been reported in both pathologies. We analyzed the choroidal thickness using optical coherence tomography (OCT) and the foveal avascular zone (FAZ) using OCT-angiography and compared the results with ApoE gene expression, AD FH+, and the presence or absence of hard drusen (HD) in 184 cognitively healthy subjects. Choroidal thickness was statistically significantly different in the (FH−, ɛ4−, HD+) group compared with (i) both the (FH−, ɛ4−, HD−) and the (FH+, ɛ4+, HD+) groups in the superior and inferior points at 1500 μm, and (ii) the (FH+, ɛ4−, HD+) group in the superior point at 1500 μm. There were statistically significant differences in the superficial FAZ between the (FH+, ɛ4−, HD+) group and (i) the (FH+, ɛ4−, HD−) group and (ii) the (FH+, ɛ4+, HD−) group. In conclusion, ocular vascular changes are not yet evident in participants with a genetic risk of developing AD

Characterization of retinal drusen in subjects at high genetic risk of developing sporadic Alzheimer’s disease: An exploratory analysis

Having a family history (FH+) of Alzheimer’s disease (AD) and being a carrier of at least one ε4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aβ plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH-or FH+) and their allelic characterization of ApoE ε4 (ApoE ε4-or ApoE ε4+) and considering cardiovascular risk factors (hypercholesterolemia, hypertension, and diabetes mellitus). In addition, we analyzed the choroidal thickness by OCT and the area of the foveal avascular zone with OCTA. We did not find a relationship between a family history of AD or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared to patients without drusen, and thinning could trigger changes in choroidal perfusion that may give rise to the deposits that generate drusen

The Role of Autophagy in Eye Diseases

This research was funded by the Ophthalmological Network OFTARED (Enfermedades oculares: Prevención, detección precoz, tratamiento y rehabilitación de las patologías oculares) (RD16/0008/0005 and RD16/0008/0026) of the Institute of Health of Carlos III of the Spanish Ministry of Economy and by the European programme FEDER; and Network RETiBRAIN (La retina un modelo para investigar Neuroprotección en patologías del Sistema Nervioso Central) (RED2018-102499-T) of Spanish Ministry of Science and Innovation. And J.A.F.-A. is currently funded by a Predoctoral Fellowship (FPU17/01023) from the Spanish Ministry of Science, Innovation, and Universities; and I.L.-C. is currently funded by a Predoctoral Fellowship (CT42/18-CT43/18) from the Complutense University of Madrid.Autophagy is a catabolic process that ensures homeostasis in the cells of our organism. It plays a crucial role in protecting eye cells against oxidative damage and external stress factors. Ocular pathologies of high incidence, such as age-related macular degeneration, cataracts, glaucoma, and diabetic retinopathy are of multifactorial origin and are associated with genetic, environmental factors, age, and oxidative stress, among others; the latter factor is one of the most influential in ocular diseases, directly affecting the processes of autophagy activity. Alteration of the normal functioning of autophagy processes can interrupt organelle turnover, leading to the accumulation of cellular debris and causing physiological dysfunction of the eye. The aim of this study is to review research on the role of autophagy processes in the main ocular pathologies, which have a high incidence and result in high costs for the health system. Considering the role of autophagy processes in cell homeostasis and cell viability, the control and modulation of autophagy processes in ocular pathologies could constitute a new therapeutic approach.Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEUnión EuropeaMinisterio de Ciencia e Innovación (España)Instituto de Salud Carlos IIIUniversidad Complutense de Madridpu

Microglial Hemoxygenase-1 Deletion Reduces Inflammation in the Retina of Old Mice with Tauopathy

Tauopathies such as Alzheimer’s disease are characterized by the accumulation of neurotoxic aggregates of tau protein. With aging and, especially, in Alzheimer’s patients, the inducible enzyme heme oxygenase 1 (HO-1) progressively increases in microglia, causing iron accumulation, neuroinflammation, and neurodegeneration. The retina is an organ that can be readily accessed and can reflect changes that occur in the brain. In this context, we evaluated how the lack of microglial HO-1, using mice that do not express HO-1 in microglia (HMO-KO), impacts retinal macro and microgliosis of aged subjects (18 months old mice) subjected to tauopathy by intrahippocampal delivery of AAV-hTauP301L (TAU). Our results show that although tauopathy, measured as anti-TAUY9 and anti-AT8 positive immunostaining, was not observed in the retina of WT-TAU or HMO-KO+TAU mice, a morphometric study of retinal microglia and macroglia showed significant retinal changes in the TAU group compared to the WT group, such as: (i) increased number of activated microglia, (ii) retraction of microglial processes, (iii) increased number of CD68+ microglia, and (iv) increased retinal area occupied by GFAP (AROA) and C3 (AROC3). This retinal inflammatory profile was reduced in HMO-KO+TAU mice. Conclusion: Reduction of microglial HO-1 could be beneficial to prevent tauopathy-induced neuroinflammation.Depto. de Inmunología, Oftalmología y ORLUnidad Docente de Inmunología, Oftalmología y ORLFac. de MedicinaFac. de Óptica y OptometríaTRUEMinisterio de Ciencia e Innovación de EspañaMinisterio de Ciencia, Innovación y Universidades de EspañaUniversidad Complutense de Madridpu

Retinal Thickness Changes Over Time in a Murine AD Model APP NL-F/NL-F.

Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL-F/NL-F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. Results: In the APPNL-F/NL-F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. Conclusions: In the APPNL-F/NL-F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL-F/NL-F AD model may help us better understand the different retinal changes during the progression of AD.This research was funded by the Ophthalmological Network OFTARED (RD16/0008/0005) of the Institute of Health of Carlos III of the Spanish Ministry of Science and Innovation; and the Research Network RETIBRAIN (RED2018-102499-T) and Grant PID2019-106581RB-I00 of the Spanish Ministry of Science and Innovation; and Leducq Foundation for Cardiovascular Research TNE-19CVD01. IL-C was currently supported by a Pre-doctoral Fellowship (CT42/18-CT43/18) from the Complutense University of Madrid. JF-A was currently supported by a Pre-doctoral Fellowship (FPU17/01023) from the Spanish Ministry of Science, Innovation, and Universities.S

Electron transport measurements in liquid xenon with Xenoscope, a large-scale DARWIN demonstrator

The DARWIN observatory is a proposed next-generation experiment with 40 tonnes of liquid xenon as an active target in a time projection chamber. To study challenges related to the construction and operation of a multi-tonne scale detector, we have designed and constructed a vertical, full-scale demonstrator for the DARWIN experiment at the University of Zurich. Here, we present the first results from a several-months run with 343kg of xenon and electron drift lifetime and transport measurements with a 53cm tall purity monitor immersed in the cryogenic liquid. After 88days of continuous purification, the electron lifetime reached a value of (664±23)μs. We measured the drift velocity of electrons for electric fields in the range (25–75) V/cm, and found values consistent with previous measurements. We also calculated the longitudinal diffusion constant of the electron cloud in the same field range, and compared with previous data, as well as with predictions from an empirical model

Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage

Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs) leading to visual loss. Degeneration of RGCs and loss of their axons, as well as damage and remodeling of the lamina cribrosa are the main events in the pathogenesis of glaucoma. Different molecular pathways are involved in RGC death, which are triggered and exacerbated as a consequence of a number of risk factors such as elevated intraocular pressure (IOP), age, ocular biomechanics, or low ocular perfusion pressure. Increased IOP is one of the most important risk factors associated with this pathology and the only one for which treatment is currently available, nevertheless, on many cases the progression of the disease continues, despite IOP control. Thus, the IOP elevation is not the only trigger of glaucomatous damage, showing the evidence that other factors can induce RGCs death in this pathology, would be involved in the advance of glaucomatous neurodegeneration. The underlying mechanisms driving the neurodegenerative process in glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress and neuroinflammation. In glaucoma, like as other neurodegenerative disorders, the immune system is involved and immunoregulation is conducted mainly by glial cells, microglia, astrocytes, and Müller cells. The increase in IOP produces the activation of glial cells in the retinal tissue. Chronic activation of glial cells in glaucoma may provoke a proinflammatory state at the retinal level inducing blood retinal barrier disruption and RGCs death. The modulation of the immune response in glaucoma as well as the activation of glial cells constitute an interesting new approach in the treatment of glaucoma

Retinal Disorders in Humans and Experimental ALS Models

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that severely impairs the patient’s mobility, as it mainly affects the upper and lower motor neurons in the spinal cord. In addition, alterations have also been demonstrated in different parts of the central nervous system (CNS), such as the brain and brainstem. The retina is a projection to the brain and is considered as a “window” to the CNS. Moreover, it is possible to use the retina as a biomarker in several neurodegenerative diseases, even in the absence of major visual impairment. Classically, it was thought that the eyes were not affected in ALS, with respect to extraocular muscles, whereas the remainder of the muscles of the body were distressed. Nevertheless, retinal changes have recently been found in this pathology and could help in diagnosis, follow-up, and even monitoring therapies in this disease

Retinal Disorders in Humans and Experimental ALS Models

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that severely impairs the patient’s mobility, as it mainly affects the upper and lower motor neurons in the spinal cord. In addition, alterations have also been demonstrated in different parts of the central nervous system (CNS), such as the brain and brainstem. The retina is a projection to the brain and is considered as a “window” to the CNS. Moreover, it is possible to use the retina as a biomarker in several neurodegenerative diseases, even in the absence of major visual impairment. Classically, it was thought that the eyes were not affected in ALS, with respect to extraocular muscles, whereas the remainder of the muscles of the body were distressed. Nevertheless, retinal changes have recently been found in this pathology and could help in diagnosis, follow-up, and even monitoring therapies in this disease