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Background A global comprehensive database of sites and investigators does not exist. The Huntington Study Group (HSG) has a database of member sites and the European HD Network (EHDN) maintains site dossiers but there is no global database that contains a comprehensive set of data on site capabilities and contact information that is accessible by other researchers or interested sponsors. Aims To provide the Huntington9s disease (HD) Research Community with an interactive tool that will promote the sharing of information relating to clinical sites and investigators across the globe - North America, Latin America, Europe, Australia, Africa and Asia. Methods Develop an internet based tool that will promote and facilitate the matching of sites and investigators with other investigators and potential sponsors with the goal of developing therapies for HD. In addition, working with the HD community to match site locations with patients and families to promote an efficient recruitment process and ease of access for patients wishing to participate in clinical trials. Results 29 centres are registered in the GSID. Conclusions As an HD Research Community, we all share the same goal to develop treatments for HD as rapidly as possible. This sense of urgency in achieving this goal is palpable. The GSID-HD is another tool that will allow the HD research community and sponsors to be more efficient and effective in planning and executing translational research projects and clinical trials.

Background Despite large gaps in evidence-based knowledge, clinical experience supports the use of pharmacologic treatments for many symptoms of Huntington9s disease (HD). Aims The project goal is to develop consensus guidelines based on expert clinical experience to improve quality of HD care. Methods The survey was developed by 9 international experts, and designed as a highly iterative and systematic method of soliciting expert opinions on the pharmacologic treatment of irritability, perseverative behaviors, and chorea in HD. Fifty-five experts from Australia, Europe and North America responded to at least one of the surveys. Results For irritability, SSRI was first choice of 58%, an antipsychotic was first choice for 22%, a mood stabilizing anticonvulsant 14%, and benzodiazepine 2%. For perseverative behaviors, SSRI was first choice of 75%, an antipsychotic choice of 4%, a mood stabilizing anticonvulsant choice of 6%, and clomipramine 2%. The remaining 13% chose to qualify the response to include 2 first choices. For chorea, an antipsychotic was first choice for 56%, tetrabenazine 15%, amantadine 6%, and benzodiazepines 4%. The remaining 13% chose to qualify the response to include 2 first choices. Drug choice for use as adjunctive therapy was widely variable. Conclusions Many areas of variability in treatment for irritability, perseverative behaviors, and chorea in HD, have been identified. Results will guide future rounds of the Delphi process to elicit rational causes for differences identified. When complete, this process will clarify useful treatment paradigms that will improve patient care and identify areas in which clinical trials would be most useful.

Background The earliest clinical manifestations of Huntington9s (HD) disease are poorly characterized, and there is a need for clinical scales designed specifically to measure early signs and symptoms in individuals with the huntingtin gene mutation. Aims The Functional Rating Scale Taskforce for pre-Huntington9s Disease (FuRST-pHD) is comprised of a multidisciplinary team of clinical experts, drug developers, and psychometricians that work in close association with advocacy groups and HD gene carriers to develop a valid functional rating scale to assess changes in symptom severity in pre- and early-HD. Such a measurement tool is essential in order to assess the efficacy of early intervention treatments. Methods FuRST-pHD has established a data-driven, iterative, and collaborative process to develop a clinical scale to assess symptoms and their functional impact in pre- and early-HD. The process involves input from numerous sources to identify relevant symptom domains, including gene expansion carriers, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing observational studies in HD (PREDICT-HD and REGISTRY) using existing clinical scales. Clinical scale interview questions were developed by expert teams of clinicians and psychometricians in order to gather data about the identified symptom domains through field testing in pre-HD individuals. We report here the progress of the FuRST-pHD initiative. Results At present, more than 60 structured interview questions aimed at determining the presence and extent of severity in a number of symptom domains have been developed, including motor, cognitive and psychiatric symptoms. The interview questions have undergone, or are undergoing, testing at various clinical centres involved with FuRST-pHD and PREDICT-HD. We present data supporting the development of items to assess a number of symptoms in pre-HD, including Anger and Irritability, Obsessions and Compulsions, and Depression and Anxiety. Conclusions Many CAG expanded individuals clearly exhibit a range of motor, cognitive and psychiatric signs years prior to clinical diagnosis. The present data suggest a number of behavioural/psychiatric symptom clusters that should be assessed in order to capture fully the scope of dysfunction in pre-HD individuals.

Background Identifying sensitive, specific, and reliable indicators of disease progression in Huntington9s disease (HD) is key to selecting the appropriate population for clinical trials that assess novel treatments that may slow or delay the onset of HD9s debilitating symptoms. The PREDICT-HD study is an NIH and CHDI-funded study that began in 2001, with the goal of documenting the neurobiological and neurobehavioral changes that occur in HD-gene carriers in the period leading up to the diagnosis of HD. The PREDICT-HD study provides a rich source of data that can be mined to identify HD-gene carriers who show rapid progression in the early stages of the disease, prior to diagnosis based on their motor symptoms. Aims To identify a population of PREDICT-HD participants who show rapid progression in motor symptoms over the course of the first four years of the PREDICT-HD study, and to determine if there are specific measures that classify participants a priori. Methods The change in the Unified Huntington9s Disease Rating Scale (UHDRS) Total Motor score between Baseline and Year 4 was calculated for all PREDICT-HD participants who had completed four annual visits. A model was generated to distinguish rapid progressors from gene-carriers not showing progression utilizing the baseline motor, cognitive, and imaging data from PREDICT-HD participants. Results Examination of the inter-quartile ranges of change-from-baseline total motor scores showed that PREDICT-HD participants in the top (fourth) quartile had a change in score of approximately 14 points; the average change in the third quartile was only 5 points. The classification model that was developed included disease burden score, striatal volume, motor and cognitive variables. The model was 82.4% accurate in identifying HD-gene carriers in PREDICT-HD who showed rapid progression in their UHDRS motor scores; the model was 91.9% accurate in identifying HD-gene carriers in PREDICT-HD who did not show a substantial increase in their motor scores. Conclusions There is a population of HD-gene carriers in the PREDICT-HD study that show a rapid progression in their motor symptoms as assessed by the UHDRS Motor Subscale. We have developed a model that is highly accurate in identifying these patients. This model needs to be further refined and validated. This model may be useful in identifying HD-gene carriers for recruitment in therapeutic clinical trials.

Background Despite large gaps in evidence-based knowledge, clinical experience supports the use of pharmacologic treatments for many symptoms of Huntington's disease (HD). The project goal is to develop consensus guidelines based on expert clinical experience that will improve the quality of HD care. Methods/Techniques The Delphi process, which provides an iterative formal strategy to gather expert opinion and form a consensus, was utilized. First steps of this process explored expert prescribing patterns. Step 1: Nine experts from Huntington's Study Group and European HD Network created initial statements for irritability, obsessive/compulsive behaviors (O/Cs), and chorea. Step 2: Statements were submitted via a web survey to a panel of 40 additional experts. Results Thirty expert neurologists and psychiatrists from Europe and North America responded. For irritability there was lack of consensus in first choice and in sequence of drugs used in combination therapy. For O/Cs there was high agreement (>80%) on SSRI as first choice; however, there was lack of consensus on adjuvant drug therapy. For chorea there was agreement that it should be treated when quality of life or ADL is affected, but there was lack of consensus on drug of first choice. The next round of the Delphi consensus process will begin in November of 2009. Conclusions Many areas of variability in the treatment for irritability, O/Cs, and chorea in HD, even among expert clinicians, have been identified. Results will guide future rounds of the Delphi process to elicit rational causes for the differences identified. Collection of further data on consensus will begin in November of 2009. When complete, this process will clarify useful treatment paradigms that will improve patient care and identify areas in which clinical trials would be most useful.

Historically, the diagnosis of HD has been based on the presence of motor-related symptoms. There is emerging evidence, however, that prior to the manifestation of motor symptoms sufficient to warrant clinical diagnosis, many patients exhibit subtle motor, cognitive, and psychiatric signs, suggesting that people with HD may experience detectable changes before clinical diagnosis (i.e., pre-HD). There is currently a need for a rating scale that is sensitive enough to detect early symptomatic changes and disease progression in pre-HD. The Functional Rating Scale Taskforce for pre-HD (FuRST-pHD) has been established to develop such a measure. In the initial phase of this program, FuRST-pHD will identify which symptoms should be addressed in a clinical scale, and how best to measure those symptoms. Depression is thought to be a component of HD that may be present prior to clinical diagnosis. In the present study, FuRST-pHD examined the expression of signs and symptoms associated with depression using data obtained from PREDICT-HD, utilizing a non-parametric item response analysis of depression ratings (UHDRS-III, BDI-II). Item response modeling can be used to evaluate the performance of individual items (or symptoms) on rating scales, assessing the relationship between a score assigned to a particular item and overall severity of the disease. The results show that pre-HD CAG-expanded subjects (≥37 repeats, n = 752) reported greater depressive symptomatology compared to the comparison group (

There is an unmet need for the development of treatments for Huntington's disease (HD). The ideal goal would be to develop drugs that can be administered sufficiently early (i.e., pre-HD), such that the full manifestations never develop or are at least delayed. Unfortunately, there is currently no sensitive validated tool capable of measuring symptomatic changes in pre-HD that can be used in clinical trials. The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal to develop a data-driven, comprehensive, psychometrically sound, sensitive, functional rating scale to be utilized in clinical trials to measure symptoms in patients at the pre-HD stage of the disease. The Taskforce will first identify signs and symptom clusters that should be assessed in pre-HD patients, based on input from a variety of sources, including clinical experts, patients, caregivers, and regulatory agencies. The Taskforce will then develop clinical measures of these signs and symptoms using an iterative processes involving field testing and psychometric analyses. The Taskforce will also rely on the analyses of existing datasets to identify items that may have utility in measuring pre-HD symptomatology. The Taskforce is currently analyzing data from PREDICT-HD, using item response theory (IRT), an approach that has been shown to be a powerful method for evaluating the performance of individual items of rating scales by assessing the relationship between item scores and severity. The development of a new data-driven, reliable, valid, and easily administered instrument would be valuable in the assessment of pre-HD symptoms in clinical trials. This collaborative effort welcomes input from HD researchers. FuRST-pHD is sponsored by CHDI Foundation.

SynopsisThe monoamine metabolites 5-hydroxindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were measured in the lumbar cerebrospinal fluid (CSF) of 27 chronic schizophrenic patients who at some time had attempted suicide, and were compared with values from 27 chronic schizophrenic patients without a history of attempted suicide. There were no significant differences between either the violent or non-violent attempters and those without a history of attempted suicide in the mean lumbar CSF concentrations of the serotonin metabolite 5-HIAA, the dopamine metabolite HVA, or the norepinephrine metabolite MHPG. Significantly more of the suicide attempters had a previous major depressive episode, had received a course of ECT, and had significantly more psychiatric admissions than those who had never attempted suicide.