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Insufficient evidence exists to guide the long-term pharmacological management of Huntington’s disease (HD) although most current interventions rely on symptomatic management. The effect of many frontline treatments on potential endpoints for HD clinical trials remains unknown. Our objective was to investigate how therapies widely used to manage HD affect the symptom for which they are prescribed and other endpoints using data from TRACK-HD. We used longitudinal models to estimate effects of medication use on performance on tests of motor, cognitive and neuropsychiatric function using data from 123 TRACK-HD stage 1/2 participants across four study visits. Adjustment for confounding by prior medication use, prior clinical performance, concomitant use of other medications, and baseline variables (sex, disease group, age, CAG, study site, education) enabled a closer-to-causal interpretation of the associations. Adjusting for baseline variables only, medication use was typically associated with worse clinical performance, reflecting greater medication use in more advanced patients. After additional adjustment for longitudinal confounders such “inverse” associations were generally eliminated and in the expected directions: participants taking neuroleptics tended to have better motor performance, improved affect and poorer cognitive performance, and those taking SSRI/SNRIs had less apathy, less affect and better total behaviour scores. However, we uncovered few statistically significant associations. Limitations include sample size and unmeasured confounding. In conclusion, adjustment for confounding by prior measurements largely eliminated associations between medication use and poorer clinical performance from simple analyses. However, there was little convincing evidence of causal effects of medication on clinical performance and larger cohorts or trials are needed.

Diffusion tensor imaging was used to study brain related changes in white matter that may be associated with Huntington’s Disease progression. Thirty-one preclinical gene-mutation carriers were imaged cross-sectionally using diffusion tensor and anatomical brain imaging. Subjects were individuals who had a known gene mutation for HD but did not manifest motor diagnostic criteria for HD. Fractional anisotropy scalar maps showed a positive correlation with five year probability of diagnosis (based upon gene repeat length and current age) in the putamen and a negative correlation in the external capsule. This study shows that scalar maps generated from diffusion tensor imaging may be directly related to the earliest stages of disease progression within HD, even before a diagnosis is given. Findings suggest that DTI measures, therefore, may have the ability to act as a biomarker for disease progression in clinical trials of pre-manifest subjects.

Background In Huntington’s disease (HD) mutant HTT is ubiquitously expressed and has systemic effects. Availability of brain tissue is limited and postmortem samples are from advanced disease. Blood, however, is readily available, can be studied longitudinally, and contains cells shown to be dysfunctional in HD. There is marked transcriptional dysregulation in HD brain. Differential expression has also been described in muscle and blood, though changes are inconsistent and poorly replicate CNS findings, questioning their biological relevance. Aims and methods We used RNA-Seq to analyse the transcriptome of whole blood in two separate cohorts comprising a total of 186 HD subjects and 49 controls. Results Though individual transcripts were not significantly differentially expressed in either cohort, gene set enrichment analysis applied to publicly-available pathway databases and HD and control brain co-expression modules showed a significant overlap in dysregulated pathways between the cohorts. In particular, immune pathways were upregulated in both cohorts. Notably, modules previously shown to be significantly dysregulated in HD caudate were also significantly dysregulated in the same direction in both blood cohorts, as well as an independent cortex expression dataset. In addition, we identified overlapping immune upregulation in HD and Alzheimer’s disease (AD), suggesting these two distinct neurodegenerative diseases share some common pathogenic mechanisms. Conclusions We have therefore shown that transcriptional dysregulation in key pathways in HD blood parallels changes found in brain. This overlaps with the transcriptional signature in AD, raising the potential for shared therapeutic approaches. Furthermore, analysing pathways may overcome the cellular and technical heterogeneity that prevent the blood transcriptome replicating changes in the brain transcriptome at a single-gene level.

Background Huntington’s disease (HD) is commonly associated with psychiatric disturbance. Often evident in premanifest gene-carriers, little is understood about the neural bases underlying these HD symptoms. While structural imaging has so far failed to provide any major insight, Diffusion Tensor Imaging (DTI) can be used to investigate connectivity between brain regions and any putative microstructural changes that may occur in HD. Aims To examine structural connectivity associated with depression, apathy and irritability in HD gene-carriers. Methods DTI data was collected from 39 premanifest and 45 early-HD participants, as part of the TrackHD study and was analysed using whole-brain Tract-Based Spatial Statistics to extract fractional anisotropy (FA) values – a surrogate marker for tract integrity and efficacy of communication between brain regions. Regression analyses were performed on all gene-carriers using HADS depression and PBA apathy and irritability scores. Results High disease load (measured by CPO) was associated with highly significant, whole-brain corrected correlations between depression scores and reduced FA in the bilateral splenium of the corpus callosum. There were significant widespread negative associations between irritability scores and FA. Interestingly, low disease load participants demonstrated significant correlations between irritability scores and FA reduction. There were no significant associations between apathy and FA. Conclusions Both depression and irritability are associated with reductions in white matter integrity in HD. The opposite relationships between FA and measures of depression and irritability as a function of disease progression suggest that diverse mechanisms associated with both the onset and progression of psychiatric disturbance in HD.

Adverse health effects due to alcohol and illicit drug abuse and dependence have been well documented. This study examines the effect of substance misuse on five major groups of health conditions using a sample of well characterized adoptees. The sample consisted of 742 adoptees interviewed in the last wave of the Iowa Adoption Studies. Death rate analyses included an additional 34 participants who had died prior to the last follow-up. Substance use patterns and medical history were assessed using the SSAGA-II (Bucholz, K. K., Cadoret, R. J., Cloninger, C. R., Dinwiddie, S. H., Hesselbrock, V. M., Nurnberger, J. L., Jr., et al. (1994). A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. Journal of Studies on Alcohol, 55 (2), 149–158). Subjects were divided into three groups according to DSM-IV diagnostic criteria, controls, alcohol abuse or dependence only (alcohol only), and the Alcohol–Drug group (abuse or dependence diagnosis on at least one illicit substance with or without alcohol diagnosis). Incidence rates of various diseases were measured using logistic regression. Survival analyses were used to examine whether substance abusers developed cardiovascular or metabolic disease at an earlier age than control subjects. Diagnostic grouping made no difference in the incidence rates or age of onset of health conditions. The amount of alcohol consumed by males significantly predicted higher number of overall health complaints as well as higher incidence rates of cardiovascular disease. The amount of illicit drug exposure did not predict an earlier age of diagnosis for cardiovascular or metabolic disease. Individuals in the Alcohol–Drug group had an increased incidence of deaths than either the alconly or the control groups.

Background PREDICT-HD is a large multi-site study of individuals with the HD gene expansion who have not yet been diagnosed with the disorder (pre-HD), as well as a smaller group of gene-negative control subjects. Subjects have been followed-up yearly with extensive neuropsychological testing, clinical evaluation, and psychiatric assessment, and every two years with MRI. Methods The sample used for the current analysis included 215 pre-HD participants, 35 individuals newly diagnosed with HD, and 47 age- and sex-matched control subjects. At least two scans, obtained with an interscan interval of 2 years, were analyzed for each subject. Measurements included volumes of caudate, putamen, thalamus, gray, and white matter. Pre-HD subjects were divided into groups based on their estimated proximity to onset (Far, >15 years; Mid, 9-15 years; and Near, Results Longitudinal change in striatal volume was greater for the Mid, Near, and Diagnosed subjects than for the Control or Far subjects. There was no significant difference between the Far and Control subjects for amount of longitudinal change, and no significant differences among the Mid, Near, and Diagnosed groups. Results for caudate and putamen were the same as those for total striatal volume change. For thalamus, Near and Diagnosed subjects had greater longitudinal change than the other three groups. Effect sizes were calculated, as well as power analyses to demonstrate the number of subjects per treatment group that would be necessary for trials conducted at each preclinical stage. Data for total gray and white volume will also be presented. Conclusions Disease-related longitudinal change in striatal volume is observable over a two-year period in individuals who are within 15 years of estimated disease onset, and rate of change is fairly consistent over time once it begins. Observable longitudinal change for the thalamus begins later in the disease process.

Background Speeded (ST) and metronome (MT) tapping have been shown to be sensitive in distinguishing premanifest (preHD) and manifest (HD) stages of Huntington9s disease (HD) in the cross-sectional analysis of the TRACK-HD study, and to detect an early motor phenotype even more than 14 years before predicted disease manifestation. Aims To investigate whether ST and MT are able to track disease progression within a 12 month follow-up period. Methods Participants from the four TRACK-HD sites (ST/MT: controls: 120/122, preHD: 117/118, HD: 117/121) were instructed to perform two tapping tasks with their non-dominant index finger. In ST, they had to tap at maximal speed for 10s; in MT, they were instructed to continue a given tapping rate of 1.8 Hz for 10s. After one year, the assessments were repeated. The annual change in performance of gene-carriers was compared to controls and to each other. The variability of tapping intervals expressed as logarithmic standard deviations was calculated for the primary outcome measures (ie, inter-onset interval (IOI) & tap duration (TD) in ST, inter-onset intervals (ΔIOI) & mid-tap interval (ΔMTI) in MT). Results The annual change in IOI and TD for ST showed significant results for HD versus controls and HD versus preHD. ΔIOI and ΔMTI, both MT variables, failed to make this distinction. Conclusions ST is able to detect changes in manifest HD within only one year of follow-up and may thus be applicable as an outcome measure for disease modifying clinical trials in early manifest HD. Possible changes in preHD may require longer follow-up periods or larger cohorts. The hypothesis that force-transducer-based MT and ST tasks may track the progression of a premanifest motor phenotype will be tested in the TRACK-HD study.

Background TRACK-HD is a multi-centre, longitudinal study investigating a range of motor, cognitive, neuropsychiatric and imaging measures as potential biomarkers for clinical trials in Huntington9s disease (HD). The neuropsychiatric battery includes the Frontal Systems Behaviour Scale (FrSBe), a 46-item scale measuring behaviours associated with damage to the frontal lobes of the brain. In addition to subjects rating their own behaviour on the FrSBe, companions also rated subjects9 behaviour. This provided an opportunity to investigate HD patients9 insight into their behaviour by studying discrepancies between subject and companion ratings. Method 225 TRACK-HD subjects (62 premanifest gene carriers far from onset, 52 near to onset, 70 stage 1 HD and 41 stage 2 HD) completed the FrSBe. In addition, 164 companions (77 of premanifest subjects and 87 of early HD subjects) rated subjects9 behaviour with the FrSBe. Results Companion ratings indicate a worsening of FrSBe scores with disease progression, especially in subjects with manifest HD. In contrast, subjects9 self ratings did not show the same deterioration in FrSBe scores across the pre-HD and stage 1 subgroups, with the biggest discrepancy between subject and companion ratings at stage 1 HD. Surprisingly, self-ratings of stage 2 subjects were markedly worse than those at stage 1, almost eliminating this discrepancy between companion and self-ratings. Companion FrSBe ratings correlated more strongly with objective measures of cognitive and behavioural function than did subjects own ratings. Conclusion The existence of a discrepancy between companion and subjects9 own ratings using the FrSBe in stage 1 HD but not in those with more advanced disease suggests that denial (as a psychological defence mechanism) is a more likely explanation than a loss of insight secondary to cognitive impairment.

Background/aims TRACK-HD is a multinational prospective, observational study of Huntington9s disease (HD) that aims to examine longitudinal change in premanifest carriers of the mutant HTT gene and subjects with early stage disease (Tabrizi et al. Lancet Neurology 2009). New data from the first follow-up assessment are reported here, and build on previous findings from baseline 3T MRI and novel clinical, cognitive, quantitative motor, oculomotor and neuropsychiatric assessments. Of 366 subjects enrolled at baseline, 345 (115 controls, 116 premanifest (preHD) and 114 early HD) completed 12 months of follow-up. Statistical analysis was performed to assess annualised change in all modalities. Methods/techniques Annualised rates of global and regional atrophy were higher in both the pre- and early HD groups than in controls (p≤0.007). Whole brain atrophy rates were 0.3%, 0.5% and 0.9%, and caudate atrophy rates 0.6%, 2.0% and 3.5%, in controls, pre and early HD, respectively, over 1 year. Whole brain image analysis techniques also revealed striking cortical and subcortical grey and white matter atrophy over just 1 year even in subjects furthest from predicted disease onset. Quantitative imaging showed significant associations with disease burden and total functional capacity, a widely used clinical measure of disease severity. Cognitive deterioration was detectable in both HD groups. However, rates of decline in cognitive, quantitative motor and oculomotor tasks were greater after onset of motor signs. Results/outcome HD is characterised by a long premanifest state, slow progression and a disease course of around 20 years. After 1 year, we have identified robust change in a range of measures across modalities in both premanifest and early stage HD. Quantitative imaging showed the greatest differentiation across the spectrum of the disease and a number of functional measures of decline were sensitive in early HD with cognitive impairment also detectable in the pre-HD group. Conclusions TRACK-HD is the first multi-site study to report whole brain, regional and subcortical atrophy in premanifest subjects many years from predicted disease onset using 3T MR imaging; and demonstrates the feasibility of obtaining quantifiable endpoints which show robust change over just 1 year thus showing potential as endpoints for future therapeutic trials.

Background Huntington9s disease (HD) is a progressive, inherited neurodegenerative condition, with onset usually in mid-life, affecting motor, cognitive and neuropsychiatric functions. Not surprisingly, studies have suggested that HD has a detrimental effect on the quality of life (QoL) of individuals with the HD gene expansion and also by association their families. The present literature exploring the impact for spouses predominantly investigates the later stages of HD. This study, however, uses clearly defined groups of both premanifest and early-stage symptomatic gene-carriers and their spouse/partners. Methods/techniques Self-report measures of quality of life and neuropsychiatric domains (SF-36; Quality of Life Index; Frontal Systems Behaviour Inventory (FrSBe)), clinical rating of motor function (UHDRS motor), Cognitive measures (Emotion Recognition, Trails-B) and the Short version of Problem Behaviours Assessment for HD (PBA-s) were completed by 86 participants from the TRACK-HD study. This included 23 pre-manifest gene carriers, 20 early, clinical stage 1 and 2, HD patients and 43 gene-negative spouse controls. Between-group differences and relationships between neuropsychiatric and cognitive data from the premanifest and symptomatic participants and QoL for their spouses were examined. Results/outcomes Largest between-group differences were evident between spouses and their partners with early stage disease; and different QoL domains were impacted in the different participant groups. The data presented shows the QoL domains affected in each group; and the impact of specific neuropsychiatric, cognitive and motor symptoms on spouse partners. Identification of the specific domains impacted in spouse/partners at an early stage of disease is crucial for establishing appropriate and long-term support.

Background An original primary aim of PREDICT-HD was identification and quantification of clinical marker sets predictive of HD diagnosis. Such models would add substantial power and efficiency to eventual clinical trials to prevent or delay HD onset. Since the study's inception, skepticism has grown regarding the utility of “diagnosis” as an HD concept. For this analysis, we assume that illness transition can at least be crudely dichotomized by an abstract point of “diagnosis.” Nonetheless, we see substantial evidence of inter-rater variability in defining this point and make appropriate statistical adjustments. Methods As of April 2009, 2179 years of pre-diagnosis follow-up were available on 718 participants, 126 of whom had been diagnosed by UHDRS confidence level 4. We constructed multivariate models predicting “diagnosis” from the study's non–brain-imaging baseline measures. Various criteria consistently selected from among candidate variables each individually predictive of diagnosis were used. Models were tested for additional prediction beyond that achieved by CAG length and age. Cox proportional hazard modeling was used, with stratification by rater in order to minimize systematic differences in diagnostic thresholds and motor scoring. Results The combined baseline measures of maximum tapping speed, paced tapping precision, Stroop inference, and smell identification accuracy were highly predictive. Estimated hazard ratio increased 5.39 across the interquartile range of estimated risk ( p Conclusion The relative risk of transition to HD “diagnosis” is predictable using measures that have played little traditional role defining diagnosis. This demonstrates important practical utility for these predictors. Absent a highly reliable, continuous measure of early HD, the success of these results also affirms the potential value of reliable discrete endpoints for early-HD trials.

Objective To present data from 32 converter participants and 80 matched non-converter participants from the PREDICT-HD study. Methods All participants were prodromal when they enrolled in the study and all were examined yearly for at least one visit following enrollment. Converters were defined as those individuals who, on at least two consecutive visits, received a score of 4 on the HD Diagnostic Confidence Scale of the UHDRS. Non-converters were individuals who had at least two visits and never received a score of 4. Converters and non-converters were group-matched on age, gender, and CAG repeat length. MRI measurements were obtained for 4 converters 2 years before diagnosis, for 11 converters 1 year before diagnosis, and for 17 converters at the same visit that the diagnosis was made. Results and Discussion After correcting for intracranial volume (ICV), converters had significantly smaller total brain volume (p = 0.001), total white matter volume (p = 0.004), and total striatum volume (p

Objective Declines in functional skills are observed in patients with Huntington's disease (HD) and have both clinical and research implications. However, the specific areas of early decline have not been investigated. We sought to determine which skill domains weaken most frequently in patients prior to formal diagnosis, as well as the clinical correlates of these early declines. Methods Using a large cohort of prediagnosed patients (i.e., DCL Results Occupational decline was the most frequently reported decline, with 30.10% (TFC) and 26.32% (FAS) of patients reporting some loss of ability to engage in their typical work. Inability to manage finances (TFC 21.87%, FAS 17.42%) and inability to drive safely (FAS 16.24%) were other common functional declines. A minority of patients with DCL = 0 or 1 reported functional decline (TFC 15.84%, FAS 14.26%); however, a majority of those with a DCL = 2 reported functional decline (TFC 77.54%, FAS 71.03%). The most common functional declines showed relationships with motor functioning, cognitive tests, and depression in a multivariate analysis where all 3 factors were considered simultaneously. Conclusions Our analysis of the TFC and FAS provides additional clues as to the earliest functional losses in patients at risk for HD. Fruitful areas for expanded assessment of functional status are performance at work, ability to manage finances, and driving changes. Additionally, existing functional measures may have limited utility when detecting changes in patients with no or minimal motor signs.

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 (

Background Cognitive symptoms are highly associated with functional disability in HD, yet few controlled clinical trials have examined treatments aimed at improving cognition, which could improve patients' levels of independence and quality of life. Methods Atomoxetine is a norepinephrine reuptake inhibitor approved for the treatment of attention deficit/hyperactivity disorder. Twenty participants with mild HD who complained of inattention were given atomoxetine (80 mg) or placebo in a 10-week, double-blind, crossover study. The primary outcome measures were a self-report of attention and an attention and executive neuropsychological composite score. Secondary outcomes were psychiatric and motor symptoms, which were not expected to change. Results Regarding safety and tolerability, the rate of any reported side effects while on atomoxetine was 56% (versus 22% on placebo). The most common side effects were dry mouth (39%), loss of appetite (22%), insomnia (22%), and dizziness (17%). There were no serious adverse events related to atomoxetine. There were statistically significant, mild increases in heart rate and diastolic blood pressure on atomoxetine, consistent with other studies, and these increases did not require medical referral. One participant taking creatine had a mildly elevated creatinine level while on atomoxetine. There were no significant improvements while on atomoxetine compared to placebo on the primary outcomes. However, there was evidence of significant placebo effects. There was a significant improvement in global psychiatric functioning under both treatment conditions. There were no group differences on UHDRS total motor score. Discussion There were small but significant improvements in self-reported attention and psychiatric ratings while on atomoxetine, but there was also a significant placebo effect obscuring efficacy results. There were mild but common side effects that are not ideal in HD, such as dizziness and loss of appetite. Although atomoxetine was not effective at improving attention at this dose, its safety and tolerability were similar to other studies.

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.