The aim of this thesis is to explore fear of choking and fear of falling in people with Huntington's disease (HD) and their caregivers. Dysphagia and falls are common in HD and may lead to fear of... Show moreThe aim of this thesis is to explore fear of choking and fear of falling in people with Huntington's disease (HD) and their caregivers. Dysphagia and falls are common in HD and may lead to fear of choking and fear of falling. However, knowledge about this is mostly lacking, as well as knowledge about the relationship between cognitive and emotional factors and these types of fear. The study confirms that fall prevalence (29% over a 30-day period) and prevalence of dysphagia symptoms (90%) are high. However, a prevalence of about 50% is also reported for fear of choking and fear of falling in people with HD. However, their informal caregivers report the most fear. Severity of dysphagia symptoms was a predictor of fear of choking, and anticipatory awareness of fall risks and gender were found to be predictors of fear of falling. In most individuals with HD, a combination of preventive measures was used.Future research can improve both management of dysphagia and fear of choking and management of falls and fear of falling. Because questioning people with HD is sometimes difficult, due to speech and cognitive difficulties, diagnostic tools may be sought to facilitate this, such as wearable electronic devices. Show less
This thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre... Show moreThis thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre-frail elderly and Huntington’s disease patients, we used phosphorous magnetic resonance spectroscopy as the main method to measure mitochondrial function in vivo. Other in vivo methods included Near Infrared Spectroscopy and the novel Protoporphorin-9 Triplet State Lifetime Technique, besides in vitro ELISA methods to measure activity of separate complexes of the mitochondrial electron transport chain. Using these modalities, we showed mitochondrial dysfunction in pre-frail elderly, emphasizing the importance of an active lifestyle in the prevention of sarcopenia and frailty. Using the mitotoxicity of simvastatin, and its reversibility by ubiquinol, we validated the first proof-of-pharmacology model in healthy volunteers to evaluate efficacy of novel mitochondrial function improving compounds. We also described the importance of measuring (mitochondrial) oxygen consumption as a means to measure mitotoxicity of commonly described medications. Lastly, we evaluated the safety and efficacy of the novel compound SBT-020 in a placebo-controlled, double-blinded, randomized controlled trial in mild to moderate Huntington’s disease patients and compared central to peripheral mitochondrial function for the first time, gaining inside into therapeutic possibilities in this complex and devastating disease. Show less
Neurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks... Show moreNeurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks of neurodegeneration are still not fully understood. In this thesis, we make use of bioinformatics approaches to analyze a high-resolution spatial gene expression atlas of the healthy human brain generated by the Allen Institute of Brain Science. Spatial transcriptomics allows examining the molecular and functional organization of the human brain and can be combined with neuroimaging data to identify brain regions and anatomical structures that are vulnerable to cell loss in neurodegenerative diseases. By combining both data modalities, we examined healthy molecular functions in brain regions associated with disease vulnerability based on neuroimaging features, namely gray matter loss within brain networks in individuals with Parkinson’s disease, Huntington’s disease, and individuals at risk of schizophrenia. With this thesis, we have shown that by applying data-driven computational methods we can explore the whole genome and find gene expression patterns informative of regional brain vulnerability in neurodegenerative diseases. Our methods can similarly be applied to unravel the molecular mechanisms in other neurodegenerative diseases, and potentially even reveal shared mechanisms between neurological disorders. 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
Huntington’s disease (HD) is a progressive neurodegenerative disorder, which is clinically characterized by motor impairment, cognitive decline, and behavioral symptoms. In this thesis we have... Show moreHuntington’s disease (HD) is a progressive neurodegenerative disorder, which is clinically characterized by motor impairment, cognitive decline, and behavioral symptoms. In this thesis we have investigated measurement properties of the Unified Huntington’s Disease Rating Scale (UHDRS) and the Unified Huntington’s Disease Rating Scale-For Advanced Patients (UHDRS-FAP). These assessment scales have been developed to monitor the presence, severity, and progression of symptoms systematically over time. To measure change of symptoms accurately, reliable and valid scales are essential. Poor interrater reliability was found for all dystonia items of the UHDRS. We concluded that the rating of these items is difficult to interpret, probably as a consequence of the subjective nature of the response options. Future studies are required to explore how the dystonia items can be improved. We have also demonstrated that the motor and cognitive scores of the UHDRS-FAP deteriorated in patients with advanced HD during six months follow-up, while the motor and cognitive scores of the UHDRS did not show any change. This finding suggests that the UHDRS-FAP can detect disease progression in late stage HD, contrary to the UHDRS. Therefore, we recommended the use of the UHDRS-FAP motor and cognitive scores in long-term care facilities to optimize HD care. Show less
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
Huntington’s disease (HD) is a devastating neurodegenerative disease caused by a single mutation, a CAG expansion, in the huntingtin (HTT) gene. The resultant mutant HTT protein has been shown to... Show moreHuntington’s disease (HD) is a devastating neurodegenerative disease caused by a single mutation, a CAG expansion, in the huntingtin (HTT) gene. The resultant mutant HTT protein has been shown to be the predominant toxic entity in the HD pathogenesis and therapeutic strategies that aim to lower the mutant HTT show a great promise. The main objective of this work is to demonstrate a preclinical efficacy of an adeno-associated virus (AAV)-delivery of micro (mi)RNA-based gene therapy for the treatment of HD. We have tested various therapeutic miRNAs to achieve overall HTT protein lowering in HD rodent models and induced pluripotent stem cell (iPSC)-derived HD patient neuronal cultures. Excitingly, we have demonstrated HTT lowering by the AAV5-miHTT in all HD models tested so far with no undesired events, which strongly supported the continuation of preclinical testing in large animals. Furthermore, we provided an evidence suggesting that therapeutic miRNAs can be also active in the nucleus, extending their range of applicability. The possibility to use exosome-enriched vesicles as carriers of pharmacokinetic/pharmacodynamic (PK/PD) measures for the AAV5-miHTT gene therapy, that would signal the presence of the active therapeutic miRNAs in the brain, was further explored in preparation for a first clinical trial in humans. Show less
The aim of this thesis was to get a better understanding of the incidence and course of neuropsychiatric symptoms in HD, particularly irritability that is a core behavioral symptoms. Also, we aimed... Show moreThe aim of this thesis was to get a better understanding of the incidence and course of neuropsychiatric symptoms in HD, particularly irritability that is a core behavioral symptoms. Also, we aimed to investigate the realtionship between activity of the immune system and presence of neuropsychiatric symptoms. In this thesis, the psychometric properties of the Irritability Scale, and cross sectional and longitudinal analyses of irritability are described. The role of the innate immune system was investigated using both plasma acute-phase proteins and cytokines. Show less
The thesis reports about the effects of music therapy with patients in the late stage of Huntington's disease. A literature review, a focus group study, a randomized controlled trial, an... Show moreThe thesis reports about the effects of music therapy with patients in the late stage of Huntington's disease. A literature review, a focus group study, a randomized controlled trial, an evaluation for complex interventions and a case report study are integrated in the thesis. The beneficial effects of music therapy could not be proven with the RCT-design and outcome measures that have been used. The beneficial effects of music therapy could not be proven with the RCT-design and outcome measures that have been used in the effect study. This outcome could imply that either music therapy is not effective in HD, or that the chosen study design or the primary endpoints (communication and expressive skills and behavior) were not appropriate to show the effectiveness of music therapy. A process evaluation of the RCT was executed to elucidate the results and to investigate how the study was performed. Show less
In this thesis the epidemiology of suicidal ideation and suicide attempts (together referred to as 'suicidality') in Huntington's disease (HD) is investigated and coping styles and support... Show moreIn this thesis the epidemiology of suicidal ideation and suicide attempts (together referred to as 'suicidality') in Huntington's disease (HD) is investigated and coping styles and support strategies that may serve to help suicidal HD mutation carriers are explored. Suicidality frequently occurs in HD, with a 1-month prevalence of up to 20%. Mutation carriers who were most likely to currently experience suicidal ideation or suicidality had a shorter disease duration, were anxious, aggressive, previously attempted suicide, used antidepressants, and had a depressed mood. The presence of a depressed mood and use of benzodiazepines were the only significant independent predictors of incident suicidal ideation or suicidality. Biological parameters, in particular functioning of the immune system and the hypothalamus-pituitary-adrenal axis were not found to be associated with suicidality in HD. In a qualitative study it was shown that suicidal HD mutation carriers generally used four strategies to cope with suicidality: talking about suicidality, employing self-management activities, using medication, and discussing end-of-life wishes. Lastly, in a meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide. Effect estimates differed substantially among different populations, but none of the included studies investigated this association in HD. Show less
In this thesis, a perspective of attachment theory is used to investigate relationships between adverse childhood experiences, adult attachment style, emotion regulation strategies, and distress... Show moreIn this thesis, a perspective of attachment theory is used to investigate relationships between adverse childhood experiences, adult attachment style, emotion regulation strategies, and distress before and after predictive testing, in persons from families with a late onset hereditary disorder. The hereditary disorders at issue are Huntington__s disease (HD), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Hereditary Cerebral Hemorrhage With Amyloidosis __ Dutch type (HCHWA-D), or BRCA1 or BRCA2 Hereditary Breast and Ovarian Cancer (HBOC).The aim of the studies described in this thesis was to find out whether growing up with a parent who has one of these hereditary diseases is associated with adverse childhood experiences in offspring, whether there is a relationship between these experiences and adult psychological characteristics, especially attachment style and style of emotion regulation, and whether these characteristics are associated with the level of distress during and after predictive genetic testing. Show less
Huntington__s disease (HD) is a progressive neurodegenerative disease with an autosomal, dominant mode of inheritance. Patients with HD suffer from dysphagia which can have serious consequences,... Show moreHuntington__s disease (HD) is a progressive neurodegenerative disease with an autosomal, dominant mode of inheritance. Patients with HD suffer from dysphagia which can have serious consequences, such as weight loss, dehydration, and pneumonia leading to death. Many patients with HD die of aspiration pneumonia. In order to start monitoring dysphagia in HD patients systematically during different stages of the disease, a new measurement instrument was needed. We developed the Huntington__s Disease Dysphagia Scale. The availability of this new scale now allows prospective monitoring of dysphagia in patients with HD. Another aim was to investigate specific dysphagia features in HD using videofluoroscopy. We found that 78% of our patients suffered from dysphagia. Swallowing difficulties start already in the first stage of HD, and become more severe as the disease progresses. The final aim was to initiate intervention studies on dysphagia in HD. We began by developing a guideline based on best practice. The guideline describes dysphagia problems per stage of HD, and makes recommendations for intervention and clinical advice. One of the recommendations in the European guideline is the chin tuck position while swallowing. As there is no evidence for improvement with this intervention for HD patients, we carried out a videofluoroscopic swallowing test with and without the chin tuck test procedure. No significant differences were found for spilling, aspiration or residue in swallowing with the head in normal upright position or the chin tuck posture. We therefore recommend that the chin tuck intervention should not be used in HD patients. Show less
Motor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep... Show moreMotor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep and circadian disturbances and autonomic nervous system dysfunction. The nature of these features supports a pivotal role of the hypothalamus in the HD disease process. In this thesis data is presented from immunocytochemical and in situ hybridization studies demonstrating substantial pathology in hypothalamic neuropeptide expression in HD patients. Main findings include neuropeptide changes in the suprachiasmatic nucleus, the body__s master clock, that will likely be responsible for disruption of 24h circadian rhythmicity. Secondly, the neuronal histaminergic system is hyperactive at both the level of the hypothalamic tuberomamillary nucleus as well as in the cerebral neocortex. These changes could partly explain weight loss and cognitive decline in patients. The expression of neuropeptides in the hypothalamic paraventricular and infundibular nuclei, however, seems to be relatively unaffected by the HD disease process. Finally, a discrepancy between mRNA expression and protein expression of many hypothalamic neuropeptides was observed that can be partly explained by a decrease of prohormone convertase expression. Interestingly, hypothalamic changes in existing HD transgenic rodent models are largely non-representative of hypothalamic changes in HD patients. 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
Falls in Parkinson__s (PD) and Huntington__s disease (HD) are common. 50 % of moderately affected PD patients sustained two or more falls during a prospective follow-up of 6 months. During a 3... Show moreFalls in Parkinson__s (PD) and Huntington__s disease (HD) are common. 50 % of moderately affected PD patients sustained two or more falls during a prospective follow-up of 6 months. During a 3 month period 40 % of HD patients reported one or more fall. Many falls resulted in minor injuries and 42 % of PD patients reported a fear of future falls. A different study on quality of life in PD showed that quality of life scores were significantly related to fear of falling in PD. In order to predict future falls several clinical tests and risk factors were studied. However, it proved difficult to identify future fallers and asking for prior falls was the best predictor of falls in the near future in PD. Analysis with quantative measurements in HD patients showed that an increased medio lateral trunk sway and a decreased stride length were associated with an increased fall risk. Based on the findings in these studies and on a literature study, the thesis concludes with a proposal for a multidisciplinary intervention program to prevent falls in Parkinson__s disease. Show less
The general aim of this thesis was to assess the effectiveness of a standardized psychosocial education program. The first studies of this thesis were aimed to assess the effectiveness of the... Show moreThe general aim of this thesis was to assess the effectiveness of a standardized psychosocial education program. The first studies of this thesis were aimed to assess the effectiveness of the Patient Education Program for Parkinson__s disease (PEPP), as the original program was directed at Parkinson__s disease. Thereafter, it was aimed to assess the program__s feasibility in other diseases. A second step in the thesis was an evaluation of the feasibility of the program adapted to a new disease-specific form for Huntington__s disease (PEP-HD). The third step was to evaluate a generic form of the program in a heterogeneous group of patients with chronic diseases and co-morbid psychiatric problems (PEP-CD). Show less
The nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include... Show moreThe nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include unintended weight loss, sleep and circadian rhythm disturbances, as well as autonomic nervous system dysfunction. However, the pathogenesis of these less well-known features of HD is poorly understood and currently no effective treatment options are available. It is thus of paramount importance to elucidate the pathological basis of these symptoms and signs in order to design and apply more effective therapeutic interventions. Recently, substantial dysfunction of the hypothalamus was reported in both human studies and various knock-in and transgenic animal models of HD. The hypothalamus consists of groups of interconnected neuronal nuclei located at the base of the brain that regulate a broad array of physiologic, homeostatic and behavioural activities. Therefore, in this thesis we attempt to substantiate the premise that hypothalamic dysfunction per se, as well as secondary (neuro)endocrine and metabolic alterations could contribute to the pathogenesis of several non-motor symptoms and signs of HD. Show less
Dit proefschrift begint met een overzichtsartikel van oorspronkelijke onderzoek naar psychopathologie bij mutatiedragers voor de ziekte van Huntington. Aansluitend worden de resultaten van een... Show moreDit proefschrift begint met een overzichtsartikel van oorspronkelijke onderzoek naar psychopathologie bij mutatiedragers voor de ziekte van Huntington. Aansluitend worden de resultaten van een cohortstudie naar de aanwezigheid en ernst van psychopathologie bij mensen met de ziekte van Huntington in verschillende ziektestadia en bij eerstegraads niet-dragers beschreven. Show less
The first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington... Show moreThe first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington__s Disease. To determine whether the hypocretin system is affected in these disorders, the total number of hypocretin neurons was determined using quantitative techniques in post-mortem human hypothalami. The reason why hypocretin neurons disappear in narcolepsy is still a mystery. A putative autoimmune aetiology has been hypothesized, but a screening for autoantibodies and a n=1 trial with intravenous immunoglobulins yielded no unequivocal results in favor of this hypothesis. In the second part, the consequences of hypocretin deficiency in narcoleptic patients are explored, focussing on vigilance, metabolism and the autonomic nervous system and skin temperature regulation. The ability of a specific neuropsychological test to measure vigilance as a severity indicator for narcolepsy is explored. Two possible causes for the obesity commonly seen in narcolepsy are a decreased basal metabolic rate and a changed autonomic tone. To assess the influence of hypocretin deficiency on skin temperature regulation, thermoregulatory profiles of the proximal and distal skin of narcoleptic subjects were compared to profiles of healthy controls during a daytime sleep registration. Show less
Predictive testing for Huntington's disease appears to have long lasting psychological effects. The predictive test for Huntington's disease (HD), a hereditary disease of the nervous system, was... Show morePredictive testing for Huntington's disease appears to have long lasting psychological effects. The predictive test for Huntington's disease (HD), a hereditary disease of the nervous system, was introduced in the Netherlands in the late eighties. As adverse consequences of the test were anticipated, the effects of testing were studied conscientiously. The general conclusions of these studies were that the negative effects of testing were limited and temporary. The positive consequences of testing seemed to outweigh the negative ones. Knowing if one carried the gene put an end to the unbearable uncertainty of becoming diseased in the future. Testing made it possible to make important decisions, such as concerning having children, pursuing further studies or buying a house. However, long-term investigation at the Leiden University Medical Centre (LUMC) now demonstrates that ten years after the test, when the first symptoms are likely to occur in the near future, the distress of carriers increases again. Strikingly, the current findings are based on a selection of psychologically more stable participants. Individuals who withdrew from the study directly after receiving an unfavourable test result reported (pre-test) considerably less well-being, a worse view of the future, and more evasive behaviour. It is expected that the psychological distress of these dropouts is even greater than that of the retained individuals. It is worrisome that these dropouts stay out of reach of further psychological counselling. Reinier Timman LUMC Centre for Human and Clinical Genetics, and dept. of Neurology Show less
