Browsing by Author "Castelo-Branco, Miguel"
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- 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.
- Exploring immersive multimodal virtual reality training, affective states, and ecological validity in healthy firefighters: quasi-experimental studyPublication . Oliveira, Joana; Dias, Joana Aires; Correia, Rita; Pinheiro, Raquel; Reis, Vitor; Sousa, Daniela; Agostinho, Daniel; Simões, Marco; Castelo-Branco, MiguelBackground: Firefighters face stressful life-threatening events requiring fast decision-making. To better prepare for those situations, training is paramount, but errors in real-life training can be harmful. Virtual reality (VR) simulations provide the desired realism while enabling practice in a secure and controlled environment. Firefighters’ affective states are also crucial as they are a higher-risk group. Objective: To assess the impact on affective states of 2 simulated immersive experiences in a sample of healthy firefighters (before, during, and after the simulation), we pursued a multivariate approach comprising cognitive performance, situational awareness, depression, anxiety, stress, number of previous adverse events experienced, posttraumatic stress disorder (PTSD) severity, and emotions. The efficacy and ecological validity of an innovative VR haptic system were also tested, exploring its impact on performance. Methods: In collaboration with the Portuguese National Fire Service School, we exposed 22 healthy firefighters to 2 immersive scenarios using the FLAIM Trainer VR system (neutral and arousing scenarios) while recording physiological data in a quasi-experimental study. Baseline cognitive performance, depression, anxiety, stress, number of adverse events, and severity of PTSD symptoms were evaluated. Positive and negative affective states were measured before, between, and after each scenario. Situational awareness, sense of presence, ecological validity, engagement, and negative effects resulting from VR immersion were tested. Results: Baseline positive affect score was high (mean 32.4, SD 7.2) and increased after the VR tasks (partial η2=0.52; Greenhouse-Geisser F1.82,32.78=19.73; P<.001). Contrarily, mean negative affect score remained low (range 11.0-11.9) throughout the study (partial η2=0.02; Greenhouse-Geisser F2.13,38.4=0.39; P=.69). Participants’ feedback on the VR sense of presence was also positive, reporting a high sense of physical space (mean score 3.9, SD 0.8), ecological validity (mean score 3.8, SD 0.6), and engagement (mean score 3.8, SD 0.6). Engagement was related to the number of previously experienced adverse events (r=0.49; P=.02) and positive affect (after the last VR task; r=0.55; P=.02). Conversely, participants reported few negative effects (mean score 1.7, SD 0.6). The negative effects correlated positively with negative affect (after the last VR task; r=0.53; P=.03); and avoidance (r=0.73; P<.001), a PTSD symptom, controlling for relevant baseline variables. Performance related to situational awareness was positive (mean 46.4, SD 34.5), although no relation was found to metacognitively perceived situational awareness (r=–0.12; P=.59). Conclusions: We show that VR is an effective alternative to in-person training as it was considered ecologically valid and engaging while promoting positive emotions, with few negative repercussions. This corroborates the use of VR to test firefighters’ performance and situational awareness. Further research is needed to ascertain that firefighters with PTSD symptomatology are not negatively affected by VR. This study favors the use of VR training and provides new insights on its emotional and cognitive impact on the trainee.
- 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.
- 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.
- Retinal aging in 3× Tg-AD mice model of Alzheimer's diseasePublication . Guimarães, Pedro; Serranho, Pedro; Martins, João; Moreira, Paula I.; Ambrósio, António Francisco; Castelo-Branco, Miguel; Bernardes, RuiThe retina, as part of the central nervous system (CNS), can be the perfect target for in vivo, in situ, and noninvasive neuropathology diagnosis and assessment of therapeutic efficacy. It has long been established that several age-related brain changes are more pronounced in Alzheimer’s disease (AD). Nevertheless, in the retina such link is still under-explored. This study investigates the differences in the aging of the CNS through the retina of 3×Tg-AD and wild-type mice. A dedicated optical coherence tomograph imaged mice’s retinas for 16 months. Two neural networks were developed to model independently each group’s ages and were then applied to an independent set containing images fromboth groups. Our analysis shows amean absolute error of 0.875±1.1×10−2 and 1.112 ± 1.4 × 10−2 months, depending on training group. Our deep learning approach appears to be a reliable retinal OCT aging marker. We show that retina aging is distinct in the two classes: the presence of the three mutated human genes in the mouse genome has an impact on the aging of the retina. For mice over 4 months-old, transgenic mice consistently present a negative retina age-gap when compared to wildtype mice, regardless of training set. This appears to contradict AD observations in the brain. However, the ‘black-box” nature of deep-learning implies that one cannot infer reasoning. We can only speculate that some healthy age-dependent neural adaptations may be altered in transgenic animals.
- 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.
- 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.
- Stage-independent biomarkers for Alzheimer’s disease from the living retina: an animal studyPublication . Ferreira, Hugo; Serranho, Pedro; Guimarães, Pedro; Trindade, Rita; Martins, João; Moreira, Paula I.; Ambrósio, António Francisco; Castelo-Branco, Miguel; Bernardes, RuiThe early diagnosis of neurodegenerative disorders is still an open issue despite the many efforts to address this problem. In particular, Alzheimer’s disease (AD) remains undiagnosed for over a decade before the first symptoms. Optical coherence tomography (OCT) is now common and widely available and has been used to image the retina of AD patients and healthy controls to search for biomarkers of neurodegeneration. However, early diagnosis tools would need to rely on images of patients in early AD stages, which are not available due to late diagnosis. To shed light on how to overcome this obstacle, we resort to 57 wild-type mice and 57 triple-transgenic mouse model of AD to train a network with mice aged 3, 4, and 8 months and classify mice at the ages of 1, 2, and 12 months. To this end, we computed fundus images from OCT data and trained a convolution neural network (CNN) to classify those into the wild-type or transgenic group. CNN performance accuracy ranged from 80 to 88% for mice out of the training group’s age, raising the possibility of diagnosing AD before the first symptoms through the non-invasive imaging of the retina.
- Texture for neuroimagingPublication . Nunes, Ana; Serranho, Pedro; Castelo-Branco, Miguel; Bernardes, RuiTexture analysis is an umbrella term for multiple image analysis techniques that quantify and characterize the distribution of the image’s gray levels. It has a natural application in biomedical image analysis, where texture-based techniques are increasingly being incorporated into neuroimaging research. In this chapter, the role of texture analysis in the field of neuroimaging is addressed. Neuroimaging applications of texture-based approaches are contextualized within past and recent developments in image texture analysis, the categories of texture analysis methods, and the typical texture-based problem types, namely, classification and segmentation. Neuroimaging applications using magnetic resonance imaging, positron emission tomography, and optical coherence tomography are individually reviewed, and some considerations on the future perspectives for texture-based approaches in neuroimaging are made.
- The effect of menopause on the sexual dimorphism in the human retina: texture analysis of optical coherence tomography dataPublication . Nunes, Ana; Serranho, Pedro; Quental, Hugo; Castelo-Branco, Miguel; Bernardes, RuiSexual dimorphism in the human retina has recently been connected to gonadal hormones. In the study herein presented, texture analysis was applied to computed mean value fundus (MVF) images from optical coherence tomography data of female and male healthy adult controls. Two separate age-group analyses that excluded the probable perimenopause period of the women in the present study were performed, using a modified MVF image computation method that further highlights texture differences present in the retina. While distinct texture characteristics were found between premenopausal females and age-matched males, these differences almost disappeared in the older groups (postmenopausal women vs age-matched men), suggesting that sex-related texture differences in the retina can be correlated to the hormonal changes that women go through during the menopausal transition. These findings suggest that texture-based metrics may be used as biomarkers of physiology and pathophysiology of the retina and the central nervous system.