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Proposals - Announcements - REGISTRY -
The progression of different motor subtypes in Huntington's disease and their relationship to general and cognitive functioning
The aim of the project is to investigate the progression of different motor subtypes in Huntington’s disease (HD) and their relationship to general and cognitive functioning. We want to investigate if the motor disturbances seen in HD change from predominantly choreatic to predominantly hypokinetic-rigid when the disease progresses. A previous cross-sectional study showed that predominantly choreatic patients perform better on general and cognitive assessments. The Registry database gives an opportunity to study this further on a large scale and longitudinally. Longitudinal study of the motor subtypes could provide a better understanding of the different motor phenotypes in HD and may have implications for future care and clinical trials.
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The impact of biological and environmental factors on independence in Huntington’s Disease
Huntington’s disease invariably leads to debilitating motor signs, cognitive decline and sometimes behavioural signs. In the course of the illness patients loose the ability to live independently . The impact of HD on patients’ independence can have a great effect on the patients’ sense of well-being. Thus it is important to identify factors that influence independence in order to promote those factors that maintain independence and try and avoid those that negatively influence it. We wish to use the REGISTRY data to identify some of these factors. The results of the study may help clinicians in their management of HD patients.
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Cag repeat length and JHD
It is frequently stated that the patients with JHD have more than 60 repeats. This is partially correct. In fact the median CAG repeat length is around 60 and in some cases JHD patients may have a CAG repeat length in the 40's. Descriptive data on the age of onset and CAG repeat length for JHD patients will be analysed. The negative correlation between age of onset and CAG repeat length is well established but in two populations Andressen et all (Ann Hum Genet 71:295-301, 2006) demonstrated a better fit with a two segment regression line. The inflection points were at 53 and 49 CAG repeats in the respective populations. The aim of this data mining project is to establish descriptive statistics for the spread of the age of onset of JHD patients and to obtain a third result for an inflection point in a two segment analysis of the correlation between age of onset and CAG repeat length.
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Cancer prevalence in HD
Studies in Scandinavian cohorts have found that people with expanded repeats in their HD gene (HTT) and their SBMA gene (the androgen receptor, AR) have significantly reduced cancer incidence. We wish to explore these findings further and examine the relationship between the CAG repeat in HTT and cancer prevalence in the EHDN Registry population. We will access the medical history, comorbidity and medication data to examine cancer incidence and prevalence. Though it is unclear how increased CAG length could mediate cancer risk, determining the relationship between CAG length in HTT may reveal fundamental biology underlying both cancer risk and neurodegeneration.
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Prevalence and clinical correlates of the intermediate CAG repeats in Huntington's disease
The underlying genetic cause of HD is a CAG trinucleotide repeat expansion in the HTT gene. CAG expansions above 39 account for the majority of HD presentations. CAG expansions in the 27-35 range are referred to as intermediate alleles. Based on last reports, it remains controversial whether intermediate alleles can cause HD. In this study, we will use data from the EHDN registry and include participants with intermediated CAG repeats (>27-35, cases) and controls (< 27 CAG repeats). The aim of this study is to determine the prevalence and clinical characteristics of intermediate CAG repeats carriers, which might have important implications for the pathogenesis of the disease and genetic counseling.
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Completed suicide in a European Huntington’s disease population
Although the prevalence of suicide in Huntington’s disease (HD) is four to eight times higher compared with the general population, no prospective studies on risk factors of completed suicide in HD have been carried out so far. In this study we aim to identify the incidence rate of completed suicide in the REGISTRY population. Furthermore, we aim to determine sociodemographic, clinical, and neuropsychiatric predictors of completed suicide in HD.
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Psychological predictors of pain in people with Huntington’s Disease
The proposed project is a data mining study to identify psychological factors that predict pain severity in people with Huntington's Disease (HD) at their most recent assessment and develop a model to account for the variance in pain severity. Factors to be investigated include low mood, anxiety, aggression, irritability, apathy, delusions and hallucinations with ordinal regression being used to analyse the data. The secondary aim of this research is to gain an understanding of the prevalence of pain in HD. This will be considered alongside the disease stage, to investigate whether pain severity differs according to disease stage.
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The Economics of Huntington's Disease
Research underway will begin to examine under-explored economic aspects of HD by using individual participant data from the EHDN. The research has two streams: i) estimation of resource use/costs of care for people with HD and; ii) estimation of health outcomes data (health state values) suitable for use in health policy contexts. Such health state values are needed to calculate quality-adjusted life-years (QALYs), which are used for exploring the effectiveness of treatments and their value for money. This research aims to highlight the impact of HD and provide information for use in decision-making regarding the care of people with HD.
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Investigating irritability in Huntington's Disease; is there a relationship between executive dysfunction and irritability (both internally and externally-directed)?
We are performing a study that looks at how people with Huntington's Disease become irritable. We have divided irritability into that directed at other people, which can be recognised as shouting, snapping and sudden outbursts; and that directed towards oneself. We know that some people with Huntington’s Disease have problems performing certain mental tasks. We predict that irritability directed at others may be related to problems with processing lots of information at once. To investigate this, we will use data from performance on cognitive tasks which probe the ability to deal with mental interference, and establish whether this relates to irritability.
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Estimating costs of health and social care resource use associated with Huntington’s disease in the United Kingdom
As Huntington’s disease (HD) progresses, intensive support from health and social care services is likely to be needed yet little is known about the economic cost of HD. This project will use REGISTRY data on health and social care use, informal care time and impact on employment to estimate an annual cost per person with HD in the UK, stratified by age and disease severity. Identifying the patterns and cost of service use associated with HD could potentially lead to improved resource allocation and ultimately care for people with HD.
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Does age of onset affect the clinical phenotype and its progression in adult onset Huntington’s disease? An observational 5 year follow up study
It is established that the age at onset of Huntington's disease is affected by the size of CAG repeats. It is also known that patients with juvenile onset (below the age of 20 years) have different physical characteristics such as more akintetic rigid (Parkinsonian) features. On the other hand, patients with late onset disease (over 50 years) could have more cognitive features. However, it is not clear whether age at onset affects the clinical manifestations of the disease in the most commonly affected age group (30-60 years). Understanding such differences would have implications in managing patients in terms of counselling on prognosis, and for measuring effects of drugs. This study aims at studying the effect of age at onset on the clinical features of HD (motor, psychiatric and cognitive) and the rate of symptom progression.
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COHORT vs REGISTRY – comparison of two similar observational cohort studies on two continents
As HD is relatively rare, we need advanced, multi-centre, multi national frameworks that allow us to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research. In the analysis of the Registry cross-sectional data it was shown that across different European regions CAG repeat genotypes and phenotypes were similar, suggesting that treatment results are generalizable across Europe. We do not know, whether this holds true for North-America. We therefore plan to investigate whether there are any differences in genotype, phenotype or treatment characteristics between Europe and North-American HD patients, using the Registry and Cohort databases.
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Late-onset Huntington's disease
Huntington's disease (HD) is a neurodegenerative disease clinically characterized by the triad of an extrapyramidal movement disorder, cognitive decline, and behavioral changes. HD is caused by an abnormal expansion of CAG-triplets in the huntingtin gene. Carriers of this mutated HD gene typically first develop symptoms in their mid-thirties to mid-forties, but age of onset for HD ranges from early childhood to the seventies and eighties. Little is known on the natural history of late-onset HD. The aims of this project are to characterize the phenotype and to determine the progression of patients with late-onset HD.
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Huntington’s disease causes of death: a prospective observational study
It is well known that Huntington's disease (HD) patients experience premature death. Nevertheless, HD mortality has not been extensively studied and additional knowledge on causes of death is important to plan care and supportive services for HD patients and their families.
With this study we propose to evaluate HD patients causes and places of death, the time between symptoms onset/diagnosis and death and the overall survival of HD patients. Additionally, we intend to determine the influence of demographics, family history, genotype, phenotype, medication and co-morbidities on the above-mentioned variables.
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Suicidal ideation and behaviour in a European Huntington’s disease population
In this study we aim to identify the lifetime prevalence, incidence rate, and severity of suicidal ideation and behaviour according to the Columbia Suicide Severity Rating Scale (C-SSRS) in the Registry population. Furthermore, we also aim to determine sociodemographic, clinical, and neuropsychiatric associations and predictors of suicidal ideation and behaviour.
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Using Registry data to inform choice of outcome measures and optimal design of future clinical trials in Huntington’s Disease
The aim of this project is to use statistical modelling of longitudinal data from the Registry cohort to inform the design of future randomised controlled trials in Huntington?s Disease. The project will explore the potential of a range of functional, cognitive, and motor score variables as possible clinical trial outcomes. Questions concerning the optimal length of trials, the ideal frequency of interim visits, the best inclusion criteria and the merits of alternative designs such as those in which all patients are ultimately given an active treatment, will all be addressed.
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Data quality in REGISTRY: completeness, plausibility and the effect of monitoring
REGISTRY, EHDN’s observational study, collects phenotypic and biological data. REGISTRY aims for high quality data. To this end, REGISTRY adheres to the principles of GCP, similar to a clinical trial, and employs data monitoring. This project aims to appraise critically 1) data quality, and 2) the quality control measures employed in REGISTRY. First we will evaluate the completeness of data entered into the data base. Second, we wish to use the data to define what is ‘plausible’. Third, we wish to examine the effect of monitoring on the above. The outcome will help 1) define what is good quality data 2) improve the monitoring process.
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Defining the phenotype of Huntington’s disease in Europe: The European Huntington's disease Network Registry Study
Registry aims to study the natural history and clinical care of individuals affected by and at risk of developing Huntington’s disease. The establishment of this cohort will facilitate trials of putative HD treatments and will enable meaningful analysis of both major topics requiring large absolute sample sizes, and topics requiring smaller numbers of patients from subgroups of interest across centres. The organisation of Registry together with its emphasis on the collection of high quality of data has never been done in this way. Therefore, the focus of our analyses will be to describe the main characteristics of the population sample and the type and quality of data collection. In summary, this report will aim to provide an overview of the scale, scope and potential of Registry.
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