Age-Related Retinal Layer Thickness Changes Measured by OCT in APPNL-F/NL-F Mice: Implications for Alzheimer's Disease.

In Alzheimer's disease (AD), transgenic mouse models have established links between abnormalities in the retina and those in the brain. APPNL-F/NL-F is a murine, humanized AD model that replicates several pathological features observed in patients with AD. Research has focused on obtaining quantitative parameters from optical coherence tomography (OCT) in AD. The aim of this study was to analyze, in a transversal case-control study using manual retinal segmentation via SD-OCT, the changes occurring in the retinal layers of the APPNL/F-NF/L AD model in comparison to C57BL/6J mice (WT) at 6, 9, 12, 15, 17, and 20 months of age. The analysis focused on retinal thickness in RNFL-GCL, IPL, INL, OPL, and ONL based on the Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. Both APPNL-F/NL-F-model and WT animals exhibited thickness changes at the time points studied. While WT showed significant changes in INL, OPL, and ONL, the AD model showed changes in all retinal layers analyzed. The APPNL-F/NL-F displayed significant thickness variations in the analyzed layers except for the IPL compared to related WT. These thickness changes closely resembled those found in humans during preclinical stages, as well as during mild and moderate AD stages, making this AD model behave more similarly to the disease in humans.

Cilastatin as a Potential Anti-Inflammatory and Neuroprotective Treatment in the Management of Glaucoma.

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.

The Role of Citicoline and Coenzyme Q10 in Retinal Pathology.

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.

Retinal Tissue Shows Glial Changes in a Dravet Syndrome Knock-in Mouse Model.

Dravet syndrome (DS) is an epileptic encephalopathy caused by mutations in the Scn1a gene encoding the α1 subunit of the Nav1.1 sodium channel, which is associated with recurrent and generalized seizures, even leading to death. In experimental models of DS, histological alterations have been found in the brain; however, the retina is a projection of the brain and there are no studies that analyze the possible histological changes that may occur in the disease. This study analyzes the retinal histological changes in glial cells (microglia and astrocytes), retinal ganglion cells (RGCs) and GABAergic amacrine cells in an experimental model of DS (Syn-Cre/Scn1aWT/A1783V) compared to a control group at postnatal day (PND) 25. Retinal whole-mounts were labeled with anti-GFAP, anti-Iba-1, anti-Brn3a and anti-GAD65/67. Signs of microglial and astroglial activation, and the number of Brn3a+ and GAD65+67+ cells were quantified. We found retinal activation of astroglial and microglial cells but not death of RGCs and GABAergic amacrine cells. These changes are similar to those found at the level of the hippocampus in the same experimental model in PND25, indicating a relationship between brain and retinal changes in DS. This suggests that the retina could serve as a possible biomarker in DS.

Retinal Ganglion Cell Loss and Microglial Activation in a SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

The neurodegenerative disease amyotrophic lateral sclerosis (ALS) affects the spinal cord, brain stem, and cerebral cortex. In this pathology, both neurons and glial cells are affected. However, few studies have analyzed retinal microglia in ALS models. In this study, we quantified the signs of microglial activation and the number of retinal ganglion cells (RGCs) in an SOD1G93A transgenic mouse model at 120 days (advanced stage of the disease) in retinal whole-mounts. For SOD1G93A animals (compared to the wild-type), we found, in microglial cells, (i) a significant increase in the area occupied by each microglial cell in the total area of the retina; (ii) a significant increase in the arbor area in the outer plexiform layer (OPL) inferior sector; (iii) the presence of cells with retracted processes; (iv) areas of cell groupings in some sectors; (v) no significant increase in the number of microglial cells; (vi) the expression of IFN-γ and IL-1ß; and (vii) the non-expression of IL-10 and arginase-I. For the RGCs, we found a decrease in their number. In conclusion, in the SOD1G93A model (at 120 days), retinal microglial activation occurred, taking a pro-inflammatory phenotype M1, which affected the OPL and inner retinal layers and could be related to RGC loss.

Retinal Molecular Changes Are Associated with Neuroinflammation and Loss of RGCs in an Experimental Model of Glaucoma.

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-ß 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-1ß 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.

Microglial Activation in the Retina of a Triple-Transgenic Alzheimer's Disease Mouse Model (3xTg-AD).

Alzheimer's disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-ß (Aß) 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.

Neuroprotective and Anti-Inflammatory Effects of a Hydrophilic Saffron Extract in a Model of Glaucoma.

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.

OCT Imaging in Murine Models of Alzheimer's Disease in a Systematic Review: Findings, Methodology and Future Perspectives.

The murine models of Alzheimer's disease (AD) have advanced our understanding of the pathophysiology. In vivo studies of the retina using optical coherence tomography (OCT) have complemented histological methods; however, the lack of standardisation in OCT methodologies for murine models of AD has led to significant variations in the results of different studies. A literature search in PubMed and Scopus has been performed to review the different methods used in these models using OCT and to analyse the methodological characteristics of each study. In addition, some recommendations are offered to overcome the challenges of using OCT in murine models. The results reveal a lack of consensus on OCT device use, retinal area analysed, segmentation techniques, and analysis software. Although some studies use the same OCT device, variations in other parameters make the direct comparison of results difficult. Standardisation of retinal analysis criteria in murine models of AD using OCT is crucial to ensure consistent and comparable results. This implies the application of uniform measurement and segmentation protocols. Despite the absence of standardisation, OCT has proven valuable in advancing our understanding of the pathophysiology of AD.

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 Vascular and Structural Changes in the Murine Alzheimer's APPNL-F/NL-F Model from 6 to 20 Months.

Alzheimer's disease (AD) may manifest retinal changes preceding brain pathology. A transversal case-control study utilized spectral-domain OCT angiography (SD-OCTA) and Angio-Tool software 0.6a to assess retinal vascular structures and OCT for inner and outer retina thickness in the APPNL-F/NL-F AD model at 6, 9, 12, 15, 17, and 20 months old. Comparisons to age-matched wild type (WT) were performed. The analysis focused on the three vascular plexuses using AngiooTool and on retinal thickness, which was represented with the Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. Compared to WT, the APPNL-F/NL-F group exhibited both vascular and structural changes as early as 6 months persisting and evolving at 15, 17, and 20 months. Significant vascular alterations, principally in the superficial vascular complex (SVC), were observed. There was a significant decrease in the vessel area and the total vessel length in SVC, intermediate, and deep capillary plexus. The inner retina in the APPNL-F/NL-F group predominantly decreased in thickness while the outer retina showed increased thickness in most analyzed time points compared to the control group. There are early vascular and structural retinal changes that precede the cognitive changes, which appear at later stages. Therefore, the natural history of the APPNL-F/NL-F model may be more similar to human AD than other transgenic models.

Laser-Induced Ocular Hypertension in a Mouse Model of Glaucoma.

Glaucoma is a neurodegenerative disease that leads to the loss of retinal ganglion cells (RGC) and thus to blindness. There are numerous experimental models used for the study of this pathology. Among the different models, episcleral vein photocoagulation is one of the most widely used. In this model there is a transient increase in intraocular pressure that returns to normal values about 7 days after induction of ocular hypertension (OHT). In addition, typical glaucoma changes, such as loss of RGC, thinning of the optic nerve fiber layer, and glial activation, occur in this model. All these changes have been described in detail over time after OHT induction. In this chapter, we describe the detailed method of OHT induction in Swiss albino mice by diode laser photocoagulation of limbal and episcleral veins.

Alzheimer's disease: a continuum with visual involvements.

Introduction: Alzheimer's disease (AD) is the most common form of dementia affecting the central nervous system, and alteration of several visual structures has been reported. Structural retinal changes are usually accompanied by changes in visual function in this disease. The aim of this study was to analyse the differences in visual function at different stages of the pathology (family history group (FH+), mild cognitive impairment (MCI), mild AD and moderate AD) in comparison with a control group of subjects with no cognitive decline and no family history of AD. Methods: We included 53 controls, 13 subjects with FH+, 23 patients with MCI, 25 patients with mild AD and, 21 patients with moderate AD. All were ophthalmologically healthy. Visual acuity (VA), contrast sensitivity (CS), colour perception, visual integration, and fundus examination were performed. Results: The analysis showed a statistically significant decrease in VA, CS and visual integration score between the MCI, mild AD and moderate AD groups compared to the control group. In the CS higher frequencies and in the colour perception test (total errors number), statistically significant differences were also observed in the MCI, mild AD and moderate AD groups with respect to the FH+ group and also between the control and AD groups. The FH+ group showed no statistically significant difference in visual functions compared to the control group. All the test correlated with the Mini Mental State Examination score and showed good predictive value when memory decline was present, with better values when AD was at a more advanced stage. Conclusion: Alterations in visual function appear in subjects with MCI and evolve when AD is established, being stable in the initial stages of the disease (mild AD and moderate AD). Therefore, visual psychophysical tests are a useful, simple and complementary tool to neuropsychological tests to facilitate diagnosis in the preclinical and early stages of AD.

Exploratory Longitudinal Study of Ocular Structural and Visual Functional Changes in Subjects at High Genetic Risk of Developing Alzheimer's Disease.

This study aimed to analyze the evolution of visual changes in cognitively healthy individuals at risk for Alzheimer's disease (AD). Participants with a first-degree family history of AD (FH+) and carrying the Ε4+ allele for the ApoE gene (ApoE ε4+) underwent retinal thickness analysis using optical coherence tomography (OCT) and visual function assessments, including visual acuity (VA), contrast sensitivity (CS), color perception, perception digital tests, and visual field analysis. Structural analysis divided participants into FH+ ApoE ε4+ and FH- ApoE ε4- groups, while functional analysis further categorized them by age (40-60 years and over 60 years). Over the 27-month follow-up, the FH+ ApoE ε4+ group exhibited thickness changes in all inner retinal layers. Comparing this group to the FH- ApoE ε4- group at 27 months revealed progressing changes in the inner nuclear layer. In the FH+ ApoE ε4+ 40-60 years group, no progression of visual function changes was observed, but an increase in VA and CS was maintained at 3 and 12 cycles per degree, respectively, compared to the group without AD risk at 27 months. In conclusion, cognitively healthy individuals at risk for AD demonstrated progressive retinal structural changes over the 27-month follow-up, while functional changes remained stable.

Retinal Changes in Astrocytes and Müller Glia in a Mouse Model of Laser-Induced Glaucoma: A Time-Course Study.

Macroglia (astrocytes and Müller glia) may play an important role in the pathogenesis of glaucoma. In a glaucoma mouse model, we studied the effects of unilateral laser-induced ocular hypertension (OHT) on macroglia in OHT and contralateral eyes at different time points after laser treatment (1, 3, 5, 8 and 15 days) using anti-GFAP and anti-MHC-II, analyzing the morphological changes, GFAP-labelled retinal area (GFAP-PA), and GFAP and MHC-II immunoreactivity intensities ((GFAP-IRI and MHC-II-IRI)). In OHT and contralateral eyes, with respect to naïve eyes, at all the time points, we found the following: (i) astrocytes with thicker somas and more secondary processes, mainly in the intermediate (IR) and peripheral retina (PR); (ii) astrocytes with low GFAP-IRI and only primary processes near the optic disc (OD); (iii) an increase in total GFAP-RA, which was higher at 3 and 5 days, except for at 15 days; (iv) an increase in GFAP-IRI in the IR and especially in the PR; (v) a decrease in GFAP-IRI near the OD, especially at 1 and 5 days; (vi) a significant increase in MHC-II-IRI, which was higher in the IR and PR; and (vii) the Müller glia were GFAP+ and MHC-II+. In conclusion, in this model of glaucoma, there is a bilateral macroglial activation maintained over time involved in the inflammatory glaucoma process.

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.

Retinal Vascular Study Using OCTA in Subjects at High Genetic Risk of Developing Alzheimer's Disease and Cardiovascular Risk Factors.

In 103 subjects with a high genetic risk of developing Alzheimer's disease (AD), family history (FH) of AD and ApoE ɛ4 characterization (ApoE ɛ4) were analyzed for changes in the retinal vascular network by OCTA (optical coherence tomography angiography), and AngioTool and Erlangen-Angio-Tool (EA-Tool) as imaging analysis software. Retinal vascularization was analyzed by measuring hypercholesterolemia (HCL) and high blood pressure (HBP). Angio-Tool showed a statistically significant higher percentage of area occupied by vessels in the FH+ ApoE ɛ4- group vs. in the FH+ ApoE ɛ4+ group, and EA-Tool showed statistically significant higher vascular densities in the C3 ring in the FH+ ApoE ɛ4+ group when compared with: i)FH- ApoE ɛ4- in sectors H3, H4, H10 and H11; and ii) FH+ ApoE ɛ4- in sectors H4 and H12. In participants with HCL and HBP, statistically significant changes were found, in particular using EA-Tool, both in the macular area, mainly in the deep plexus, and in the peripapillary area. In conclusion, OCTA in subjects with genetic risk factors for the development of AD showed an apparent increase in vascular density in some sectors of the retina, which was one of the first vascular changes detectable. These changes constitute a promising biomarker for monitoring the progression of pathological neuronal degeneration.

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 ɛ4 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 (Aß 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 ɛ4 (ApoE ɛ4- or ApoE ɛ4+) 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 relationship between retinal layers and brain areas in asymptomatic first-degree relatives of sporadic forms of Alzheimer's disease: an exploratory analysis.

BACKGROUND: Two main genetic risks for sporadic Alzheimer's disease (AD) are a family history and ɛ4 allele of apolipoprotein E. The brain and retina are part of the central nervous system and share pathophysiological mechanisms in AD. METHODS: We performed a cross-sectional study with 30 participants without a family history of sporadic AD (FH-) and noncarriers of ApoE ɛ4 (ApoE ɛ4-) as a control group and 34 participants with a family history of sporadic AD (FH+) and carriers of at least one ɛ4 allele (ApoE ɛ4+). We analyzed the correlations between macular volumes of retinal layers and thickness of the peripapillary retinal nerve fiber layer (pRNFL) measured by optical coherence tomography (OCT) with the brain area parameters measured by magnetic resonance imaging (MRI) in participants at high genetic risk of developing AD (FH+ ApoE ɛ4+). RESULTS: We observed a significant volume reduction in the FH+ ApoE ɛ4+ group compared with the control group in some macular areas of (i) macular RNFL (mRNFL), (ii) inner plexiform layer (IPL), (iii) inner nuclear layer (INL), and (iv) outer plexiform layer (OPL). Furthermore, in the FH+ ApoE ɛ4+ group, the retinal sectors that showed statistically significant volume decrease correlated with brain areas that are affected in the early stages of AD. In the same group, the peripapillary retinal nerve fiber layer (pRNFL) did not show statistically significant changes in thickness compared with the control group. However, correlations of these sectors with the brain areas involved in this disease were also found. CONCLUSIONS: In cognitively healthy participants at high genetic risk of developing sporadic forms of AD, there are significant correlations between retinal changes and brain areas closely related to AD such as the entorhinal cortex, the lingual gyrus, and the hippocampus.

Neuro-Ophthalmological Findings in Friedreich's Ataxia.

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a severe autosomal recessive genetic disorder of the central nervous (CNS) and peripheral nervous system (PNS), affecting children and young adults. Its onset is before 25 years of age, with mean ages of onset and death between 11 and 38 years, respectively. The incidence is 1 in 30,000-50,000 persons. It is caused, in 97% of cases, by a homozygous guanine-adenine-adenine (GAA) trinucleotide mutation in the first intron of the frataxin (FXN) gene on chromosome 9 (9q13-q1.1). The mutation of this gene causes a deficiency of frataxin, which induces an altered inflow of iron into the mitochondria, increasing the nervous system's vulnerability to oxidative stress. The main clinical signs include spinocerebellar ataxia with sensory loss and disappearance of deep tendon reflexes, cerebellar dysarthria, cardiomyopathy, and scoliosis. Diabetes, hearing loss, and pes cavus may also occur, and although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.