Non-Invasive and Early Diagnosis of Ocular and Systemic Diseases Using "Eye as a Window to the Body"
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Ansari, Rafat R.↗
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Dynamic Light Scattering of Diabetic Vitreopathy
Diabetes induces pathology throughout the body via nonenzymatic glycation of proteins. Vitreous, which is replete with type 11 collagen, undergoes significant changes in diabetes. The resultant diabetic vitreopathy plays an important role in diabetic retinopathy. Detecting these molecular changes could provide insight into diabetic eye disease as well as molecular effects elsewhere in the body. Human eyes were obtained at autopsy and studied in the fresh, unfixed state. Sclera, choroid, and retina were dissected off the vitreous for dark-field slit microscopy and dynamic light scattering (DLS). For the former, the entire vitreous was exposed. For the latter, only a window at the equator was dissected in some specimens, and the anterior segment was removed leaving the posterior lens capsule intact in others. DLS was performed to determine particle sizes at multiple sites 0.5 mm apart, spanning the globe at the equator (window dissections) and along the antero-posterior axis. Dark-field slit microscopy in diabetic subjects detected findings typical of age-related vitreous degeneration, but at much younger ages than nondiabetic controls. Noninvasive DLS measurements found a greater heterogeneity and larger particle sizes in vitreous of subjects with diabetes as compared to age-matched controls. DLS can detect and quantify the early molecular effects that cause vitreous collagen fibrils to cross-link and aggregate. This could provide valuable insight into ocular and systemic effects of hyperglycemia, because the molecular changes in diabetic vitreopathy could serve as an index of such effects throughout the body. In addition to the diagnostic implications, this methodology could provide a rapid, reproducible way to monitor the response to therapy with novel agents intended to prevent the complications of diabetes on a molecular level.
Sebag, J.↗
Contribution of Spaceflight Environmental Factors to Vision Risks
The risk of visual impairment and elevated intracranial pressure as a result of low-earth orbit microgravity exposure has directed our attention and research efforts to the eye. While the alterations observed in astronauts returning from long duration missions include vision and neuroanatomical changes observed by non-invasive methods, other effects and subsequent tissue responses at the molecular and cellular level can only be studied by accessing the tissue itself. As a result of this need, several studies are currently taking place within the Human and Health Countermeasures Element (HHC) that use animal models for eye research. The rodent eye has many similarities to the human eye, and both rats and mice have historically been used as models of human eye disease, aiding in the identification of the disease genes, elucidation of mechanisms of disease, as well as in the assessment of therapeutic treatments. These studies attempt to answer two central questions in the etiology of possible vision alterations in the environment of space exploration missions. The first is: what effects and response mechanisms take place in the different eye structures at the cellular and molecular level? The second question is directed to elucidate the contribution of the various environmental stressors (radiation, nutrition, fluid shift) to these effects. Collaborative approaches with internal and external investigators have allowed performing these studies in a most cost-effective fashion, providing preliminary data and laying the bases for testing further hypotheses in future and specifically designed animal experiments. From a study centered on the radioadaptive response in mice, we have learned that the retina responds to low and high dose gamma radiation by elevating antioxidant-related genes at early time points (4hrs) and that this response returns to control levels after 1 day post-irradiation. We are expanding this research with another collaborative study that investigates the combined effects of radiation exposure and iron overload on sensitivity to radiation injury in rat eyes. All main eye structures will be analyzed in this study: retina, lens and cornea. A study in collaboration with the Space Human Factors and Habitability Element (SHFH) investigates the effects of lunar dust exposure on the rat cornea. It is anticipated that common underlying oxidative stress mechanisms of damage may be observed as a result of these three stressors: radiation, nutritional iron and lunar dust. The contribution of fluid shift is addressed by a study using rats subjected to hindlimb suspension. The hypothesis to be tested in this study is that the mechanical stress imparted by the pressure differential across the optic disc and lamina cribosa will impact oxygenation (therefore causing oxidative stress and hypoxia) and cell survival. This study also includes the assessment of two nutritional antioxidant countermeasures: epigallocatechin gallate (green tea) and resveratrol. Finally, as a result of two successful tissue sharing efforts, we are proceeding with the analysis of eye samples of mice aboard two shuttle missions: STS-133 and STS-135. Results from the STS-133 study are presented in an independent abstract. Briefly, the results show that spaceflight represents a source of environmental stress that directly translates into oxidative and cellular stress in the retina. Similar analysis is also planned for the cornea. These samples add large value to our current vision research as they provide data on the direct effects of low-earth orbit spaceflight on eye structures and physiology.
Zanello, Susana B.↗
Quantitative X-ray tomographic analysis reveals calcium precipitation in cataractogenesis
Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in lens cells. We have applied synchrotron phase contrast X-ray micro-computed tomography to directly examine an age-related nuclear cataract model in Cx46 knockout (Cx46KO) mice. High-resolution 3D X-ray tomographic images reveal amorphous spots and strip-like dense matter precipitates in lens cores of all examined Cx46KO mice at different ages. The precipitates are predominantly accumulated in the anterior suture regions of lens cores, and they become longer and dense as mice age. Alizarin red staining data confirms the presence of calcium precipitates in lens cores of all Cx46KO mice. This study indicates that the spatial and temporal calcium precipitation is an age-related event associated with age-related nuclear cataract formation in Cx46KO mice, and further suggests that the loss of Cx46 promotes calcium precipitates in the lens core, which is a new mechanism that likely contributes to the pathological light scattering in this age-related cataract model.
60 APPLIED LIFE SCIENCES↗
Non-Invasive Health Diagnostics using Eye as a 'Window to the Body'
As a 'window to the body', the eye offers the opportunity to use light in various forms to detect ocular and systemic abnormalities long before clinical symptoms appear and help develop preventative/therapeutic countermeasures early. The effects of space travel on human body are similar to those of normal aging. For example, radiation exposure in space could lead to formation of cataracts and cancer by damaging the DNA and causing gene mutation. Additionally, the zero-gravity environment causes fluid shifts in the upper extremities of the body and changes the way blood flows and organ system performs. Here on Earth, cataract, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma are major eye diseases and are expected to double in next two decades. To detect, prevent, and treat untoward effects of prolonged space travel in real-time requires the development of non-invasive diagnostic technologies that are compact and powerful. We are developing fiber-optic sensors to evaluate the ocular tissues in health, aging, and disease employing the techniques of dynamic light scattering (cataract, uveitis, Alzheimer's, glaucoma, DR, radiation damage, refractive surgery outcomes), auto-fluorescence (aging, DR), laser-Doppler flowmetry (choroidal blood flow), Raman spectroscopy (AMD), polarimetry (diabetes), and retinal oximetry (occult blood loss). The non-invasive feature of these technologies integrated in a head-mounted/goggles-like device permits frequent repetition of tests, enabling evaluation of the results to therapy that may ultimately be useful in various telemedicine applications on Earth and in space.
Ansari, Rafat R.↗
A Bright Idea for the Eyes
The WEstinghouse Lighting Corporation's Eye Saver[TM] Easy Reading Light Bulb is the result of collaboration between Westinghouse, Marshall Research LLC, and NASA's Space Optics Manufacturing Technology Center at Marshall Space Flight Center. The light bulb contains a chrome top that directs light to areas where it is needed most. The bulb, which lasts 2,000 hours, provides 40 percent more surface illumination on work and reading surfaces, compared to a standard incandescent bulb. The lightly frosted finish reduces glare, which helps to reduce eyestrain. The bulb is particularly helpful for people with low vision and eye diseases such as macular degeneration.
Source record↗
Dissemination of information about the technologies of the Vision Research Lab through the World Wide Web
The Vision Research Lab at NASA John Glenn Research Center is headed by Dr. Rafat Ansari. Dr. Ansari and other researchers have developed technologies that primarily use laser and fiber optics to non-invasively detect different ailments and diseases of the eye. One of my goals as a LERCIP intern and ACCESS scholar for the 2004 summer is to inform other NASA employees, researchers and the general public about these technologies through the development of a website. The website incorporates the theme that the eye is a window to the body. Thus by investigating the processes of the eye, we can better understand and diagnosis different ailments and diseases. These ailments occur in not only earth bound humans, but astronauts as well as a result of exposure to elevated levels of radiation and microgravity conditions. Thus the technologies being developed at the Vision Research Lab are invaluable to humans on Earth in addition to those astronauts in space. One of my first goals was to research the technologies being developed at the lab. The first several days were spent immersing myself in the various articles, journals and reports about the theories behind Dynamic Light Scattering, Laser Doppler Flowmetry, Autofluoresence, Raman Spectroscopy, Polarimetry and Oximetry. Interviews with the other researchers proved invaluable to help understand these theories as well gain hands on experience with the devices being developed using these technologies. The rest of the Vision Research Team and I sat down and discussed how the overall website should be presented. Combining this information with the knowledge of the theories and applications of the hardware being developed, I worked out different ideas to present this information. I quickly learned Paint Shop Pro 8 and FrontPage 2002, as well as using online tutorials and other resources to help design an effective website. The Vision Research Lab website incorporates the anatomy and physiology of the eye, different diseases that affect the eye and the technologies being develop at the lab to help diagnosis these diseases. It also includes background information on Dr. Ansari as well as other researchers involved in the lab and it includes segments on patents, awards and achievements. There are links to help viewers navigate to internal and external websites to further investigate different ideas and hrther understand the implications of these technologies at being developed.
Dorais, Christopher M.↗
Cell transdifferentiation in ocular disease: Potential role for connexin channels
Highlights: • Cell transdifferentiation including EMT and EndMT is a pathological process in a number of ocular diseases. • Gap junction channels and connexin hemichannels play a role in cell transdifferentiation in ocular diseases. • Connexin-blocking therapies demonstrate efficacy in ocular disease models. • Future studies could explore connexin-based therapies for prevention and treatment of pathological transdifferentiation. Cell transdifferentiation is the conversion of a cell type to another without requiring passage through a pluripotent cell state, and encompasses epithelial- and endothelial-mesenchymal transition (EMT and EndMT). EMT and EndMT are well defined processes characterized by a loss of epithelial/endothelial phenotype and gain in mesenchymal spindle shaped morphology, which results in increased cell migration and decreased apoptosis and cellular senescence. Such cells often develop invasive properties. Physiologically, these processes may occur during embryonic development and can resurface, for example, to promote wound healing in later life. However, they can also be a pathological process. In the eye, EMT, EndMT and cell transdifferentiation have all been implicated in development, homeostasis, and multiple diseases affecting different parts of the eye. Connexins, constituents of connexin hemichannels and intercellular gap junctions, have been implicated in many of these processes. In this review, we firstly provide an overview of the molecular mechanisms induced by transdifferentiation (including EMT and EndMT) and its involvement in eye diseases. We then review the literature for the role of connexins in transdifferentiation in the eye and eye diseases. The evidence presented in this review supports the need for more studies into the therapeutic potential for connexin modulators in prevention and treatment of transdifferentiation related eye diseases, but does indicate that connexin channel modulation may be an upstream and unifying approach for regulating these otherwise complex processes.
60 APPLIED LIFE SCIENCES↗
Abnormal Eye Movements in Creutzfeldt-Jakob Disease
We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.
Grant, Michael P.↗
Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease
ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function mutations cause Stargardt disease (STGD1), a macular dystrophy associated with severe vision loss. To define the mechanisms underlying substrate binding and STGD1, we determine the cryo-EM structure of ABCA4 in its substrate-free and bound states. The two structures are similar and delineate an elongated protein with the two transmembrane domains (TMD) forming an outward facing conformation, extended and twisted exocytoplasmic domains (ECD), and closely opposed nucleotide binding domains. N-Ret-PE is wedged between the two TMDs and a loop from ECD1 within the lumen leaflet consistent with a lateral access mechanism and is stabilized through hydrophobic and ionic interactions with residues from the TMDs and ECDs. Our studies provide a framework for further elucidating the molecular mechanism associated with lipid transport and disease and developing promising disease interventions.
59 BASIC BIOLOGICAL SCIENCES↗
Computational Models of the Eye and their Applications in Long Duration Space Flight
Astronauts are exposed to cephalad fluid shift, increased carbon dioxide levels and other environmental factors during space flight. As a result of these conditions, it is believed that they are at risk of developing increased intracranial pressure (ICP) and intraocular pressure (IOP), which in turn may cause papilledema and other disorders of the eye that can lead to temporary or permanent changes in vision. However, the mechanisms behind this risk are not fully understood. Ground analog and flight studies pose challenges because there are limited non-invasive methods that can be used to study the eye and intracranial space. Therefore it is proposed that computational models can be applied to help address this gap by providing a low cost method for studying the effects of IOP, ICP and various properties of the eye on these diseases. The information presented by the authors provides a summary of several models found in literature that could potentially be augmented and applied to inform research. Specifically, finite element models of the optic nerve head, sclera and other structures of the eye can be readily adapted as potential building blocks. These models may also be integrated with a brain/cerebrospinal fluid (CSF) model which will take into account the interaction between the CSF fluid and its pressure on the optic nerve. This integration can enable the study of the effects of microgravity on the interaction between the vasculature system and CSF system and can determine the effects of these changes on the optic nerve, and in turn the eye. Ultimately, it can help pinpoint the influences of long-term exposure to microgravity on vision and inform the future research into countermeasure development. In addition to spaceflight, these models can provide deeper understanding of the mechanisms of glaucoma, papilledema and other eye disorders observed in terrestrial conditions.
Chen, Richard↗
Oculometric Assessment of Mild Neural Impairment
For over 100 years, neurologists have used eye movements to identify neural impairment, disease, or injury. Prior to the age of modern imaging, qualitative assessment of eye movements was a critical, routine component of diagnosis and remains today a routine law-enforcement tool for detecting impaired driving due to drugs or alcohol. We will describe the application of a simple 5-minute oculomotor tracking task coupled with a broad range of quantitative analyses of high-resolution oculomotor measurements for the sensitive detection of sub-clinical neural impairment and for the potential differentiation of various causes. Specifically, we will show that there are distinct patterns of impairment across our set of oculometric parameters observed with brain trauma, sleep and circadian disruption, and alcohol consumption. Such differences could form the basis of a self-administered medical monitoring or diagnostic support tool.
Stone, Lee↗
Oculometric Detection and Characterization of Sub-Clinical Visual/Visuomotor Impairment
It has long been known that qualitative abnormalities in eye movements can be used to diagnose overt brain pathologies (Diefendorf & Dodge, 1908; Fox & Holmes, 1926; Leigh & Zee, 2015). Here, we will examine the use of a set of quantitative measures of the human behavioral response (oculometrics) in a 5-minute radial ocular tracking task (Krukowski & Stone, 2005) with sufficient temporal, spatial, and directional uncertainty to minimize the contribution of a priori prediction or anticipation, and to emphasize the use of a posteriori visual processing of the stimulus trajectory (Liston & Stone, 2014). The derived oculometrics provide a largely independent, reliable set of metrics that are sensitive enough to detect mild sub-clinical impairment across a range of possible neural loci (Stone et al., 2019) with the pattern of impairment across the set providing specificity as to its nature (Tyson et al., 2023). We will review our earlier findings where oculometrics have been used to detect mild impairment due to traumatic brain injury, sleep loss, and low-dose alcohol (Liston et al., 2017; Stone et al., 2019; Tyson et al., 2021). We will also report on a recent clinical study of asymptomatic patients at risk of retinal pathology (Leung et al., 2022) and show that oculometrics can detect and characterize substantive loss of visual function in the absence of clinical indicators of pathology. We conclude that oculometric testing could be used as a routine non-invasive ophthalmological or neurological tool to aid in the early detection and diagnosis of neural injury, toxicity, or disease.
eye movements↗
Elastomeric Sensing of Pressure with Liquid Metal and Wireless Inductive Coupling
This project describes resistance-based soft sensors filled with liquid metal, which permit measurements of large strains (0 percent to 110 percent), associated with small forces of less than 30 Newtons. This work also demonstrates a methodology for wireless transfer of these strain measurements without connected electrodes. These sensors allow intermittent detection of pressure on soft membranes with low force. Adapting these sensors for passive wireless pressure sensing will eliminate the need for embedded batteries, and will allow the sensors to transmit pressure data through non-conductive materials including glass and acrylic. The absence of batteries allows us to embed these sensors into materials for long-term use because the sensors only use passive analog circuit elements. We found the oxidation of the liquid metal (eutectic gallium indium) plays a role in the repeatability of the soft sensors. We investigated how the oxidation layer affected the behavior of the sensor by encapsulating materials (silicone, fluorosilicone, and PVC) with varied permeabilities to oxygen. We measured the effects of mechanical loading on the oxidation layer and the effects of wireless inductive coupling on the oxidation layer. We concluded our research by investigating the effects of embedding self-resonant circuits into polydimethylsiloxane (PDMS). Efforts to design engineered systems with soft materials are a growing field with progress in soft robotics, epidermal electronics, and wearable electronics. In the field of soft robotics, PDMS-based grippers are capable of picking up delicate objects because their form-fitting properties allow them to conform to the shape of objects more easily than conventional robotic grippers. Epidermal devices also use PDMS as a substrate to hold electronic components such as radios, sensors, and power supply circuits. Additionally, PDMS-based soft sensors can monitor human motion with liquid metal embedded within micro-channels. Passive wireless sensors have applications in structural health monitoring and medical health monitoring. Doctors can take wireless blood pressure measurements inside arteries to monitor the progression of heart disease. Glaucoma patients can use this technology to monitor the pressure in their eyes to track the progression of the disease.
Dick, Jacob↗
Comparison of smooth pursuit and combined eye-head tracking in human subjects with deficient labyrinthine function
The effects of deficient labyrinthine function on smooth visual tracking with the eyes and head were investigated, using ten patients with bilateral peripheral vestibular disease and ten normal controls. Active, combined eye-head tracking (EHT) was significantly better in patients than smooth pursuit with the eyes alone, whereas normal subjects pursued equally well in both cases. Compensatory eye movements during active head rotation in darkness were always less in patients than in normal subjects. These data were used to examine current hypotheses that postulate central cancellation of the vestibulo-ocular reflex (VOR) during EHT. A model that proposes summation of an integral smooth pursuit command and VOR/compensatory eye movements is consistent with the findings. Observation of passive EHT (visual fixation of a head-fixed target during en bloc rotation) appears to indicate that in this mode parametric gain changes contribute to modulation of the VOR.
Leigh, R. J.↗
Dynamic Light Scattering Developed to Look Through the Eye's Window Into the Body
Microgravity researcher Dr. Rafat R. Ansari, from the NASA Glenn Research Center, has found that the eye operates much like a camera and is the "window to the body." The eye contains transparent tissue through which light passes, providing us a view of what's going on inside. These transparent tissues represent nearly every tissue type that exists throughout the body. With the correlations and comparisons of these tissues done at Glenn, we hope to improve doctors' ability to diagnose diseases at much earlier stages. The medical community will be able to look noninvasively and quantitatively into a patient's eyes to detect disease before symptoms appear. Since the eye is easily accessed by light, the optical technologies created at Glenn can be used to evaluate its structure and physiology in health, aging, and disease.
Stauber, Laurel J.↗
Defining Change Thresholds: What Change Is Outside Typical Sources of Variation?
Researchers often have a difficult time defining meaningful thresholds for change. We sometimes identify subtle changes but what amount of change is beyond typical sources of variation? This is especially complicated when trying to understand new disease pathogenesis like the constellation of eye changes leading to Spaceflight-associated Neuro-ocular Syndrome (SANS). To support decision makers in defining minimal meaningful change, we used a Bayesian hierarchical model to estimate innate sources of variability such as natural day to day variation. Healthy subjects were recruited and imaged with MRI, OCT, and US on separate days and measured by several technicians. Models were developed specifying random effects for the sources of variation – between left and right eyes, within-individuals over time, between raters, and finally between individuals. This allowed us to find the posterior distribution for the total typical variation, within an eye, which we use to define a threshold where change beyond typical sources of variation is likely. This threshold is now used as our earliest indicator of systematic increase in Total Retinal Thickness (a precursor to optic disc edema).
Millennia Young↗
Effectiveness of Botulinum Toxin Administered to Abolish Acquired Nystagmus
We injected botulinum toxin into the horizontal rectus muscles of the right eyes of two patients who had acquired pendular nystagmus with horizontal, vertical, and torsional components. This treatment successfully abolished the horizontal component of the nystagmus in the injected eye in both patients for approximately 2 months. Both patients showed a small but measurable improvement of vision in the injected eye that may have been limited by coexistent disease of the visual pathways. The vertical and torsional components of the nystagmus persisted in both patients. In one patient, the horizontal component of nystagmus in the noninjected eye increased; we ascribe this finding to plastic-adaptive changes in response to paresis caused by the botulinum toxin. Such plastic-adaptive changes and direct side effects of the injections - such as diplopia and ptosis - may limit the effectiveness of botulinum toxin in the treatment of acquired nystagmus. Neither patient elected to repeat the botulinum treatment.
Leigh, R. John↗