Huntington’s disease (HD) is a progressive autosomal dominant inherited neurodegenerative disorder.The primary aim of this thesis is to examine alterations in the cerebral cortex in HD gene... Show moreHuntington’s disease (HD) is a progressive autosomal dominant inherited neurodegenerative disorder.The primary aim of this thesis is to examine alterations in the cerebral cortex in HD gene carriers. Different image modalities and approaches will be used to extent the knowledge on both structural and functional cortical brain changes in early disease. Although striatal atrophy is more extensively present in HD, changes in the cerebral cortex can also be detected in the pre-symptomatic stage. Different methodological approaches used in our studies all showed a consistent pattern of cortical atrophy making volumetric MRI a reliable and effective tool to assess early in-vivo cortical brain changes, even in a rare neurodegenerative disorder such as HD. The influence of cortical changes on other clinical signs that occur in HD should not be overlooked. Our results demonstrate that volume loss and thinning of the cerebral cortex, especially the posterior brain regions, is detectable in early stages and contributes to the presence of specific motor signs and cognitive impairments. We believe that intervention trials could benefit from using cortical volumes as outcome measures, instead of using striatal volumes alone. Show less
We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2... Show moreWe studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p < 0.001) and PKD/IC in two (p = 0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes. Show less
In the chronic stage of Complex Regional Pain Syndrome (CRPS), motor disturbances are common and cause significant disability. The motor dysfunction of CRPS is a poorly understood phenomenon that... Show moreIn the chronic stage of Complex Regional Pain Syndrome (CRPS), motor disturbances are common and cause significant disability. The motor dysfunction of CRPS is a poorly understood phenomenon that is characterized predominantly by a decrease or loss of voluntary muscle control. This thesis aims to obtain a better understanding of the pathophysiology underpinning the motor dysfunction of CRPS by examining the potential roles of decreased inhibition of the motor system, changes in sensory processing and problems in sensory-motor integration. In specific, characteristics of muscle activity recordings are scrutinized in order to determine whether the loss of voluntary motor control and abnormal postures in CRPS exhibit characteristics of dystonia that are associated with reduced inhibition of the motor system (i.e., excessive muscle activation and enhanced mirror activity). The potential role of impaired processing of proprioceptive information related to wrist orientation and force production is examined, as well as the involuntary and voluntary (sensory-)motor interactions between the affected and unaffected arm. Furthermore, a systematic review of the literature on the motor consequences of experimental pain in healthy humans is presented in order to gain insight into the potential role of pain-related processes in the motor and sensory and motor disturbances of CRPS. Show less
Huntington's disease (HD) is a genetic neurodegenerative disease. Carriers of the HD gene without clinical symptoms of the disease can be identified and studied. The study of these premanifest... Show moreHuntington's disease (HD) is a genetic neurodegenerative disease. Carriers of the HD gene without clinical symptoms of the disease can be identified and studied. The study of these premanifest subjects is of importance for the understanding of preclinical disease progression and for the design of future clinical trials. HD is characterized by progressive decline in motor functioning, cognition and behaviour. The unwanted motor disturbances that patients experience are likely to be of influence on cognitive functioning, as cognitive tests almost always require a motoric response. In this thesis we investigated cognitive functioning in both premanifest HD gene carriers and HD patients by taking into account the motor disturbances that have been reported in both pre- and manifest phases of the disease. We also reports on the influence of time on cognition in HD by means of several longitudinal reports with follow-up periods as long as ten years. We found both carriers and patients deteriorate most on memory and executive functioning domains, with the latter being most sensitive in the premanifest phase. We have also found evidence for the presence of premanifest (cognitive) compensatory mechanisms. As expected, there is a substantial (negative) effect of motor functioning on cognition in HD. Show less
Gooijer-van de Groep, K.L. de; Vlugt, E. de; Groot, J.H. de; Heijden-Maessen, H.C.M. van der; Wielheesen, D.H.M.; Wijlen-Hempel, R.S. van; ... ; Meskers, C.G.M. 2013
The aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain... Show moreThe aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain characteristics and intrinstic functional brain connectivity of premanifest and early HD subjects were examined. Cortical, subcortical and the intermediate white matter brain tissue shows evidence of structural and functional decline. We found evidence that disease processes, such as altered metabolism, excessive iron accumulation and cell loss, play a role in the changes. We conclude that changes occur throughout the brain from the earliest disease phase onwards. Hence, both premanifest and manifest HD should not be regarded as a disorder of the basal ganglia, but as a disease affecting the whole brain. Candidate biomarkers that have the potential to objectively reflect the early changes and the progressive nature of the disease are measures of subcortical atrophy, integrity of white matter pathways and of intrinsic functional brain connectivity. Iron, creatine, and N-acetylaspartate concentrations in the caudate nucleus and putamen may prove to be useful as markers of disease state for objectifying transitional disease processes from premanifest to manifest HD. Visuospatial working memory could be applied as a state marker for stage two HD. Show less
The aim of this thesis was to find potential MRI biomarkers for Huntington__s disease (HD). Therefore, after an overview of the current literature on MRI biomarkers, followed by examinations of... Show moreThe aim of this thesis was to find potential MRI biomarkers for Huntington__s disease (HD). Therefore, after an overview of the current literature on MRI biomarkers, followed by examinations of volumetric MRI, magnetization transfer imaging (MTI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were applied in patients in different disease stages of HD. The main conclusions demonstrate that choosing the optimal biomarker for evaluating therapeutic effects is dependent on the disease stage and therapeutic compound. To evaluate the premanifest stages of the disease volumetric MRI and DTI are most suitable. When the transition period is the desired timeframe for evaluation, also MRS can be very useful, especially if the compound in question has a direct potential influence on certain pathogenic pathways which in turn have an impact on specific metabolites. Future research should focus on combining multiple imaging techniques; __multimodal imaging__. A composite MRI biomarker has the potential to distinguish between disease groups more accurately than a single biomarker and in this way improve the evaluation of therapeutic compounds. Show less
