Video-oculographic Examination of Oculomotor Function in Presymptomatic ALS Mutation Carriers

Master's Thesis, 2018

73 Pages, Grade: 1,0


Table of Contents

Table of Contents


1. Introduction
1.1 General Description of Amyotrophic Lateral Sclerosis
1.2 Motivation of the Present Study
1.3 Current State of Research in ALS/FTD
1.4 Executive Control and Oculomotor Correlate
1.5 Pathomechanisms in the ALS-FTD Spectrum
1.6 Abnormalities of Eye Movement Control in ALS
1.7 Video-oculography
1.8 Motivation and Hypotheses

2. Methods
2.1 Participants and emographic haracterization
2.2 Experimental Design
2.3 Statistical nalysis

3. Results
3.1 Altered Oculomotor Performance in Asymptomatic ALS Mutation Carriers
3.2 Altered Oculomotor Performance in Symptomatic ALS Mutation Carriers
3.3 Differences Between C9orf72 MC and Non- C9orf72 ALS-MC
3.4 Oculomotor Performance Differences Between ‘Classical’ ALS and ALS/FTD

4. Discussion
4.1 Presymptomatic ALS
4.2 Executive Dysfunctions in ALS
4.3 Influence of Genetic Variant
4.4 Differences between ALS and ALS/FTD
4.5 ALS Staging Models
4.6 Video-oculography
4.7 Limitations and trengths
4.8 Prospects of the Study

5. Summary

References and Bibliography

List of Tables



Abbildung in dieser Leseprobe nicht enthalten

1. Introduction

1.1 General Description of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease (Heiko Braak et al., 2013; Kiernan et al., 2011). As for now, causal therapeutic options are still limited for ALS (Ludolph et al., 2018). The devastating disease is defined as a fast progressive, multisystem degenerative disorder, which is clinically characterized by a predominant loss of motor neurons that disrupts signals to all voluntary innervated muscles. This leads to a progressive weakness of the respective muscles following an almost complete paresis after a couple of years. ALS usually ends in death due to respiratory failure after 30 months on average from disease onset. The disease was first mentioned 1824 by Charles Bell (Kiernan et al., 2011). Jean-Martin Charcot linked the disease symptoms to its underlying pathology and began to use the term amyotrophic lateral sclerosis in 1874 (Rowland, 2001). ALS is also known under the term Lou Gehrig's disease. The name Lou Gehrig’s disease derives from the famous American baseball player who suffered of ALS and brought the disease in the focus of the North American public. In Europe ALS has an incidence of 2.6/100,000 persons per year and a prevalence of 7–9/100,000 persons (Hardiman et al., 2017).

1.2 Motivation of the Present Study

In a yet not curable disease, one of the biggest obstacles in the development of new therapeutic concepts to counteract pathological symptoms or further to prevent the onset of the disease itself, is to find the origin of the to this day unidentified pathogen (Burrell et al., 2016). Furthermore, heterogeneity in symptoms and disease patterns complicate and aggravate efforts in understanding underlying pathological pathways. Understanding of the disease mechanisms is crucial for the development of disease-modifying therapeutic concepts (Golde, 2009).

It is presumed in neurodegenerative diseases, such as the ALS-FTD spectrum, that pathological processes begin long time before symptom onset. This is supported by the fact that presymptomatic and early stage patients suffering of neurodegenerative diseases are able to show functional performance on the level of the healthy normal population, although a considerable cortical and subcortical loss could be already observed. Therefore, concepts of brain and cognitive reserve and neuronal compensation were developed. They suggest that patients could show normal behavior in the presence of neuronal loss through adaptation of neural networks, i.e. recruitment of a brain region outside the usual task region or changes in the activation within a function-specific network (Barulli & Stern, 2013; Gregory, Long, Tabrizi, & Rees, 2017; Papoutsi, Labuschagne, Tabrizi, & Stout, 2014; Scheller, Minkova, Leitner, & Klöppel, 2014).

Neurodegenerative diseases show irrevocable damages in neuronal networks long before symptom onset. Therefore, it is of great importance to develop disease-modifying therapeutics that act immediately at the disease onset when damage to neuronal networks is limited. To achieve this, reliable clinical readouts which enable to track or better predict the course of the disease are of outmost importance. Investigating the potential of such early biomarkers in a prodromal or asymptomatic phase in the ALS-FTD spectrum offers unique opportunities (Ludolph, 2017).

1.3 Current State of Research in ALS/FTD

Up to this moment, underlying mechanisms of ALS are quite occluded. Severe and moderate traumatic brain injury (TBI) increases the risk for ALS (Gardner & Yaffe, 2015). Additionally, genetic factors are found in most ALS patients; if they are, the sole trigger is unknown. Most cases occur without familial accumulation (sporadic ALS, sALS). However, in a small but not insignificant proportion of cases (around 10%) a familial accumulation is observed (familial ALS, fALS). First-degree relatives of those with ALS have a 1.1% lifetime risk of ALS in the US (Wingo, Cutler, Yarab, Kelly, & Glass, 2011). Environmental and genetic factors appear nearly equally important for the development of ALS ibid. Mutations in TARDBP, C9 orf ORF 72, VAPB, FUS and SOD1 are found in a majority of cases. Their expressed proteins could have a prion-like activity and form inclusion bodies (Bräuer, Zimyanin, & Hermann, 2018; Lau et al., 2018). It was suggested that they lead to the probably pathological accumulation or premature degradation of the protein transactive response DNA-binding protein 43 kDs (TDP-43), FUS or SOD1, which ultimately triggers the neurodegeneration, comparable to Tau in tauopathies (Ince et al., 2011). A strong genetic link of ALS to FTD also points to the higher complexity of ALS than that of a primary motor neuron disorder (Burrell et al., 2016; Weishaupt, Hyman, & Dikic, 2016). It seems that most ALS/FTD disease genes can be grouped into a few major common pathways critically involved in disease pathogenesis, namely RNA dysmetabolism, autophagy, cytoskeleton dynamics, and DNA damage repair (Weishaupt, Hyman, & Dikic, 2016).

ALS was originally classified as a motor neuron disease, which affect both the upper motor neurons (UMN) and the lower motor neurons (LMN) (Kiernan et al., 2011). Despite its traditionally description the underlying pathology affects also widespread extramotor areas (Lomen-Hoerth et al., 2003; Phukan et al., 2012). Moreover, gentle cognitive deficits especially executive functions seem to accompany the disease (Gorges et al., 2015; Kiernan et al., 2011). Furthermore, it was also suggested that ALS may be characterized as a corticoefferent syndrome (Gorges et al., 2018), affecting primarily the cerebral cortex (Heiko Braak et al., 2013). In this model the progressive development of neuronal inclusions in other central nervous system areas are a secondary manifestation of the disease. ALS seems to originate in somato motor neurons of the spinal cord, lower brainstem and in portions of the agranular frontal neocortex (Braak et al., 2013; Brettschneider et al., 2014; Lulé et al., 2018). The neocortex and spinal cord are mostly affected through lesions in ALS and are separated by remarkable distance. It is worth noting that nearly all vulnerable neurons in ALS receive strong afferents from neocortical pyramidal cells. Furthermore, all neurons with phosphorylated TPD-43 inclusions in ALS patients are controlled through the neocortex (Braak et al., 2013) (Heiko Braak et al., 2013) . Current evidence from neuropsychological assessment, T1-weighted magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI) in asymptomatic C9orf72 mutation carriers suggested cognitive performance parameters within a normative range but may indicate subtle alterations in ALS/FTD specific cognitive domains including executive functions (Papma et al., 2017).


Excerpt out of 73 pages


Video-oculographic Examination of Oculomotor Function in Presymptomatic ALS Mutation Carriers
University of Ulm  (Klinik für Neurologie)
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ISBN (eBook)
ISBN (Book)
motor neuron disease, diffusion tensor imaging, Braak stages, MRI, in vivo spreading model, neurodegeneration, VOG, Video-oculography, ALS, Amyotrophic lateral sclerosis, bvFTD, C9orf72, fALS, FTD, Frontotemporal Dementia, SOD1, Superoxide Dismutase [Cu-Zn], TARDBP, Transactive Response DNA binding protein, TDP-43, Visually Guided Reactive Saccades, Smooth pursuit eye movements, Peak Eye Velocity, Genetic Study, FUS, Mutation Carrier, Presymptomatic, oculomotor function
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Daniel Höfer (Author), 2018, Video-oculographic Examination of Oculomotor Function in Presymptomatic ALS Mutation Carriers, Munich, GRIN Verlag,


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