Week in Review: Number 38

Alu cDNA Strongly Implicated in Geographic Atrophy
Geographic atrophy (GA) is often considered an advanced form of nonexudative age-related macular degeneration (dry AMD), and although the etiology of centrifugal (outward) spread of the disease from the midperiphery of the retina to the central retina is well studied, the underlying mechanism of pathophysiology is poorly understood. New research strongly suggests that toxic levels Alu complementary DNA (cDNA) at the active leading edge of the "geography of atrophy," confirmed for the first time in human eye specimens (n=20), is responsible for the expansion of the lesion that gradually leads to vision loss. The Alu cDNA, a cytoplasmic self-priming retrotransposon reverse-transcribed from noncoding RNA, triggers activation of the inflammasome, a multiprotein complex of the innate immune system found in the cell cytosol that triggers inflammation and ultimately leads to cytotoxicity and damage to the retinal pigmented epithelium (RPE) that supports retinal health and function. The accumulation of Alu RNA repeats in turn is due to age-related decline in an enzyme called DICER1. In terms of mechanism, the Alu RNA leads to Alu cDNA formation via L1 reverse transcriptase. The Alu cDNA engages a DNA sensing enzyme called cGAS to trigger the escape of mitochondrial DNA into the cell’s cytosol, which in turn amplifies cGAS in a feedback loop (due to the presence of two DNA populations) that triggers the inflammasome (specifically the NLRP3 component of this protein), ultimately resulting in RPE and retinal degeneration.

In an earlier obervational study, senior author Jayakrishna Ambati, MD, demonstrated that FDA-approved nucleoside reverse transcriptase inhibitors (NRTIs) are associated with reduced risk of developing advanced dry macular degeneration in people. His company Inflammasome Therapeutics is working on alkylated derivatives called Kamuvudines that are safer (less toxic) in that they inhibit inflammasome activation but not the reverse transcription of Alu RNA. When asked why he chose to target the endpoint of the inflammasome rather than upstream points in this pathway, such as the complement pathway, Ambati replied, “Alu cDNA causes RPE degeneration via the DNA sensor cGAS. However, there are other toxic substances such as amyloid-beta, complement, and iron, which also play a role in Geographic Atrophy. Therefore, we believe that Kamuvudines which block inflammasome activation induced by these various toxic substances are a rational therapeutic approach to block this multipronged assault.” Given the strong data related to NRTIs, Ambati's team plans on starting clinical trials in 2022. He states, "[T]he planned clinical trial will enroll patients who have early stages of Geographic Atrophy, not involving the center of the retina. The goal of Kamuvudine treatment is to stop or reduce the rate of progression of the disease. This has been the typical strategy of most clinical trials to date with other drug candidates." Although limited by pre-clinical studies, Jayakrishna Ambati's meticulous research methodology and astounding findings are a major clinical advance for a devastating disease that thus far as no treatment.

Aquaporin 5 Induction to Treat Corneal Defects
A new study provides evidence that aquaporins play an important role in corneal cell proliferation and nerve regeneration. Aquaporins, or water channels, are transmembrane proteins that facilitate the transport of water (and small solutes), thereby maintaining cell water homeostasis. There are 13 types of aquaporins found in mammals. The study explored induction of aquaporin 5 (AQP5), which is expressed in the cornea, as a potential therapy to accelerate the resurfacing of corneal defects. In previous studies, the researchers found that deficiencies in AQP5 and nerve growth factor (NGF) resulted in delayed repair of corneal epithelial injury in mice. The present study sought to examine the mechanism of AQP5. The investigators engineered 189 male Aqp5 knockout (Aqp5-/-) mice and compared them to 75 normal (Aqp5+/+) male mice after their epithelial cells had been debrided. Corneal epithelial and nerve regeneration rates were significantly delayed in the Aqp5-/- mice, but were significantly increased in Aqp5-/- mice treated with NGF. NGF also improved the recovery of corneal nerve fiber density and sensitivity, and accompanied recovered levels of phosphorylated Akt in the Aqp5-/- mice. Unsurprisingly, when an Akt inhibitor was administered with the NGF, this led to reversal of Akt reactivation and corneal epithelial and nerve regeneration. The lead investigator comments, “It is exciting to find that Aqp5 deficiency can affect the nerve regeneration of mice by affecting the activation of NGF and Akt signaling pathways, which is not found in previous studies. These results need to be confirmed in a clinical setting, but they provide evidence for the involvement of aquaporins in cell proliferation and nerve regeneration and suggest AQP5 induction as a possible therapy to accelerate the resurfacing of corneal defects.”

Systematic Review & Meta-Analysis: Smart Device Exposure and its Associations with Myopia
Researchers in the U.K. conducted a systematic review and meta-analysis investigating smart device exposure and myopia in children and young adults between 3 months and 33 years of age. They report this being the most comprehensive study yet regarding the myopia epidemic. From a database search that yielded over 3,000 articles, the two reviewers assessed 286 full-text articles for eligibility, resulting in 33 articles included in the systematic review and 11 articles included in the meta-analysis. A high heterogeneity between studies was noted, due to factors such as variability in sample size, the mean age of participants (3-16 years), the standard error of the estimated odds of prevalent or incident myopia, and the use of continuous versus categorical screen time variables. Nonetheless, the authors extrapolate that "[s]mart device exposure might be associated with an increased risk of myopia." In particular, they found that high levels of smart device screen time was associated with roughly 30% higher risk of myopia; when combined with excessive computer use, that risk rose to roughly 80%. The researchers caution that "[r]esearch with objective measures of screen time and myopia-related outcomes that investigates smart device exposure as an independent risk factor is required." However, they also note the importance of research in this topic, especially at a time when millions of children and young people around the world are spending substantial amounts of time doing near work and using digital devices during the COVID-19 pandemic.

Alzheimer's Risk Gene APOE4 Could Be Associated with Better Visual Working Memory
To date, scientists have found versions of at least 30 different genes associated with an altered risk of developing Alzheimer's disease, the most common cause of dementia. Of these, the gene APOE, which encodes apolipoprotein E, has the largest effect on Alzheimer's disease risk. APOE  comes in three variants (E2, E3, and E4), and each of us carries two copies of this gene, one from each parent. Individuals who inherit one copy of the E4 version of APOE  (approximately 25% of people) are roughly three times more likely to develop Alzheimer’s disease compared to those who do not carry the E4 version. Individuals with two copies of the E4 version are more than eight times more likely to develop Alzheimer's disease. It is curious, then, that some individuals who possess the APOE4  risk gene demonstrate better performance in visual working memory. Researchers in the U.K. studied 400 volunteers from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth Cohort, this cohort being characterized by being born in the same week in 1946. The researchers assessed the effects of the APOE4  risk gene and beta-amyloid (a hallmark of Alzheimer's disease), as measured by a brain PET scan, on visual working memory, which was measured using a computerized "What was where?" task (recalling identities and locations). The findings showed that having the APOE4  gene and the presence of beta-amyloid in the brain had opposing effects on object identification, with APOE4  predicting better recall (and more precise location recall) and amyloid build-up predicting poorer recall. This suggests that having a copy of the APOE4  gene could confer some benefits in older age, even in the presence of amyloid plaques, and could provide clues as to why this gene variant is so common. Some earlier studies point to APOE4  conferring some benefits in younger age; the researchers suggest that this benefit could persist into older age. Although the connection might be of little comfort to patients living with Alzheimer's, building a more complete picture of the disease, such as why APOE4  might result in better memory, may also help us to understand why it also leads to increased risk for Alzheimer’s.

Reading Performance as a Suitable Indicator of Functional Impairment in Geographic Atrophy
In geographic atrophy (GA), an advanced form of dry age-related macular degeneration (AMD), reading ability is a functional indicator that is closely related to changes in retinal structure. German researchers, along with U.S. colleagues, are studying how reading speed is a better reflection of functional impairment in geographic atrophy compared to best-corrected visual acuity (BCVA). They argue that even when central visual acuity is still good, retinal imaging can be used to detect changes that affect reading performance. While conventional assessments are important to guide therapeutic decisions, "conventional functional tests such as visual acuity do not capture all the dismal functional consequences of the disease," one of the authors states. These limitations can be severe enough to affect everyday quality of life. The study involved 85 participants with geographic atrophy, with reading ability assessed using Radner charts and retinal assessment performed with longitudinal fundus autofluorescence and infrared reflectance images. According to their findings, reading acuity was most strongly associated with BCVA and structural biomarkers; reading speed was most strongly associated with BCVA, low-luminance visual acuity, and structural biomarkers. The binocular inhibition phenomenon, a negative influence of the worse-seeing eye in binocular vision (in this case, reading), was not observed, leading the researchers to recommend that clinical and low-vision care be focused primarily on the better-seeing eye. They conclude that both reading ability and reading speed can be suitable functional tests (endpoints) for clinical studies.

In Other News
(1) Smartphone use associated with higher myopia in teenagers
(2) Intraocular epidermal growth factor concentration, axial length, and high axial myopia
(3) Myopia in the news: Article#1, Article#2, Article#3, Article#4, Article#5
(4) Millions with eye conditions at higher risk of dementia

Alzheimer's Risk Gene APOE4 Could Be Associated with Better Visual Working Memory

Article: Potential cognitive benefits of major Alzheimer’s risk gene 
Source: University College London (U.K.)
Published: October 7, 2021 

To date, scientists have found versions of at least 30 different genes associated with an altered risk of developing Alzheimer's disease, the most common cause of dementia. Of these, the gene APOE, which encodes apolipoprotein E, has the largest effect on Alzheimer's disease risk. APOE  comes in three variants (E2, E3, and E4), and each of us carries two copies of this gene, one from each parent. Individuals who inherit one copy of the E4 version of APOE  (approximately 25% of people) are roughly three times more likely to develop Alzheimer’s disease compared to those who do not carry the E4 version. Individuals with two copies of the E4 version are more than eight times more likely to develop Alzheimer's disease. It is curious, then, that some individuals who possess the APOE4  risk gene demonstrate better performance in visual working memory. Researchers in the U.K. studied 400 volunteers from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth Cohort, this cohort being characterized by being born in the same week in 1946. The researchers assessed the effects of the APOE4  risk gene and beta-amyloid (a hallmark of Alzheimer's disease), as measured by a brain PET scan, on visual working memory, which was measured using a computerized "What was where?" task (recalling identities and locations). The findings showed that having the APOE4  gene and the presence of beta-amyloid in the brain had opposing effects on object identification, with APOE4  predicting better recall (and more precise location recall) and amyloid build-up predicting poorer recall. This suggests that having a copy of the APOE4  gene could confer some benefits in older age, even in the presence of amyloid plaques, and could provide clues as to why this gene variant is so common. Some earlier studies point to APOE4  conferring some benefits in younger age; the researchers suggest that this benefit could persist into older age. Although the connection might be of little comfort to patients living with Alzheimer's, building a more complete picture of the disease, such as why APOE4  might result in better memory, may also help us to understand why it also leads to increased risk for Alzheimer’s.

My rating of this study: ⭐⭐🌸

Lu K, Nicholas JM, Pertzov Y, et al. "Dissociable effects of APOE ε4 and β-amyloid pathology on visual working memory." Nature Aging.  1:1002-1009. 7 October 2021. https://doi.org/10.1038/s43587-021-00117-4 

Systematic Review & Meta-Analysis: Smart Device Exposure and its Associations with Myopia

Article: Screen time linked to risk of myopia in young people
Source: Anglia Ruskin University (U.K.)
Published: October 7, 2021 

Researchers in the U.K. conducted a systematic review and meta-analysis investigating smart device exposure and myopia in children and young adults between 3 months and 33 years of age. They report this being the most comprehensive study yet regarding the myopia epidemic. From a database search that yielded over 3,000 articles, the two reviewers assessed 286 full-text articles for eligibility, resulting in 33 articles included in the systematic review and 11 articles included in the meta-analysis. A high heterogeneity between studies was noted, due to factors such as variability in sample size, the mean age of participants (3-16 years), the standard error of the estimated odds of prevalent or incident myopia, and the use of continuous versus categorical screen time variables. Nonetheless, the authors extrapolate that "[s]mart device exposure might be associated with an increased risk of myopia." In particular, they found that high levels of smart device screen time was associated with roughly 30% higher risk of myopia; when combined with excessive computer use, that risk rose to roughly 80%. The researchers caution that "[r]esearch with objective measures of screen time and myopia-related outcomes that investigates smart device exposure as an independent risk factor is required." However, they also note the importance of research in this topic, especially at a time when millions of children and young people around the world are spending substantial amounts of time doing near work and using digital devices during the COVID-19 pandemic.

My rating of this study: ⭐⭐⭐

Foreman J, Salim AT, Praveen A, et al. "Association between digital smart device use and myopia: a systematic review and meta-analysis." The Lancet Digital Health.  5 October 2021. https://doi.org/10.1016/S2589-7500(21)00135-7 

Reading Performance as a Suitable Indicator of Functional Impairment in Geographic Atrophy

Article: AMD: Reading ability crucial indicator of functional loss 
Source: University of Bonn (Germany)
Published: September 30, 2021 

In geographic atrophy (GA), an advanced form of dry age-related macular degeneration (AMD), reading ability is a functional indicator that is closely related to changes in retinal structure. German researchers, along with U.S. colleagues, are studying how reading speed is a better reflection of functional impairment in geographic atrophy compared to best-corrected visual acuity (BCVA). They argue that even when central visual acuity is still good, retinal imaging can be used to detect changes that affect reading performance. While conventional assessments are important to guide therapeutic decisions, "conventional functional tests such as visual acuity do not capture all the dismal functional consequences of the disease," one of the authors states. These limitations can be severe enough to affect everyday quality of life. The study involved 85 participants with geographic atrophy, with reading ability assessed using Radner charts and retinal assessment performed with longitudinal fundus autofluorescence and infrared reflectance images. According to their findings, reading acuity was most strongly associated with BCVA and structural biomarkers; reading speed was most strongly associated with BCVA, low-luminance visual acuity, and structural biomarkers. The binocular inhibition phenomenon, a negative influence of the worse-seeing eye in binocular vision (in this case, reading), was not observed, leading the researchers to recommend that clinical and low-vision care be focused primarily on the better-seeing eye. They conclude that both reading ability and reading speed can be suitable functional tests (endpoints) for clinical studies.

My rating of this study: ⭐🌸

Künzel SH, Lindner M, Sassen J, et al. "Association of Reading Performance in Geographic Atrophy Secondary to Age-Related Macular Degeneration With Visual Function and Structural Biomarkers." JAMA Ophthalmology.  139(11):1191-1199. 30 September 2021. https://doi.org/10.1001/jamaophthalmol.2021.3826 

Alu cDNA Strongly Implicated in Geographic Atrophy

Article: DNA in Cell Cytoplasm Implicated in Age-Related Blindness
Source: The Scientist
Published: September 29, 2021
Article: Toxic DNA Buildup in Eye May Drive Macular Degeneration
Source: University of Virginia Medicine
Published: September 30, 2021
Article: Inhibiting Inflammation Blocks Retinal Death in Animal Models of an Untreatable Blindness
Source: Genetic Engineering & Biotechnology News
Published: September 30, 2021 

Retina cross-section: photoreceptors at top (green) with RPE above, not pictured

Geographic atrophy (GA) is often considered an advanced form of nonexudative age-related macular degeneration (dry AMD), and although the etiology of centrifugal (outward) spread of the disease from the midperiphery of the retina to the central retina is well studied, the underlying mechanism of pathophysiology is poorly understood. New research strongly suggests that toxic levels Alu complementary DNA (cDNA) at the active leading edge of the "geography of atrophy," confirmed for the first time in human eye specimens (n=20), is responsible for the expansion of the lesion that gradually leads to vision loss. The Alu cDNA, a cytoplasmic self-priming retrotransposon reverse-transcribed from noncoding RNA, triggers activation of the inflammasome, a multiprotein complex of the innate immune system found in the cell cytosol that triggers inflammation and ultimately leads to cytotoxicity and damage to the retinal pigmented epithelium (RPE) that supports retinal health and function. The accumulation of Alu RNA repeats in turn is due to age-related decline in an enzyme called DICER1. In terms of mechanism, the Alu RNA leads to Alu cDNA formation via L1 reverse transcriptase. The Alu cDNA engages a DNA sensing enzyme called cGAS to trigger the escape of mitochondrial DNA into the cell’s cytosol, which in turn amplifies cGAS in a feedback loop (due to the presence of two DNA populations) that triggers the inflammasome (specifically the NLRP3 component), ultimately resulting in RPE and retinal degeneration.

In an earlier obervational study, senior author Jayakrishna Ambati, MD, demonstrated that FDA-approved nucleoside reverse transcriptase inhibitors (NRTIs) are associated with reduced risk of developing advanced dry macular degeneration in people. His company Inflammasome Therapeutics is working on alkylated derivatives called Kamuvudines that are safer (less toxic) in that they inhibit inflammasome activation but not the reverse transcription of Alu RNA. When asked why he chose to target the endpoint of the inflammasome rather than upstream points in this pathway, such as the complement pathway, Ambati replied, “Alu cDNA causes RPE degeneration via the DNA sensor cGAS. However, there are other toxic substances such as amyloid-beta, complement, and iron, which also play a role in Geographic Atrophy. Therefore, we believe that Kamuvudines which block inflammasome activation induced by these various toxic substances are a rational therapeutic approach to block this multipronged assault.” Given the strong data related to NRTIs, Ambati's team plans on starting clinical trials in 2022. He states, "[T]he planned clinical trial will enroll patients who have early stages of Geographic Atrophy, not involving the center of the retina. The goal of Kamuvudine treatment is to stop or reduce the rate of progression of the disease. This has been the typical strategy of most clinical trials to date with other drug candidates." Although limited by pre-clinical studies, Jayakrishna Ambati's meticulous research methodology and astounding findings are a major clinical advance for a devastating disease that thus far as no treatment.

My rating of this study: ⭐⭐⭐⭐⭐

Fukuda S, Narendran S, Varshney A, et al. "Alu  complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity." Science Advances.  7(40). 29 September 2021. https://doi.org/10.1126/sciadv.abj3658

Aquaporin 5 Induction to Treat Corneal Defects

Article: New study suggests that aquaporin could be key to repairing corneal defects
Source: Elsevier
Published: September 29, 2021

Loss of AQP5 inhibits corneal reepithelialization (top), NGF
promotes corneal epithelial wound healing and nerve regeneration
in AQP5-/- mice (middle), Akt inhibitor reverses corneal epithelial
wound healing and nerve regeneration in AQP5-/- mice (bottom)

A new study provides evidence that aquaporins play an important role in corneal cell proliferation and nerve regeneration. Aquaporins, or water channels, are transmembrane proteins that facilitate the transport of water (and small solutes), thereby maintaining cell water homeostasis. There are 13 types of aquaporins found in mammals. The study explored induction of aquaporin 5 (AQP5), which is expressed in the cornea, as a potential therapy to accelerate the resurfacing of corneal defects. In previous studies, the researchers found that deficiencies in AQP5 and nerve growth factor (NGF) resulted in delayed repair of corneal epithelial injury in mice. The present study sought to examine the mechanism of AQP5. The investigators engineered 189 male Aqp5 knockout (Aqp5-/-) mice and compared them to 75 normal (Aqp5+/+) male mice after their epithelial cells had been debrided. Corneal epithelial and nerve regeneration rates were significantly delayed in the Aqp5-/- mice, but were significantly increased in Aqp5-/- mice treated with NGF. NGF also improved the recovery of corneal nerve fiber density and sensitivity, and accompanied recovered levels of phosphorylated Akt in the Aqp5-/- mice. Unsurprisingly, when an Akt inhibitor was administered with the NGF, this led to reversal of Akt reactivation and corneal epithelial and nerve regeneration. The lead investigator comments, “It is exciting to find that Aqp5 deficiency can affect the nerve regeneration of mice by affecting the activation of NGF and Akt signaling pathways, which is not found in previous studies. These results need to be confirmed in a clinical setting, but they provide evidence for the involvement of aquaporins in cell proliferation and nerve regeneration and suggest AQP5 induction as a possible therapy to accelerate the resurfacing of corneal defects.”

My rating of this study: ⭐⭐⭐

Liu Y, Di G, Wang Y, et al. "Aquaporin 5 Facilitates Corneal Epithelial Wound Healing and Nerve Regeneration by Reactivating Akt Signaling Pathway." American Journal of Pathology.  11 August 2021. https://doi.org/10.1016/j.ajpath.2021.07.010 

Week in Review: Number 37

Corneal Epithelial Stem Cell Topical Therapy in DED
Dry eye disease is estimated to affect up to half of the U.S. population. Depending on the underlying etiology, a wide range of therapies are available. Pharmaceutical scientists, along with clinical colleagues, are exploring a topical delivery of corneal epithelial stem cells, located and obtained solely at the limbus, as a potentially safer and more effective treatment option. They report excellent results in the first stage of clinical trials. Collaborating with a Good Manufacturing Practice (GMP) facility, they isolated and expanded the human corneal stem cells, obtained from donor tissues from an eye bank, to derive a topically applied medicine in this case. The study recruited 17 participants (34 eyes) suffering from advanced dry eye disease, each of whom have documented attempts to treat their dry eyes using between 6 and 14 conventional dry eye therapies. These participants also qualified for the trial based on a score greater than or equal to 14 on the Standardized Patient Evaluation of Eye Dryness (SPEED™) questionnaire and a score greater than or equal to 40 on the Ocular Surface Disease Index (OSDI©). The lead researcher of the study remarks, “Nothing was helping them; they were in a very severe condition. Some of them could only go outside in the dark because their inflammation was so bad that sunlight would burn their eyes.”

During the trial, each patient self-administered the topical corneal epithelial stem cell-derived product four times daily in both eyes for 12 weeks. Compared to baseline, there was a 23% improvement in SPEED™ scores and a 17% improvement in OSDI© scores (but not statistically significant). An additional dry eye assessment questionnaire (University of North Carolina Dry Eye Management Scale) showed a 14% score improvement. Objective measurements included best-corrected visual acuity (BCVA), corneal topography, and tear film osmolarity, none of which changed significantly in the 12 weeks. None of the study participants reported any adverse effects and, as the authors are keen to note, all asked to resume use of the drops after the study. The project lead speculates that the success of the therapy is likely because it both reduces inflammation and regenerates damaged tissue, as stem cells would. They conclude that topical corneal epithelial stem cell-derived supernatant that can be self-administered by the patient shows promise at improving patient symptoms and quality of life in severe DED that is unresponsive to conventional therapies. They next plan a double-blinded study and have filed patents for their product.

RGC Dendrite Mosaics are Optimized for Efficiency
Neurobiologists studying the cellular organization of the retina found that it closely mimics a concept known as efficient coding theory, an optimization model of sensory coding in the nervous system. In two papers on retinal structure, they show that natural selection and evolution shaped the patterns of sensitivity in the retina to closely follow what efficient coding theory would predict. Specifically, these sensitivity patterns are seen in the layer of dendrites of the retinal ganglion cells (RGCs), i.e., the inner plexiform layer. Although the ganglion cells downstream only output in binary fashion, either depolarization or not, it is the three-dimensional dendrite mosaic that is sensitive to different stimuli. One of the researchers explains, “The mosaics don’t just randomly overlap, but they don’t overlap in a highly ordered way.” And those mosaics adapt to current conditions. This results in a retina that is not merely one mosaic but many stacked mosaics that each encodes something different about the visual field, parsing as many as 40 different features that together add up to form an image. Furthermore, the depth of the mosaic serves as a kind of address for the type of information that that layer encodes. For example, the deeper layers receive "off" signals, while the more shallow layers get "on" signals, meaning that even when the same (cross-section) area of the retina is stimulated, different layers of the dendrite mosaic can convey different kinds of signals.

One reason the array is so efficient is that the cells conserve energy by not responding to some stimuli. In environments that are "noisy," the receptors tune out most of the static and only respond to something that’s very bright. One of the researchers states, “The more noise there is in the world, the pickier the cell can be about what it will respond to...And when they get pickier, it turns out that there's less redundancy in them.” Moreover, the more noise, the greater the offset between on and off RGC detector pairs. In technical terms, "[I]nformation is maximized when these mosaic pairs are anti-aligned," when the distances between them are greater than average. In other words, the retina is optimized to handle high noise conditions in order to detect things that stand out, and it does so by minimizing the amount of redundant information it encodes. The researchers hope that studying how the retina is optimized for efficiency will help to design smartphone sensors; however, they acknowledge that we are a long ways away from replicating the natural arrangement in the retina.

NeuroD1-Mediated Gene Therapy Restores Visual Function in Mice after Stroke
Strokes happen when blood flow to neural tissue stops, leading to neuronal loss and gliosis. A large portion of the cerebrum is devoted to processing vision, thus when an artery is blocked in these regions, vision loss can result. Researchers are exploring the use of gene therapy to directly reprogram endogenous astrocytes into neurons in situ as a means to restore vision in the aftermath of irreversible death of neurons. As compared to the plasticity found when the brain remaps its pathways, a slow and inefficient process, the new gene therapy offers a more efficient solution. The technique shows promise thus far in a model of ischemic stroke affecting the visual centers in the brains of mice, in particular using adeno-associated viruses to deliver transcription factor NeuroD1 in vivo to glial cells in the affected area of the brain. These cells were observed to reprogram into neurons and integrate into the microcircuits of the visual cortex. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. One of the researchers comments, “We don’t have to implant new cells, so there’s no immunogenic rejection. This process is easier to do than stem cell therapy, and there’s less damage to the brain. We are helping the brain heal itself. We can see the connections between the old neurons and the newly reprogrammed neurons get reestablished. We can watch the mice get their vision back.” They conclude, "Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury." The researchers hope that the techniques they develop to restore function in the visual cortex will then help in perfecting techniques to restore motor function after stroke.

CRISPR Gene Therapy in LCA Patients Shows Positive Results
Scientists report encouraging results for the first few cases of CRISPR gene-editing for Leber congenital amaurosis (LCA), presenting their findings at the International Symposium on Retinal Degeneration. The gene-editing was notable in this case for being the first trial to inject CRISPR in vivo in human subjects, as compared to explanting cells, editing them in vitro, and then infusing them back into tissues of the body. Thus far, seven patients have volunteered to have the experimental therapy. NPR interviewed two of those patients, Carlene Knight and Michael Kalberer. Knight reports, "I was bumping into the cubicles and really scaring people that were sitting at them." With vision improved enough to make out doorways, navigate hallways, spot objects and even see colors, she says she no longer scares people and has fewer bruises from bumping into things. Knight also says that colors are more vivid, which she has appreciated since she was a kid. "I've always loved colors. Since I was a kid it's one of those things I could enjoy with just a small amount of vision. But now I realize how much brighter they were as a kid because I can see them a lot more brilliantly now," she says. Similarly, Kalberer reports being thrilled at his improved vision, which he noticed starting one month after the treatment. For example, he is now able to recognize shapes and light much better, and has regained more peripheral vision. It was an especially joyous moment for him to watch the DJ's strobe lights change color at his cousin's wedding and seeing the sunset again for the first time. One of the clinical researchers at HMS says, "We're thrilled about this. This is the first time we're having evidence that gene editing is functioning inside somebody and it's improving — in this case — their visual function." They next plan on trials at higher doses, and in age brackets that have the best chance of benefiting. Although the treatment is far from a cure, vision never returned to normal, and visual improvement is not seen in all seven patients at this point, for some patients in the trial, the changes experienced are enough to have a meaningful impact on their daily lives.

Handheld Screening Device to Detect Amblyopia
Colloquially called "lazy eye," amblyopia results when there is an underdeveloped connection between the eye and the brain, leading the brain to favor the vision in the better-seeing eye as those synapses strengthen and the synapses with the worse-seeing eye diminish. This can occur as a result of a variety of underlying causes, with anisometropia (or unequal refractive error) being the most common cause. Other factors leading to amblyopia include strabismus or tropia (an eye misalignment), visual deprivation, and high astigmatism. Where strabismus is the underlying etiology, detection of an eye misalignment in early childhood can prevent difficulties in academic performance. However, many pediatricians and primary care providers are not exposed to vision testing beyond basic visual acuity. Funded by the National Eye Institute, researchers are exploring a prototype handheld screening device to assess the eyes' ability to fixate together. The Pediatric Vision Scanner (PVS) simultaneously scans both retinas, specifically the fovea, with a polarized laser to detect even small-angle deviations. The device then provides a binocularity score, which is used to determine whether the child needs referral for more specialized assessment. The study recruited 300 children ages 2 to 6 with no known eye disorders. Two non-ophthalmic research associates were trained to use the device to screen each child, and the results were compared to eye examination performed by a pediatric ophthalmologist who was masked to the device's results. The device showed a 100% sensitivity, detecting all 6 cases of amblyopia and/or strabismus that agreed with the professional eye examination. However, the device also flagged an additional 45 children as possibly having amblyopia and/or strabismus who were later determined by the eye examination to be normal. The study did not compare this prototype with photo-screening devices which detect risk factors of amblyopia via differences in light reflexes between the two eyes. Despite a relatively low threshold of sensitivity (resulting in a high rate of false positives) in this prototype, the test requires only 2.5 seconds to perform, which could be a beneficial addition to busy pediatric practices.

In Other News
(1) Why can’t we identify music notes as well as colors?
(2) CRISPR gene editing in Leber congenital amaurosis
(3) Children's visual perception continues to develop up to age 10

Corneal Epithelial Stem Cell Topical Therapy in DED

Article: TTUHSC Technology Leads Successful Clinical Trial to Treat Dry Eye Disease
Source: Texas Tech University Health Sciences Center, School of Pharmacy
Published: September 29, 2021

Dry eye disease is estimated to affect up to half of the U.S. population. Depending on the underlying etiology, a wide range of therapies are available. Pharmaceutical scientists, along with clinical colleagues, are exploring a topical delivery of corneal epithelial stem cells, located and obtained solely at the limbus, as a potentially safer and more effective treatment option. They report excellent results in the first stage of clinical trials. Collaborating with a Good Manufacturing Practice (GMP) facility, they isolated and expanded the human corneal stem cells, obtained from donor tissues from an eye bank, to derive a topically applied medicine in this case. The study recruited 17 participants (34 eyes) suffering from advanced dry eye disease, each of whom have documented attempts to treat their dry eyes using between 6 and 14 conventional dry eye therapies. These participants also qualified for the trial based on a score greater than or equal to 14 on the Standardized Patient Evaluation of Eye Dryness (SPEED™) questionnaire and a score greater than or equal to 40 on the Ocular Surface Disease Index (OSDI©). The lead researcher of the study remarks, “Nothing was helping them; they were in a very severe condition. Some of them could only go outside in the dark because their inflammation was so bad that sunlight would burn their eyes.”

During the trial, each patient self-administered the topical corneal epithelial stem cell-derived product four times daily in both eyes for 12 weeks. Compared to baseline, there was a 23% improvement in SPEED™ scores and a 17% improvement in OSDI© scores (but not statistically significant). An additional dry eye assessment questionnaire (University of North Carolina Dry Eye Management Scale) showed a 14% score improvement. Objective measurements included best-corrected visual acuity (BCVA), corneal topography, and tear film osmolarity, none of which changed significantly in the 12 weeks. None of the study participants reported any adverse effects and, as the authors are keen to note, all asked to resume use of the drops after the study. The project lead speculates that the success of the therapy is likely because it both reduces inflammation and regenerates damaged tissue, as stem cells would. They conclude that topical corneal epithelial stem cell-derived supernatant that can be self-administered by the patient shows promise at improving patient symptoms and quality of life in severe DED that is unresponsive to conventional therapies. They next plan a double-blinded study and have filed patents for their product.

My rating of this study: ⭐⭐⭐

Rush SW, Chain J, Das H, et al. "Corneal Epithelial Stem Cell Supernatant in the Treatment of Severe Dry Eye Disease: A Pilot Study." Journal of Clinical Ophthalmology.  15:3097-3107. 16 July 2021. https://doi.org/10.2147/OPTH.S322079

CRISPR Therapy in LCA Patients Shows Positive Results

Article: A Gene-Editing Experiment Let These Patients With Vision Loss See Color Again
Source: NPR
Published: September 29, 2021

Scientists report encouraging results for the first few cases of CRISPR gene-editing for Leber congenital amaurosis (LCA), presenting their findings at the International Symposium on Retinal Degeneration. The gene-editing was notable in this case for being the first trial to inject CRISPR in vivo in human subjects, as compared to explanting cells, editing them in vitro, and then infusing them back into tissues of the body. Thus far, seven patients have volunteered to have the experimental therapy. NPR interviewed two of those patients, Carlene Knight and Michael Kalberer. Knight reports, "I was bumping into the cubicles and really scaring people that were sitting at them." With vision improved enough to make out doorways, navigate hallways, spot objects and even see colors, she says she no longer scares people and has fewer bruises from bumping into things. Knight also says that colors are more vivid, which she has appreciated since she was a kid. "I've always loved colors. Since I was a kid it's one of those things I could enjoy with just a small amount of vision. But now I realize how much brighter they were as a kid because I can see them a lot more brilliantly now," she says. Similarly, Kalberer reports being thrilled at his improved vision, which he noticed starting one month after the treatment. For example, he is now able to recognize shapes and light much better, and has regained more peripheral vision. It was an especially joyous moment for him to watch the DJ's strobe lights change color at his cousin's wedding and seeing the sunset again for the first time. One of the clinical researchers at HMS says, "We're thrilled about this. This is the first time we're having evidence that gene editing is functioning inside somebody and it's improving — in this case — their visual function." They next plan on trials at higher doses, and in age brackets that have the best chance of benefiting. Although the treatment is far from a cure, vision never returned to normal, and visual improvement is not seen in all seven patients at this point, for some patients in the trial, the changes experienced are enough to have a meaningful impact on their daily lives.

My rating of this article: ⭐⭐🌸

RGC Dendrite Mosaics are Optimized for Efficiency

Article: Living Retina Achieves Sensitivity and Efficiency Engineers Can Only Dream About
Source: Duke University
Published: September 28, 2021

Retina cross-section showing retinal ganglion cells at top,
and the inner plexiform layer of their dendrites below

Neurobiologists studying the cellular organization of the retina found that it closely mimics a concept known as efficient coding theory, an optimization model of sensory coding in the nervous system. In two papers on retinal structure, they show that natural selection and evolution shaped the patterns of sensitivity in the retina to closely follow what efficient coding theory would predict. Specifically, these sensitivity patterns are seen in the layer of dendrites of the retinal ganglion cells (RGCs), i.e., the inner plexiform layer. Although the ganglion cells downstream only output in binary fashion, either depolarization or not, it is the three-dimensional dendrite mosaic that is sensitive to different stimuli. One of the researchers explains, “The mosaics don’t just randomly overlap, but they don’t overlap in a highly ordered way.” And those mosaics adapt to current conditions. This results in a retina that is not merely one mosaic but many stacked mosaics that each encodes something different about the visual field, parsing as many as 40 different features that together add up to form an image. Furthermore, the depth of the mosaic serves as a kind of address for the type of information that that layer encodes. For example, the deeper layers receive "off" signals, while the more shallow layers get "on" signals, meaning that even when the same (cross-section) area of the retina is stimulated, different layers of the dendrite mosaic can convey different kinds of signals.

One reason the array is so efficient is that the cells conserve energy by not responding to some stimuli. In environments that are "noisy," the receptors tune out most of the static and only respond to something that’s very bright. One of the researchers states, “The more noise there is in the world, the pickier the cell can be about what it will respond to...And when they get pickier, it turns out that there's less redundancy in them.” Moreover, the more noise, the greater the offset between on and off RGC detector pairs. In technical terms, "[I]nformation is maximized when these mosaic pairs are anti-aligned," when the distances between them are greater than average. In other words, the retina is optimized to handle high noise conditions in order to detect things that stand out, and it does so by minimizing the amount of redundant information it encodes. The researchers hope that studying how the retina is optimized for efficiency will help to design smartphone sensors; however, they acknowledge that we are a long ways away from replicating the natural arrangement in the retina.

My rating of this study: ⭐⭐⭐

Roy S, Jun NY, Davis EL, et al. "Inter-mosaic coordination of retinal receptive fields." Nature.  592:409–413. 10 March 2021. https://doi.org/10.1038/s41586-021-03317-5

Jun NY, Field GD, and Pearson J, et al. "Scene statistics and noise determine the relative arrangement of receptive field mosaics." PNAS.  118(39):e2105115118. 28 September 2021. https://doi.org/10.1073/pnas.2105115118

NeuroD1-Mediated Gene Therapy Restores Cortical Connectivity & Visual Function in Mice after Stroke

Article: Gene therapy can restore vision after stroke
Source: Purdue University
Published: September 28, 2021

Reprogrammed cells (orange) are integrated into the
microcircuit and hyper-connected at an early stage

Strokes happen when blood flow to neural tissue stops, leading to neuronal loss and gliosis. A large portion of the cerebrum is devoted to processing vision, thus when an artery is blocked in these regions, vision loss can result. Researchers are exploring the use of gene therapy to directly reprogram endogenous astrocytes into neurons in situ as a means to restore vision in the aftermath of irreversible death of neurons. As compared to the plasticity found when the brain remaps its pathways, a slow and inefficient process, the new gene therapy offers a more efficient solution. The technique shows promise thus far in a model of ischemic stroke affecting the visual centers in the brains of mice, in particular using adeno-associated viruses to deliver transcription factor NeuroD1 in vivo to glial cells in the affected area of the brain. These cells were observed to reprogram into neurons and integrate into the microcircuits of the visual cortex. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. One of the researchers comments, “We don’t have to implant new cells, so there’s no immunogenic rejection. This process is easier to do than stem cell therapy, and there’s less damage to the brain. We are helping the brain heal itself. We can see the connections between the old neurons and the newly reprogrammed neurons get reestablished. We can watch the mice get their vision back.” They conclude, "Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury." The researchers hope that the techniques they develop to restore function in the visual cortex will then help in perfecting techniques to restore motor function after stroke.

My rating of this study: ⭐⭐

Tang Y, Wu Q, Gao M, et al. "Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy." Frontiers in Cell and Developmental Biology.  18 August 2021. https://doi.org/10.3389/fcell.2021.720078

Handheld Screening Device to Detect Amblyopia

Article: NIH-funded study shows screening device accurately detects amblyopia (lazy eye)
Source: National Eye Institute
Published: September 27, 2021

The PVS measures bilateral fixation via
retinal nerve fiber birefringence at the fovea

Colloquially called "lazy eye," amblyopia results when there is an underdeveloped connection between the eye and the brain, leading the brain to favor the vision in the better-seeing eye as those synapses strengthen and the synapses with the worse-seeing eye diminish. This can occur as a result of a variety of underlying causes, with anisometropia (or unequal refractive error) being the most common cause. Other factors leading to amblyopia include strabismus or tropia (an eye misalignment), visual deprivation, and high astigmatism. Where strabismus is the underlying etiology, detection of an eye misalignment in early childhood can prevent difficulties in academic performance. However, many pediatricians and primary care providers are not exposed to vision testing beyond basic visual acuity. Funded by the National Eye Institute, researchers are exploring a prototype handheld screening device to assess the eyes' ability to fixate together. The Pediatric Vision Scanner (PVS) simultaneously scans both retinas, specifically the fovea, with a polarized laser to detect even small-angle deviations. The device then provides a binocularity score, which is used to determine whether the child needs referral for more specialized assessment. The study recruited 300 children ages 2 to 6 with no known eye disorders. Two non-ophthalmic research associates were trained to use the device to screen each child, and the results were compared to eye examination performed by a pediatric ophthalmologist who was masked to the device's results. The device showed a 100% sensitivity, detecting all 6 cases of amblyopia and/or strabismus that agreed with the professional eye examination. However, the device also flagged an additional 45 children as possibly having amblyopia and/or strabismus who were later determined by the eye examination to be normal. The study did not compare this prototype with photo-screening devices which detect risk factors of amblyopia via differences in light reflexes between the two eyes. Despite a relatively low threshold of sensitivity (resulting in a high rate of false positives) in this prototype, the test requires only 2.5 seconds to perform, which could be a beneficial addition to busy pediatric practices.

My rating of this study: ⭐⭐

Shah SS, Jimenez JJ, Rozema EJ, et al. "Validation of the Pediatric Vision Scanner in a normal preschool population." J AAPOS.  25(4):216.e1-216.e4. 1 August 2021. https://doi.org/10.1016/j.jaapos.2021.03.010

Week in Review: Number 36

Age-Related Ophthalmic Conditions Associated with Increased Risk of Dementia Independently and Concurrently with Systemic Conditions
It is thought that reduced stimulation of the visual sensory pathways can accelerate cognitive decline, and a few small studies have suggested a link between ophthalmic conditions such as age-related macular degeneration, cataract, diabetes-related eye disease and glaucoma with cognitive impairment. Other studies have noted that systemic risk factors, such as as diabetes, high blood pressure, heart disease, depression and stroke also increase in incidence with increasing age. Researchers sought to investigate whether these ophthalmic conditions are associated with a higher incidence of dementia independently of these systematic conditions. They analysed data on 12,364 adults aged 55-73 years from the UK Biobank study; these individuals were initially assessed between 2006 and 2010 at baseline and followed up until early 2021. In the 1,263,513 data points collected, 2,304 cases of dementia were recorded. The data showed that age-related macular degeneration, cataract and diabetes-related eye disease, but not glaucoma, were independently associated with increased risk of dementia from any cause. In particular, compared with people who did not have ophthalmic conditions at the start of the study, the risk of dementia was 26% higher in those with age-related macular degeneration, 11% higher in those with cataract, and 61% higher in those with diabetes-related eye disease. They add that while glaucoma was not associated with increased risk of Alzheimer’s disease, it was associated with a higher risk of vascular dementia. Having both an ophthalmic condition and a system condition increased the risk of dementia further compared to having only an ophthalmic condition, with the greatest risk being concurrent diabetes-related eye disease and a systemic condition. Newly developed hypertension, diabetes, stroke, heart disease and depression mediated the association between cataract/diabetes-related eye disease and dementia. Finally, having more ophthalmic conditions showed a larger relative risk for dementia. The authors caution that this is an observational study based on self-reported and inpatient record data. Nonetheless, they conclude, "AMD, cataract and DRED but not glaucoma are associated with an increased risk of dementia. Individuals with both ophthalmic and systemic conditions are at higher risk of dementia compared with those with an ophthalmic or systemic condition only."

Aerosol Fluid Dynamics in Non-Contact Tonometry
Scientists in India were interested in studying the aerosol transmission of pathogens, especially in the context of SARS-CoV-2, and non-contact tonometers used to measure intraocular pressures as a screening for glaucoma. Based on tracking the speed of tear droplets ejected from the eye during "the air puff test," they predicted that tear droplets could travel up to a meter away from the patient, potentially presenting a pathway for spreading viral particles and transmitting the disease. The authors write, "The interaction finally leads to the rupture and breakup of the tear film culminating into sub-millimeter sized droplet projectiles traveling at speeds of 0.2 m/s. The calculated droplet spread radius (∼0.5 m) confirms the likelihood of the procedure to generate droplets that may disperse in air as well as splash on instruments, raising the potential of infection." The distance also depended on factors such as air flow in the room. Eyes with more tears created more droplets than dry eyes, leading them to recommend against the use of eye drops prior to the test. Although most pertinent in the context of the COVID-19 pandemic, these fluid dynamics are applicable to the spread of aerosol pathogens in general. The researchers conclude that although non-contact tonometry is considered a relatively safe test, caution should be considered in improving room ventilation and cleaning nearby instruments and surfaces that had not been thought of previously.

GLP-1R Agonists as Glaucoma Treatment in Diabetics
A retrospective study examining a class of diabetes medications called glucagon-like peptide-1 receptor (GLP-1R) agonists (Trulicity and Rybelsus) shows a possible protective effect against glaucoma in patients with diabetes. GLP-1R agonists are normally used to regulate blood glucose in type 2 diabetes mellitus. However, evidence in animal models shows that this class of drugs provides some neuroprotection against Alzheimer's and Parkinson's diseases, with clinical trials underway to test the drug against neurodegenerative diseases in humans. An earlier study from 2020 similarly found that the GLP-1R agonist NLY01 reduced retinal neuroinflammation and glial activation to rescue retinal ganglion cells in a mouse model of glaucoma, spurring the researchers to investigate whether exposure to GLP-1R agonists influences glaucoma risk. The investigators looked at an insurance claims database (Clinformatics Data Mart), with cohorts comprised of 1961 new users of GLP-1R agonists matched to 4371 unexposed controls. They found that after 150 days on average, 10 patients (0.51%) in the medicated group were newly diagnosed with glaucoma compared to 58 patients (1.3%) in the control group. After adjustment, the data shows a reduced hazard ratio of 0.56, suggesting that exposure to GLP-1 receptor agonists may decrease a diabetic patient’s risk of developing glaucoma by half. The researchers remark that the encouraging findings from their study warrant further investigation into the potential of GLP-1R agonists in glaucoma prevention.

Varying Eye Contact Enhances Conversation
Eye contact can be immersive and powerful. However, a new study suggests that varying eye contact, repeatedly making and breaking eye contact, enhances the dynamics of a conversation. As graduate student and lead author of the study explains, “When two people are having a conversation, eye contact signals that shared attention is high—that they are in peak synchrony with one another. As eye contact persists, that synchrony then decreases.” In particular, she and her research advisor examined pupillary synchrony, when two speakers' pupils dilate in sync, during moments of shared attention. The principle investigator of the study further comments, “We make eye contact when we are already in sync, and, if anything, eye contact seems to then help break that synchrony. Eye contact may usefully disrupt synchrony momentarily in order to allow for a new thought or idea.” The study involved 47 pairs of students having 10-minute recorded conversations about whatever they wanted while wearing eye-tracking glasses. The participants were asked to watch the recordings and rate how engaged they were. The data showed that people make eye contact as pupillary synchrony is at its peak, immediately decreases, only to sync again once eye contact is broken. They also found that instances of eye contact correlated with moments with higher levels of engagement during a conversation. The findings highlight that conversation is a shared creative process, with the rise and fall in pupillary synchrony and eye contact allowing for both moments of shared attention and moments of independent novelty. Moving into and out of alignment enhances connection. The authors conclude that "[E]ye contact may be a key mechanism for enabling the coordination of shared and independent modes of thought, allowing conversation to both cohere and evolve."

Pupil Shape Reveals GAN-Generated Faces
Computer scientists interested in studying differences between real photos and computer-generated photos developed a detection software to analyze differences in human faces generated by deep learning artificial intelligence systems called generative adversarial networks (GAN). Images of real faces are fed into the deep learning system, which then generates synthetic faces. These faces are then tested against another neural network that attempts to spot the fake images, so that the first network can learn from its mistakes; the back and forth between the “adversarial networks” quickly improves the output, to the point where the synthetic faces are difficult to distinguish from real ones. The results are, for example, "deep fake" photos for fake social media accounts. However, these systems are not perfect. While the faces themselves are realistic enough, details such as earrings and glasses contain artifacts that give them away. The present research found another tell-tale sign, namely, in the shape of pupils. Whereas real pupils are round or slightly elliptical, the pupils in computer-generated models are irregular, which the researchers speculate is due to the GAN models' "lack of physiological constraints," or lacking an understanding of eye anatomy. They then applied a detection tool to extract and analyze the regularity of pupil shape from a database of 2000 images (1000 real faces and 1000 synthetically generated faces), reporting that the software could reliably distinguish between the two based on pupil shape. They conclude that evaluation of pupil shape can be used as a simple, yet effective, method to detect GAN-generated faces, and thereby help to counter the malicious use of "deep fake" photos to deceive people on social media and other platforms.

In Other News
(1) FDA approves Lucentis biosimilar to treat wet AMD
(2) People tend to conceptualize vision of 2D objects in 3D
(3) Abstract learning begins in the primary visual cortex

GLP-1R Agonists as Glaucoma Treatment in Diabetics

Article: Diabetes Medications Linked to Glaucoma Prevention
Source: University of Pennsylvania Medicine
Published: September 20, 2021

A retrospective study examining a class of diabetes medications called glucagon-like peptide-1 receptor (GLP-1R) agonists (Trulicity and Rybelsus) shows a possible protective effect against glaucoma in patients with diabetes. GLP-1R agonists are normally used to regulate blood glucose in type 2 diabetes mellitus. However, evidence in animal models shows that this class of drugs provides some neuroprotection against Alzheimer's and Parkinson's diseases, with clinical trials underway to test the drug against neurodegenerative diseases in humans. An earlier study from 2020 similarly found that the GLP-1R agonist NLY01 reduced retinal neuroinflammation and glial activation to rescue retinal ganglion cells in a mouse model of glaucoma, spurring the researchers to investigate whether exposure to GLP-1R agonists influences glaucoma risk. The investigators looked at an insurance claims database (Clinformatics Data Mart), with cohorts comprised of 1961 new users of GLP-1R agonists matched to 4371 unexposed controls. They found that after 150 days on average, 10 patients (0.51%) in the medicated group were newly diagnosed with glaucoma compared to 58 patients (1.3%) in the control group. After adjustment, the data shows a reduced hazard ratio of 0.56, suggesting that exposure to GLP-1 receptor agonists may decrease a diabetic patient’s risk of developing glaucoma by half. The researchers remark that the encouraging findings from their study warrant further investigation into the potential of GLP-1R agonists in glaucoma prevention.

My rating of this study: ⭐⭐

Sterling J, Hua P, Dunaief JL, et al. "Glucagon-like peptide 1 receptor agonist use is associated with reduced risk for glaucoma." British Journal of Ophthalmology.  19 August 2021. https://doi.org/10.1136/bjophthalmol-2021-319232

Varying Eye Contact Enhances Conversation

Article: Make and Break Eye Contact for Livelier Conversation
Source: Dartmouth College
Published: September 16, 2021
Article: Making Eye Contact Signals a New Turn in a Conversation
Source: Scientific American
Published: September 21, 2021

Rather than elicit synchrony, eye contact commences as synchrony peaks
and predicts its immediate and subsequent decline until eye contact breaks.

Eye contact can be immersive and powerful. However, a new study suggests that varying eye contact, repeatedly making and breaking eye contact, enhances the dynamics of a conversation. As graduate student and lead author of the study explains, “When two people are having a conversation, eye contact signals that shared attention is high—that they are in peak synchrony with one another. As eye contact persists, that synchrony then decreases.” In particular, she and her research advisor examined pupillary synchrony, when two speakers' pupils dilate in sync, during moments of shared attention. The principle investigator of the study further comments, “We make eye contact when we are already in sync, and, if anything, eye contact seems to then help break that synchrony. Eye contact may usefully disrupt synchrony momentarily in order to allow for a new thought or idea.” The study involved 93 pairs of students having 10-minute recorded conversations about whatever they wanted while wearing eye-tracking glasses. The participants were asked to watch the recordings and rate how engaged they were. The data showed that people make eye contact as pupillary synchrony is at its peak, immediately decreases, only to sync again once eye contact is broken. They also found that instances of eye contact correlated with moments with higher levels of engagement during a conversation. The findings highlight that conversation is a shared creative process, with the rise and fall in pupillary synchrony and eye contact allowing for both moments of shared attention and moments of independent novelty. Moving into and out of alignment enhances connection. The authors conclude that "[E]ye contact may be a key mechanism for enabling the coordination of shared and independent modes of thought, allowing conversation to both cohere and evolve."

My rating of this study: ⭐⭐

Wohltjen S and Wheatley T. "Eye contact marks the rise and fall of shared attention in conversation." PNAS.  118(37):e2106645118. 14 September 2021. https://doi.org/10.1073/pnas.2106645118

Aerosol Fluid Dynamics in Non-Contact Tonometry

Article: Noninvasive Eye Procedure Provides Potential Pathway for Virus, Disease Carriers
Source: American Institute of Physics Publishing
Published: September 14, 2021

Scientists in India were interested in studying the aerosol transmission of pathogens, especially in the context of SARS-CoV-2, and non-contact tonometers used to measure intraocular pressures as a screening for glaucoma. Based on tracking the speed of tear droplets ejected from the eye during "the air puff test," they predicted that tear droplets could travel up to a meter away from the patient, potentially presenting a pathway for spreading viral particles and transmitting the disease. The authors write, "The interaction finally leads to the rupture and breakup of the tear film culminating into sub-millimeter sized droplet projectiles traveling at speeds of 0.2 m/s. The calculated droplet spread radius (∼0.5 m) confirms the likelihood of the procedure to generate droplets that may disperse in air as well as splash on instruments, raising the potential of infection." The distance also depended on factors such as air flow in the room. Eyes with more tears created more droplets than dry eyes, leading them to recommend against the use of eye drops prior to the test. Although most pertinent in the context of the COVID-19 pandemic, these fluid dynamics are applicable to the spread of aerosol pathogens in general. The researchers conclude that although non-contact tonometry is considered a relatively safe test, caution should be considered in improving room ventilation and cleaning nearby instruments and surfaces that had not been thought of previously.

My rating of this study: ⭐⭐

Durbar R, Maggelakis S, Rasheed A, et al. "Fluid dynamics of droplet generation from corneal tear film during non-contact tonometry in the context of pathogen transmission." Physics of Fluids.  33:092109. 14 September 2021. https://doi.org/10.1063/5.0061956

Age-Related Ophthalmic Conditions Associated with Increased Risk of Dementia Independently and Concurrently with Systemic Conditions

Article: Eye conditions linked to heightened risk of dementia
Source: British Medical Journal newsroom (U.K.)
Published: September 13, 2021

It is thought that reduced stimulation of the visual sensory pathways can accelerate cognitive decline, and a few small studies have suggested a link between ophthalmic conditions such as age-related macular degeneration, cataract, diabetes-related eye disease and glaucoma with cognitive impairment. Other studies have noted that systemic risk factors, such as as diabetes, high blood pressure, heart disease, depression and stroke also increase in incidence with increasing age. Researchers sought to investigate whether these ophthalmic conditions are associated with a higher incidence of dementia independently of these systematic conditions. They analysed data on 12,364 adults aged 55-73 years from the UK Biobank study; these individuals were initially assessed between 2006 and 2010 at baseline and followed up until early 2021. In the 1,263,513 data points collected, 2,304 cases of dementia were recorded. The data showed that age-related macular degeneration, cataract and diabetes-related eye disease, but not glaucoma, were independently associated with increased risk of dementia from any cause. In particular, compared with people who did not have ophthalmic conditions at the start of the study, the risk of dementia was 26% higher in those with age-related macular degeneration, 11% higher in those with cataract, and 61% higher in those with diabetes-related eye disease. They add that while glaucoma was not associated with increased risk of Alzheimer’s disease, it was associated with a higher risk of vascular dementia. Having both an ophthalmic condition and a system condition increased the risk of dementia further compared to having only an ophthalmic condition, with the greatest risk being concurrent diabetes-related eye disease and a systemic condition. Newly developed hypertension, diabetes, stroke, heart disease and depression mediated the association between cataract/diabetes-related eye disease and dementia. Finally, having more ophthalmic conditions showed a larger relative risk for dementia. The authors caution that this is an observational study based on self-reported and inpatient record data. Nonetheless, they conclude, "AMD, cataract and DRED but not glaucoma are associated with an increased risk of dementia. Individuals with both ophthalmic and systemic conditions are at higher risk of dementia compared with those with an ophthalmic or systemic condition only."

My rating of this article: ⭐⭐⭐⭐

Shang X, Zhu Z, Huang Y, et al. "Associations of ophthalmic and systemic conditions with incident dementia in the UK Biobank."British Journal of Ophthalmology.  13 September 2021. http://dx.doi.org/10.1136/bjophthalmol-2021-319508

Pupil Shape Reveals GAN-Generated Faces

Article: Something in The Eyes Reveals if You're Looking at a Person Who Doesn't Exist
Source: ScienceAlert
Published: September 13, 2021

A comparison of round and irregular pupils
in a real photo (left) and a GAN-generated photo (right)

Computer scientists interested in studying differences between real photos and computer-generated photos developed a detection software to analyze differences in human faces generated by deep learning artificial intelligence systems called generative adversarial networks (GAN). Images of real faces are fed into the deep learning system, which then generates synthetic faces. These faces are then tested against another neural network that attempts to spot the fake images, so that the first network can learn from its mistakes; the back and forth between the “adversarial networks” quickly improves the output, to the point where the synthetic faces are difficult to distinguish from real ones. The results are, for example, "deep fake" photos for fake social media accounts. However, these systems are not perfect. While the faces themselves are realistic enough, details such as earrings and glasses contain artifacts that give them away. The present research found another tell-tale sign, namely, in the shape of pupils. Whereas real pupils are round or slightly elliptical, the pupils in computer-generated models are irregular, which the researchers speculate is due to the GAN models' "lack of physiological constraints," or lacking an understanding of eye anatomy. They then applied a detection tool to extract and analyze the regularity of pupil shape from a database of 2000 images (1000 real faces and 1000 synthetically generated faces), reporting that the software could reliably distinguish between the two based on pupil shape. They conclude that evaluation of pupil shape can be used as a simple, yet effective, method to detect GAN-generated faces, and thereby help to counter the malicious use of "deep fake" photos to deceive people on social media and other platforms.

My rating of this study: ⭐

Guo H, Hu S, Wang X, et al. "Eyes Tell All: Irregular Pupil Shapes Reveal GAN-generated Faces." arXiv.org.  1 September 2021. https://arxiv.org/abs/2109.00162

Week in Review: Number 35

Robotic White Cane for Assistive Navigation
Although many advances have been made in navigation assistive devices for the blind and visually impaired, the white cane remains the most functional and reliable navigation tool for most people who are visually impaired. A project co-funded by the National Institutes of Health’s National Eye Institute (NEI) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) sought to improve upon this century-old technology with modern electronics. As the lead author of the study explains, while GPS-based applications have revolutionized navigation in outdoor settings, helping the blind find their way around in large spaces inside buildings can present challenges, a gap he hopes to close through his robotic white cane. These improvements include the integration of a color 3D camera, an inertial measurement sensor, and an on-board computer, whose software can be paired with a building’s architectural blueprints or floorplans to guide users to destinations using auditory and sensory cues. The color depth camera, in particular, uses infrared light (similar to the front-facing camera of most smartphones) to determine the distance between the user and other physical objects. This information is processed by the onboard computer, which then maps the user's location onto the building's architectural drawings to alert the user to obstacles. The project lead adds, “The rolling tip on our robotic cane can guide you to turn at just the right point and exactly the right number of degrees, whether it’s 15 degrees or 90. This version can also alert you to overhanging obstacles, which a standard white cane cannot.” The robotic white cane is still in development to slim down some of its features for regular use. Nonetheless, the ability to switch between the automated mode and the simpler, non-robotic mode could provide additional independence for people who are blind or visually impaired without losing the time-tested attributes of the traditional white cane.

Eyeglasses to Boost Academic Performance in School
Researchers at Johns Hopkins University Wilmer Eye Institute and School of Education conducted a large clinical study, the most robust study in the U.S. to date on the impact of glasses on education. Vision for Baltimore was a project launched by Johns Hopkins researchers in 2016 in an effort to address the acute need for vision care among the city’s public school students. In addition to providing more than $1 million in support, Johns Hopkins works closely with the program team to provide technical assistance. In the five years, the program has tested the vision of more than 64,000 students and distributed more than 8,000 pairs of glasses. Now in its sixth year, Vision for Baltimore is operated and funded in partnership with the Johns Hopkins schools of Education and Medicine, Baltimore City Public Schools, the Baltimore City Health Department, eyewear brand Warby Parker, and national nonprofit Vision To Learn. The study, a three-year randomized clinical trial, analyzed the performance of 2,304 students in grades 3 to 7 who received screenings, eye examinations and eyeglasses from Vision for Baltimore, looking in particular at their scores on standardized reading and math tests over 1 and 2 years. They found significant improvements in math scores in the elementary school grades, and improvements in reading scores in the first year. The researchers encourage sustained use of glasses to maintain gains in academic achievement thereafter. As the senior author of the study states, “We rigorously demonstrated that giving kids the glasses they need helps them succeed in school...[and] has major implications for advancing health and educational equity all across the country.” Johns Hopkins President Ron Daniels adds, “These results validate the dedication of all of the program’s committed partners, from the principals, staff and teachers across Baltimore City schools to the optometrists at Vision to Learn and the school vision advocates from Johns Hopkins. Looking forward, we hope to work with our state and city leaders to ensure that this impactful program has sustainable funding for years to come.”

Blue Widefield SLO to Evaluate Diabetic Retinopathy
In a retrospective study, researchers in Japan examined blue widefield scanning laser ophthalmoscopy (SLO) in the evaluation of non-perfusion areas (ischemia) and retinal thinning in diabetic retinopathy (DR). This method follows earlier imaging techniques using fluorescein angiography (FA) and multicolor widefield SLO, which uses laser light in simultaneous red, green, and blue wavelengths. The researchers found that the blue images captured by conventional SLO could reveal hyporeflective areas in the retina indicative of damage, and sought to explore this finding further in widefield SLO. The retrospective observational case series compared blue widefield SLO with fluorescein angiography in 90 patients with diabetes; in individuals with diabetic retinopathy, retinal morphology was further examined with optical coherence tomography (OCT). The senior author of the study explains, “We found that the hyporeflective areas in the blue widefield SLO images appeared to correspond with areas of ischemia in the fluorescein angiogram images of patients with DR. We were pleased to find that the rate of concordance was high.” Scanning laser ophthalmoscopy, however, is advantageous in that it is non-invasive compared to fluorescein angiography, which uses an intravenous dye. Furthermore, they found that the ischemic areas correspond with retinal thinning. As another researcher comments, “It’s possible that the blue wavelength of light can pass more easily through these thinned areas of the retina, which present as hyporeflective areas in the SLO images." Given its non-invasive nature and wider field of view, now enhanced with the detection of ischemia and retinal thinning via the blue wavelength, blue widefield SLO could offer new advantages in the detection and evaluation of diabetic retinopathy.

Tetrodotoxin Explored as a Treatment for Amblyopia
Amblyopia results when there are underdeveloped connections between the eye and the brain, and can have etiologies ranging from congenital cataracts to strabismus (an eye misalignment), to anisometropia (unequal refractive state), all of which prevent the affected eye from resolving clear images to form the necessary neural connections. The predominant view is that there is a critical period during childhood after which amblyopia cannot be reversed, even after the underlying etiology is corrected. Aside from behavioral approaches, clinicians have relied on "patching" of the unaffected eye with the thought that the affected eye would form stronger synapses with the brain. This "patching" can be a physical patch over the eye, the same concept of which is retained in more recent uses of atropine eye drops to blur vision in the unaffected eye. Neuroscientists exploring ways to reverse amblyopia have found success in a novel approach, namely, by injection of tetrodotoxin (TTX), which temporarily (reversibly) anesthetizes the retina of the unaffected eye. Experiments in two animal models (mice and cats) have produced "an unequaled profile of recovery" in the amblyopic eye even after the critical period. This recovery was seen in every animal they tested. At the neurological level, synapses that are weak wither in a process known as "long-term depression." However, the researchers explain that temporarily, but completely, suspending visual input creates a condition in which the synaptic connections can fully restrengthen, as if being “rebooted.”

In an earlier study from 2016, the researchers showed that they could reverse amblyopia by anesthetizing both retinas. In the present study, they were able to limit the effect of TTX to the retina of only the non-amblyopic eye. Additionally, the current study was conducted in mature amblyopic animals that were not responsive to other forms of treatment. The scientists even observed that neurons that shrink with amblyopia regained normal size after treatment. Finally, in addition to improving vision in the amblyopic eye (i.e., reversing amblyopia), visual responses recovered to normal levels in the eye that received the TTX in every animal tested, demonstrating no lasting negative effects. It should be noted that a major difference between this approach and prior variations of "patching" is in the complete inactivation of vision that triggers strengthening of synapses in the affected eye. The researchers will pursue further studies to explore tetrodotoxin as an option for adults who suffer from amblyopia. As co-lead author of the study remarks, “I am hopeful and optimistic that this study can provide a pathway for a new and more effective approach to amblyopia treatment. I am very proud to have been part of this rewarding collaboration.”

Case Report: Direct Voluntary Control of Pupil Size
Pupil contriction and dilation are controlled by the autonomic nervous system, a process that was once thought to be automatic in response to stimuli, such as light/darkness, arousing emotions, or mental effort. While indirect voluntary control of pupil size in response to imaginary light has been documented in the literature—for example, imagining a "sunny sky" or a "dark room" resulted in pupillary constriction and dilation, respectively—directly controlling the iris sphincter and dilator musculature was thought to be impossible. That is, until a psychology student in Germany approached his professor, one of the researchers, about his unusual ability to "tremble" his eyeballs. Known by his initials D.W., the student reports, "Constricting the pupil feels like gripping, tensing something; making it larger feels like fully releasing, relaxing the eye." Interestingly, D.W. described having initially practiced the ability by focusing in front of or behind an object, not unlike the miosis and mydriasis that occurs as a result of convergence and divergence of the eyes, respectively. According to the authors, "[I]t seems plausible that [D.W.] could have learned to gain control over the pupillary response by decoupling pupil size changes from accommodation and vergence in the near triad." After a while, D.W. states that all he needed to do to change his pupil size was to concentrate, noting that he doesn't have to imagine bright or dark environments.

The researchers performed a variety of tests, such as measuring the voltage on the skin as a proxy for mental effort, to rule out indirect ways of controlling pupil size. They then measured D.W.'s dilation of pupil diameter to be around 0.8 mm and constriction of pupil diameter to be around 2.4 mm. Moreover, even closer than his near point of accommodation or NPA (that is, the distance at which accommodation is maximal, at which a small object held in front of the eye, such as the tip of a pen, cannot be clearly resolved), D.W. could voluntarily constrict his pupils further. The authors report, "Even at maximal accommodation, [D.W.] voluntarily constricted his pupil without changing vergence and could improve visual acuity by >6 diopters." Task-based functional magnetic resonance imaging (fMRI) showed increased activity in brain areas responsible for volitional impulses, in this case, the dorsolateral prefrontal cortex, adjacent premotor areas, and supplementary motor area. And although the researchers cannot elucidate any connections between these cortical areas and the sympathetic or parasympathetic pathways that ultimately control autonomic pupillary reactions, nor can they definitively rule out that D.W. was using indirect strategies to change his pupil size, they found no evidence of such from the tests they performed. Accordingly, they conclude that this is the first reported case of direct voluntary control of pupil size.

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