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- Normative mice retinal thickness: 16-month longitudinal characterization of wild-type mice and changes in a model of Alzheimer's diseasePublication . Batista, Ana; Guimarães, Pedro; Martins, João; Moreira, Paula I.; Ambrósio, António F.; Castelo-Branco, Miguel; Serranho, Pedro; Bernardes, RuiAnimal models of disease are paramount to understand retinal development, the pathophysiology of eye diseases, and to study neurodegeneration using optical coherence tomography (OCT) data. In this study, we present a comprehensive normative database of retinal thickness in C57BL6/129S mice using spectral-domain OCT data. The database covers a longitudinal period of 16 months, from 1 to 16 months of age, and provides valuable insights into retinal development and changes over time. Our findings reveal that total retinal thickness decreases with age, while the thickness of individual retinal layers and layer aggregates changes in different ways. For example, the outer plexiform layer (OPL), photoreceptor inner segments (ILS), and retinal pigment epithelium (RPE) thickened over time, whereas other retinal layers and layer aggregates became thinner. Additionally, we compare the retinal thickness of wild-type (WT) mice with an animal model of Alzheimer's disease (3×Tg-AD) and show that the transgenic mice exhibit a decrease in total retinal thickness compared to age-matched WT mice, with statistically significant differences observed at all evaluated ages. This normative database of retinal thickness in mice will serve as a reference for future studies on retinal changes in neurodegenerative and eye diseases and will further our understanding of the pathophysiology of these conditions.
- Characterization of the retinal changes of the 3×Tg-AD mouse model of Alzheimer’s diseasePublication . Ferreira, Hugo; Martins, João; Nunes, Ana; Moreira, Paula I.; Castelo-Branco, Miguel; Ambrósio, António F.; Serranho, Pedro; Bernardes, RuiAlzheimer’s disease (AD) is a progressive neurodegenerative disorder whose diagnosis remains a notable challenge. The literature suggests that cerebral changes precede AD symptoms by over two decades, implying a significantly advanced stage of AD by the time it is usually diagnosed. In the study herein, texture analysis was applied to computed optical coherence tomography ocular fundus images to identify differences between a group of the transgenic mouse model of the Alzheimer’s disease (3×Tg-AD) and a group of wild-type mice, at the ages of one and two-months-old. A substantial difference between groups was found at both time-points across all neuroretina’s layers. Here, the inner nuclear layer stands out both in the level of statistically significant differences and on the extension of these differences which span through the imaged area. Also, the progression of AD is suggested to be spotted by texture analysis as demonstrated by the significant difference found in the inner plexiform and the outer nuclear layers from the age of one to the age of two-months-old. These findings demonstrate the potential of the use of the retina and texture analysis to the diagnosis of AD and monitor AD progression. Besides, the differences between groups found in this study suggest that the 3×Tg-AD model may be inappropriate to study early changes associated with the AD and other animal models should be tested following the same path and rationale. Moreover, these results also suggest that the human genes present in these transgenic mice may have an impact on the neurodevelopment of offspring which would justify the significant changes found at the age of one-month-old.
- Retinal imaging in animal models: searching for biomarkers of neurodegenerationPublication . Batista, Ana; Guimarães, Pedro; Serranho, Pedro; Nunes, Ana; Martins, João; Moreira, Paula I.; Ambrósio, António F.; Morgado, Miguel; Castelo-Branco, Miguel; Bernardes, RuiThere is a pressing need for novel diagnostic and progression biomarkers of neurodegeneration. However, the inability to determine disease duration and stage in patients with Alzheimer’s disease (AD) hinders their discovery. Because animal models of disease allow us to circumvent some of these limitations, they have proven to be of paramount importance in clinical research. Due to the clear optics of the eye, the retina combined with optical coherence tomography (OCT) offers the perfect opportunity to image neurodegeneration in the retina in vivo, non-invasively, directly, quickly, and inexpensively. Based on these premises, our group has worked towards uncovering neurodegeneration-associated changes in the retina of the triple-transgenic mouse model of familial AD (3×Tg-AD). In this work, we present an overview of our work on this topic. We report on thickness variations of the retina and retinal layers/layer aggregates caused by healthy aging and AD-like conditions and discuss the implications of focusing research efforts solely on retinal thickness. We explore what other information is embedded in the OCT data, extracted based on texture analysis and deep-learning approaches, to further identify biomarkers that could be used for early detection and diagnosis. We were able to detect changes in the retina of the animal model of AD as early as 1 month of age. We also discuss our work to develop an optical coherence elastography system to measure retinal elasticity, which can be used in conjunction with conventional OCT. Finally, we discuss the potential application of these technologies in human patients and the steps needed to make OCT a helpful screening tool for the detection of neurodegeneration.
- Retinal biomarkers of Alzheimer’s disease: insights from transgenic mouse modelsPublication . Bernardes, Rui; Silva, Gilberto; Chiquita, Samuel; Serranho, Pedro; Ambrósio, António F.In this paper, we use the retina as a window into the central nervous system and in particular to assess changes in the retinal tissue associated with the Alzheimer’s disease. We imaged the retina of wild-type (WT) and transgenic mouse model (TMM) of Alzheimer’s disease with optical coherence tomography and classify retinas into the WT and TMM groups using support vector machines with the radial basis function kernel. Predictions reached an accuracy over 80% at the age of 4 months and over 90% at the age of 8 months. Texture analysis of computed fundus reference images suggests a more heterogeneous organization of the retina in transgenic mice at the age of 8 months in comparison to controls.
- Longitudinal normative OCT retinal thickness data for wild-type mice, and characterization of changes in the 3×Tg-AD mice model of Alzheimer's diseasePublication . Ferreira, Hugo; Martins, João; Moreira, Paula I.; Ambrósio, António F.; Castelo-Branco, Miguel; Serranho, Pedro; Bernardes, RuiMice are widely used as models for many diseases, including eye and neurodegenerative diseases. However, there is a lack of normative data for retinal thickness over time, especially at young ages. In this work, we present a normative thickness database from one to four-months-old, for nine layers/layer-aggregates, including the total retinal thickness, obtained from the segmentation of spectral-domain optical coherence tomography (SD-OCT) data from the C57BL6/129S mouse strain. Based on fifty-seven mice, this normative database provides an opportunity to study the ageing of control mice and characterize disease models' ageing, such as the triple transgenic mouse model of Alzheimer's disease (3×Tg-AD) used in this work. We report thickness measurements, the differences in thickness per layer, demonstrate a nasal-temporal asymmetry, and the variation of thickness as a function to the distance to the optic disc center. Significant differences were found between the transgenic group's thickness and the normative database for the entire period covered in this study. Even though it is well accepted that retinal nerve fiber layer (RNFL) thinning is a hallmark of neurodegeneration, our results show a thicker RNFL-GCL (RNFL-Ganglion cell layer) aggregate for the 3×Tg-AD mice until four-months-old.
- Sexual dimorphism of the adult human retina assessed by optical coherence tomographyPublication . Nunes, Ana; Serranho, Pedro; Quental, Hugo; Ambrósio, António F.; Castelo-Branco, Miguel; Bernardes, RuiSexual dimorphism in the human visual system is a well-established phenomenon, and recent research has unveiled possible connections between gonadal hormones and the retina status. In the literature, the findings are quite diverse and inconclusive results have been reported as well. In the study herein, texture analysis was applied to computed optical coherence tomography (OCT) fundus images to identify differences between female and male healthy adult controls at the six neuroretinal layers. Furthermore, younger and older groups were formed to assess differences across the adult lifespan. Besides local and global texture features, the thickness of each retinal layer at study was also analysed. The vast majority of the differences between female and male groups were found from the ganglion cell layer (GCL) to the outer plexiform layer (OPL), with the retinal nerve fibre layer (RNFL) layer being the least distinct one. For the sub-study by age, the younger group show similar results as those for the entire population, except for the RNFL. On the other hand, the older group presents minute differences between female and male subjects. These findings suggest that studies should be well balanced by sex, and particular care should be taken in the age span of the study groups. In the present study, we also demonstrate that texture and thickness are independent, for the most part, that thickness conveys the least information, and that texture is a strong candidate biomarker of eye and central nervous system status in health and disease.