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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Alzheimer's disease (AD) is a degenerative neurological disorder characterized by the progressive loss of neurons and their synapses in the brain. Similar alterations have been observed in the retina even before they manifest in the brain. The retina has been proposed as a readily accessible biomarker for AD. In a previous work utilizing a murine model of AD (APPNL‐F/NL‐F), changes in retinal thickness, as measured by optical coherence tomography (OCT), were observed at 15 and 17 months. The objective of this study was to quantitatively assess the population of retinal ganglion cells (RGCs) in this same AD murine model over a specified time period and compare it with wild‐type (WT) mice. Methods: To quantitatively assess the population of retinal ganglion cells we used two study groups: the APPNL‐F/NL‐F model throughout the time period of (6, 9, 12, 17, and 20 months) and compared with wild‐type (WT) mice age matched (n = 30 in both groups). The quantification of retinal ganglion cells (RGCs) was conducted using immunohistochemical analysis with the Brn3a marker. This analysis was performed using a semi‐automatic algorithm implemented in the MatLab environment, which was developed by the Ramón Castroviejo Institute for Ophthalmic Research. For the analysis, the entire retina was considered and segmented into the peripapillary, intermediate, and peripheral zones. Results: A statistically significant decresase (p < 0.05) in the population of Brn3a + cells was observed in the APPNL‐F/NL‐F group compared to the WT group. This decreased was found in the total retina at 12 months, in the peripapillary zone at 9, 12, and 20 months, and in the intermediate zone at 12 months of the study. Conclusions: The APPNL‐F/NL‐F mouse model exhibits RGCs loss at 9, 12, and 20 months, mirroring the patterns observed in human cases. These findings suggest that the model holds promise for investigating and studying mechanisms related to RGC degeneration in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Aims/Purpose: The progression of Alzheimer's disease (AD) manifests from a preclinical stage, characterized by asymptomatic pathological alterations, to an advanced stage of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum, from individuals with a high genetic predisposition to those in the moderate phase of the disease. Methods: All participants underwent a visual examination and had to be visually healthy to be included. The study contained five groups: controls (n = 53), individuals with a positive family history of AD (HF+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25) and moderate AD (n = 21). The study analysed the results of errors in colour perception. Results: A significant increase in the total number of errors was observed between the control group and the moderate AD group. And also when comparing the FH+ group with the MCI group, the mild AD group and the moderate AD group. Significant differences were found on the tritan axis between the control group and the mild AD group, as well as in the moderate AD group. Significant differences were observed between the FH+ group and the mild AD group, as well as in the moderate AD group. A significant increase in the number of errors on the deutan axis was observed between the control group and both the mild and moderate AD groups. In addition, a statistically significant increase was observed when comparing the FH+ group with the moderate AD group. The test correlated with the MMSE score and also showed good predictive value when memory impairment was present. Conclusions: Understanding the importance of changes in colour perception in AD continuum can aid in the early detection and treatment of AD, potentially improving patient outcomes and facilitating targeted interventions. [ABSTRACT FROM AUTHOR]

Aims/Purpose: The use of murine models of Alzheimer's disease (AD) in the study of its pathophysiology is essential. In addition to a histological study of the retina, optical coherence tomography (OCT) allows a cost‐effective in vivo analysis of the retina. However, there is no standardization in the use of OCT in murine models of AD, leading to significant variations in study results. A review of the literature on murine models of AD analysed by OCT has been carried out. The characteristics of the animal model, the types of OCT, the retinal sectors analysed, the segmentation layers and the software used for segmentation were examined. Methods: We performed a literature search up to April 2023 using "MESH" terms in PubMed. The terms used were: "Alzheimer's mouse model", "Optical Coherence Tomography", "retinal optical coherence tomography" ... as well as their combinations. We filter the articles by author criteria: the terms had to be in the title, in the abstract or in the article and they should be written in English or Spanish. Finally, 76 articles were used to the manuscript. Results: In comparison to studies using OCT in AD patients, only fourteen studies have utilized this technique to examine the retinas of murine AD models. Six different models, both first and second generation, were analysed, with most featuring presenilin mutations. There is no consensus regarding the measuring instrument, retinal area analysed, segmentation techniques, or software employed for analysis. Although some authors used the same OCT device, variations in other parameters hinder direct result comparison. Conclusions: It is essential to establish a unified criteria for OCT analysis of the retina in murine models of AD. This would allow the comparison of results and the establishment of measurement protocols. The use of OCT to understand the pathophysiology of AD would facilitate the longitudinal analysis of the disease and the possible identification of biomarkers. [ABSTRACT FROM AUTHOR]

Aims/Purpose: The progression of Alzheimer's disease (AD) is manifested by a gradual transition from a preclinical phase, characterized by asymptomatic pathological alterations, to an advanced phase of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum. Methods: Each participant underwent a comprehensive visual examination, with only visually healthy individuals being selected for the study. The study comprised the following groups: controls (n = 53), positive family history of AD (FH+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25), and moderate AD (n = 21). The study analysed the results of visual acuity (VA) and contrast sensitivity (CS). Results: A significant reduction in VA was identified between the control group and the MCI, mild AD and moderate AD groups. CS showed significant changes in all cognitive impairment groups compared to the control group and the FH+ group at spatial frequencies of 12 and 18 cpd. In contrast, significant differences were only observed at spatial frequencies of 3 and 6 cpd between the cognitively impaired groups, starting from moderate AD, with no detectable decrease in CS during the MCI phase. No differences were detected between the control group and the FH+ group. The tests showed a positive correlation with the Mini Mental State Examination score and exhibited a favourable predictive ability in the presence of memory impairment, with higher predictive performance observed in the advance stages of AD. Conclusions: The presence of alterations in VA and CS can be observed as early as the MCI stage in individuals with AD. Recognizing the continuum of AD holds significant significance in early detection, with visual examination offering a straightforward and cost‐effective diagnostic tool for AD. Healthcare professionals can leverage this knowledge to gain a better understanding of the progressive nature of the disease. [ABSTRACT FROM AUTHOR]