European Huntington ’s Disease Network Research Articles

P17. Early Huntington’s disease patients demonstrate micro-structural and functional connectivity changes in motor and basal ganglia-thalamic networks

In Huntington’s disease (HD), cerebral white matter changes have been reported in a number of studies using diffusion tensor imaging (DTI) or T1-weighted magnetic resonance imaging (MRI). A key question is how brain structure changes (both grey and white matter) influence brain function. Intrinsic functional connectivity (ifc) MRI investigates intrinsic connectivity networks (ICN), i.e. large-scale distributed functionally coupled brain regions observed in the absence of a specific task. The objective of our study was to integrate structural connectivity data as assessed by DTI with ifcMRI changes in order to obtain a comprehensive picture of structural and functional changes with an emphasis on motor and basal ganglia thalamic networks. Thirty-five early HD subjects (TFC stage 1 and 2) and 32 age- and sex-matched healthy controls underwent3T-MRI (T1w, DTI and ifcMRI sequences). DTI and ifcMRI data analyses were performed using the Tensor Imaging and Fiber Tracking (TIFT) software (Müller et al., 2007) for complementary DTI fiber tracking (FT) and ifcMRI data analysis. For the motor ICN ifcMRI analyses, the dominant M1 was used as the seed, for the basal ganglia-thalamic ICN the thalamus was used. In addition, the cortico-spinal tract (CST) and the thalamocortical pathway were used for comparisons at the group level. Structural connectivity measured by DTI at the group level showed an increase of FA values in the basal ganglia as well as FA reductions in the external and internal capsule, in parts of the thalamus, and in subcortical white matter. Intrinsic functional connectivity (brain function) showed hyper-connectivity in the motor ICN, i.e. the insula was less connected in HD than in controls. The basal ganglia-thalamic ICN connectivity differed between HD and controls in the insula and the basal ganglia in both hemispheres. At the group level, we confirmed microstructural changes identified in previous DTI studies in HD (e.g. (Rosas et al., 2006)). There is evidence that the insula becomes disconnected from the motor cortex. The caudatum seems to lose its functional integration with widely distributed cortical areas (basal ganglio-thalamic ICN). Abnormal connectivity of the insula and caudatum may be relevant in the emergence of clinical signs of HD. This work was partially supported by the European Union under the Seventh Framework programme - PADDINGTON Project, Grant Agreement No.261358, and the European Huntington’s Disease Network (EHDN), project 070 - PADDINGTON.

Meet the Editorial Board:

Pr Christian Neri, Ph.D, Research Director at INSERM and Associate Professor at the University of Montreal has a long-standing experience in the field of genome science and degenerative disease research. The Neri lab is part of the Institute of Biology Paris-Seine (IBPS) on the UPMC campus of Jussieu in Paris and studies of how neurons may use longevity-promoting systems to compensate for the cellular stress associated with neuronal dysfunction in neurodegenerative diseases such as Hun-tington’s disease (HD). The Neri lab used C. elegans models to discover that key longevity modulators such as sirtuin SIRT1 and transcription factor FOXO3 help neurons maintain function and resist neurodegenerative disease, has extended this notion to other degenerative diseases. In 2014, the Neri lab discovered that the capacity of neurons to properly use FOXO3 factors and cope with chronic cellular stress in HD is disrupted by abnormal neurodevelopmental signaling activity from the earliest phases of the disease process, emphasizing the importance of understanding the regulation of stress response gene regulatory networks in diseased neurons and value of sustaining neuronal resistance to fight neurodegenerative disease. The current re-search interest of the Neri lab is on the genetic/epigenetic regulation and clinical potential of neuronal-stress response networks in HD and age-related diseases. Pr. Neri serves as Lead Facilitator of the European HD Network (EHDN), Chairman of the Sci-entific Council of Association Huntington France (AHF) and Director of Science of the AP-HP University Hospital Department ‘Fight Aging and Stress’, promoting international research efforts on stress resilience and brain longevity in neurodegenerative disease and ageing.

A17 Physiotherapy in HD: Clinical Guidelines and Tips

In 2009, the European Huntington’s Disease Network (EHDN) Physiotherapy working group produced a comprehensive Guidance Document and subsequent Clinical Guidelines for physiotherapists in response to the overt need for practice guidelines to guide therapy interventions. At the time, however, there was insufficient literature in support of physiotherapy interventions and approaches to be able to conduct a full, structured evidenced-based review, therefore, physiotherapy expert subgroups were formed to consider the evidence and incorporate consensus as to best practice. Since this time, there has been a growing number of research studies that have evaluated the feasibility and potential benefits of physiotherapy and physical activity interventions for people with Huntington’s disease HD, including case studies, feasibility studies of exercise and physiotherapy, and assessment of multidisciplinary inpatient rehabilitation programmes. In this presentation, we will provide an overview of recent studies to date, and discuss their impact on the ongoing clinical validation of Physiotherapy Clinical Guidelines. We will further present the recently developed series of Clinical Tips for Physiotherapists by the EHDN Physiotherapy Working Group, which provide targeted guidance in a readily accessible format. Directions for future research in physical therapies and their potential for symptom management and disease modification across the spectrum of the disease will also be discussed.

E20 Diffusion Tensor Imaging In Huntington's Disease: Impact Of The Control For Corrupted Data In Comparisons At The Group Level

Background Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study a quality control (QC) algorithm 1 was employed to eliminate corrupted GD from DTI data. Effects of this procedure on comparisons between Huntington disease (HD) subjects and controls were assessed at the group level. Methods Sixty-one HD patients in early stages and forty matched healthy controls were studied in a longitudinal design (baseline and two follow-ups at three time points over 15 months), in a multicenter setting with standardised acquisition protocols on four different MR scanners at four European study sites 2 . QC was used to identify corrupted GD in DTI data sets. Differences in fractional anisotropy (FA) maps at the group level with and without elimination of corrupted GD were analysed. Results The elimination of corrupted GD had an impact on individual FA maps as well as on cross-sectional group comparisons between HD subjects and controls. Following application of the QC algorithm, a lower number of small clusters of FA changes were observed, compared with the analysis without QC-based elimination. However, the grosso modo pattern of regional reductions and increases in FA values was unchanged. Conclusion An impact on the result patterns of the comparison of FA maps between HD subjects and controls was observed depending on whether QC-based elimination of corrupted GD was performed. QC-based elimination of corrupted GD in DTI scans reduces the risk of type I and type II errors in cross-sectional group comparison of FA maps contributing to an increase in reliability and stability of group comparisons. Acknowledgment This work was supported by the European Union under the Seventh Framework programme – PADDINGTON Project, Grant Agreement No. 261358, and the European Huntington’s Disease Network (EHDN), project 070 – PADDINGTON. References Muller HP, et al . PLoS Curr 2011, RRN1232 Muller HP, et al . Neuroimage Clinical 2013,2:161–167

E13 Micro-structural And Functional Connectivity In Motor And Basal Ganglia-thalamic Networks In Huntington Disease

Background In Huntington’s disease (HD), cerebral white matter changes have been reported in a number of studies using diffusion tensor imaging (DTI) or T1-weighted magnetic resonance imaging (MRI). A key question is how brain structure – both grey and white matter – influences brain function. Intrinsic functional connectivity MRI (ifcMRI) investigates intrinsic connectivity networks (ICN), i.e., brain regions which are active when the brain does not engage in a functional task. The objective of our study is to integrate structural data (assessed by DTI) with ifcMRI changes in order to obtain a comprehensive picture of structural and functional changes with an emphasis on motor and basal ganglia thalamic networks. Methods Thirty-three early stage HD subjects (HD – TFC stage 1 and 2) and 25 age- and gender-matched healthy control subjects were included in the study. All participants underwent MRI on a 3T scanner with T1w, DTI and ifcMRI sequences. DTI and ifcMRI data analyses were performed in a standardised manner using the Tensor Imaging and Fibre Tracking (TIFT) software for complementary DTI fibre tracking (FT) and ifcMRI data analysis. For motor network ifcMRI analyses the dominant M1 was used as seed, for basal ganglia-thalamic network the thalamus was used. In addition, the cortico-spinal tract (CST) and the thalamocortical pathway were used for comparisons at the group level. Results At the group level, we confirm microstructural changes identified in previous DTI studies in HD. These include an increase of FA values in the basal ganglia, and FA reductions in the external and internal capsule, in parts of the thalamus, and in subcortical white matter. Within the motor ICN, the insula was less connected in HD than controls. For the basal ganglia-thalamic ICN connectivity differed in the insula and the basal ganglia between HD and controls in both hemispheres.. Conclusion The integration of structural connectivity, assessed by DTI FT and functional connectivity, assessed by ifcMRI revealed that the insula was less connected as a part of two different networks, the motor and the basal ganglia-thalamic networks. This suggests that abnormal connectivity of the insula may be relevant in the emergence of signs of HD. Acknowledgement This work was partially supported by the European Union under the Seventh Framework programme – PADDINGTON Project, Grant Agreement No. 261358, and the European Huntington’s Disease Network (EHDN), project 070 – PADDINGTON.

I21 Causes Of Death In A European Huntington's Disease Cohort (registry)

<h3>Background</h3> Huntington’s disease (HD) is a genetic neurodegenerative disease that leads to premature death. However little evidence is available regarding late-stage HD including causes and places of death. <h3>Aims</h3> This retrospective study aims to ascertain HD causes and places of death in a European Huntington’s disease cohort – the REGISTRY. <h3>Methods</h3> REGISTRY, the European HD Network’s prospective observational study, was used for data collection from 2001 to 2013. Our study population consisted of manifest HD patients having attended more than one study visit. For deceased subjects data was extracted from the death report form and incorporated information such as cause and place of death. Statistical analysis included descriptive statistics and survival analysis through Kaplan Meier estimates of median survival time using SPSS and R software. <h3>Results</h3> A total of 5164 participants were analysed (50.9% women and 98.1% Caucasians). At the end of the study period there were 533 deaths (10.3% of cases). For deceased subjects, the median age of diagnosis was 49 years (9–85) and the median age of death was 58 years (16–93). The most frequent cause of death was pneumonia (25.6%) followed by: other infections (9.1%), suicide (8.6%), cancer (4.4%), stroke (3.4%), and trauma (1.2%). The cause of death was undetermined in 47.7% of deaths. The most frequent place of death was the hospital (29.8%) followed by: home (23.9%), nursing houses (19.8%), and hospice care facilities (3.3%). The place of death was undetermined in 23.1% of deaths. The median survival time as time from diagnosis to death was 24 years (95% CI: 20.8–27.2); and as time from symptom onset to death was 35 years (95% CI: 29.2–40.8). <h3>Conclusion</h3> In the REGISTRY cohort HD patients succumb to the same conditions shown in former HD and other neurodegenerative diseases studies. Still, our results show HD has its own natural history, being the age of death and the survival after the diagnosis unique among neurodegeneration.

A3 Studying and managing the behavioural phenotypes of Huntington's disease

Honorary Consultant in Neuropsychiatric Genetics. David graduated in Medicine from London University (St. Bartholomew9s) in 1976 and moved to Manchester to study Psychiatry in 1979. After completing his training in general psychiatry, he arranged a temporary secondment to Clinical Genetics in 1986 to pursue an interest in the genetic aspects of psychiatric disorders, and ended up “going native”. He is now a senior lecturer and honorary consultant in neuropsychiatric genetics. His research interests are concerned mainly with the neuropsychiatric aspects of Huntington9s disease (HD), and with the psychological and social impact of predictive DNA testing for late-onset genetic disorders. He set up the UK9s first multidisciplinary management clinic for HD, currently the largest contributing site to the European HD Network (EHDN) case registry, and is actively involved in a number of European and worldwide research projects and clinical trials. He is a member of the Scientific Review Committee of the EHDN, leads the EHDN Behavioural Phenotype Working Group and is a former Secretary-General of the World Federation of Neurology Research Group on HD. He is co-Director of the MSc programme and teaches on the Clinical Genetics and Advanced Genetic Counselling modules. Behavioural symptoms have been recognised as a key component of the clinical phenotype of HD ever since the first description by Huntington in 1872, but remain a relatively under-researched aspect of the condition. Depression has received more attention than other psychiatric symptoms, but factor analysis of several large datasets has revealed that apathy and irritability are more common, and arguably cause more distress and disability. Longitudinal analysis of behavioural symptoms has confirmed that these three symptom clusters follow different trajectories over time, suggesting that each has a different neurobiological basis, and recent imaging studies lend some support to this hypothesis. It has long been recognised that many affected individuals display characteristic behavioural changes for some years before the onset of motor symptoms, and there has been considerable recent interest in the possibility of using these early manifestations as end points for clinical trials of disease-modifying interventions in known gene carriers prior to diagnosis. However, it has proved difficult to detect substantial changes in well-conducted longitudinal studies of pre-manifest subjects such as PREDICT and TRACK-HD. One reason may be the emergence of impaired insight (or denial) as the behavioural symptoms begin to occur, a phenomenon which has been noted by clinicians for many years; another is likely to be the use of concomitant medication for symptomatic treatment. Mood disturbances, anxiety, irritability and perseveration all respond to treatment with serotonin reuptake inhibitors, but apathy may be exacerbated by the use of neuroleptic medication for symptomatic treatment of involuntary movements or aggressive behaviours.

B22 Does a peripheral immune response influence muscle pathology in Huntington's disease?

<h3>Background</h3> Classical symptoms of Huntington9s Disease (HD) include progressive motor disturbances, cognitive decline and psychiatric problems. In addition to these, HD is further complicated by peripheral pathology, including weight loss and skeletal-muscle wasting. Changes in gene expression in brain, blood and peripheral tissues, such as skeletal muscle, have been shown in human HD as well as in the R6/2 mouse model. Possibly, gene expression alterations in skeletal muscle could offer valuable insight into HD pathology, as well as offer a source of potential disease markers. We have previously shown an early immune activation in HD. Primary monocytes are abnormally activated in response to LPS stimulation and there are increased levels of circulating proinflammatory cytokines early on in the disease. Interestingly, among these are TNF-α and IL-6, which are cytokines that are also known to affect muscle atrophy. <h3>Aim</h3> In this study we wanted to investigate the possible relationship between peripheral cytokines and muscle atrophy in HD. <h3>Methods</h3> We investigated gene expression of muscle protein genes and selected genes previously shown to be activated by cytokines and linked to muscle atrophy, in skeletal muscle from R6/2 mice and WT littermates by RT-qPCR. <h3>Results and conclusions</h3> Here, we describe R6/2 skeletal muscle gene expression changes linked to muscle atrophy and an increase in peripheral cytokines. We find increased expression of caspases as well as decreased expression of muscle proteins, myosin and troponin. <h3>Conclusions</h3> Our preliminary results show a plausible link between these gene expression changes and increased levels of cytokines. <h3>Funding</h3> This study is supported by EHDN (European Huntington9s Disease Network).

A06 Better global and cognitive functioning for choreatic compared to hypokinetic-rigid huntington's disease

Background Motor disturbances in Huntington9s disease can be subdivided into a predominantly choreatic or hypokinetic-rigid subtype. The relation between these motor subtypes and cognitive and general functioning is poorly understood, but can be of importance in the care for Huntington9s disease patients. Aims Investigating the possible clinical differences between predominantly choreatic and predominantly hypokinetic-rigid Huntington9s disease. Methods/technique Cross-sectional data from the European Huntington9s Disease Network Registry study up until 2011 were analysed. Data of the first visit of all subjects with an expanded CAG ≥36 and a total motor score ≥5 and complete cognitive, function and motor assessments were retrieved. A total of 1882 subjects were classified as predominantly choreatic (N=528) or predominantly hypokinetic-rigid (N=432), according to their score on those items of the total motor score a priori labelled as either choreatic or hypokinetic-rigid items; the other 922 patients were of a mixed motor type. The relationship between motor type and cognitive (total cognitive score) and general functioning (total functional capacity) was investigated using a linear regression model. Results/outcome Motor subtype was a significant predictor of both cognitive and general functioning (p Conclusions We conclude that Huntington9s disease patients with a predominant choreatic motor phenotype exhibit better global and cognitive functioning than patients with a predominant hypokinetic-rigid motor phenotype.

I10 Fall risk in Huntington's disease

<h3>Background</h3> Maintaining balance and mobility is a challenge in Huntington9s disease.¹ The balance and walking problems result in increased fall risk during the course of the disease.² Falls are common. Contributing factors include bradykinesia of gait, stride variability and chorea as well as cognitive and behavioural issues.³ The “Physiotherapy Guidance Document” of the European Huntington9s Disease Network describes all measurement instruments which can be used in Huntington9s disease. Until now no fall risk screening tool has been identified as most accurate and reliable. <h3>Aims</h3> Description of correlation between actual falls and three fall risk screening tools: Berg Balance Scale, Tinetti and Timed Up and Go Test. <h3>Methods</h3> Data of 28 patients from our outpatient clinic were used. Fall risk was assessed using Berg Balance Scale (BBS), Timed Up and Go (TUG) and Tinetti. Patients were scored on falling by asking patient and care giver (“fallers” (≥2 falls/year) or “non-fallers” (≤1 fall/year)). <h3>Results</h3> 16 of the 28 patients were “fallers”. 18 patients lived at home and 17 patients had physiotherapy. The TUG showed a relatively strong significant relation (0.458; p=0.02) with falling. The BBS, Tinetti and TUG significantly correlated with each other (r=0.693–0.862; p&lt;0.01). <h3>Conclusions</h3> In this small group of patients the TUG showed a significant correlation with actual falls. The three tests appeared to correlate well with each other. More research needs to be done in a larger group of patients to establish the sensitivity and specificity of the tests for Huntington9s disease patients. <h3>References</h3> 1. <b>Tian J</b>, Herdman SJ, Zee DS, <i>et al.</i> Postural stability in patients with Huntington9s disease. <i>Neurology</i> 1992;<b>42</b>:1232–8. 2. <b>Busse ME</b>, Wiles CM, Rosser AE. Mobility and Falls in Huntington9s Disease. <i>J Neurol Neurosurg Psychiatry</i> 2009;<b>80</b>:88–90. 3. <b>Grimbergen YA</b>, Knol MJ, Bloem BR, <i>et al</i>. Falls and gait disturbances in Huntington9s disease. <i>Mov Disord</i> 2008;<b>23</b>:970–6.

Oral Feeding in Huntington’s Disease: A Guideline Document for Speech and Language Therapists

SUMMARY Speech and language therapy has an important role in the management of Huntington’s disease (HD). Swallowing difficulties affect most individuals with HD. Throughout the disease process these difficulties require management with timely and effective therapeutic intervention. Currently there are no European guidelines for the assessment and management of swallowing impairments in HD. The European Huntington’s Disease Network (EHDN) Standards of Care Speech and Language Therapy Working Group has brought together expert speech and language therapists from across Europe to produce guidelines to improve the management of swallowing disorders for individuals with Huntington’s disease. The guidelines were developed with the aim of promoting timely and appropriate assessment of the swallowing process and focused management throughout all stages of the disease. Literature was systematically searched in an attempt to ensure that the recommendations are based on sound evidence. Where evidence was lacking, specific guidance is based on expert consensus. The provision of care varies widely between countries in Europe and the implementation of those guidelines should improve the quality of care delivered to individuals with HD.

Development of Guidelines for Occupational Therapy in Huntington’s Disease

SUMMARY This paper introduces the ‘Guidelines for Occupational Therapists working with people with Huntington’s disease’ which is currently being developed by the European Huntington’s Disease Network (EHDN) Standards of Care Occupational Therapists working group. This article aims to describe the everyday functional problems experienced by people with Huntington’s disease, the role of the occupational therapist, the systematic literature review which preceded the formulation of the guidelines and use excerpts from the guideline to illustrate some of the issues raised.

Development of Physiotherapy Guidance and treatment-based Classifications for People With Huntington’s Disease

SUMMARY Background: Physiotherapy may provide a means of delaying onset or progression of Huntington’s disease (HD), resulting in improved daily functioning and quality of life. Physiotherapy is being more frequently recommended for people with HD, but there have been no specific guidelines published for implementation of a structured physiotherapy program. The Physiotherapy Working Group (PWG) of the European Huntington’s Disease Network (EHDN) set out to develop a comprehensive Guidance Document for physiotherapists to provide best practice guidelines. Methods: A review of the literature was conducted using a systematic approach. There was insufficient literature in support of physiotherapy interventions and approaches to be able to conduct a complete evidenced-based review, therefore, physiotherapy expert subgroups were formed to incorporate consensus as to best practice. A draft document was distributed to the entire membership of the working group, to outside physiotherapists and other healthcare professionals within EHDN to elicit feedback and comments. Results: A Guidance Document covering eight specific areas pertaining to physiotherapy management of HD was developed. In order to facilitate the document’s practical usability among clinicians, a treatment-based classification system is proposed to categorize patients based on presenting signs and symptoms, and provide a foundation for development of a more standardized intervention approach. Discussion: The Physiotherapy Guidance for HD is a comprehensive, consensus- and evidence-based document that can be used by physiotherapists to implement a plan of care that is currently consistent with best practice for individuals at all stages of HD. As evidence becomes available, future systematic reviews will be required in order to inform further development. The use of treatment-based classifications, which aim to better categorize common signs and symptoms and link them to appropriate intervention plans, may be useful in relatively rare diseases, such as HD, to aid clinical reasoning and promote effective outcome evaluation.

F22 An assessment of alcohol abuse on cognitive abilities, executive functions and motor signs in huntington's disease

BackgroundIt has been acknowledged that high levels of alcohol use in Huntington's disease (HD) patients is associated with greater ratings of psychiatric symptoms, increased psychiatric symptom progression, and a younger...