ABSTRACT
Spin-triplet topological superconductors should exhibit many unprecedented electronic properties, including fractionalized electronic states relevant to quantum information processing. Although UTe2 may embody such bulk topological superconductivity1-11, its superconductive order parameter Δ(k) remains unknown12. Many diverse forms for Δ(k) are physically possible12 in such heavy fermion materials13. Moreover, intertwined14,15 density waves of spin (SDW), charge (CDW) and pair (PDW) may interpose, with the latter exhibiting spatially modulating14,15 superconductive order parameter Δ(r), electron-pair density16-19 and pairing energy gap17,20-23. Hence, the newly discovered CDW state24 in UTe2 motivates the prospect that a PDW state may exist in this material24,25. To search for it, we visualize the pairing energy gap with µeV-scale energy resolution using superconductive scanning tunnelling microscopy (STM) tips26-31. We detect three PDWs, each with peak-to-peak gap modulations of around 10 µeV and at incommensurate wavevectors Pi=1,2,3 that are indistinguishable from the wavevectors Qi=1,2,3 of the prevenient24 CDW. Concurrent visualization of the UTe2 superconductive PDWs and the non-superconductive CDWs shows that every Pi:Qi pair exhibits a relative spatial phase Î´Ï ≈ π. From these observations, and given UTe2 as a spin-triplet superconductor12, this PDW state should be a spin-triplet PDW24,25. Although such states do exist32 in superfluid 3He, for superconductors, they are unprecedented.
ABSTRACT
Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.
Subject(s)
Retinal Cone Photoreceptor Cells , Retinal Degeneration , Sciuridae , Tomography, Optical Coherence , Animals , Retinal Degeneration/chemically induced , Retinal Degeneration/pathology , Retinal Cone Photoreceptor Cells/pathology , Retinal Cone Photoreceptor Cells/drug effects , Disease Models, Animal , Intravitreal Injections , Ophthalmoscopy , Nitroprusside/pharmacology , Female , MaleABSTRACT
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Genome, Human/genetics , Genomics , Leukemia, Myeloid, Acute/genetics , Core Binding Factor Alpha 2 Subunit/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , Datasets as Topic , Exome/genetics , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Male , Molecular Targeted Therapy , Nuclear Proteins/genetics , Nucleophosmin , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Sequence Analysis, RNA , Serine-Arginine Splicing Factors/geneticsABSTRACT
Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
Subject(s)
Activating Transcription Factor 6/genetics , Color Vision Defects/genetics , Retina/cytology , Retinal Cone Photoreceptor Cells/pathology , Activating Transcription Factor 6/agonists , Activating Transcription Factor 6/metabolism , Cone Opsins/genetics , Gene Expression , HEK293 Cells , Humans , Induced Pluripotent Stem Cells/cytology , Organoids , Retina/diagnostic imaging , Retinal Cone Photoreceptor Cells/physiology , Vision, Ocular/geneticsABSTRACT
SIGNIFICANCE: Foveal avascular zone (FAZ) area is a frequently used biomarker in diseases impacting the retinal vasculature in pediatric populations. Variation in axial length between individuals results in differences in lateral image scale, which affect the accuracy of FAZ area measurements. Accordingly, changes in axial length over time within individual children would affect estimates of FAZ area change. PURPOSE: This study aimed to quantify how changes in axial length over time affect estimates of FAZ area change using optical coherence tomography angiography (OCT-A) images. METHODS: Twenty pediatric participants (<18 years old) and 40 adult participants were imaged on Optovue's Avanti system (Fremont, CA) and had axial length measurements acquired at two time points. The FAZ was segmented twice using the OCT-A image at each time point. Foveal avascular zone area was estimated at both time points using the assumed/fixed axial length of the OCT-A device (unscaled) and using the participant's axial length (scaled). Changes in FAZ area over time were compared between the pediatric and adult groups using both unscaled and scaled data. RESULTS: The average ± standard deviation follow-up time was 3.35 ± 1.66 years for the pediatric group and 2.90 ± 1.65 years for the adult group. Using unscaled data, FAZ area seemed to decrease between visits in the pediatric group (P = .004), whereas the FAZ area increased between visits in the adult group (P = .003). When correctly scaled data were used, the FAZ area still increased between visits for the adult group (P < .001), although the FAZ area no longer showed a significant change between visits for the pediatric group (P = .37). When comparing the normalized FAZ area change across visits between unscaled and scaled data, a significant difference was found between the adult and pediatric groups (P < .001). CONCLUSIONS: Scaled data should be used when measuring FAZ area in pediatric populations, especially in longitudinal studies.
Subject(s)
Fovea Centralis , Macula Lutea , Adolescent , Adult , Child , Fluorescein Angiography/methods , Fovea Centralis/blood supply , Fovea Centralis/diagnostic imaging , Humans , Retinal Vessels/diagnostic imaging , Tomography, Optical Coherence/methodsABSTRACT
Retinotopic organization is a fundamental feature of visual cortex thought to play a vital role in encoding spatial information. One important aspect of normal retinotopy is the representation of the right and left hemifields in contralateral visual cortex. However, in human albinism, many temporal retinal afferents decussate aberrantly at the optic chiasm resulting in partially superimposed representations of opposite hemifields in each hemisphere of visual cortex. Previous functional magnetic resonance imaging (fMRI) studies in human albinism suggest that the right and left hemifield representations are superimposed in a mirror-symmetric manner. This should produce imaging voxels which respond to two separate locations mirrored across the vertical meridian. However, it is not yet clear how retino-cortical miswiring in albinism manifests at the level of single voxel population receptive fields (pRFs). Here, we used pRF modeling to fit both single and dual pRF models to the visual responses of voxels in visual areas V1 to V3 of five subjects with albinism. We found that subjects with albinism (but not controls) have sizable clusters of voxels with unequivocal dual pRFs consistently corresponding to, but not fully coextensive with, regions of hemifield overlap. These dual pRFs were typically positioned at locations roughly mirrored across the vertical meridian and were uniquely clustered within a portion of the visual field for each subject.
Subject(s)
Albinism , Visual Cortex , Brain Mapping , Humans , Magnetic Resonance Imaging , Optic Chiasm , Visual Cortex/diagnostic imaging , Visual Fields , Visual PathwaysABSTRACT
Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.
Subject(s)
Acid Ceramidase/genetics , Farber Lipogranulomatosis , Mutation, Missense , Optic Nerve , Retina , Vision Disorders , Acid Ceramidase/metabolism , Amino Acid Substitution , Animals , Ceramides/genetics , Ceramides/metabolism , Disease Models, Animal , Farber Lipogranulomatosis/enzymology , Farber Lipogranulomatosis/genetics , Farber Lipogranulomatosis/pathology , Inflammation/enzymology , Inflammation/genetics , Inflammation/pathology , Mice , Mice, Mutant Strains , Optic Nerve/enzymology , Optic Nerve/pathology , Retina/enzymology , Retina/pathology , Sphingolipids/genetics , Sphingolipids/metabolism , Vision Disorders/enzymology , Vision Disorders/genetics , Vision Disorders/pathologyABSTRACT
The human fovea lies at the center of the retina and supports high-acuity vision. In normal visual system development, the highest acuity is correlated with both a high density of cone photoreceptors in the fovea and a magnified retinotopic representation of the fovea in the visual cortex. Both cone density and the cortical area dedicated to each degree of visual space-the latter describing cortical magnification (CM)-steadily decrease with increasing eccentricity from the fovea. In albinism, peak cone density at the fovea and visual acuity are decreased, but seem to be within normal limits in the periphery, thus providing a model to explore the correlation between retinal structure, cortical structure, and behavior. Here, we used adaptive optics scanning light ophthalmoscopy to assess retinal cone density and functional magnetic resonance imaging to measure CM in the primary visual cortex of normal controls and individuals with albinism. We find that retinotopic organization is more varied among individuals with albinism than previously appreciated. Additionally, CM outside the fovea is similar to that in controls, but also more variable. CM in albinism and controls exceeds that which might be predicted based on cone density alone, but is more accurately predicted by retinal ganglion cell density. This finding suggests that decreased foveal cone density in albinism may be partially counteracted by nonuniform connectivity between cones and their downstream signaling partners. Together, these results emphasize that central as well as retinal factors must be included to provide a complete picture of aberrant structure and function in albinism.
Subject(s)
Albinism/physiopathology , Retinal Cone Photoreceptor Cells/physiology , Visual Cortex/physiology , Adolescent , Adult , Cell Count , Female , Humans , Magnetic Resonance Imaging , Male , Ophthalmoscopy/methods , Optics and Photonics , Retina/physiology , Retinal Cone Photoreceptor Cells/cytology , Retinal Ganglion Cells/physiology , Visual Acuity/physiology , Young AdultABSTRACT
Tree shrews are small mammals with excellent vision and are closely related to primates. They have been used extensively as a model for studying refractive development, myopia, and central visual processing and are becoming an important model for vision research. Their cone dominant retina (â¼95% cones) provides a potential avenue to create new damage/disease models of human macular pathology and to monitor progression or treatment response. To continue the development of the tree shrew as an animal model, we provide here the first measurements of higher order aberrations along with adaptive optics scanning light ophthalmoscopy (AOSLO) images of the photoreceptor mosaic in the tree shrew retina. To compare intra-animal in vivo and ex vivo cone density measurements, the AOSLO images were matched to whole-mount immunofluorescence microscopy. Analysis of the tree shrew wavefront indicated that the optics are well-matched to the sampling of the cone mosaic and is consistent with the suggestion that juvenile tree shrews are nearly emmetropic (slightly hyperopic). Compared with in vivo measurements, consistently higher cone density was measured ex vivo, likely due to tissue shrinkage during histological processing. Tree shrews also possess massive mitochondria ("megamitochondria") in their cone inner segments, providing a natural model to assess how mitochondrial size affects in vivo retinal imagery. Intra-animal in vivo and ex vivo axial distance measurements were made in the outer retina with optical coherence tomography (OCT) and transmission electron microscopy (TEM), respectively, to determine the origin of sub-cellular cone reflectivity seen on OCT. These results demonstrate that these megamitochondria create an additional hyper-reflective outer retinal reflective band in OCT images. The ability to use noninvasive retinal imaging in tree shrews supports development of this species as a model of cone disorders.
Subject(s)
Corneal Wavefront Aberration/physiopathology , Refractive Errors/physiopathology , Retina/diagnostic imaging , Retinal Cone Photoreceptor Cells/cytology , Aberrometry , Animals , Cell Count , Microscopy, Electron, Transmission , Ophthalmoscopy , Optical Imaging , Refraction, Ocular/physiology , Retina/physiopathology , Retinal Cone Photoreceptor Cells/physiology , Tomography, Optical Coherence/methods , TupaiaABSTRACT
PURPOSE: To examine the features of the tapetal-like reflex (TLR) in female carriers of RPGR-associated retinopathy by means of adaptive optics scanning light ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography. METHODS: Nine molecularly confirmed RPGR carriers and three healthy controls underwent ocular examination and the following retinal imaging modalities: color photography, near-infrared reflectance, fundus autofluorescence, spectral domain optical coherence tomography, and AOSLO. After identifying TLR areas across all imaging modalities, normalized local contrast of outer retinal bands on spectral domain optical coherence tomography was calculated and AOSLO-acquired photoreceptor mosaic analysis was performed. RESULTS: Seven carriers had TLR areas, which colocalized with increased rod photoreceptor reflectivity on confocal AOSLO and reduced cone photoreceptor densities. Parafoveal TLR areas also exhibited reduced local contrast (i.e., increased reflectivity) of the outer retinal bands on spectral domain optical coherence tomography (inner segment ellipsoid zone and outer segment interdigitation zone). Healthy controls did not show TLR. CONCLUSION: The cellular resolution provided by AOSLO affords the characterization of the photoreceptor mosaic in RPGR carriers with a TLR. Features revealed include reduced cone density, increased cone inner segment diameter, and increased rod outer segment reflectivity.
Subject(s)
Eye Proteins/genetics , Retina/pathology , Retinitis Pigmentosa , Adult , Female , Genetic Carrier Screening , Heterozygote , Humans , Male , Middle Aged , Ophthalmoscopy/methods , Retinal Cone Photoreceptor Cells/pathology , Retinal Rod Photoreceptor Cells/pathology , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/pathology , Visual AcuityABSTRACT
PURPOSE: To characterize and quantify early foveal development in preterm infants and to compare this development between eyes treated with intravitreal bevacizumab or laser photocoagulation (LPC) and untreated eyes. DESIGN: Observational case series. PARTICIPANTS: One hundred thirty-one preterm infants undergoing retinopathy of prematurity (ROP) screenings. METHODS: Handheld OCT imaging was performed longitudinally on all patients. Thickness measurements of the inner and outer retinal layers were obtained at the foveal center and the nasal and temporal foveal rims. Comparisons between treated and untreated eyes were adjusted for age and other confounding variables. MAIN OUTCOME MEASURES: Weekly change in inner and outer retinal thickness and presence of inner retinal layers, ellipsoid zone (EZ), and cystoid macular changes (CMCs). RESULTS: Outer retinal thickness at the foveal center increased by 3.1 µm/week in untreated eyes and 7.2 µm/week in bevacizumab-treated eyes (P = 0.038). Eyes treated with LPC had a lower probability of having all inner retinal layers present at the foveal center (odds ratio, 0.04; P = 0.001) and a lower probability of having the EZ present at the foveal center (odds ratio, 0.07; P = 0.024) compared with untreated eyes. Cystoid macular changes were found in 53% of patients and 22% of imaging sessions. The age-adjusted incidence of CMCs was not correlated with bevacizumab or LPC treatment. CONCLUSIONS: Intravitreal bevacizumab therapy for ROP is associated with more rapid outer retinal thickening at the foveal center, whereas LPC is associated with earlier extrusion of the inner retinal layers and delayed development of the EZ at the foveal center. Long-term follow-up is needed to determine the visual significance of these findings.
Subject(s)
Bevacizumab/administration & dosage , Fovea Centralis/pathology , Infant, Premature , Laser Coagulation/methods , Retinopathy of Prematurity/therapy , Visual Acuity/physiology , Angiogenesis Inhibitors/administration & dosage , Disease Progression , Female , Gestational Age , Humans , Infant , Infant, Newborn , Intravitreal Injections , Male , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/physiopathology , Tomography, Optical Coherence/methods , Treatment OutcomeABSTRACT
Indocyanine green (ICG) is routinely used during surgery to stain the inner limiting membrane (ILM) and provide contrast on white light surgical microscopy. While translation of optical coherence tomography (OCT) for intraoperative imaging during ophthalmic surgery has enhanced visualization, the ILM remains difficult to distinguish from underlying retinal structures and ICG does not provide additional OCT contrast. We present photothermal OCT (PT-OCT) for high-specificity detection of ICG on retinal OCT images. We demonstrate our technique by performing an ILM peel in ex vivo eyes using low ICG concentrations and laser powers. These results establish the feasibility of PT-OCT for intraoperative guidance during retinal surgery.
Subject(s)
Basement Membrane/diagnostic imaging , Coloring Agents/administration & dosage , Epiretinal Membrane/diagnostic imaging , Indocyanine Green/administration & dosage , Tomography, Optical Coherence/methods , Animals , Retina/diagnostic imaging , SwineABSTRACT
Zebrafish (Danio rerio) are widely used as an experimental model for a wide range of retinal diseases. Previously, optical coherence tomography (OCT) was introduced for quantitative analysis of the zebrafish cone photoreceptor cell mosaic; however no data exists on the intersession reproducibility or intrasession repeatability of such measurements. We imaged 14 wild-type (WT) fish three times each, with 48 h between each time point. En face images of the UV cone mosaic were generated from the OCT volume scans at each time point. These images were then aligned and the overlapping area cropped for analysis. Using a semiautomated cone-counting algorithm, a single observer identified each cone to calculate the cone density for every image, counting each image twice (84 total counts). The OCT cone density measurements were found to have an intersession reproducibility of 0.9988 (95% CI = 0.9978-0.9999) and an intrasession repeatability of 136.0 ± 10.5 cones/mm2 (about 0.7%). Factors affecting image quality include gill movement during acquisition of the OCT volume and variable inclusion of non-UV cone mosaics in the contours used to generate the en face images.
Subject(s)
Retina/cytology , Retinal Cone Photoreceptor Cells , Tomography, Optical Coherence/methods , Zebrafish/anatomy & histology , Animals , Artifacts , Cell Count , Image Processing, Computer-Assisted/methods , Reproducibility of Results , Ultraviolet RaysABSTRACT
PURPOSE: To characterize outer retina structure in best vitelliform macular dystrophy (BVMD) and to determine the effect of macular lesions on overlying and adjacent photoreceptors. METHODS: Five individuals with BVMD were followed prospectively with spectral domain optical coherence tomography and confocal and nonconfocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO). The AOSLO cone photoreceptor mosaic images were obtained within and around retinal lesions. Cone density was measured inside and outside lesions. In 2 subjects, densities were compared with published measurements acquired â¼2.5 years before. One subject was imaged 3 times over a 5-month period. RESULTS: The AOSLO imaging demonstrated that photoreceptor morphology within BVMD retinal lesions was highly variable depending on the disease stage, with photoreceptor structure present even in advanced disease. The AOSLO imaging was repeatable even in severe disease over short-time and long-time intervals. Photoreceptor density was normal in retinal areas immediately adjacent to lesions and stable over â¼2.5 years. Mobile disk-like structures possibly representing subretinal macrophages were also observed. CONCLUSION: Combined confocal and nonconfocal split-detector AOSLO imaging reveals substantial variability within clinical lesions in all stages of BVMD. Longitudinal cellular photoreceptor imaging could prove a powerful tool for understanding disease progression and monitoring emerging therapeutic treatment response in inherited degenerations such as BVMD.
Subject(s)
Retinal Cone Photoreceptor Cells/pathology , Retinal Photoreceptor Cell Inner Segment/pathology , Vitelliform Macular Dystrophy/pathology , Adolescent , Adult , Cell Count , Female , Humans , Male , Middle Aged , Ophthalmoscopy/methods , Prospective Studies , Tomography, Optical Coherence/methods , Young AdultABSTRACT
PURPOSE: Congenital achromatopsia is an autosomal recessive disease causing substantial reduction or complete absence of cone function. Although believed to be a relatively stationary disorder, questions remain regarding the stability of cone structure over time. In this study, the authors sought to assess the repeatability of and examine longitudinal changes in measurements of central cone structure in patients with achromatopsia. METHODS: Forty-one subjects with CNGB3-associated achromatopsia were imaged over a period of between 6 and 26 months using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Outer nuclear layer (ONL) thickness, ellipsoid zone (EZ) disruption, and peak foveal cone density were assessed. RESULTS: ONL thickness increased slightly compared with baseline (0.184 µm/month, P = 0.02). The EZ grade remained unchanged for 34/41 subjects. Peak foveal cone density did not significantly change over time (mean change 1% per 6 months, P = 0.126). CONCLUSION: Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6-26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. These data will be useful in assessing foveal cone structure after therapeutic intervention.
Subject(s)
Color Vision Defects/genetics , Cyclic Nucleotide-Gated Cation Channels/genetics , DNA/genetics , Fovea Centralis/pathology , Mutation , Retinal Cone Photoreceptor Cells/pathology , Visual Acuity , Adolescent , Adult , Child , Color Vision Defects/diagnosis , Color Vision Defects/physiopathology , Cyclic Nucleotide-Gated Cation Channels/metabolism , DNA Mutational Analysis , Electroretinography , Female , Fovea Centralis/physiopathology , Humans , Longitudinal Studies , Male , Ophthalmoscopy/methods , Retinal Cone Photoreceptor Cells/physiology , Tomography, Optical Coherence/methods , Young AdultSubject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , COVID-19 , Humans , Retina/pathology , Retina/virology , SARS-CoV-2ABSTRACT
The ability to noninvasively image the cone photoreceptor mosaic holds significant potential as a diagnostic for retinal disease. Central to the realization of this potential is the development of sensitive metrics for characterizing the organization of the mosaic. Here we evaluated previously-described and newly-developed (Fourier- and Radon-based) methods of measuring cone orientation in simulated and real images of the parafoveal cone mosaic. The proposed algorithms correlated well across both simulated and real mosaics, suggesting that each algorithm provides an accurate description of photoreceptor orientation. Despite high agreement between algorithms, each performed differently in response to image intensity variation and cone coordinate jitter. The integration property of the Fourier transform allowed the Fourier-based method to be resistant to cone coordinate jitter and perform the most robustly of all three algorithms. Conversely, when there is good image quality but unreliable cone identification, the Radon algorithm performed best. Finally, in cases where the cone coordinate reliability was excellent, the method previously described by Pum and colleagues performed best. These descriptors are complementary to conventional descriptive metrics of the cone mosaic, such as cell density and spacing, and have the potential to aid in the detection of photoreceptor pathology.
Subject(s)
Algorithms , Diagnostic Imaging/methods , Diagnostic Techniques, Ophthalmological , Retinal Cone Photoreceptor Cells/cytology , Adult , Anisotropy , Cell Count , Female , Fourier Analysis , Humans , Male , Ophthalmoscopy/methodsABSTRACT
Zebrafish (Danio rerio) provide many advantages as a model organism for studying ocular disease and development, and there is great interest in the ability to non-invasively assess their photoreceptor mosaic. Despite recent applications of scanning light ophthalmoscopy, fundus photography, and gonioscopy to in vivo imaging of the adult zebrafish eye, current techniques either lack accurate scaling information (limiting quantitative analyses) or require euthanizing the fish (precluding longitudinal analyses). Here we describe improved methods for imaging the adult zebrafish retina using spectral domain optical coherence tomography (OCT). Transgenic fli1:eGFP zebrafish were imaged using the Bioptigen Envisu R2200 broadband source OCT with a 12-mm telecentric probe to measure axial length and a mouse retina probe to acquire retinal volume scans subtending 1.2 × 1.2 mm nominally. En face summed volume projections were generated from the volume scans using custom software that allows the user to create contours tailored to specific retinal layer(s) of interest. Following imaging, the eyes were dissected for ex vivo fluorescence microscopy, and measurements of blood vessel branch points were compared to those made from the en face OCT images to determine the OCT lateral scale as a function of axial length. Using this scaling model, we imaged the photoreceptor layer of five wild-type zebrafish and quantified the density and packing geometry of the UV cone submosaic. Our in vivo cone density measurements agreed with measurements from previously published histology values. The method presented here allows accurate, quantitative assessment of cone structure in vivo and will be useful for longitudinal studies of the zebrafish cone mosaics.