== Voor een Nederlandse beschrijving van sommige gepubliceerde studies, zie onderaan ==
EGRET-cofund fellows have published the results of their research in high-ranked scientific journals. Below you can read a summary of their published work.
For an overview of all our work, see also our project page on ResearchGate
Nigus Gebrmedhin Asefa and Anna Neustaeter:
Glaucoma is a chronic disease of the eye affecting the optic nerve head. The optic nerve is a collection of many nerve fibers that transmit a visual message from the eye to the brain so that visual signals are converted into objects that we see. When the optic nerve is damaged, it leads to irreversible vision loss. Besides other risk factors (e.g. age, intraocular pressure, and ethnicity) positive family history is a strong risk factor, suggesting that glaucoma is a hereditary eye disease. Family and twin studies have been conducted to establish the relative importance of genes and environment in glaucoma risk. These studies continue to confirm that glaucoma and related traits(endophenotypes) have a genetic component and are heritable. Heritability is the proportion of the variation in a trait (glaucoma, in this case) attributable to genetic differences between individuals in a population. Heritability estimates for glaucoma and related endophenotype differ between studies. Indeed, no systematic review has comprehensively reviewed nor meta-analysed these heritability estimates, we have developed a protocol (a guide to carry out the review) for summarising the evidence through meta-analysis. The protocol describes how to systematically search data, inclusion criteria, quality control, and data extraction methods, data analysis methods, etc.
This work is published in British Medical Journal Open in February 2018. The paper, entitled “Heritability of glaucoma and glaucoma-related endophenotypes: systematic review and meta-analysis protocol”, can be accessed here.
Nigus Gebrmedhin Asefa and Anna Neustaeter:
Heritability (h2) is a measure that describes how people within a population are different, and how much of this difference is explained by genetics. The best example is height; some people are tall and some people are short. How much is the variation in height in a population due to genetic differences? Heritability is the answer; it ranges from 0 to 1, where the higher the score, the more the variation of the trait (like height) is due to genetics. In our study, we systematically reviewed and meta-analysed the h2 of glaucoma, and related eye traits, termed ‘endophenotypes’. Glaucoma, the second leading cause of irreversible blindness in the world, is a general term for a group of eye diseases that are progressive, asymptomatic, and irreversibly damage vision. Glaucoma-related endophenotypes are intraocular pressure (IOP), anterior chamber size (ACS), central corneal thickness (CCT), and the cup-to-disc ratio (CDR). The h2 of primary open-angle glaucoma ranged from 0.17 to 0.81, and was 0.65 for primary angle-closure glaucoma in a single study. The pooled endophenotype h2 estimates and 95% confidence intervals (in brackets) were: IOP: 0.43(0.38-0.48), ACS: 0.67(0.60-0.74), CCT: 0.81(0.73-0.87), and CDR: 0.56(0.44-0.68). The main factors creating variation in h2 of glaucoma was age (h2 of glaucoma is higher in populations younger than 50 years of age), ethnicity (h2 of the endophenotype ACS is higher in people with East Asian ancestry), and study design (h2 is higher within twin-based studies). This paper confirms the strong influence of genetic factors on glaucoma and its endophenotypes.
This work is published in Survey of Opthalmology in June 2019. The paper, entitled “Heritability of glaucoma and glaucoma-related endophenotypes: Systematic review and meta-analysis”, can be accessed here.
Allison Loiselle (1):
There is a theory that glaucoma patients have a lower brain pressure than healthy subjects, but it is controversial. The aim of this study was to measure brain pressure noninvasively through the ear. We can measure this using characteristics of sounds that the ear produces that are altered when brain pressure changes. We measured in different body positions using a bed that can be tilted, and compared our results between glaucoma patients with high eye pressure (17 people), glaucoma patients with low or normal eye pressure (15 people), and healthy subjects (32 people). The sounds recorded from the ear had a clear relationship with body position, and therefore brain pressure, and were the same between all of the groups tested. This indicates that there is no evidence that glaucoma patients have a lower brain pressure. More broadly, these noninvasive measurements from the ear could be used in the future to monitor changes in brain pressure in a clinical setting and to measure changes over the day or changes caused by certain medications.
This work is published in PLoSONE in October 2018. The paper, entitled “Noninvasive intracranial pressure assessment using otoacoustic emissions: An application in Glaucoma”, can be accessed here.
De theorie die zegt dat glaucoompatiënten een lagere hersendruk hebben dan gezonde mensen is controversieel. In dit onderzoek hebben we, op een niet-invasieve manier, via het oor de hersendruk gemeten. Geluiden die door het oor geproduceerd worden veranderen wanneer de hersendruk verandert. Dus door deze geluiden op te nemen, kunnen we veranderingen in hersendruk meten. Zo hebben we de hersendruk gemeten in mensen terwijl we hun lichaamspositie veranderen met behulp van een kanteltafel. We hebben metingen gedaan bij 17 glaucoom patiënten met hoge oogdruk, 15 glaucoom patiënten met een lage of normale oogdruk en 32 gezonde deelnemers, en deze met elkaar vergeleken. De opgenomen geluiden (en dus ook de hersendruk) veranderde wanneer de positie van het lichaam veranderde. Deze observatie was gelijk voor alle groepen. Dit betekent dat glaucoom patiënten dus geen lagere hersendruk hebben dan gezonde mensen. In de toekomst kan deze niet-invasieve methode ook gebruikt worden om veranderingen in hersendruk te meten in een klinische setting. Zo kunnen bijvoorbeeld veranderingen gedurende de dag of veranderingen die worden veroorzaakt door medicatie worden gemeten.
Dit werk is gepubliceerd in PLoSONE in October 2018. Het geschrift, met de titel “Noninvasive intracranial pressure assessment using otoacoustic emissions: An application in Glaucoma”, kan hier worden gevonden.
Allison Loiselle (2), in collaboration with Konstantinos Pappelis (EGRET+)
This study looks into how systemic treatment of seemingly unrelated pathologies pertains to the progression of glaucoma, as well as to the probability of glaucoma suspects fully converting to the disease. This is important, as it is currently not being taken into account in clinical decisions, when managing glaucoma. The population we used comes from the extensive Groningen Longitudinal Glaucoma Study and consists of subjects followed in the clinic for more than 15 years. We found that certain medication used for the treatment of blood pressure (Angiotensin II receptor blockers and ACE inhibitors) were associated with more favorable glaucoma outcomes. It is possible that these medications exhibit a neuroprotective effect, perhaps mediated through improved blood supply to the retina and the optic nerve. We hope that more extensive studies will help further elucidate this interesting observation, in order to better understand the mechanisms of the disease, but also to improve treatment protocols.
This work is published in Investigative Ophthalmology & Visual Science in November 2019. The paper, entitled “Association of Systemic Medication Exposure With Glaucoma Progression and Glaucoma Suspect Conversion in the Groningen Longitudinal Glaucoma Study.”, can be accessed here.
The visual system in Parkinson’s Disease has been the subject of research interest since the 1980’s, with multiple studies beginning to build a picture that a disease known for motor problems, is also responsible for impaired vision. The visual abilities often disturbed include the ability to identify faces and discriminate between shades of black, and the perception of color. In order to better understand these visual disturbances, the first place to look is at the retina, in the back of the eye. Retinal cells process incoming light and forward the information to the brain. Recent imaging advances – namely optical coherence tomography – allows us to take pictures of the living retina and investigate the well-being of these retinal cells.
A large amount of studies have been published investigating the retina in Parkinson’s with optical coherence tomography. These studies present different outcomes, with some suggesting pathological retinal damage in the disease, yet others reporting no differences between healthy and Parkinson patient. In order to provide a complete systematic summary of evidence of retinal changes in Parkinson’s, we conducted a meta-analysis of all available published studies. Studies comparing the retina between healthy people and Parkinson’s patients with optical coherence tomography were included.
Based on our data synthesis, comparing 1916 patients and 2006 healthy controls, we concluded that retinal thinning exists in Parkinson’s disease, in the inner but not outer retinal layers. This pattern is similar to that seen in Alzheimer’s, other neurodegenerative diseases and also the eye disease glaucoma. New longitudinal studies in newly diagnosed patients could aid us in understanding the progression of the disease, and the progressive impact on vision.
This work is published in Parkinsonism and Related Disorders in April 2019. The paper, entitled “Retinal layers in Parkinson’s disease: A meta-analysis of spectral-domain optical coherence tomography studies”, can be accessed here.
Al sinds de ’80 wordt het visuele systeem van mensen met de ziekte van Parkinson uitvoerig onderzocht. Deze onderzoeken laten zien dat deze ziekte, die voornamelijk bekend staat om de motorische problematiek, ook visuele problemen kan veroorzaken. Problemen worden ondervonden bij het onderscheiden van gezichten en verschillende tinten zwart en bij kleurperceptie. Om deze verstoringen beter te begrijpen wordt er vaak eerst naar het netvlies van het oog gekeken. Licht het oog binnenkomt wordt door cellen in het netvlies verwerkt, die de informatie doorsturen naar de hersenen. Met behulp van OCT-angiografie kunnen we foto’s maken van het netvlies en zo de gesteldheid van de cellen in het netvlies onderzoeken.
Er zijn een heleboel onderzoeken die op deze manier het netvlies van Parkinsonpatiënten heeft onderzocht. Deze onderzoeken laten echter verschillende uitkomsten zien, uit sommige onderzoeken blijkt er schade aan het netvlies en bij andere onderzoeken niet. In dit onderzoek hebben we een meta-analyse uitgevoerd, waarbij we de uitkomsten van gepubliceerde studies hebben samengevoegd en geëvalueerd. Alle onderzoeken waarin het netvlies van Parkinsonpatiënten en gezonde mensen met behulp van OCT zijn vergeleken werden geïncludeerd.
Op basis van onze samengestelde dataset, waarin in totaal 1916 patiënten zijn vergeleken met 2006 gezonde mensen, concluderen wij dat het netvlies dunner is in Parkinsonpatiënten, maar alleen in de binnenste lagen. Dit is vergelijkbaar met het patroon dat we zien in de ziekte van Alzheimer, andere neurodegeneratieve ziektes en glaucoom. Nieuwe longitudinale onderzoeken in, recent gediagnosticeerde, Parkinsonpatiënten zouden ons kunnen helpen het verloop van van de ziekte, en het effect daarvan op het netvlies, in kaart te brengen.
Dit werk is gepubliceerd in Parkinsonism and Related Disorders in April 2019. Het geschrift, met de titel “Retinal layers in Parkinson’s disease: A meta-analysis of spectral-domain optical coherence tomography studies”, kan hier worden gevonden.
In this paper we present a novel resting-state fMRI (rs-fMRI) based approach, using fast Eigenvector Centrality Mapping (fECM), to identify regions of high connectivity (“hubs”) within a functional brain network for the definition of proper targets for focused repetitive Transcranial Magnetic Stimulation (rTMS). The application of this technique is described extensively in a case of a patient with both the Charles Bonnet Syndrome and Parkinson’s disease, hence suffering from therapy-resistant visual hallucinations (VH). We showed how this approach successfully reduced the intensity of the VH over a period of six months. Moreover, we present how fECM, in combination with rs-fMRI, can be used to monitor the efficacy of the rTMS treatment. Our case-report shows selective changes in functional connectivity of the target area, but also of other regions connected to the target area that are likely to be involved in the pathogenesis of VH. We also discuss the stable position of these hubs over time, which potentially expands the therapeutic options of rTMS, and at the same time indicates the complexity of the mechanisms underlying pathologies, in this case visual hallucinations in Parkinson’s disease.
This work is published in Brain Stimulation in September 2019. The paper, entitled ‘rTMS treatment of visual hallucinations using a connectivity-based targeting method – A case study’, can be accessed here.
Previous questionnaire studies have suggested that glaucoma patients may see well with good light but have poor vision in the dark as well as if the light changes rapidly. Glaucoma is usually tested with perimetry (visual field testing). In perimetry, small white stimuli are presented on a constant, bright background light, and the patient has to report whether the stimulus was seen. We studied the influence of changing light conditions by using perimetry with a rapidly changing background light; this was done with normal and reduced light, and with black and white stimuli. In this way we investigated if perimetry can be improved.
We compared 12 glaucoma patients to 25 healthy subjects of the same age (50–70 years). We did perimetry with black and white stimuli, with normal light and reduced light, and with a constant background light and a changing background light. For all these combinations we compared the visual field of glaucoma patients to that of healthy subjects.
Perimetry is currently done with white targets on a bright background. However, black targets on a dimly lit background are better to see a difference between glaucoma and healthy. The changing background light did not make perimetry better.
This work is published in Investigative Ophthalmology and Visual Science in October 2019. The paper, entitled ‘Retinal Contrast Gain Control and Temporal Modulation Sensitivity Across the Visual Field in Glaucoma at Photopic and Mesopic Light Conditions’, can be accessed here.
How do individual ears decode complex sounds into its frequency components? This question remains one of the main focuses of hearing research. The sound decoding mechanism takes already place in the inner ear and is termed frequency selectivity. In other words: frequency selectivity describes how specific the ears are tuned to differentiate frequencies. To measure the frequency selectivity of an individual objectively and non-invasively, spontaneous otoacoustic emissions (SOAEs) can be used. SOAEs are sounds emitted by the inner ear in absence of any stimulation. These emissions can be recorded as continues tones by placing a sensitive microphone in the ear canal. SOAEs are related to healthy inner ear activity and have been observed in a variety of different vertebrates.
During the frequency selectivity measurement, the SOAEs are suppressed by presenting external tones of different frequencies and levels. The external tones have a characteristic and selective suppression effect on the emission amplitude. Suppression effects with a criterion of 2 dB suppression were quantified by deriving suppression tuning curves (STCs).This objective measurement at inner ear level allows intra- and interspecific comparisons of frequency selectivity. Moreover, this method can be compared to different measurements of frequency selectivity, such as subjective behavioural measurements or invasive neural recordings (of which the latter are not applicable in human research).
In this study we measured the frequency selectivity of the barn owl (Tyto alba), the only bird known so far with SOAEs. We compared the selectivity of the barn owl to different species. Furthermore, we determined the differences of frequency selectivity, when applying different methods.
SOAEs were detected in all tested barn owls ears (N=14). In contrast to human data, the level of the suppressor tone correlated negatively with the emission width. Moreover, the STCs of the barn owl did not show evidence for secondary selectivity side lobes, as can be seen in humans. Suppression measurements of SOAEs to evaluate the frequency selectivity did not directly mirror the frequency tuning measured from single unit recordings of auditory nerve fibers.
This work will published in Hearing Research in January 2020. The paper, entitled ‘Suppression tuning of spontaneous otoacoustic emissions in the barn owl (Tyto alba)’, can be accessed here.