Early detection of Alzheimer’s dementia with ophthalmological psychophysical tests and optical coherence tomography as complementary diagnostic tests

Tesis de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Inmunología, Oftalmología y Otorrinolaringología, leída el 21/03/2019La Enfermedad de Alzheimer (EA) es una degeneración primaria, caracterizada por la afectación de las funciones cognitivas corticales, con un alto impacto a nivel funcional, un establecimiento lento y progresivo y por la aparición de depósitos de beta amiloide y los ovillos neurofibrilares. La retina es una proyección embrionaria del diencéfalo, y se consideran parte del sistema nervioso central. La degeneración producida en la retina y en el nervio óptico en la EA puede originarse por vía retrógrada desde la corteza visual o por vía directa desde la propia retina causada por los depósitos. Estos cambios anatómicos pueden ser detectados con técnicas de diagnóstico oftalmológicas que posibiliten el seguimiento de los cambios según progresa la neurodegeneración. Objetivos: Detectar los cambios que se producen en la retina, así como los cambios funcionales que se originan secundariamente, mediante pruebas psicofísicas oftalmológicas no invasivas y tomografía de coherencia óptica, en dos poblaciones de pacientes con EA, diferenciadas por el grado de evolución de la patología; comparando los resultados con una población control...Alzheimer's disease (AD) is a primary degenerative disease that establishes itself slowly and progressively, involves the appearance of amyloid beta deposits and neurofibrillary tangles and affects cortical cognitive functions in ways that strongly reduce level of functioning. AD can cause degeneration in the retina and optic nerve either directly as a result of amyloid beta deposits or secondarily as a result of degradation of the visual cortex. This raises the possibility that tracking ophthalmologic changes in the retina can be used to assess neurodegeneration in AD. Aim: To detect retinal changes and associated functional changes in two groups of AD patients with mild and moderate disease and in a group of healthy controls using non-invasive psychophysical ophthalmological tests and optical coherence tomography...Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEunpu

Cystoid Macular Edema: Causes, Diagnosis and Treatment

The purpose of this paper is to conduct a review of studies on cystoid macular edema published in the last seven years. Cystoid macular edema is a major cause of loss of visual acuity. It is the final common pathway of many diseases and can be caused by numerous processes including inflammatory, vascular, adverse drug reactions, retinal dystrophy or intraocular tumors. These processes disrupt the blood-retinal barrier, with fluid extravasation to the macular parenchyma. Imaging tests are essential for both detection and monitoring of this pathology. Fluorescein angiography and autofluorescence show the leakage of liquid from perifoveal vessels into the tissue where it forms cystic spaces. Optical coherence tomography is currently the gold standard technique for diagnosis and monitoring. This allows objective measurement of retinal thickness, which correlates with visual acuity and provides more complete morphological information. Based on the underlying etiology, the therapeutic approach can be either surgical or medical with anti-inflammatory drugs. We found that disruption of the blood-retinal barrier for various reasons is the key point in the pathogenesis of cystoid macular edema, therefore we believe that studies on its treatment should proceed on this path

The Impact of the Eye in Dementia: The Eye and its Role in Diagnosis and Follow‐up

Over the last few decades, the importance of ophthalmic examination in neurodegenerative diseases of the CNS has reportedly increased. The retina is an extension of the CNS and thus should not be surprising to find abnormal results in both the test exploring visual processing and those examining the retina of patients with CNS degeneration. Current in vivo imaging techniques are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of Alzheimer’s disease (AD) patients and may help to reveal unsuspected retinal and optic‐nerve repercussions of other CNS diseases. In this chapter, we perform an analysis of the physiological changes in ocular and cerebral ageing. We analyse the ocular manifestations in CNS disorders such as stroke, AD and Parkinson’s disease. In addition, the pathophysiology of both the eye and the visual pathway in AD are described. The value of the visual psychophysical tests in AD diagnosis is reviewed as well as the main findings of the optical coherence tomography as a contribution to the diagnosis and monitoring of the disease. Finally, we examine the association of two neurodegenerative diseases, AD and glaucoma, as mere coincidence or possible role in the progression of the neurodegeneration

Ocular Exploration in the Diagnosis and Follow-Up of the Alzheimer’s Dementia

The retina is part of the central nervous system (CNS), and therefore, in Alzheimer’s disease (AD), retinal and optic nerve degeneration could take place. This degeneration leads to neurofunctional changes that can be detected early and followed up throughout the evolution of the disease. As opposed to other CNS structures, the eye is easily accessible for in vivo observation. Retinal organization allows for the identification of its different neurons, and in consequence, detection of minimal changes taking place during neurodegeneration is possible. Functional vision studies performed on AD patients in recent years have shown how visual acuity, contrast sensitivity, color vision, and visual integration vary with the progression of neurodegeneration. The development of optical coherence tomography in ophthalmology has meant a breakthrough in retinal exploratory techniques, allowing the obtention of high-resolution images using light. This technique enables retinal analysis in the earliest stages of AD, being considered as a biomarker of neuronal damage. Given AD’s high prevalence and its expected increase, it is important to perform easy tests that cause minimal discomfort to the patients at a low cost while offering abundant information on the stage of the disease

Macular Thickness as a Potential Biomarker of Mild Alzheimer's Disease

Although several postmortem findings in the retina of patients with Alzheimer's disease (AD) are available, new biomarkers for early diagnosis and follow-up of AD are still lacking. It has been postulated that the defects in the retinal nerve fiber layer (RNFL) may be the earliest sign of AD, even before damage to the hippocampal region that affects memory. This fact may reflect retinal neuronal-ganglion cell death and axonal loss in the optic nerve in addition to aging

The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma

Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial-mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration

Roughness of retinal layers in Alzheimer’s disease

There is growing evidence that thinned retinal regions are interspersed with thickened regions in all retinal layers of patients with Alzheimer’s disease (AD), causing roughness to appear on layer thickness maps. The hypothesis is that roughness of retinal layers, assessed by the fractal dimension (FD) of their thickness maps, is an early biomarker of AD. Ten retinal layers have been studied in macular volumes of optical coherence tomography from 24 healthy volunteers and 19 patients with mild AD (Mini-Mental State Examination 23.42 ± 3.11). Results show that FD of retinal layers is greater in the AD group, the differences being statistically significant (p < 0.05). Correlation of layer FD with cognitive score, visual acuity and age reach statistical significance at 7 layers. Nearly all (44 out of 45) FD correlations among layers are positive and half of them reached statistical significance (p < 0.05). Factor analysis unveiled two independent factors identified as the dysregulation of the choroidal vascular network and the retinal inflammatory process. Conclusions: surface roughness is a holistic feature of retinal layers that can be assessed by the FD of their thickness maps and it is an early biomarker of AD

Beneficial effects of saffron (Crocus sativus L.) in ocular pathologies, particularly neurodegenerative retinal diseases

Saffron (Crocus sativus L.) has been traditionally used in food preparation and as a medicinal plant. It currently has numerous therapeutic properties attributed to it, such as protection against ischemia, as well as anticonvulsant, antidepressant, anxiolytic, hypolipidemic, anti-atherogenic, anti-hypertensive, antidiabetic, and anti-cancer properties. In addition, saffron has remarkable beneficial properties, such as anti-apoptotic, anti-inflammatory and antioxidant activities, due to its main metabolites, among which crocin and crocetin stand out. Furthermore, increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, both in experimental models and in clinical studies in patients. Currently, saffron supplementation is being tested for ocular neurodegenerative pathologies, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration and glaucoma, among others, and shows beneficial effects. The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases. This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases

Macular Thickness Decrease in Asymptomatic Subjects at High Genetic Risk of Developing Alzheimer’s Disease: An OCT Study

In this case control study, we examined the retinal thickness of the different layers in the macular region and peripapillary retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT) in healthy cognitive subjects (from 51 to 74 years old) at high genetic risk for developing Alzheimer’s disease (AD). Thirty-five subjects with a family history of Alzheimer disease (AD) (FH+) and ApoE ɛ4 carriers and 29 age-matched control subjects without a family history of AD (FH−) and ApoE ɛ4 non-carriers were included. Compared to FH− ApoE ɛ4 non-carriers, in FH+ ApoE ɛ4 carriers, there were statistically significant decreases (p < 0.05) in (i) the foveal area of mRNFL; (ii) the inferior and nasal sectors in the outer and inner macular ring in the inner plexiform layer (IPL); (iii) the foveal area and the inferior sector in the outer macular ring in the inner nuclear layer (INL); and (iv) the inferior sector of the outer macular ring in the outer plexiform layer (OPL). However, no statistically significant differences were found in the peripapillary thickness of RNFL between both study groups. In subjects with cognitive health and high genetic risk for the development of AD, initial changes appeared in the macular area. OCT could be a promising, cost-effective and non-invasive test useful in early AD, before the onset of clinical symptoms