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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.
- Synthetic volume from real optical coherence tomography dataPublication . Serranho, Pedro; Bernardes, Rui; Maduro, Cristina; Santos, Torcato; Cunha-Vaz, JoséPurpose: To build a mathematical model to mimic a real OCT b-scan/volume without noise, in order to establish a ground truth for image processing performance metrics. Methods: Current image processing techniques (eg. despeckling filtering methods) with application to optical coherence tomography (OCT) rely on the respective qualitative evaluation of its results. Quantitative approaches are reduced to using synthetic images which consists of an homogeneous background and a set of abstract objects, eg. cubes and spheres. In this work, we suggest a mathematical model to address this issue by creating a synthetic b-scan/volume based on any real OCT data scan, that can be used as ground truth for processing methods testing. Eye scans of healthy volunteers and eyes of patients with age-related macular degeneration and diabetic retinopathy were used following Cirrus OCT (Carl Zeiss Meditec, Dublin, CA, USA) scans using both the 200x200x1024 and the 512x128x1024 Macular Cube Protocols. Each of these eye scans was processed in order to extract required parameters. For healthy subjects, only the segmentation of the inner limiting membrane (ILM) and the retinal pigment epithelium (RPE) are needed, though for pathologic eyes, the segmentation of other structures to be preserved might also be needed. In each segmented region, OCT data is surface fitted using appropriate basis functions. Results: A total of 45 scans were processed resulting in the synthetic data representing the major characteristics of the respective real OCT scans. These results have been used for testing the performance of an improved complex diffusion despeckling method proposed by some of the authors. Conclusions: This process allows to automatically compute a synthetic OCT scan mimicking a real one. In this way, this process makes it possible to quantify the result of any processing (eg. filtering) by providing adequate synthetic data as ground truth.
- 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.
- Noninvasive evaluation of retinal leakage using optical coherence tomographyPublication . Bernardes, Rui; Santos, Torcato; Serranho, Pedro; Lobo, Conceição; Cunha-Vaz, JoséPurpose: To demonstrate the association between changes in the blood-retinal barrier (BRB) identified by fluorescein leakage and those in the optical properties of the human retina determined by optical coherence tomography (OCT) and show how these changes can be quantified and their location identified within the retina. Methods: Two imaging techniques were applied: the retinal leakage analyzer, to map BRB function into intact or disrupted regions, and OCT, to measure refractive index changes along the light path within the human ocular fundus. Results: A total of 140 comparisons were made, 77 between areas of regions receiving the same classification (intact or disrupted BRB) and 63 between areas of regions receiving distinct classifications, from 4 pathological cases: 2 eyes with nonproliferative diabetic retinopathy and 2 eyes with wet age-related macular degeneration. In all cases, the distribution of OCT data between regions of intact and regions of disrupted BRB, identified by the retinal leakage analyzer, was quantified and was statistically significantly different (p < 0.001). In addition, it was found that the differences could be localized in the retina to specific structural sequences. Conclusions: Using a novel method to analyze OCT data, we showed that it may be possible to quantify differences in the extracellular compartment in eyes with retinal disease and alterations of the BRB. Based on quantitative techniques, our findings demonstrate the presence of indirect information on the BRB status within noninvasive OCT data.
- Time-dependent elastic numerical model for Optical Coherence Elastography of the murine retinaPublication . Correia, Carlos; Batista, Ana; Barbeiro, Sílvia; Cardoso, João; Domingues, José Paulo; Henriques, Rafael; Loureiro, Custódio; Santos, Mário J.; Serranho, Pedro; Bernardes, Rui; Morgado, MiguelWe present the initial stages of development of a Finite Element Method-based time-dependent elastic numerical model which seeks to support the employment of our Optical Coherence Elastography system for assessing murine retinal elasticity. The current model is able to reconstruct displacement maps in both homogeneous and heterogeneous domains with errors up to a few hundredths relatively to a known exact displacement map, within 1 millisecond. The results demonstrate the robustness of the numerical algorithm under different elastic domains, and model parametrization with real Optical Coherence Elastography data is already in progress.
- Ocular fundus Imaging: from structure to functionPublication . Serranho, Pedro; Maduro, Cristina; Santos, Torcato; Bernardes, Rui; Vaz, José Cunha; Araújo, Adérito; Barbeiro, SílviaImaging the ocular fundus, namely the retina, to detect and/or monitor changes over time from the healthy condition is of fundamental importance to assess onset and disease progression and is a valuable tool to understand the basic mechanisms of ocular diseases. Current trends point to the need for less or non-invasive approaches, to the need for detailed (higher spatial and temporal resolution) imaging systems and to the quantification as opposed to qualitative classification of any findings. In this work we present a snapshot of our research by presenting two examples of technical development aiming to obtain structural and function information from the human retina, in vivo, using non-invasive techniques, namely optical coherence tomography imaging. Based on our experience and developed work, we are now starting to bridge the gap to brain imaging as the eye is only the starting point of vision.
- Notas de análise de sobrevivência: uma introdução com RPublication . Serranho, PedroEste texto serve de apoio à unidade curricular de Análise de Sobrevivência (22111) da Universidade Aberta e serve para introduzir o estudante ao estudo da análise de sobrevivência e do uso de R neste contexto.
- Phase-resolved optical coherence elastography: an insight into tissue displacement estimationPublication . Batista, Ana; Serranho, Pedro; Santos, Mário; Correia, Carlos; Domingues, José P.; Loureiro, Custódio; Cardoso, João; Barbeiro, Sílvia; Morgado, António Miguel; Bernardes, RuiRobust methods to compute tissue displacements in optical coherence elastography (OCE) data are paramount, as they play a significant role in the accuracy of tissue elastic properties estimation. In this study, the accuracy of different phase estimators was evaluated on simulated OCE data, where the displacements can be accurately set, and on real data. Displacement (∆𝑑) estimates were computed from (i) the original interferogram data (Δ𝜑𝑜𝑟𝑖) and two phase-invariant mathematical manipulations of the interferogram: (ii) its first-order derivative (Δ𝜑𝑑) and (iii) its integral (Δ𝜑𝑖𝑛𝑡). We observed a dependence of the phase difference estimation accuracy on the initial depth location of the scatterer and the magnitude of the tissue displacement. However, by combining the three phase-difference estimates (Δ𝑑𝑎𝑣), the error in phase difference estimation could be minimized. By using Δ𝑑𝑎𝑣, the median root-mean-square error associated with displacement prediction in simulated OCE data was reduced by 85% and 70% in data with and without noise, respectively, in relation to the traditional estimate. Furthermore, a modest improvement in the minimum detectable displacement in real OCE data was also observed, particularly in data with low signal-to-noise ratios. The feasibility of using Δ𝑑𝑎𝑣 to estimate agarose phantoms’ Young’s modulus is illustrated.
- The method of fundamental solutions for the direct elastography problem in the human retinaPublication . Barbeiro, Sílvia; Serranho, PedroThis paper addresses the numerical simulation of the mechanical waves propagation and induced displacements in the human retina, for the elastography imaging modality. In this way, we use a model for the human eye and numerically approximate the propagation of time-harmonic acoustic waves through the different media of the eye and the respective elastic excitation in the retina, through a layered representation approach based on the method of fundamental solutions. We present numerical results showing the feasibility of the method.