Corrigendum: Normative mice retinal thickness: 16-month longitudinal characterization of wild-type mice and changes in a model of Alzheimer's disease.

[This corrects the article DOI: 10.3389/fnagi.2023.1161847.].

Retinal OCT biomarkers and their association with cognitive function-clinical and AI approaches.

Retinal optical coherence tomography (OCT) biomarkers have the potential to serve as early, noninvasive, and cost-effective markers for identifying individuals at risk for cognitive impairments and neurodegenerative diseases. They may also aid in monitoring disease progression and evaluating the effectiveness of interventions targeting cognitive decline. The association between retinal OCT biomarkers and cognitive performance has been demonstrated in several studies, and their importance in cognitive assessment is increasingly being recognized. Machine learning (ML) is a branch of artificial intelligence (AI) with an exponential number of applications in the medical field, particularly its deep learning (DL) subset, which is widely used for the analysis of medical images. These techniques efficiently deal with novel biomarkers when their outcome for the applications of interest is unclear, e.g., for diagnosis, prognosis prediction, disease staging, or any other relevance to clinical practice. However, using AI-based tools for medical purposes must be approached with caution, despite the many efforts to address the black-box nature of such approaches, especially due to the general underperformance in datasets other than those used for their development. Retinal OCT biomarkers are promising as potential indicators for decline in cognitive function. The underlying mechanisms are currently being explored to gain deeper insights into this relationship linking retinal health and cognitive function. Insights from neurovascular coupling and retinal microvascular changes play an important role. Further research is needed to establish the validity and utility of retinal OCT biomarkers as early indicators of cognitive decline and neurodegenerative diseases in routine clinical practice. Retinal OCT biomarkers could then provide a new avenue for early detection, monitoring and intervention in cognitive impairment with the potential to improve patient care and outcomes.

[Retinal optical coherence tomography biomarkers and their association with cognitive functions : Clinical and artificial intelligence approaches. German version]. / Retinale optische Kohärenztomographie Biomarker und ihr Zusammenhang mit kognitiven Funktionen : Klinische Praxis und künstliche Intelligenz Ansätze.

Retinal optical coherence tomography (OCT) biomarkers have the potential to serve as early, noninvasive, and cost-effective markers for identifying individuals at risk for cognitive impairments and neurodegenerative diseases. They may also aid in monitoring disease progression and evaluating the effectiveness of interventions targeting cognitive decline. The association between retinal OCT biomarkers and cognitive performance has been demonstrated in several studies, and their importance in cognitive assessment is increasingly being recognized. Machine learning (ML) is a branch of artificial intelligence (AI) with an exponential number of applications in the medical field, particularly its deep learning (DL) subset, which is widely used for the analysis of medical images. These techniques efficiently deal with novel biomarkers when their outcome for the applications of interest are unclear, e.g., for the diagnosis, prognosis prediction and disease staging. However, using AI-based tools for medical purposes must be approached with caution, despite the many efforts to address the black-box nature of such approaches, especially due to the general underperformance in datasets other than those used for their development. Retinal OCT biomarkers are promising as potential indicators for decline in cognitive function. The underlying mechanisms are currently being explored to gain deeper insights into this relationship linking retinal health and cognitive function. Insights from neurovascular coupling and retinal microvascular changes play an important role. Further research is needed to establish the validity and utility of retinal OCT biomarkers as early indicators of cognitive decline and neurodegenerative diseases in routine clinical practice. Retinal OCT biomarkers could then provide a new avenue for early detection, monitoring and intervention in cognitive impairment with the potential to improve patient care and outcomes.

Subtractive adaptation is a more effective and general mechanism in binocular rivalry than divisive adaptation.

The activity of neurons is influenced by random fluctuations and can be strongly modulated by firing rate adaptation, particularly in sensory systems. Still, there is ongoing debate about the characteristics of neuronal noise and the mechanisms of adaptation, and even less is known about how exactly they affect perception. Noise and adaptation are critical in binocular rivalry, a visual phenomenon where two images compete for perceptual dominance. Here, we investigated the effects of different noise processes and adaptation mechanisms on visual perception by simulating a model of binocular rivalry with Gaussian white noise, Ornstein-Uhlenbeck noise, and pink noise, in variants with divisive adaptation, subtractive adaptation, and without adaptation. By simulating the nine models in parameter space, we find that white noise only produces rivalry when paired with subtractive adaptation and that subtractive adaptation reduces the influence of noise intensity on rivalry strength and introduces convergence of the mean percept duration, an important metric of binocular rivalry, across all noise processes. In sum, our results show that white noise is an insufficient description of background activity in the brain and that subtractive adaptation is a stronger and more general switching mechanism in binocular rivalry than divisive adaptation, with important noise-filtering properties.

Textural properties of microglial activation in Alzheimer's disease as measured by (R)-[11C]PK11195 PET.

Alzheimer's disease is the most common form of dementia worldwide, accounting for 60-70% of diagnosed cases. According to the current understanding of molecular pathogenesis, the main hallmarks of this disease are the abnormal accumulation of amyloid plaques and neurofibrillary tangles. Therefore, biomarkers reflecting these underlying biological mechanisms are recognized as valid tools for an early diagnosis of Alzheimer's disease. Inflammatory mechanisms, such as microglial activation, are known to be involved in Alzheimer's disease onset and progression. This activated state of the microglia is associated with increased expression of the translocator protein 18 kDa. On that account, PET tracers capable of measuring this signature, such as (R)-[11C]PK11195, might be instrumental in assessing the state and evolution of Alzheimer's disease. This study aims to investigate the potential of Gray Level Co-occurrence Matrix-based textural parameters as an alternative to conventional quantification using kinetic models in (R)-[11C]PK11195 PET images. To achieve this goal, kinetic and textural parameters were computed on (R)-[11C]PK11195 PET images of 19 patients with an early diagnosis of Alzheimer's disease and 21 healthy controls and submitted separately to classification using a linear support vector machine. The classifier built using the textural parameters showed no inferior performance compared to the classical kinetic approach, yielding a slightly larger classification accuracy (accuracy of 0.7000, sensitivity of 0.6957, specificity of 0.7059 and balanced accuracy of 0.6967). In conclusion, our results support the notion that textural parameters may be an alternative to conventional quantification using kinetic models in (R)-[11C]PK11195 PET images. The proposed quantification method makes it possible to use simpler scanning procedures, which increase patient comfort and convenience. We further speculate that textural parameters may also provide an alternative to kinetic analysis in (R)-[11C]PK11195 PET neuroimaging studies involving other neurodegenerative disorders. Finally, we recognize that the potential role of this tracer is not in diagnosis but rather in the assessment and progression of the diffuse and dynamic distribution of inflammatory cell density in this disorder as a promising therapeutic target.

Phase-Resolved Optical Coherence Elastography: An Insight into Tissue Displacement Estimation.

Robust 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.

Normative mice retinal thickness: 16-month longitudinal characterization of wild-type mice and changes in a model of Alzheimer's disease.

Animal 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 imaging in animal models: Searching for biomarkers of neurodegeneration.

There 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.

When Sex Matters: Differences in the Central Nervous System as Imaged by OCT through the Retina.

BACKGROUND: Retinal texture has gained momentum as a source of biomarkers of neurodegeneration, as it is sensitive to subtle differences in the central nervous system from texture analysis of the neuroretina. Sex differences in the retina structure, as detected by layer thickness measurements from optical coherence tomography (OCT) data, have been discussed in the literature. However, the effect of sex on retinal interocular differences in healthy adults has been overlooked and remains largely unreported. METHODS: We computed mean value fundus images for the neuroretina layers as imaged by OCT of healthy individuals. Texture metrics were obtained from these images to assess whether women and men have the same retina texture characteristics in both eyes. Texture features were tested for group mean differences between the right and left eye. RESULTS: Corrected texture differences exist only in the female group. CONCLUSIONS: This work illustrates that the differences between the right and left eyes manifest differently in females and males. This further supports the need for tight control and minute analysis in studies where interocular asymmetry may be used as a disease biomarker, and the potential of texture analysis applied to OCT imaging to spot differences in the retina.

The hemodynamic response function as a type 2 diabetes biomarker: a data-driven approach.

Introduction: There is a need to better understand the neurophysiological changes associated with early brain dysfunction in Type 2 diabetes mellitus (T2DM) before vascular or structural lesions. Our aim was to use a novel unbiased data-driven approach to detect and characterize hemodynamic response function (HRF) alterations in T2DM patients, focusing on their potential as biomarkers. Methods: We meshed task-based event-related (visual speed discrimination) functional magnetic resonance imaging with DL to show, from an unbiased perspective, that T2DM patients' blood-oxygen-level dependent response is altered. Relevance analysis determined which brain regions were more important for discrimination. We combined explainability with deconvolution generalized linear model to provide a more accurate picture of the nature of the neural changes. Results: The proposed approach to discriminate T2DM patients achieved up to 95% accuracy. Higher performance was achieved at higher stimulus (speed) contrast, showing a direct relationship with stimulus properties, and in the hemispherically dominant left visual hemifield, demonstrating biological interpretability. Differences are explained by physiological asymmetries in cortical spatial processing (right hemisphere dominance) and larger neural signal-to-noise ratios related to stimulus contrast. Relevance analysis revealed the most important regions for discrimination, such as extrastriate visual cortex, parietal cortex, and insula. These are disease/task related, providing additional evidence for pathophysiological significance. Our data-driven design allowed us to compute the unbiased HRF without assumptions. Conclusion: We can accurately differentiate T2DM patients using a data-driven classification of the HRF. HRF differences hold promise as biomarkers and could contribute to a deeper understanding of neurophysiological changes associated with T2DM.

Stage-independent biomarkers for Alzheimer's disease from the living retina: an animal study.

The 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.

Retinal Aging in 3× Tg-AD Mice Model of Alzheimer's Disease.

The 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 from both groups. Our analysis shows a mean 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 wild-type 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.

Intraocular implants loaded with A3R agonist rescue retinal ganglion cells from ischemic damage.

Retinal ganglion cell (RGC) loss underlies several conditions which give rise to significant visual compromise, including glaucoma and ischaemic optic neuropathies. Neuroprotection of RGCs is a clinical well-defined unmet need in these diseases, and adenosine A3 receptor (A3R) activation emerges as a therapeutic pharmacological approach to protect RGCs. A porous biodegradable intraocular implant loaded with 2-Cl-IB-MECA (selective A3R agonist) was used as a strategy to protect RGCs. Drug-loaded PCL implants released 2-Cl-IB-MECA for an extended period and the released 2-Cl-IB-MECA limited glutamate-evoked calcium (Ca2+) rise in RGCs. Retinal thinning due to transient ischemia was not prevented by 2-Cl-IB-MECA-PCL implant. However, 2-Cl-IB-MECA-PCL implants decreased retinal cell death, promoted the survival of RGCs, preserved optic nerve structure and anterograde axonal transport. We further demonstrated that 2-Cl-IB-MECA-loaded PCL implants were able to enhance RGC function that was compromised by transient ischemia. Taking into consideration the beneficial effects afforded by 2-Cl-IB-MECA released from the PCL implant, this can be envisaged a good therapeutic strategy to protect RGCs.

Texture Analysis and Its Applications in Biomedical Imaging: A Survey.

Texture analysis describes a variety of image analysis techniques that quantify the variation in intensity and pattern. This paper provides an overview of several texture analysis approaches addressing the rationale supporting them, their advantages, drawbacks, and applications. This survey's emphasis is in collecting and categorising over five decades of active research on texture analysis. Brief descriptions of different approaches are presented along with application examples. From a broad range of texture analysis applications, this survey's final focus is on biomedical image analysis. An up-to-date list of biological tissues and organs in which disorders produce texture changes that may be used to spot disease onset and progression is provided. Finally, the role of texture analysis methods as biomarkers of disease is summarised.

Longitudinal normative OCT retinal thickness data for wild-type mice, and characterization of changes in the 3×Tg-AD mice model of Alzheimer's disease.

Mice 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 characterise 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 centre. 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 fibre 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.

The Retinal Inner Plexiform Synaptic Layer Mirrors Grey Matter Thickness of Primary Visual Cortex with Increased Amyloid ß Load in Early Alzheimer's Disease.

The retina may serve as putative window into neuropathology of synaptic loss in Alzheimer's disease (AD). Here, we investigated synapse-rich layers versus layers composed by nuclei/cell bodies in an early stage of AD. In addition, we examined the associations between retinal changes and molecular and structural markers of cortical damage. We recruited 20 AD patients and 17 healthy controls (HC). Combining optical coherence tomography (OCT), magnetic resonance (MR), and positron emission tomography (PET) imaging, we measured retinal and primary visual cortex (V1) thicknesses, along with V1 amyloid ß (Aß) retention ([11C]-PiB PET tracer) and neuroinflammation ([11C]-PK11195 PET tracer). We found that V1 showed increased amyloid-binding potential, in the absence of neuroinflammation. Although thickness changes were still absent, we identified a positive association between the synapse-rich inner plexiform layer (IPL) and V1 in AD. This retinocortical interplay might reflect changes in synaptic function resulting from Aß deposition, contributing to early visual loss.

Interplay Between Macular Retinal Changes and White Matter Integrity in Early Alzheimer's Disease.

This study aims to investigate the relationship between structural changes in the retina and white matter in the brain, in early Alzheimer's disease (AD). Twenty-three healthy controls (mean age = 63.4±7.5 years) and seventeen AD patients (mean age = 66.5±6.6 years) were recruited for this study. By combining two imaging techniques-optical coherence tomography and diffusion tensor imaging (DTI)-the association between changes in the thickness of individual retinal layers and white matter dysfunction in early AD was assessed. Retinal layers were segmented, and thickness measurements were obtained for each layer. DTI images were analyzed with a quantitative data-driven approach to evaluating whole-brain diffusion metrics, using tract-based spatial statistics. Diffusion metrics, such as fractional anisotropy, are markers for white matter integrity. Multivariate and partial correlation analyses evaluating the association between individual retinal layers thickness and diffusion metrics were performed. We found that axial diffusivity, indexing axonal integrity, was significantly reduced in AD (p = 0.016, Cohen's d = 1.004) while in the retina, only a marginal trend for significance was found for the outer plexiform layer (p = 0.084, Cohen's d = 0.688). Furthermore, a positive association was found in the AD group between fractional anisotropy and the inner nuclear layer thickness (p < 0.05, r = 0.419, corrected for multiple comparisons by controlling family-wise error rate). Our findings suggest that axonal damage in the brain dominates early on in this condition and shows an association with retinal structural integrity already at initial stages of AD. These findings are consistent with an early axonal degeneration mechanism in AD.

Retinal texture biomarkers may help to discriminate between Alzheimer's, Parkinson's, and healthy controls.

A top priority in biomarker development for Alzheimer's disease (AD) and Parkinson's disease (PD) is the focus on early diagnosis, where the use of the retina is a promising avenue of research. We computed fundus images from optical coherence tomography (OCT) data and analysed the structural arrangement of the retinal tissue using texture metrics. We built clinical class classification models to distinguish between healthy controls (HC), AD, and PD, using machine learning (support vector machines). Median sensitivity is 88.7%, 79.5% and 77.8%, for HC, AD, and PD eyes, respectively. When the same subject has the same classification for both eyes, 94.4% (median) of the classifications are correct. A significant amount of information discriminating between multiple neurodegenerative states is conveyed by OCT imaging of the human retina, even when differences in thickness are not yet present. This technique may allow for simultaneously diagnosing Alzheimer's and Parkinson's diseases.

Is the Retina a Mirror of the Aging Brain? Aging of Neural Retina Layers and Primary Visual Cortex Across the Lifespan.

How aging concomitantly modulates the structural integrity of the brain and retina in healthy individuals remains an outstanding question. Given the strong bottom-up retinocortical connectivity, it is important to study how these structures co-evolve during healthy aging in order to unravel mechanisms that may affect the physiological integrity of both structures. For the 56 participants in the study, primary visual cortex (BA17), as well as frontal, parietal and temporal regions thicknesses were measured in T1-weighted magnetic resonance imaging (MRI), and retinal macular thickness (10 neuroretinal layers) was measured by optical coherence tomography (OCT) imaging. We investigated the statistical association of these measures and their age dependence. We found an age-related decay of primary visual cortical thickness that was significantly correlated with a decrease in global and multiple layer retinal thicknesses. The atrophy of both structures might jointly account for the decline of various visual capacities that accompany the aging process. Furthermore, associations with other cortical regions suggest that retinal status may index cortical integrity in general.

The retinal ganglion cell layer predicts normal-appearing white matter tract integrity in multiple sclerosis: A combined diffusion tensor imaging and optical coherence tomography approach.

We investigated the relationship between retinal layers and normal-appearing white matter (WM) integrity in the brain of patients with relapsing-remitting multiple sclerosis (MS), using a combined diffusion tensor imaging and high resolution optical coherence tomography approach. Fifty patients and 62 controls were recruited. The patients were divided into two groups according to presence (n = 18) or absence (n = 32) of optic neuritis. Diffusion tensor data were analyzed with a voxel-wise whole brain analysis of diffusion metrics in WM with tract-based spatial statistics. Thickness measurements were obtained for each individual retinal layer. Partial correlation and multivariate regression analyses were performed, assessing the association between individual retinal layers and diffusion metrics across all groups. Region-based analysis was performed, by focusing on tracts associated with the visual system. Receiver operating characteristic (ROC) curves were computed to compare the biomarker potential for the diagnosis of MS, using the thickness of each retinal layer and diffusion metrics. In patients without optic neuritis, both ganglion cell layer (GCL) and inner plexiform layer thickness correlated with the diffusion metrics within and outside the visual system. GCL thickness was a significant predictor of diffusion metrics in the whole WM skeleton, unlike other layers. No association was observed for either controls or patients with a history of optic neuritis. ROC analysis showed that the biomarker potential for the diagnosis of MS based on the GCL was high when compared to other layers. We conclude that GCL integrity is a predictor of whole-brain WM disruption in MS patients without optic neuritis.