Week in Review: Number 18

Increased Risk of Alzheimer's in APOE4 Carriers
Scientists at UCSF conducted a study using optical coherence tomography angiography (OCTA) to detect early signs of Alzheimer's disease in the brain, as well as explored how the APOE4 gene contributes to the disease. The angiography function of OCT visualizes the blood flow in retinal vasculature. Although it is still unclear as to how the APOE4 gene (encoding apolipoprotein 4) increases risk for neurodegenerative diseases, prior research in mice indicates that it affects blood vessels, including the capillaries in the brain and, by extension, the retina. Since capillaries deliver nutrients and oxygen, carry away waste, and form the blood-brain barrier, the researchers wanted to explore how damage to blood vessels could contribute to protein buildup and cognitive decline seen in diseases such as Alzheimer's. OCTA scans showed reduced capillary density in APOE4 carriers, which increased with participant age. Furthermore, measurement of retinal blood flow via OCTA correlated with measurement of blood flow in the brain via MRI; people with higher retinal capillary density also had greater blood flow in the brain. There was no correlation, however, between retinal capillary density and beta-amyloid plaques as measured by PET scan, suggesting that capillary abnormalities are not likely (directly) driven by amyloid pathology. As the lead researcher states, “This is the first time that we have demonstrated in living, asymptomatic humans that the smallest blood vessels are affected in APOE4 gene carriers,” which suggests that the increased risk of neurodegeneration in APOE4 carriers may be through its effect on blood vessels.

Nicotinamide as Neuroprotection in Glaucoma
An international study led by researchers in Sweden investigated the effects of nicotinamide, the amide form of vitamin B3, in neuroprotection against glaucoma. Although control of intraocular pressure remains the only modifiable factor in glaucoma treatment to date, new avenues of research are exploring neuroprotection of retinal ganglion cells and regeneration of diseased nerve fibers. Previous research identified decline of the molecule nicotinamide adenine dinucleotide (NAD) as rendering retinal ganglion cells susceptible to neurodegeneration. Administration of nicotinimide robustly prevents glaucoma in animal models, as well as improves visual function in existing glaucoma patients. The current study in cell and animal models investigated NAD metabolism, and the metabolism of other essential metabolites, in the visual system. As one of the researchers states, "We demonstrated that systemic nicotinamide administration has limited molecular side-effects, but provides a robust reversal of the disease metabolic profile of glaucoma prone animals." These neuroprotective effects include buffering and preventing metabolic stress and increasing mitochondrial size and motility to provide an environment where retinal ganglion cells are less susceptible to glaucoma-related stresses. They plan to begin clinical trials in autumn 2021.

Itaconate to Reduce Inflammation in Eye Infection
Itaconate, a metabolite of the Kreb's cycle, may play a role in protecting the eye from excessive inflammation during eye infection. Naturally produced by host innate immune cells to counteract inflammation, itaconate is non-immunosuppressive, thus making it an ideal adjunct therapy to antibiotics for conditions such as bacterial endophthalmitis, one of the most common infections after eye surgery. Current treatment of endophthalmitis involves local or systemic antibiotics, which kill the bacteria but do not address inflammation. The researchers applied high-throughput techniques of transcriptomics and metabolomics to visualize global changes in genes and metabolites to study the pathobiology of endophthalmitis in animal and cell culture-based models. These techniques revealed a strong correlation between itaconate and the expression of a gene called immunoresponsive gene 1 (Irg-1). Using a large biobank of vitreous samples from endophthalmitis patients, the researchers found that itaconate was also elevated in these eyes. They next intend to investigate the potential of itaconate to treat inflammatory diseases such as uveitis, where current treatment with steroids could lead to worsening of microbial infections.

Progress in Cataract Research and Treatment
Research presented at ARVO 2021 reported on the role of aquaporins, channels that allow for water transport through cell membranes, in the development of the lens of the eye in a zebrafish model. Disruption of aquaporins leads to opacification of the lens, known as a cataract. The study took an optics approach using a synchrotron, a particle accelerator that produces powerful X-rays by accelerating electrons to the speed of light. Specifically, the research relied on SPring-8, the world’s largest and most powerful synchrotron, in Japan. This allowed for measurements of the optical properties of the eye with the highest accuracy yet. Their team was also the first in the world to measure how the optics of the eye lens develop. Although studied in a zebrafish model at this point, discoveries pertaining to the optical properties of the lens can add to avenues for drug-based therapies for cataracts, especially in countries where surgical resources are scarce.

Munker-White Optical Illusion
Inspired by the work of Akiyoshi Kitaoka, David Novick started crafting optical illusions for his own research program on human-computer interaction. One such illusion posted on his Twitter account went "unexpectedly viral," and appeared in the newspaper in 2018, to his surprise. Since then, Novick has been tweeting two new illusions each week, sometimes getting rediscovered in the media. Depicted is an example of the Munker-White optical illusion. In this case, twelve orbs are shown which are perceived to be of varying colors, although they are all the same shade of beige. Each orb is overlaid with stripes of varying colors. As Novick explains, the illusion works because our acuity for shape is better than our acuity for color; the presence of the stripes in the foreground causes the colors to blend with the adjacent spaces, though the outlines of the spheres remain distinct. Removing the stripes eliminates the illusion; however, changing the colors to grayscale does not. Referred to as White's illusion, the illusion in that case pertains to lightness instead of color. Gray orbs with white stripes in the foreground will appear lighter, while gray orbs with black foreground stripes will appear darker. Changing the lightness or color of the foreground stripes amplifies or diminishes the effect of the illusion, which can be replicated by zooming in or out of the image on a screen. Using complementary colors, such as red and green, cancels out the effect of the illusion, resulting in spheres that look white or gray. Novick next plans to experiment with different color combinations as well as 3D versus 2D images to see how these alter the perception of the illusion.

In Other News
(1) In the News: Supplemental 2
(2) Optical illusion of orangutan wins award
(3) Optical illusions: Cats enjoy sitting on illusory boxes