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European Glaucoma Research Training Program

Periodic Reporting for period 2 - EGRET (European Glaucoma Research Training Program)

Reporting period: 2017-10-01 to 2020-09-30

Glaucoma is the most common age-related neurodegenerative eye-disease in western society and one of the four major blinding eye diseases. Presently, while glaucoma progression can be slowed down, there is no cure for the disease. Better and earlier detection and follow-up are therefore critical. To achieve this, in EGRET - the European Glaucoma Research Training program - we trained young researchers on how to study functional, structural and genetic aspects of the visual system of patients and healthy participants. In this way, they can gain new knowledge on glaucoma and the ageing visual system that is required to boost innovation in glaucoma care and to improve long term patient prospects.

After four years of PhD training, the early-stage researchers (ESRs) gained a deeper understanding of the genetic background and epidemiology of glaucoma. Moreover, they improved standard vision tests, developed improved eye and brain imaging tools and improved the current rehabilitation techniques. Together, they paved the way for improving the clinical diagnostics, follow-up and treatment of glaucoma.
EGRET organized training events and secondments during which its trainees learned how to use innovative research tools and techniques. They applied their newly learned skills and booked considerable scientific, technological and medical progress. At the time of writing this report, this has led to the publication of 21 peer-reviewed articles in high-ranked scientific journals, with many more foreseen. Below follows a short overview of each of the ESRs their findings.

Catarina Joao (ESR1) investigated the influence of dynamic light conditions on visual functioning in glaucoma and showed that contrast gain control occurs not only in the centre of the visual field but also in the periphery. It occurs also at medium light levels, albeit at slower modulations. Furthermore, she found a disturbed binocular balance in glaucoma patients with non-overlapping visual field defects (that is, in patients with an intact binocular visual field).

Lorenzo Scanferla (ESR2) developed psychophysical experiments directed towards motion detection. He showed that patients require a line to move a much greater distance before the movement was detected than control subjects. Furthermore, he showed that straylight levels are elevated in glaucoma patients. Both his and the findings of Joao suggest that perimetry can be made better by adapting the test situation to those situations that are reported to be difficult by the glaucoma patients.

Birte Gestefeld (ESR3) developed the computational tools to reconstruct various simulated visual field defects based on eye-movement recordings made while observers freely watched short movie clips. She also applied these tools on data acquired from patients with glaucoma. Her work sets out directions for developing easier visual field testing. Moreover, she demonstrated the relevance of using eye-tracking and virtual reality in visual rehabilitation.

Allison Loiselle (ESR4) showed that it is possible to use spontaneous sounds made by the ear itself to noninvasively measure intracranial pressure (ICP). She found no difference in ICP between glaucoma patients and healthy controls. As an incidental finding, she discovered a relationship between tinnitus (ear ringing) and glaucoma, and a role for a specific blood regulating molecule. This may open new diagnostic and therapeutic directions.

Tuomas Heikka (ESR5) compared different eye imaging (Optical Coherence Tomography (OCT) machines and analysis software and showed that image quality and different software packages prevent easy exchange and comparison of images even though the hardware is fairly standardised. Therefore, Heikka developed a new bias-free software tool that segments the
different layers of the retina and is currently investigating its usability in glaucoma progression detection.

Azzurra Invernizzi (ESR6) developed advanced neuro-imaging analysis methods for establishing (changes in) the cortical topography in patients with glaucoma based on resting-state (RS) fMRI data. She has applied and evaluated her methods on visual field mapping and RS data of healthy subjects and applied these methods on fMRI data obtained in glaucoma patients with visual field defects of various degrees of severity. Her results point towards widely and individually varying levels of brain plasticity that may potentially explain the different degrees to which patients have adapted to their vision loss. She also developed a method to find brain regions suitable for the treatment of neurological patients with magnetic pulses.

Asterios Chrysou (ESR7) conducted and published a meta-analysis on the retinal layer changes in Parkinson’s disease, as measured by OCT. He showed broad degeneration in the neuroretina of the patients compared to healthy people. He also compared glaucoma and Parkinson’s disease and showed the two diseases to be distinct and independent.

Sina Engler (ESR8) developed a new automated and objective method to measure the selectivity of the inner ear (cochlea) based on assessing tones spontaneously generated by the inner ear itself. To validate her method, she compared outcomes to those measured with behavioural methods. So far, this measurement is the only automated, objective and non-invasive way to assess the selectivity of the cochlea in humans.

Nigus Asefa (ESR9) and Anna Neustaeter (ESR10) quantified the genetic heritability of glaucoma and showed that the most common phenotypes strongly inherit (highest was the estimate for central corneal thickness). Furthermore, Asefa showed that high blood pressure and low heart-rate variability may be important to consider when screening for glaucoma. In addition, Neustaeter developed a genetic risk score for glaucoma which she applied to a large cohort of people living in the Northern Netherlands. Using a comprehensive eye screening she now investigates the feasibility of genetic screening for early detection of glaucoma. The new risk factors and the genetic risk score will make such screening and early detection of glaucoma more efficient.
Our new OCT algorithm has potential to have a major impact on the accuracy of retinal thickness measurements. As this measurement is used daily in glaucoma care, its impact is potentially high. The method to assess frequency selectivity of the human inner ear is objective and non-invasive and therefore less of a burden for the patients.

Our method to find brain regions suitable for treatment with magnetic pulses has the potential to become a standard for treatment of visual hallucinations in neurology.

Our improved brain analysis tools can be applied both in fundamental and applied brain science. They are being implemented on the open-access cloud-based analysis platform brainlife.io making the tools available free of charge to a world-wide audience.

Our eye-movement based tools provide means to screen for and assess the presence of visual field defects in patients who are unable to carry out standard visual field measurements. As such, these methods can have big impact on the clinical care for such patients. Moreover, the future implementation of VR and eye-tracking methods promise a more effective vision rehabilitation.

Our genetic risk score has potential for early screening of glaucoma, while the identification of two additional risk factors may help improve glaucoma screening.
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