Tag Archives: #visionloss

Nerve Fibre Loss And Rise in Key Immune Cells On Eye Surface May Signal ‘Long COVID’ (Medicine)

Nerve fibre loss and an increase in key immune (dendritic) cells on the surface of the eye (cornea) may be an identifying feature of ‘long COVID’, suggests a small study published in the British Journal of Ophthalmology.

These changes were particularly evident among those with neurological symptoms, such as loss of taste and smell, headache, dizziness, numbness, and neuropathic pain, following COVID-19 infection, the findings show.

Long COVID is characterised by a range of potentially debilitating symptoms which continue for more than 4 weeks after the acute phase of the infection has passed and which aren’t explained by an alternative diagnosis.

Around 1 in 10 of all those with COVID-19 infection will develop long COVID, and it has been suggested that small nerve fibre damage may underlie its development.

To explore this further, the researchers used a real time, non-invasive, high-resolution imaging laser technique called corneal confocal microscopy, or CCM for short, to pick up nerve damage in the cornea.

The cornea is the transparent part of the eye that covers the pupil, iris, and the fluid-filled interior. Its main function is to focus most of the light entering the eye.

CCM has been used to identify nerve damage and inflammatory changes attributable to diabetic neuropathy, multiple sclerosis, and fibromyalgia (all over body pain).

Forty people who had recovered from confirmed COVID-19 infection between 1 and 6 months earlier completed a National Institute of Health and Clinical Excellence (NICE) questionnaire to find out if they had long COVID.

This questionnaire consists of 28 items in nine domains including generalised, respiratory, cardiovascular, neurological, musculoskeletal, psychological/psychiatric, gastrointestinal, dermatological, and ear, nose and throat symptoms, with a total score ranging from 0 to 28.

Neurological symptoms were present at 4 and 12 weeks in 22 out of 40 (55%) and 13 out of 29 (45%) patients, respectively.

Participants’ corneas were then scanned using CCM to look for small nerve fibre damage and the density of dendritic cells. These cells have a key role in the primary immune system response by capturing and presenting antigens from invading organisms.

The corneal scans were compared with those of 30 healthy people who hadn’t had COVID-19 infection.

Twenty two (55%) of the 40 COVID patients had no clinical signs of pneumonia; 11 (28%) had clinical signs of pneumonia not requiring oxygen therapy; four (10%) had been admitted to hospital with pneumonia and received oxygen therapy; and three (8%) with pneumonia had been admitted to the intensive care.

The corneal scans revealed that patients with neurological symptoms 4 weeks after they had recovered from acute COVID-19 had greater corneal nerve fibre damage and loss, with higher numbers of dendritic cells, than those who hadn’t had COVID-19 infection.

Those without neurological symptoms had comparable numbers of corneal nerve fibres as those who hadn’t been infected with COVID-19, but higher numbers of dendritic cells.

The questionnaire responses indicative of long COVID symptoms correlated strongly with corneal nerve fibre loss.

This is an observational study, and as such, can’t establish cause. The researchers also acknowledge several limitations, including the relatively small number of study participants. the absence of longer term monitoring, and reliance on questionnaires to establish the severity of neurological symptoms rather than more objective measures.

But they write: “To the best of our knowledge, this is the first study reporting corneal nerve loss and an increase in [dendritic cell] density in patients who have recovered from COVID-19, especially in subjects with persisting symptoms consistent with long COVID.”

They add: “We show that patients with long COVID have evidence of small nerve fibre damage which relates to the severity of long COVID and neuropathic as well as musculoskeletal symptoms.”

And they conclude: “Corneal confocal microscopy may have clinical utility as a rapid objective ophthalmic test to evaluate patients with long COVID.”

Featured image credit: Daniil Kuželev/Unsplash

Reference: Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID, British Journal of Ophthalmology (2021). DOI: 10.1136/bjophthalmol-2021-319450

Provided by British Medical Journal

Scientists Discover Gene Therapy Which Provides Neuroprotection To Prevent Glaucoma Vision Loss (Medicine)

An NIH-funded research project found that calcium modulator CaMKII protects the optic nerve in mice, opening the door to new sight-saving therapy

A form of gene therapy protects optic nerve cells and preserves vision in mouse models of glaucoma, according to research supported by NIH’s National Eye Institute. The findings suggest a way forward for developing neuroprotective therapies for glaucoma, a leading cause of visual impairment and blindness. The report was published in Cell.

Glaucoma results from irreversible neurodegeneration of the optic nerve, the bundle of axons from retinal ganglion cells that transmits signals from the eye to the brain to produce vision. Available therapies slow vision loss by lowering elevated eye pressure, however some glaucoma progresses to blindness despite normal eye pressure. Neuroprotective therapies would be a leap forward, meeting the needs of patients who lack treatment options.

“Our study is the first to show that activating the CaMKII pathway helps protect retinal ganglion cells from a variety of injuries and in multiple glaucoma models,” said the study’s lead investigator, Bo Chen, Ph.D., associate professor of ophthalmology and neuroscience at the Icahn School of Medicine at Mount Sinai in New York City.

The CaMKII (calcium/calmodulin-dependent protein kinase II) pathway regulates key cellular processes and functions throughout the body, including retinal ganglion cells in the eye. Yet the precise role of CaMKII in retinal ganglion cell health is not well understood. Inhibition of CaMKII activity, for example, has been shown to be either protective or detrimental to retinal ganglion cells, depending on the conditions.

Using an antibody marker of CaMKII activity, Chen’s team discovered that CaMKII pathway signaling was compromised whenever retinal ganglion cells were exposed to toxins or trauma from a crush injury to the optic nerve, suggesting a correlation between CaMKII activity and retinal ganglion cell survival.

Searching for ways to intervene, they found that activating the CaMKII pathway with gene therapy proved protective to the retinal ganglion cells. Administering the gene therapy to mice just prior to the toxic insult (which initiates rapid damage to the cells), and just after optic nerve crush (which causes slower damage), increased CaMKII activity and robustly protected retinal ganglion cells.

Among gene therapy-treated mice, 77% of retinal ganglion cells survived 12 months after the toxic insult compared with 8% in control mice. Six months following optic nerve crush, 77% of retinal ganglion cells had survived versus 7% in controls.

Similarly, boosting CaMKII activity via gene therapy proved protective of retinal ganglion cells in glaucoma models based on elevated eye pressure or genetic deficiencies.

Increasing retinal ganglion cell survival rates translated into greater likelihood of preserved visual function, according to cell activity measured by electroretinogram and patterns of activity in the visual cortex.

Three vision-based behavioral tests also confirmed sustained visual function among the treated mice. In a visual water task, the mice were trained to swim toward a submerged platform on the basis of visual stimuli on a computer monitor. Depth perception was confirmed by a visual cliff test based on the mouse’s innate tendency to step to the shallow side of a cliff. Lastly, a looming test determined that treated mice were more apt to respond defensively (by hiding, freezing or tail rattling) when shown an overhead stimulus designed to simulate a threat, compared with untreated mice.

“If we make retinal ganglion cells more resistant and tolerant to the insults that cause cell death in glaucoma, they might be able to survive longer and maintain their function,” Chen concluded.

This study was supported by NEI grants R01EY028921, R01EY024986. NEI is part of the National Institutes of Health.

Featured image: Graphical abstract by authors


Guo X, Zhou J, Starr C, Mohns EJ, Li Y, Chen E, Yoon Y, Kellner CP, Tanaka K, Wang H, Liu W, LR, Demb JB, Crair MC, and Chen B. “Preservation of vision after CaMKII-mediated protection of retinal ganglion cells.” Published online July 22, 2021 in Cell. DOI: https://doi.org/10.1016/j.cell.2021.06.031

Provided by NIH/NEI

Can Echolocation Help People With Vision Loss? (Medicine)

Known as nature’s own sonar system, echolocation occurs when an animal emits a sound that bounces off objects in the environment, returning echoes that provide information about the surrounding space.

While echolocation is well known in whale or bat species, previous research has also indicated that some blind people may use click-based echolocation to judge spaces and improve their navigation skills.

Equipped with this knowledge a team of researchers, led by Dr Lore Thaler, delved into the factors that determine how people learn this skill.

Click for more

Over the course of a 10-week training programme, the team investigated how blindness and age affect learning of click-based echolocation. They also studied how learning this skill affects the daily lives of people who are blind.

The study involved blind and sighted participants between 21 and 79 years of age who trained over the course of 10 weeks. Blind participants also took part in a 3-month follow up survey assessing the effects of the training on their daily life.

Both sighted and blind people improved considerably on all measures, and in some cases performed comparatively to expert echolocators at the end of training. Somewhat surprisingly, in some cases sighted people even performed better than those who were blind.

Importantly, however, neither age nor blindness was a limiting factor in participants’ rate of learning or in their ability to apply their echolocation skills to novel, untrained tasks.

Furthermore, in the follow up survey, all participants who were blind reported improved mobility, and 83% reported better independence and wellbeing.

Not limited by age or vision

Overall, the results suggest that the ability to learn click-based echolocation is not strongly limited by age or level of vision. This has positive implications for the rehabilitation of people with vision loss or in the early stages of progressive vision loss.

Currently, click-based echolocation is not taught as part of mobility training and rehabilitation for blind people. There is also the possibility that some people are reluctant to use click-based echolocation due to a perceived stigma around making the required clicks in social environments.

Despite this, the results indicate that blind people who use echolocation and people new to echolocation are confident to use it in social situations, indicating that the perceived stigma is perhaps much smaller than previously thought.

Find out more

The work was funded by a grant of the Biotechnology and Biological Sciences Research Council United Kingdom, and a grant from the Network for Social Change.

Provided by Durham University

Insights From Color-blind Octopus Help Fight Human Sight Loss (Biology)

University of Bristol research into octopus vision has led to a quick and easy test that helps optometrists identify people who are at greater risk of macular degeneration, the leading cause of incurable sight loss.

The basis for this breakthrough was published in the latest issue of the Journal of Experimental Biology and describes new technology developed by lead researcher, Professor Shelby Temple, to measure how well octopus- which are colour-blind – could detect polarized light, an aspect of light that humans can’t readily see. Using this novel technology, the research team showed that octopus have the most sensitive polarization vision system of any animal tested to date. Subsequent research used the same technology in humans and led to the development of a novel medical device that assesses the risk factor for sight loss later in life.

Prof Shelby Temple, who holds honorary positions at the School of Biological Sciences, University of Bristol and the School of Optometry, Aston University, explained the impact of the team’s findings. He said: “We knew that octopus, like many marine species, could see patterns in polarized light much like we see colour, but we had no idea that they could do so when the light was only 2% polarized – that was an exciting surprise, but even more surprising was when we then tested humans and found that they were able to see polarization patterns when the light was only 24% polarized.

“Humans can perceive polarized because macular pigments in our eyes differentially absorb violet-blue light depending on its angle of polarization, an effect known as Haidinger’s brushes. It’s like a super sense most of us don’t even know we have, revealing a faint yellow bow-tie shape on the retina. The more of these pigments a person has, the better protected they are against sight-loss.

“By inventing a method to measure polarization vision in octopuses, we were able to use the core technology to develop a novel ophthalmic device that can quickly and easily screen people for low macular pigments, a strong risk factor for increased susceptibility to macular degeneration.”

Macular pigments are the body’s natural protection against damaging violet-blue light. This new testing approach enables optometrists to provide preventative advice to patients. Empowering patients to make simple lifestyle choices, like wearing sunglasses or eating more dark green and brightly coloured fruits and vegetables that can help them protect their sight through life.

Prof Temple said, “I am so happy this work has been published, as it was the foundation upon which we developed our exciting new technology for measuring macular pigments.”

Macular pigments are the carotenoids lutein, zeaxanthin and meso-zeaxanthin that we can only acquire from our diet. They provide long term protection to the retina and this helps prevent age-related macular degeneration by acting as antioxidants and by strongly absorbing the most damaging high energy visible (violet-blue) wavelengths (380-500 nm) of light that reach our retina. A challenge to the eye care industry is that it is not possible to determine someone’s macular pigment levels without measurement, and until now most techniques have been too time consuming, difficult, or expensive to become part of regular eye exams. The new technology developed by Prof Temple through his start-up company Azul Optics Ltd, enables rapid screening of macular pigment levels and can be used on patients from 5 -95 years of age. Prof Temple added: “We are all living longer and expecting to do more in our older age, so I hope this serendipitous invention will help empower people to do more to look after our eyes, so they don’t suffer from this devastating disease.”

Featured image: Octopus eye © Prof Shelby Temple

Paper: Shelby E. Temple, Martin J. How, Samuel B. Powell, Viktor Gruev, N. Justin Marshall, Nicholas W. Roberts; Thresholds of polarization vision in octopuses. J Exp Biol 1 April 2021; 224 (7): jeb240812. doi: https://doi.org/10.1242/jeb.240812

Provided by University of Bristol

Genetic Discovery Gives Insight Into Causes of Eye Disease (Medicine)

A genetic defect could hold the key to preventing or delaying the onset of a debilitating eye disease that can lead to vision loss and blindness.

A genetic defect could hold the key to preventing or delaying the onset of a debilitating eye disease that can lead to vision loss and blindness.

MacTel (macular telangiectasia type 2) affects one in 1,000 Australians. Symptoms include slow loss of vision, distorted vision and trouble reading. Because early signs of the disorder are subtle, it is difficult to diagnose.

Researchers have identified an additional seven regions in the human genome that increase the risk of developing the condition, including a rare DNA mutation in the PHGDH gene, which will help clinicians to better diagnose and treat it.

The study builds on earlier WEHI research, which pinpointed that MacTel was associated with low levels of serine, an amino acid used in many pathways of the body.

Led by WEHI Professor Melanie Bahlo in conjunction with Dr Brendan Ansell, Dr Victoria Jackson and Dr Roberto Bonelli and published in Communications Biology, the research provides a new genetic risk calculator for predicting retinal disorders. The research was conducted in collaboration with The Lowy Medical Research Institute, USA and Moorfield’s Eye Hospital, UK.

At a glance

  • MacTel is primarily caused by slight changes to the levels of several fundamental amino acids in an individual’s blood
  • Researchers identified a further, rare, PHGDH gene mutation, which makes people five times more susceptible to developing MacTel, as well as seven other new genetic regions.
  • Understanding the genetic mutations that cause MacTel will allow clinicians to better screen for the condition and potentially prevent it from developing.

PHGDH increases MacTel risk

Researchers identified that a rare mutation in a gene – called PHGDH – dramatically increases the risk of developing MacTel.

“Amongst our new gene findings, we identified a new rare mutation in the PHGDH gene. These new findings further increase our understanding of retinal biology and the way the eye uses energy,” Professor Bahlo said.

“People with this newly discovered PHGDH mutation are five times more likely to develop MacTel than people without this genetic mutation.”

Eye disorder often diagnosed late

“MacTel is a really unique eye disease, which is caused by slight changes to levels of fundamental amino acids that have no impact on any other part of the body,” she said.

“What we found is that the disease is driven by two factors; metabolic amino acid on one side and then risk factors related to the cellular health of the retina on the other side, which are probably involved in transporting crucial amino acids into the retina. Both of these factors contribute to whether someone is genetically predisposed to getting MacTel in later life.”

Findings provide hope for improved diagnosis and treatment 

Professor Bahlo said the findings could help improve diagnosis and treatment of MacTel.

“By understanding the causes of the condition, we can tailor treatment to each individual patient to ensure the best outcomes for them,” she said.

“This disease is really hard to diagnose, so understanding the risk factors will allow clinicians to better predict and treat the condition.”

Retinal disease usually progresses with age so early detection is vital to preserving eyesight in patients with the condition.

“By diagnosing this condition earlier, patients may be able to take mitigating steps to delay or prevent it developing,” Professor Bahlo said.

The research team will now carry out further work with collaborators to look at identifying further genes involved in MacTel, with the aim of working towards better treatments and therapeutics.

This work was made possible with funding from the Lowy Medical Research Institute, the National Health and Medical Research Council, the John and Patricia Farrant Foundation and the Victorian Government.

Featured image: WEHI researchers identified genetic differences in MacTel patients that affect the structure of blood vessels in the retina (pictured), and the production and delivery of critical amino acids to this tissue. © WEHI

Reference: R Bonelli, VE Jackson, A Prasad, JE Munro, S Farashi, TFC Heeren, N Pontikos, L Scheppke, M Friedlander, MacTel Consortium, CA Egan, R Allikmets, BRE Ansell, M Bahlo, “Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder”, medRxiv 2020.08.02.20161117; doi: https://doi.org/10.1101/2020.08.02.20161117

Provided by Walter and Eliza Hall Institute

New Research Sheds Light on Vision Loss in Batten Disease (Medicine)

Progressive vision loss, and eventually blindness, are the hallmarks of juvenile neuronal ceroid lipofuscinosis (JNCL) or CLN3-Batten disease.  New research shows how the mutation associated with the disease could potentially lead to degeneration of light sensing photoreceptor cells in the retina, and subsequent vision loss.

 “The prominence and early onset of retinal degeneration in JNCL makes it likely that cellular processes that are compromised in JNCL are critical for health and function of the retina,” said Ruchira Singh, Ph.D., an associate professor in the Department of Ophthalmology and Center for Visual Science and lead author of the study which appears in the journal Communications Biology. “It is important to understand how vision loss is triggered in this disease, what is primary and what is secondary, and this will allow us to develop new therapeutic strategies.”

Batten disease is caused by a mutation in the CLN3 gene, which is found on chromosome 16.  Most children suffering from JNCL have a missing part in the gene which inhibits the production of certain proteins.  Rapidly progressive vision loss can start in children as young as 4 and eventually develop learning and behavior problems, slow cognitive decline, seizures, and loss of motor control.  Most patients with the disease die between the ages of 15 and 30.

It has been well established that vision loss in JNCL is due to degeneration of the light-sensing tissue in the retina. The vision loss associated with JNCL can precede other neurological symptoms by many years in some instances, which often leads to patients being misdiagnosed with other more common retinal degenerations. However, one of the barriers to studying vision loss in Batten disease is that mouse models of CLN3 gene mutation do not produce the retinal degeneration or vision loss found in humans.  Additionally, examination of eye tissue after death reveals extensive degeneration of retinal cells which does not allow researchers to understand the precise mechanisms that lead to vision loss.

URMC is a hub for Batten disease research.  The Medical Center is home to the University of Rochester Batten Center (URBC), one of the nation’s premier centers dedicated to the study and treatment of this condition. The URBC is led by pediatric neurologist Jonathon Mink, M.D., Ph.D., who is a co-author of the study.  Batten disease is also one of the key research projects that will be undertaken by the National Institute of Child Health and Human Development-supported University of Rochester Intellectual and Development Diseases Research Center

To study Batten disease in patient’s own cells, the research team reengineered skin cells from patients and unaffected family members to create human-induced pluripotent stem cells.  These cells, in turn, were used to create retinal cells which possessed the CLN3 mutation. Using this new human cell model of the disease, the new study shows for the first time that proper function of CLN3 is necessary for retinal pigment epithelium cell structure, the cell layer in the retina that nourishes light sensing photoreceptor cells in the retina and is critical for their survival and function and thereby vision.

Singh points out that understanding how RPE cell dysfunction contributes to photoreceptor cell loss in Batten disease is important first step, and it will enable researchers to target specific cell type in the eye using potential future gene therapies, cell transplantation, and drug-based interventions.

Additional co-authors of the study include Cynthia Tang, Jimin Han, Sonal Dalvi, Kannan Marian, Lauren Winschel, Celia Soto, Chad Galloway, Whitney Spencer, Michael Roll, Lisa Latchney, Erika Augustine, Vamsi Gullapalli, and Mina Chung with URMC, David Williams and Stephanie Volland with the University of California, Los Angeles, Vera Boniha with the Cleveland Clinic, and Tyler Johnson with Sanford Research.  The research was supported with funding from the National Eye Institute BrightFocus Foundation, the David Bryant Trust, the Foundation of Fighting Blindness, the Knights Templar Eye Foundation, the Retina Research Foundation, and Research to Prevent Blindness.

Reference: Cynthia Tang, Jimin Han, Sonal Dalvi, Kannan Manian, Lauren Winschel, Stefanie Volland, Celia A. Soto, Chad A. Galloway, Whitney Spencer, Michael Roll, Caroline Milliner, Vera L. Bonilha, Tyler B. Johnson, Lisa Latchney, Jill M. Weimer, Erika F. Augustine, Jonathan W. Mink, Vamsi K. Gullapalli, Mina Chung, David S. Williams, Ruchira Singh. A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface. Communications Biology, 2021; 4 (1) DOI: https://www.nature.com/articles/s42003-021-01682-5

Provided by University of Rochester Medical Center

Brain Pressure Disorder that Causes Headache, Vision Problems on Rise (Psychiatry)

Increase Corresponds with Obesity Rates, Linked to Low Socioeconomic Status in Women

A new study has found a brain pressure disorder called idiopathic intracranial hypertension is on the rise, and the increase corresponds with rising obesity rates. The study is published in the January 20, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study also found that for women, socioeconomic factors like income, education and housing may play a role in their risk.

Silhouette of man with left hand on forehead. Brain is outlined with red at the center © AAN

Idiopathic intracranial hypertension is when the pressure in the fluid surrounding the brain rises. It can mimic the symptoms of a brain tumor, causing chronic, disabling headaches, vision problems and in rare cases, vision loss. It is most often diagnosed in women of childbearing age. Treatment is often weight loss. In some cases, surgery may be required.

“The considerable increase in idiopathic intracranial hypertension we found may be due to many factors but likely mostly due to rising obesity rates,” said study author William Owen Pickrell, Ph.D., M.R.C.P., of Swansea University in Wales in the United Kingdom and a member of the American Academy of Neurology. “What is more surprising from our research is that women who experience poverty or other socioeconomic disadvantages may also have an increased risk independent of obesity.”

For the study, researchers used a national healthcare database in Wales to analyze 35 million patient years of data over a 15-year period, between 2003 and 2017. They identified 1,765 people with idiopathic intracranial hypertension during that time. Of the group, 85% were women. Researchers recorded body mass index measurements for study participants. Body mass index is calculated by dividing weight by height. For every one person with the disorder, researchers compared three people without it who were matched for gender, age and socioeconomic status.

The socioeconomic status of each person with the disorder was determined by where they live, using a national scoring system that considers factors like income, employment, health, education and access to services. People in the study were then divided into five groups ranging from those with the fewest socioeconomic advantages to those with the most.

Overall, researchers found a six-fold increase in the number of cases of the disorder over the course of the study. In 2003, for every 100,000 people, 12 were living with the disorder, compared to 76 people in 2017. Also, in 2013, for every 100,000 people, two were diagnosed during that year, compared to eight people in 2017.

Researchers found that the increasing number of people living with the disorder corresponded to rising obesity rates in Wales during the study, with 29% of the population being obese in 2003 compared to 40% in 2017.

“The worldwide prevalence of obesity nearly tripled between 1975 and 2016, so while our research looked specifically at people in Wales, our results may also have global relevance,” said Pickrell.

There were strong links for both men and women between body mass index and risk of the disorder. For women, there were 180 cases per 100,000 people during the study for those with high body mass index compared to 13 women with a body mass index considered to be ideal. For men, there were 21 cases per 100,000 among those with a high body mass index compared to eight cases for those with an ideal body mass index.

Researchers also found that for women only, socioeconomic factors were linked to risk. There were 452 women in the group with the fewest socioeconomic advantages compared to 197 in the group with the most. The women in the group with the fewest had a 1.5 times greater risk of developing the disorder than women in the group with the most, even after adjusting for body mass index.

“Of the five socioeconomic groups of our study participants, women in the lowest two groups made up more than half of the female participants in the study,” said Pickrell. “More research is needed to determine which socioeconomic factors such as diet, pollution, smoking or stress may play a role in increasing a woman’s risk of developing this disorder.”

A limitation of the study was that researchers identified the socioeconomic status of participants by the regions in which they lived instead of obtaining individual socioeconomic information for each participant.

Reference: Latif Miah, Huw Strafford, Beata Fonferko-Shadrach, Joe Hollinghurst, Inder MS Sawhney, Savvas Hadjikoutis, Mark I Rees, Rob Powell, Arron Lacey, W Owen Pickrell, “Incidence, Prevalence and Healthcare Outcomes in Idiopathic Intracranial Hypertension: A Population Study”, Neurology Jan 2021, DOI: 10.1212/WNL.0000000000011463 https://n.neurology.org/content/early/2021/01/20/WNL.0000000000011463

Provided by American Academy of Neurology

About American Academy of Neurology

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with 36,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit AAN.com or find us on FacebookTwitterLinkedInInstagram and YouTube.

TalTech’s Neuroscientists Investigate the Causes of a Widespread Eye Disease (Medicine)

Fuchs’ corneal dystrophy is one of the most common eye diseases diagnosed in almost 5% of the population of Europe aged 40 years or over. It is a hereditary eye disease that causes vision impairment and typically manifests in middle age. The first symptoms of the disease – blisters on the surface of your cornea – resemble cataract at first glance. The disease progresses from the centre of the cornea affecting all layers of the cornea. The progression of the disease varies from individual to individual and in severe cases results in vision loss.

TalTech Department of Chemistry and Biotechnology, Division of Gene Technology Early Stage Researcher Alex Sirp. © TalTech

The molecular neurobiology research group led by Professor of Molecular Biology Tõnis Timmusk published an article about Fuchs’ dystrophy in the journal Scientific Reports titled “The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters”, authored by Alex Sirp, Kristian Leite, Jürgen Tuvikene, Kaja Nurm, Mari Sepp and Tõnis Timmusk.

Professor Timmusk says, “Currently, the only method used to treat Fuchs’ corneal dystrophy is a surgical procedure, in the course of which the patient’s whole cornea is replaced. However, such a treatment is complicated because it requires availability of donor tissue. To prevent an unpleasant surgical procedure, we are working to better understand the causes of Fuchs’ dystrophy and to find ways to prevent it.”

The human genome – DNA – is composed of chains of four different types of nucleotides (abbreviated A, T, C and G). Their different combinations make us actually who we are. Repeated sequences occur in DNA, i.e. some combinations in our genome can be repeated tens or hundreds or even thousands of times. Such repeats are unstable, varying in length between individuals as well as in different tissues of the same individual.

“Expansion of certain repeats can cause repeat expansion diseases. In most cases, such diseases are caused by abnormal repeat expansion of three nucleotides, which is why they are known also as trinucleotide repeat disorders,” says one of the lead authors of the article, PhD student Alex Sirp.

Trinucleotide repeat disorders are a set of over 40 different disorders, including Huntington’s disease, fragile X syndrome, myotonic dystrophy, etc. The Fuchs’ endothelial corneal dystrophy is caused by the CTG trinucleotide repeat expansion in Transcription factor 4 (TCF4). While the repeat length in healthy persons remains below 40, the repeat length in persons with visual impairment is above 40 repeats. “TCF4 gene pays an important role in the development and functioning of the human nervous system. Mutations and variations in TCF4 are directly associated with schizophrenia, mental retardation and a very rare disorder called Pitt-Hopkins Syndrome, ” says Sirp. Tõnis Timmusk says, “The results of our study showed that CTG repeat expansion affects the expression of TCF4 in cultured cells. Due to rapid advances in genomic technologies in recent years, we were able to compare expression of the TCF4 gene in the corneal endothelium of healthy persons and patients with Fuchs’ dystrophy. The results revealed changes in TCF4 expression levels in case of Fuchs’ endothelial corneal dystrophy.

The findings of the research help to understand how these (tri)nucleotide repeats can affect development of a disease through changes in gene expression. These results may also contribute to the development of drugs for the treatment of Fuchs’ dystrophy.

“As a next step, we want to determine when and for how long changes in TCF4 level occur in people who later develop Fuchs’ endothelial corneal dystrophy. This would make it possible to develop a treatment strategy that would enable regulation of TCF4 levels in the corneal endothelium and thus prevent the disease,” says Professor Timmusk.

Reference: Sirp, A., Leite, K., Tuvikene, J. et al. The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters. Sci Rep 10, 18424 (2020). https://www.nature.com/articles/s41598-020-75437-3 https://doi.org/10.1038/s41598-020-75437-3

Provided by Estonian Research Council

AI-supported Test Predicts Eye Disease Three Years Before Symptoms (Ophthalmology / Medicine)

A pioneering new eye test, developed by scientists at UCL in collaboration with the Western Eye Hospital, London, may predict wet AMD, a leading cause of severe sight loss, three years before symptoms develop.

Researchers hope their test could be used to identify the disease early enough so that treatment can effectively prevent any vision loss.

DARC image (top) with corresponding OCT scan below © UCL

The findings of the study, funded by Wellcome, are published today in Expert Review of Molecular Diagnostics.

Wet age-related macular degeneration (AMD), also known as macular disease, is the most common cause of permanent and severe sight loss in the UK.

Currently the diagnosis of wet AMD relies on a person developing symptoms, which then leads them to seek advice from a clinician. Initially, someone with wet AMD would notice distortion in their vision, normally interfering with their reading. Very quickly, this can progress to complete central vision loss, which may be extremely troubling to elderly patients who will fear blindness and loss of independence.

Wet AMD involves abnormal growth of blood vessels, which leak fluid into the retina. The introduction of new treatments has led to much improved results for patients, for a disease that over 20 years ago was regarded as untreatable. However, patient outcomes could be even better if treatment was started in the very earliest stages of the disease.

The test, called DARC (Detection of Apoptosing Retinal Cells), involves injecting into the bloodstream (via the arm) a fluorescent dye that attaches to retinal cells, and illuminates those that are undergoing stress or in the process of apoptosis, a form of programmed cell death. The damaged cells appear bright white when viewed in eye examinations – the more damaged cells detected, the higher the DARC count.

One challenge with evaluating eye diseases is that specialists often disagree when viewing the same scans, so the researchers have incorporated an AI algorithm into their method.

Using the same technology (test) the researchers had previously found that they can detect the earliest signs of glaucoma progression.* This new study, which forms part of the same ongoing clinical trial of DARC, assessed 19 of the study participants who had already shown signs of AMD, but not necessarily in both eyes. The AI was newly trained to detect the formation of leaking and new blood vessels, which corresponded with the spots that DARC picked up.

The new analysis found that DARC can uniquely highlight endothelial cells (which line our blood vessels) under stress in the retina. These stressed cells then predict future wet AMD activity with the formation of leaking and new blood vessels seen in patients three years later, using conventional eye scans with Optical Coherence Tomography (OCT).

The researchers say their test could be valuable in detecting new lesions in someone affected by AMD, often in the opposite, unaffected eye, and may eventually be useful for screening people over a certain age or with known risk factors.

Lead researcher Professor Francesca Cordeiro (UCL Institute of Ophthalmology, Imperial College London, and Western Eye Hospital Imperial College Healthcare NHS Trust) said: “Our results are very promising as they show DARC could be used as a biomarker for wet AMD when combined with the AI-aided algorithm.

“Our new test was able to predict new wet AMD lesions up to 36 months in advance of them occurring and that is huge – it means that DARC activity can guide a clinician into treating more intensively those patients who are at high risk of new lesions of wet AMD and also be used as a screening tool.”

The study team hope to continue their research with a clinical trial with more participants, and hope to investigate the test in other eye diseases as well.

Chief Executive of eye research charity Fight for Sight, Sherine Krause said: “Our Time to Focus report on the social and economic impact of sight loss stressed the importance of early detection for prevention of sight loss, and so this is a very encouraging development in tackling the leading cause of blindness.”

DARC is being commercialised by Novai, a newly formed company of which Professor Cordeiro is Chief Scientific Officer.

Provided by UCL