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European Glaucoma Research Training Program-Plus

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

Reporting period: 2018-01-01 to 2019-12-31

Glaucoma is the most common age-related neurodegenerative eye disease. In Europe, approx. 8 million people suffer from glaucoma and, if it remains untreated or is detected too late, it results in blindness (currently in 15% of patients) yielding a profound loss of quality of life for the individual and major costs to society. Given its vast complexity, and to advance assessment and therapy beyond the current state-of-the-art, our overall objective was to train a new generation of researchers on how to study functional, structural, and genetic aspects of the visual system of glaucoma patients and healthy elderly.
Our fellows have successfully participated in high-level training and booked great progress in their research:

Giorgia Demaria [UMCG] ranked the user friendliness and discriminative power of a battery of tests (3 newly developed by EGRET+ partners) to assess the visual field based in (super) elderly.The most promising ones are now evaluated in elderly with cognitive impairment.

Iris Tigchelaar [OCU] evaluated the Ocusweep, a test for assessing ophthalmic and neurological aspects of vision. She developed, tested, validated and patented a new reaction time test that was added to the Ocusweep. She determined the predictive value of Ocusweep for driving performance in a simulator, comparing glaucoma patients and age-similar healthy elderly.

Daniel Asfaw [CITY] assessed whether visual system dysfunction is reflected by a person's gaze. He developed new metrics and concluded that eye movements recorded, while passively viewing images, could be used to uncover visual field damage in glaucoma patients.

Rijul Soans [UMCG] applied a new gaze-based paradigm to assess the integrity of the visual system in a population of Indian people and showed it could well detect those with visual field problems, amongst them patients with glaucoma. He also assessed sensitivity to motion-in-depth using a new continuous measurement paradigm and virtual reality set-up.

Stephen Kelly [CITY] produced maps of the UK, illustrating the relationship between late diagnosis of glaucoma and socioeconomic status. He evaluated treatment quality and guidelines adherence between centers and showed a faster glaucoma progression in patients with also another eye disease.

Shereif Haykal [UMCG] ​carried out the world’s first longitudinal study on structural brain changes in glaucoma. He also introduced a new structural MRI approach to quantify optic atrophy in glaucoma. This method can be used in individual patients and carries information that is complementary to OCT.

Khaldoon Al-Nosairy [OVGU] applied non-invasive retinal electrophysiology, reflecting retinal ganglion cell function, for glaucoma assessment. He optimised parameters for multifocal photopic negative response recordings as well as simultaneous recordings of multifocal pattern ERG and cortical responses.

Gokulraj Prabhakaran’s [OVGU] mapping out the deafferented visual cortex in glaucoma patients and investigating task-related brain activity. He found a good correspondence between subjective and fMRI related visual field coverage. He also found that the cortical representation of the fovea varies with the extent of the stimulated visual field.

Jeferson Jhone da Silva [ECHO] improved two pivotal technical issues that limited the non-invasive assessment of intracranial pressure (ICP) based on otoacoustic emissions. He developed algorithms for a reproducible and leakage-free probe placement and efficient noise rejection. These were implemented in a device developed by an EGRET+ partner.

Sandra Gonzalez Torrecilla [UDA] introduced absorbance measurements in the ear as a technique to assess absolute ICP, where measurements on otoacoustic emissions can only detect changes in ICP.

Konstantinos Pappelis [UMCG] developed a mathematical model for quantifying perfusion of the retina using parameters that can be collected noninvasively with clinical devices. He applied his model to a large dataset of hypotensive, normotensive, and hypertensive subjects, thereby unraveling the contribution of blood pressure and autoregulation to the pathophysiology of glaucoma.

Jacqueline van den Bosch [IMP] used an intraocular sensor for continuous intraocular pressure (IOP) assessment, developed by an EGRET+ partner, to study the effects of environmental and patient-related factors on IOP. Compared to the current clinical approach of 2 to 4 IOP readings per year, this method holds the potential to dramatically change our view on the role of IOP in glaucoma progression.
Vincenzo Pennisi [OVGU] merged techniques developed and refined in EGRET for measuring ICP (using otoacoustic emissions) and IOP (with the intraocular sensor). He showed, by manipulating body position, that IOP and ICP undergo diverging changes in response to changes in body position.

Philip Wagstaff [AMC] has set up an in-vitro model for glaucoma based on developing retinal ganglion cells. He succeeded in growing retina’s-in-a-dish, including retinal ganglion cells. He significantly accelerated the growth process, an important step towards the development of - ultimately - stem cell therapy.

Valeria Lo Faro [UMCG] used genetic data of two large cohorts from Groningen, a glaucoma cohort and a control cohort, to study the role of mitochondrial DNA in glaucoma. She also made a detailed phenotypic description of the glaucoma cohort, which is now being applied in a large genetic study.
We gained a deeper understanding of the ophthalmic disease glaucoma. Specifically, we have identified new contributing genetic factors, described the pathogenesis of the optic nerves, identified the nature of the degeneration of the visual pathways towards the brain, described neural plasticity in the visual brain and gained a better understanding of the role of blood pressure.

We applied this knowledge towards earlier and better diagnosis of glaucoma, resulting in the composition of an improved genetics-based risk analysis, improved functional tests, including very simple tests based on eye-movements. We also set major steps towards continuous intraocular pressure and novel non-invasive intracranial pressure assessment that both have the potential to change a wide range of clinical care. We found that MRI may act as a complementary technique to Optical Coherence Tomography for optic nerve assessment, made retinal perfusion and autoregulation assessable using clinical devices, pivotal for unraveling the role of systemic hypo- and hypertension. Moreover, we identified the need for age-specific visual function assessment for the (super) elderly and designed a protocol for the assessment of the fitness-to-drive of elderly patients.

We also applied our new knowledge towards better (future) treatment resulting in better insights into the factors determining the quality of glaucoma care, but also constructed a functional glaucoma-model-in-a-dish from stem cells, which can be used to test new glaucoma genes, and which forms a major step towards - ultimately - stem cell therapy. We also extended cohort data sets with genetic information on glaucoma and developed tools for identifying glaucoma patients in large population-based datasets.