The swallowing disorder in Huntington’s disease (HD): an observational, longitudinal study
Dysphagia is a common condition in Huntington´s Disease (HD). With the progression of the underlying disease the swallowing function worsens. In particular, the risk of aspiration increases, which is associated with bronchopulmonary infections and mortality. Little is known about onset, prevalence and characteristics of dysphagia in HD. Our aims are to describe frequency, onset and progression of dysphagia in HD and to determine feasibility and reliability of measurement methods that are potentially suitable for HD patients. Therefore we are currently investigating HD patients (2 centers, 60 patients) at a baseline visit and one follow-up visit using swallowing and nutrition questionnaires, a clinical swallowing examination, fiber endoscopic evaluation of swallowing and the UHDRS.
Smart phone App and optical motion sensing devices (Kinect/X-Box) as tools to assess motor function in HD – a Pilot Study
Our project aims to develop easy-to-use electronic tools to objectively assess the motor impairment in people with Huntington's disease. Motor symptoms such as chorea are debilitating diseases symptoms and also important readouts for therapeutic and genetic studies. However, objectively recording and quantifying motor symptoms remains challenging. We have developed a prototype app that takes advantage of the sophisticated movement sensors built into standard smart phones to detect and quantify hand and limb movements. This tool is currently being optimized and validated for use in the clinical assessment of patients and controls.
Time-recording Graphimetry with a Digitizing Pen in Huntington’s Disease (HD) for analysis of involuntary movements during spiral drawing
Previous research on involuntary movements in HD is mainly based on electrophysiological approaches or quantification of deficits in specific tasks.
The new measurement of time series using a Digitizing Pen (DP) allows very promising insights in hyperkinetic processes as well as analysis of corrective motor activity.
After a successful pre-pilot study we now will apply the DP to a larger number of HD patients and controls.
Our long-term goals are the development of a DP based at-home test for hyperkinetic activity and the standardization of the DP-technique for easy use in clinical trials.
Analysis of the behavioural UHDRS
In our first publication (Rickards et al, 2010) the Behavioural Working Group of the EHDN defined distinct behavioural patterns within HD, comprising a depressive factor, a dysexecutive factor, an irritability factor and a psychosis factor. Starting from this point, we plan to analyze, as a next step, the dependence of those factors on important clinical variables like sex, stage of disease, motor and cognitive functions, age of onset, duration of the disease, psychiatric medications and psychiatric history. Furthermore, we are interested in regional differences of the behavioural patterns of the whole area of EHDN.
Skeletal muscle metabolic responses to physical exercise in clinical HD trials
Metabolic abnormalities and mitochondrial dysfunction in peripheral tissues such as skeletal muscle are components of the pathophysiology of HD. There is evidence to suggest that these differences in metabolic function lead to stimulation of anaerobic energy supply pathways associated with increased plasma lactate concentrations in response to exercise. The aims of this project are: a. to establish minimally invasive fine needle muscle biopsies as a tool to evaluate differences in metabolic gene expression profiles in response to acute exercise between HD patients and age matched controls and, b. to develop suitable endurance exercise programmes adapted to the capabilities of HD patients for future exercise training studies.
PHASE1-HD: a pilot phase-contrast MRI study of cerebrospinal fluid dynamics in Huntington’s disease
Cerebrospinal fluid, or CSF, is a clear liquid which surrounds the brain and spinal cord. Research in Huntington’s disease animal models suggests CSF flow might be altered in HD, which could be important for new drugs that may be injected into the CSF. A scanning technique called Phase Contrast MRI enables CSF flow to be studied non-invasively. PHASE1-HD will develop the Phase Contrast technique for HD and test it in 10 patients and 10 controls to help understand CSF flow and design larger trials of the technique.
Longitudinal evaluation of the Registry cognitive battery across the different stages of Huntington’s disease
The Registry study provides an opportunity to carry out a longitudinal, international study of the most commonly used cognitive tasks in Huntington’s disease (HD). In HD cognitive decline can start early, can be objectively measured and influences the functional independence of an individual. This indicates that cognitive measures have the potential to be used as outcome measures in future clinical trials. But first it is pertinent to evaluate the efficacy of the Registry assessment in terms of tracking disease progression through the stages. This information is extremely important for developing future clinical trials.
Revisiting the Stroop test as a measure of cognitive deficits
The proposed project aims at a detailed analysis of UHDRS cognitive assessments employed in the REGISTRY study. Particular focus shall be on the Stroop test. Here, it is our interest to compare the subscores from the colour, word and interference card, as well as other scoring methods derived from these raw scores.
On the one hand we would like to understand how the above scores develop as HD progresses. In addition, we hope to figure out the extent to which performance on these tests is influenced by other factors such as the UHDRS Total Motor Score, age and education.
Thereby we hope to understand in more detail the dimensions of HD that are measured by the Stroop test and to provide potential optimising strategies for both, the testing procedure as well as its evaluation.
Theory of Mind Deficits in Huntington’s Disease
BACKGROUND: Studies suggest Huntington's disease (HD) can be associated with changes in
emotions and social behaviour. We are researching the changes that some patients show
when they are asked to think about other people's beliefs and emotions. AIMS: This study
will help us to understand the brain basis for patients' difficulties on particular
social cognitive tasks and ultimately, some of the behavioural changes seen in HD.
METHODS: People with HD will complete tasks which involve thinking about people's
emotions while undergoing brain scanning. Some of the patients taking part in the study
have the HD gene but have not yet developed movement symptoms so that we can investigate
relationships between social and emotional changes in HD and disease onset and
The relationship of chorea with function and cognition
HD is characterized by progressive motor impairment. These motor disturbances can be divided into two subgroups: the more rigid type (hypokinetic) and the more choreatic type (hyperkinetic). Patients with HD become increasingly more disabled in their activities of daily living as the disease progresses. Also, their cognitive capacities decline over time, eventually resulting in a dementia.
The clinical impression of many neurologists is that those with severe chorea seem to function better compared to the more rigid patients. Up to date this has not been investigated thoroughly, therefore we make use of the extended REGISTRY-database of EHDN to study this clinical idea.
In this project we aim to investigate the differences in general and cognitive functioning between predominantly choreatic and predominantly rigid HD patients.
Prevalence rates and course of suicidality and its socio-demographic and clinical associations in persons with Huntington’s disease
Suicide is a relatively frequent cause of death among patients with Huntington’s disease. Various studies show that patients with Huntington’s disease commit suicide four to eight times more often than persons from the general population. The risk of suicide seems to be related to the development of the disease and the loss of independence, and may not always be related to depression. This REGISTRY data mining project aims to identify 1) prevalence rates and severity of suicidality using the UHDRS behavior section, and 2) associated socio-demographic and clinical characteristics.
A data mining project investigating psychosis in Huntington's Disease
Psychotic symptoms have a higher prevalence rate in HD patients compared to the general population. This data mining project aims to identify the prevalence and incidences of delusions and hallucinations in the REGISTRY data. The data will then be compared to identify any differences between the data sets of those who report these symptoms and those who do not. Further analysis is also expected to be carried out between those who only report hallucinations and those who only report delusions. The data sets will comprise of demographics, history, CAG, medication, motor, cognition, behaviour, function and TFC subscales of the UHDRS.
Investigation of Time Course and Functional Impact of Voluntary Motor Function Impairment in Huntington's Disease
The UHDRS motor scale includes assessment for eye movement abnormalities,
voluntary motor function and involuntary movements. The aim of this work is
to examine the impact these three clinical domains on the functional decline
HD as measured by UHDRS functional assessments in 300 patients obtained from
the REGISTRY data base. We will also measure the rate of decline in these
measures over one year of progression of disease, as well as the impact of
concomitant medications, demographic factors and CAG repeat length.
It is hypothesized that voluntary motor function is more closely linked to
functional impairment in HD than involuntary movements. The voluntary motor
function score may thus be more useful for studying effects of experimental
therapeutics and to monitor progression of HD over time.
The familiality of psychiatric symptoms in Huntington´s disease
A wide range of behavioural problems are commonly seen in HD, including depression,
anxiety, obsessive-compulsive symptoms, irritability, aggression, disinhibition and
apathy. Improved understanding of the cause (or causes) of such psychiatric symptoms
independent of the HD gene is critical to developing effective treatments and
consequently improving the quality of life of patients. This study aims to determine
whether certain psychiatric symptoms cluster in families affected with HD. This will be
achieved by conducting a thorough, standardised interview of 80-100 families with
sibling pairs with HD as well as any siblings without the HD gene.
The accuracy of the estimation of age at onset of motor signs in HD
In Huntington’s disease (HD) the accurate determination of age at onset is important for counselling patients and critical if one tries to develop and evaluate therapies that aim to delay it. Here we compare the REGISTRY raters’ estimates of age at onset with estimates calculated using a number of algorithms such as the Langbehn or the Aylward fomula. A second aim is to calculate disease progression using data from at least three visits. Thirdly, we use longitudinal data for (backwards) extrapolation of actual age at onset and a comparison with rater’s estimates and formula estimates.
Measuring outcomes in Huntington’s disease (HD)
Rating scales are important because they are the principal outcome
measures used in drug trials. The REGISTRY data can be used to assess
the performance of the rating scales.
Two different analytic approaches were used: “traditional”
psychometric methods and Rasch analysis. This enabled us to construct
a detailed and sophisticated picture of the motor, total functional
capacity and functional assessment subscales of the UHDRS, identify
their strengths and weaknesses, and provide recommends to maximise
their ability to measure the impact of HD. The results are available
as a report to EHDN and are the basis of a grant application to
develop improved outcome measures for drug trials.
Towards an improved Functional Rating Scale for Pre-Huntington’s Disease
Current functional ratings scales are insensitive and unsuitable for pre-manifest and early Huntington’s disease (HD) subjects. Because functional outcomes are very important in drug development a new functional rating scale is needed for this subgroup. We propose to use an item response theory (IRT) approach to characterize symptoms (including psychiatric, cognitive, motor and quality of life domains) in pre-HD and all stages of HD. With data from REGISTRY, we will analyze the relationship between the score assigned to a scale item and the overall severity of HD. This analysis will identify suitable items from pre-existing scales that are particularly relevant for pre-HD and early HD, and provide valuable information that will guide the development of a new and sensitive functional scale for this particular patient sub-group.
Reliability and minimal detectable change of measures of participation, functional activities and impairments in individuals with Huntington’s disease
Huntington’s disease (HD) may be amenable to physiotherapy in terms of restoring or maintaining functional abilities. To date, there has been relatively little research to substantiate this suggestion. One of the first steps in developing intervention trials is to choose appropriate outcome measures. The purpose of this multi-centre project is to evaluate various potentially suitable measures. We will recruit a total of 80 patients with HD to undergo two assessments, with a one-week gap between, on a range of functional measures that have been chosen to reflect a range of impairments and activity limitations seen in people with HD.
Late stage HD: phenotype and current management
The clinical characteristics of late-stage Huntington’s disease (LS-HD) have not been extensively documented. The prevalence of LS-HD may, however, increase since with better general health care and possibly better clinical management patients with HD will live longer. Knowledge of the magnitude and causes of patients` disability may allow to improve the care of LS-HD patients` and to focus therapeutic interventions. Using data from REGISTRY we therefore will first describe the phenotype of LS-HD and the current management practice. We will then analyse the contribution of each symptom complex (motor, behaviour, cognitive etc) to the phenomenology of LS-HD.
The use of depression rating scales in patients with HD
Depression is a common, yet treatable complication of HD. Its recognition and assessment with the most valid rating scales is therefore very important. The Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HAM-D) are currently used in the REGISTRY study. However, they may not be ideal since they also measure e.g. physical symptoms of a degenerative disorder such as HD. Our goals are to evaluate the validity of the BDI and the HAM-D against the UHDRS Behavioural Scale. In addition, Principal Components Analysis intends to find out how helpful individual items are in measuring depression.