Alzheimer's Disease (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 the degradation of the visual ...cortex. These effects raise the possibility that tracking ophthalmologic changes in the retina can be used to assess neurodegeneration in AD. This study aimed to detect retinal changes and associated functional changes in three groups of patients consisting of AD patients with mild disease, AD patients with moderate disease and healthy controls by using non-invasive psychophysical ophthalmological tests and optical coherence tomography (OCT).
We included 39 patients with mild AD, 21 patients with moderate AD and 40 age-matched healthy controls. Both patients and controls were ophthalmologically healthy. Visual acuity, contrast sensitivity, colour perception, visual integration, and choroidal thicknesses were measured. In addition, OCT and OCT angiography (OCTA) were applied.
Visual acuity, contrast sensitivity, colour perception, and visual integration were significantly lower in AD patients than in healthy controls. Compared to healthy controls, macular thinning in the central region was significant in the mild AD patients, while macular thickening in the central region was found in the moderate AD group. The analysis of macular layers revealed significant thinning of the retinal nerve fibre layer, the ganglion cell layer and the outer plexiform layer in AD patients relative to controls. Conversely, significant thickening was observed in the outer nuclear layer of the patients. However, mild AD was associated with significant thinning of the subfovea and the nasal and inferior sectors of the choroid. Significant superonasal and inferotemporal peripapillary thinning was observed in patients with moderate disease.
The first changes in the mild AD patients appear in the psychophysical tests and in the central macula with a decrease in the central retinal thickness. When there was a disease progression to moderate AD, psychophysical tests remained stable with respect to the decrease in mild AD, but significant thinning in the peripapillary retina and thickening in the central retina appeared. The presence of AD is best indicated based on contrast sensitivity.
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.
Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs). An increase in the intraocular pressure is the principal risk factor for such loss, but controlling ...this pressure does not always prevent glaucomatous damage. Activation of immune cells resident in the retina (microglia) may contribute to RGC death. Thus, a substance with anti-inflammatory activity may protect against RGC degeneration. This study investigated the neuroprotective and anti-inflammatory effects of a hydrophilic saffron extract standardized to 3% crocin content in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Treatment with saffron extract decreased microglion numbers and morphological signs of their activation, including soma size and process retraction, both in OHT and in contralateral eyes. Saffron extract treatment also partially reversed OHT-induced down-regulation of P2RY12. In addition, the extract prevented retinal ganglion cell death in OHT eyes. Oral administration of saffron extract was able to decrease the neuroinflammation associated with increased intraocular pressure, preventing retinal ganglion cell death. Our findings indicate that saffron extract may exert a protective effect in glaucomatous pathology.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of the lower and upper motor neurons and is the most prevalent motor neuron disease. This disease is ...characterized by muscle weakness, stiffness, and hyperreflexia. Patients survive for a short period of time from the onset of the disease. Most cases are sporadic, with only 10% of the cases being genetic. Many genes are now known to be involved in familial ALS cases and some of the sporadic ones. It has also been observed that, in addition to genetic factors, there are numerous molecular mechanisms involved in these pathologies, such as excitotoxicity, mitochondrial disorders, alterations in axonal transport, oxidative stress, accumulation of misfolded proteins, and neuroinflammation. This pathology affects the motor neurons, the spinal cord, the cerebellum, and the brain, but recently, it has been shown that it also affects the visual system, not only at the level of the oculomotor system but also at the retinal level, which is why the retina is being proposed as a possible biomarker of this pathology. This review includes the main aspects mentioned above related to ALS, such as the main genes involved, the most important molecular mechanisms that affect this pathology, its ocular involvement, and the possible usefulness of the retina as a biomarker.
Signaling mediated by cytokines and chemokines is involved in glaucoma-associated neuroinflammation and in the damage of retinal ganglion cells (RGCs). Using multiplexed immunoassay and ...immunohistochemical techniques in a glaucoma mouse model at different time points after ocular hypertension (OHT), we analyzed (i) the expression of pro-inflammatory cytokines, anti-inflammatory cytokines, BDNF, VEGF, and fractalkine; and (ii) the number of Brn3a+ RGCs. In OHT eyes, there was an upregulation of (i) IFN-γ at days 3, 5, and 15; (ii) IL-4 at days 1, 3, 5, and 7 and IL-10 at days 3 and 5 (coinciding with downregulation of IL1-β at days 1, 5, and 7); (iii) IL-6 at days 1, 3, and 5; (iv) fractalkine and VEGF at day 1; and (v) BDNF at days 1, 3, 7, and 15. In contralateral eyes, there were (i) an upregulation of IL-1β at days 1 and 3 and a downregulation at day 7, coinciding with the downregulation of IL4 at days 3 and 5 and the upregulation at day 7; (ii) an upregulation of IL-6 at days 1, 5, and 7 and a downregulation at 15 days; (iii) an upregulation of IL-10 at days 3 and 7; and (iv) an upregulation of IL-17 at day 15. In OHT eyes, there was a reduction in the Brn3a+ RGCs number at days 3, 5, 7, and 15. OHT changes cytokine levels in both OHT and contralateral eyes at different time points after OHT induction, confirming the immune system involvement in glaucomatous neurodegeneration.
Ocular neurodegenerative diseases such as glaucoma, diabetic retinopathy, and age-related macular degeneration are common retinal diseases responsible for most of the blindness causes in the ...working-age and elderly populations in developed countries. Many of the current treatments used in these pathologies fail to stop or slow the progression of the disease. Therefore, other types of treatments with neuroprotective characteristics may be necessary to allow a more satisfactory management of the disease. Citicoline and coenzyme Q10 are molecules that have neuroprotective, antioxidant, and anti-inflammatory properties, and their use could have a beneficial effect in ocular neurodegenerative pathologies. This review provides a compilation, mainly from the last 10 years, of the main studies that have been published on the use of these drugs in these neurodegenerative diseases of the retina, analyzing the usefulness of these drugs in these pathologies.
The retina is an attractive source of biomarkers since it shares many features with the brain. Thickness differences in 10 retinal layers between 19 patients with mild Alzheimer's disease (AD) and a ...control group of 24 volunteers were investigated. Retinal layers were automatically segmented and their thickness at each scanned point was measured, corrected for tilt and spatially normalized. When the mean thickness of entire layers was compared between patients and controls, only the outer segment layer of patients showed statistically significant thinning. However, when the layers were compared point-by point, patients showed statistically significant thinning in irregular regions of total retina and nerve fiber, ganglion cell, inner plexiform, inner nuclear and outer segment layers. Our method, based on random field theory, provides a precise delimitation of regions where total retina and each of its layers show a statistically significant thinning in AD patients. All layers, except inner nuclear and outer segments, showed thickened regions. New analytic methods have shown that thinned regions are interspersed with thickened ones in all layers, except inner nuclear and outer segments. Across different layers we found a statistically significant trend of the thinned regions to overlap and of the thickened ones to avoid overlapping.
Alzheimer's disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are ...responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice.
Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies ...associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.
Glaucoma is a neurodegenerative chronic pathology, characterized by the loss of retinal ganglion cells (RGC), which leads to an irreversible vision field loss. The glaucomatous optic neuropathy is ...usually a bilateral disease, though asymmetric in time: this means that the damage initially present in one of the eyes, eventually also appears with a time delay in the contralateral eye. Notably, recent experimental models of unilateral ocular hypertension (OHT) have shown that the fellow normotensive contralateral eyes to hypertensive eyes exhibit changes in glial cells with little or no damage to RGCs.
It has been reported that although increased intraocular pressure (IOP) may be the main trigger for this pathology, other pathogenic mechanisms such as neuroinflammation are involved in the RGCs death. Microglial cells constitute the population of immune resident cells, and they play an important role in the physiology and survival of RGC.
One of the most widely used experimental models of glaucoma is the unilateral laser‐induced OHT model. In these animals, OHT induces an alteration of retrograde axonal transport in RGCs and a subsequent degeneration of these cells. In this model, at different time‐points after OHT induction (1, 3, 5, 8 and 15 days), the microglia exhibited different signs of activation, such as proliferation and migration to areas of damage, retraction, reorientation, and hyper‐ramification of their processes, soma thickening and the appearance of amoeboid‐ and rod‐like microglia with macrophagic capacity, related to RGC degeneration. All these changes were most intense at 3–5 days after OHT induction in the OHT eye. This was confirmed by the decreased expression of the purinergic receptor P2RY12, which would indicate higher microglial activation.
In this model, at all time‐points after OHT induction, the activation of the macroglia (astrocytes and Müller cells) has also been demonstrated, showing morphological changes, as well as an overexpression of glial fibrillary acidic protein (GFAP).
In this laser‐induced OHT model, an MHC‐II overexpression was observed in the microglia, astrocytes, and Müller cells, allowing these cells to induce a T‐cell mediated immune response.
Significant changes in the expression of proinflammatory (IL‐1β, IL‐6, INF‐γ, IL‐17), anti‐inflammatory (IL‐4, IL‐10) and myokines (Fractalkine, BDNF, VEGF) cytokines were also observed.
The same changes in glial cells (microglia, astrocytes and Müller cells) as well as in the expression of different cytokines and myokines were observed in the contralateral normotensive eyes at the different time points after OHT induction although with a lower intensity.
Based on the alterations found in the contralateral eye, it can be concluded that this eye should not be used as a control eye in experimental models of unilateral glaucoma. Changes in contralateral normotensive eyes could exhibit the initial events of glaucomatous neurodegeneration, probably mediated by inflammatory mechanisms. Therefore, studies focusing on contralateral eyes could improve our understanding of glaucomatous pathophysiology. The study of the contralateral eye appears to have the potential for discovering points of intervention to which future neuroprotective therapeutics can be directed.
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