This thesis describes a set of excitability measurements -transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG), nerve excitability threshold... Show moreThis thesis describes a set of excitability measurements -transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG), nerve excitability threshold tracking (NETT), and muscle velocity recovery cycles (MVRC)- and the applicability of these tools in early phase clinical drug development. We validated the biomarkers in healthy subjects with registered drugs and showed that the measurements are all repeatable and sensitive to pharmacological effects, even in a small number of subjects. Furthermore, we have evaluated effects of a novel AMPA-positive allosteric modulator with TMS-EMG/EEG, and a first-in-class skeletal muscle-specific chloride channel (ClC-1) inhibitor with MVRC, and the findings helped us to confirm proof-of-mechanism of these compounds in healthy subjects. In conclusion, these measurements proved to be valuable pharmacodynamic biomarkers in two drug development programs, encouraging their further use in clinical development of other future drug candidates targeting cortical-, neuronal-, and muscle cell excitability. The use of such clinical pharmacodynamic biomarkers could improve the quality and efficiency of the development process of drugs for e.g. amyotrophic lateral sclerosis, chronic pain, depression, treatment-resistant epilepsy, and neuromuscular diseases. Show less
Kas, M.J.H.; Jongs, N.; Mennes, M.; Penninx, B.W.J.H.; Arango, C.; Wee, N. van der; ... ; Marston, H.M. 2024
Objective To evaluate the association between neuroimaging and outcome in infants with congenital cytomegalovirus (cCMV), focusing on qualitative MRI and quantitative diffusion-weighted imaging of... Show moreObjective To evaluate the association between neuroimaging and outcome in infants with congenital cytomegalovirus (cCMV), focusing on qualitative MRI and quantitative diffusion-weighted imaging of white matter abnormalities (WMAs).Methods Multicentre retrospective cohort study of 160 infants with cCMV (103 symptomatic). A four-grade neuroimaging scoring system was applied to cranial ultrasonography and MRI acquired at <= 3 months. WMAs were categorised as multifocal or diffuse. Temporal-pole WMAs (TPWMAs) consisted of swollen or cystic appearance. Apparent diffusion coefficient (ADC) values were obtained from frontal, parieto-occipital and temporal white matter regions. Available follow-up MRI at >= 6 months (N=14) was additionally reviewed. Neurodevelopmental assessment included motor function, cognition, behaviour, hearing, vision and epilepsy. Adverse outcome was defined as death or moderate/severe disability.Results Neuroimaging scoring was associated with outcome (p<0.001, area under the curve 0.89 +/- 0.03). Isolated WMAs (IWMAs) were present in 61 infants, and WMAs associated with other lesions in 30. Although TPWMAs and diffuse pattern often coexisted in infants with IWMAs (p<0.001), only TPWMAs were associated with adverse outcomes (OR 7.8; 95% CI 1.4 to 42.8), including severe hearing loss in 20% and hearing loss combined with other moderate/severe disabilities in 15%. Increased ADC values were associated with higher neuroimaging scores, WMAs based on visual assessment and IWMAs with TPWMAs. ADC values were not associated with outcome in infants with IWMAs. Findings suggestive of progression of WMAs on follow-up MRI included gliosis and malacia.Conclusions Categorisation of neuroimaging severity correlates with outcome in cCMV. In infants with IWMAs, TPWMAs provide a guide to prognosis. Show less
Purpose: Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging... Show morePurpose: Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging together with the concept of theranostics more generally. The aim of this document is to provide guidelines for nuclear medicine departments setting up and developing their quantitative SPECT-CT service with guidance on protocols, harmonisation and clinical use cases. Methods: These practice guidelines were written by members of the European Association of Nuclear Medicine Physics, Dosimetry, Oncology and Bone committees representing the current major stakeholders in Quantitative SPECT-CT. The guidelines have also been reviewed and approved by all EANM committees and have been endorsed by the European Association of Nuclear Medicine. Conclusion: The present practice guidelines will help practitioners, scientists and researchers perform high-quality quantitative SPECT-CT and will provide a framework for the continuing development of quantitative SPECT-CT as an established modality. Show less
Purpose Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging... Show morePurpose Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging together with the concept of theranostics more generally. The aim of this document is to provide guidelines for nuclear medicine departments setting up and developing their quantitative SPECT-CT service with guidance on protocols, harmonisation and clinical use cases. Methods These practice guidelines were written by members of the European Association of Nuclear Medicine Physics, Dosimetry, Oncology and Bone committees representing the current major stakeholders in Quantitative SPECT-CT. The guidelines have also been reviewed and approved by all EANM committees and have been endorsed by the European Association of Nuclear Medicine. Conclusion The present practice guidelines will help practitioners, scientists and researchers perform high-quality quantitative SPECT-CT and will provide a framework for the continuing development of quantitative SPECT-CT as an established modality. Show less
The mechanisms involved in the autoimmune hypothesis of narcolepsy are investigated in this thesis. The role of HLA, auto- and cross-reactive T cells is explored and immune cell populations of... Show moreThe mechanisms involved in the autoimmune hypothesis of narcolepsy are investigated in this thesis. The role of HLA, auto- and cross-reactive T cells is explored and immune cell populations of interest are identified by a new technique, called mass cytometry. The second part of the thesis assesses unexplored clinical features of narcolepsy, such as weight gain and sleep state misperception. Show less
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT... Show moreHuntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. Show less
The aim of this thesis is to examine employment and driving ability in gene carriers with Huntington’s disease (HD). HD is an autosomal-dominant inherited neurodegenerative disorder and manifests... Show moreThe aim of this thesis is to examine employment and driving ability in gene carriers with Huntington’s disease (HD). HD is an autosomal-dominant inherited neurodegenerative disorder and manifests during mid adulthood. The disease is clinically characterized by motor disturbances, cognitive decline and behavioral changes. Since there is currently no cure for HD, the focus of treatment is on improving quality of life and providing the necessary support to patients and families. Maintaining independence through employment and driving, for as long and as safely as possible, has a substantial influence on a patient’s general functioning. Our results consistently showed that the cognitive and behavioral changes of HD are more debilitating in daily life than the characteristic motor signs, and are associated with employment and driving a car. Healthcare professionals should be educated about HD to allow them to provide appropriate information to patients and families when discussing possible changes in working and driving as a result of HD. Individual evaluation of driving ability is warranted and the recommendation to stop driving should not solely be based on disease stage or a genetic confirmation. Multidisciplinary screening, using a HD-specific test battery, is recommended and should be embedded in the clinic. Show less
Sporadische inclusion body myositis (IBM) is een van de meest voor voorkomende verworven spierziekte die ontstaat na het 50e levensjaar. In dit proefschrift worden de klinische aspecten van... Show moreSporadische inclusion body myositis (IBM) is een van de meest voor voorkomende verworven spierziekte die ontstaat na het 50e levensjaar. In dit proefschrift worden de klinische aspecten van sporadische IBM beschreven. Uit de studie met betrekking tot het natuurlijk beloop blijkt dat de ziekte niet levensverkortend is, maar dat de doodsoorzaken bij sporadische IBM wel verschillen ten opzichte van een voor de leeftijd gecorrigeerde populatie. De aard en frequentie van slikstoornissen worden beschreven, alsmede de potentiele betrokkenheid van het hart. Door middel van MRI's van skeletspieren is een voor sporadische IBM specifiek patroon van afwijkingen beschreven. Ten slotte is aangetoond dat TREX1 mutaties geen rol spelen in het ontstaan van de ziekte. Show less
Mutations in the CACNA1A gene, encoding neuronal Cav2.1 calcium channels, cause a wide spectrum of human neurological diseases, including familial hemiplegic migraine type 1 (FHM1). The role of... Show moreMutations in the CACNA1A gene, encoding neuronal Cav2.1 calcium channels, cause a wide spectrum of human neurological diseases, including familial hemiplegic migraine type 1 (FHM1). The role of Cav2.1 channels is to mediate neurotransmitter release. Using electrophysiological techniques, this thesis investigates the effects of several CACNA1A mutations on neurotransmitter release at the mouse neuromuscular junction (NMJ). It is concluded that the FHM1 mutations R192Q and S218L increase neurotransmitter release and do not result in compensatory contributions of other types of calcium channels. Furthermore, it is shown that spontaneous neurotransmitter at the mouse NMJ is partly Cav2.1 channel-dependent, whereas evoked release relies entirely on Cav2.1 channels. Studies on the Cav2.1 mouse mutant Rolling Nagoya show that spontaneous and evoked neurotransmitter release are controlled independently. Studies on mouse mutants that lack auxiliary Cav2.1 channel subunits revealed that these subunits are redundant and/or absent at the mouse NMJ. The studies presented in this thesis provide novel insights into the synaptic dysfunction caused by Cav2.1 channel mutations. Synaptic effects on central synapses are likely to share many features with those observed at the mouse NMJ and thought to underlie (some of) the neurological symptoms of human and mouse disorders associated with Cav2.1 channel dysfunction Show less
The purpose of this study is to discuss several aspects of facioscapulohumeral disease, also called "autosomal dominant facioscapulohumeral muscular dystrophy" or "Landouzy-Dejerine type of... Show moreThe purpose of this study is to discuss several aspects of facioscapulohumeral disease, also called "autosomal dominant facioscapulohumeral muscular dystrophy" or "Landouzy-Dejerine type of muscular dystrophy" or "Landouzy-Dejerine' s disease" . We consider this disorder well defined and recognizable, justifying the term facioscapulohumeral disease, abbreviated FSHD. Show less
