Rating Scale Total Motor Score Research Articles

Platelet-derived extracellular vesicles in Huntington's disease.

The production and release of extracellular vesicles (EV) is a property shared by all eukaryotic cells and a phenomenon frequently exacerbated in pathological conditions. The protein cargo of EV, their cell type signature and availability in bodily fluids make them particularly appealing as biomarkers. We recently demonstrated that platelets, among all types of blood cells, contain the highest concentrations of the mutant huntingtin protein (mHtt)-the genetic product of Huntington's disease (HD), a neurodegenerative disorder which manifests in adulthood with a complex combination of motor, cognitive and psychiatric deficits. Herein, we used a cohort of 59 HD patients at all stages of the disease, including individuals in pre-manifest stages, and 54 healthy age- and sex-matched controls, to evaluate the potential of EV derived from platelets as a biomarker. We found that platelets of pre-manifest and manifest HD patients do not release more EV even if they are activated. Importantly, mHtt was not found within EV derived from platelets, despite them containing high levels of this protein. Correlation analyses also failed to reveal an association between the number of platelet-derived EV and the age of the patients, the number of CAG repeats, the Unified Huntington Disease Rating Scale total motor score, the Total Functional Capacity score or the Burden of Disease score. Our data would, therefore, suggest that EV derived from platelets with HD is not a valuable biomarker in HD.

Automated Assessment of Movement Impairment in Huntington's Disease.

Quantitative assessment of movement impairment in Huntington’s disease (HD) is essential to monitoring of disease progression. This paper aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data, including age (years), gender, and unified HD rating scale total motor score (UHDRS-TMS), were recorded. For the purposes of this paper, a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity while wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous movement impairment score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this paper demonstrates the possibility of an automated objective, consistent, and sensitive assessment of the HD movement impairment.

Interrater Reliability of the Unified Huntington's Disease Rating Scale-Total Motor Score Certification.

The clinical assessment of motor symptoms in Huntington's disease is usually performed with the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS). A high interrater reliability is desirable to monitor symptom progression. Therefore, a teaching video and a system for annual online certification has been developed and implemented. The aim of this study is to investigate the interrater reliability of the UHDRS-TMS and of its subitems, and to examine the performance of raters in consecutive years. Data from the online UHDRS-TMS certification were used. The interrater reliability was assessed for all first-time participants (n = 944) between 2009 and 2016. Intraclass correlation coefficients (ICC) were calculated for each year separately and the mean was taken as the total ICC. The UHDRS-TMS (ICC = 0.847), tandem walking (0.824), pronate/supinate hands left (0.713), and retropulsion pull test (0.706) showed good interrater reliability. Poor interrater reliability was found for maximal dystonia of the left and right upper extremity (0.187 and 0.322, respectively), maximal dystonia of the left and right lower extremity (0.200 and 0.256, respectively), and maximal dystonia of the trunk (0.389), tongue protrusion (0.266), and rigidity arms left (0.390). Raters performed significantly worse on follow-up certification compared to their first certification. Our results suggest that the rating of dystonia (absent, slight, mild, moderate, or marked) is subjective and difficult to interpret, especially on video. Therefore, changing the dystonia items of the UHDRS-TMS should be explored. We also recommend that raters should watch the UHDRS-TMS teaching video before each certification.

Rating Scales for Motor Symptoms and Signs in Huntington's Disease: Critique and Recommendations.

Motor symptoms are a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the assessment of the clinimetric properties of motor rating scales in HD to make recommendations regarding their use, following previously established standardized criteria. After a systematic literature search, a total of 6 rating scales assessing motor symptoms and signs in HD were included for review. Performance testing (reviewed elsewhere) and quantitative motor rating methods were excluded. Only the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) was classified as "recommended" for assessing the severity of motor signs in HD. The following scales were classified as "suggested": Abnormal Involuntary Movement Scale, the UHDRS-TMS4, the Quantified Neurological Examination, and the Marsden and Quinn Chorea Severity Scale. The committee also concluded that further assessment of existing rating scales, including the UHDRS-TMS, is necessary to determine sensitivity to change and to screening for the presence of motor signs specific to HD. There is also a need to develop a motor rating scale to be used in positive gene carriers with subtle but not definite motor signs.

Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis

Predictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first. To determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis. This study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017. The primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test. Of Track's 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS. Reasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach.

Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea

Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study. To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD). In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control. Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen. Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points. Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001). In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003-13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10-10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10-8DHFR p=8·37 × 10-7 MTRNR2L2 p=2·15 × 10-9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10-4DHFR p=8·45 × 10-4MTRNR2L2 p=1·20 × 10-3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10-8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16-0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06-0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Chapter 18 - Motor outcome measures in Huntington disease clinical trials

Deficits in motor function are a hallmark of Huntington disease (HD). The Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) is a categoric clinical rating scale assessing multiple domains of motor disability in HD. The UHDRS-TMS or subsets of its items have served as primary or secondary endpoints in numerous clinical trials. In spite of a well-established video-based annual online certification system, intra- and interrater variability, subjective error, and rater-induced placebo effects remain a concern. In addition, the UHDRS-TMS was designed to primarily assess motor symptoms in manifest HD. Recently, advancement of technology resulted in the introduction of the objective Q-Motor (i.e., Quantitative-Motor) assessments in biomarker studies and clinical trials in HD. Q-Motor measures detected motor signs in blinded cross-sectional and longitudinal analyses of manifest, prodromal, and premanifest HD cohorts up to two decades before clinical diagnosis. In a multicenter clinical trial in HD, Q-Motor measures were more sensitive than the UHDRS-TMS and exhibited no placebo effects. Thus, Q-Motor measures are currently explored in several multicenter trials targeting both symptomatic and disease-modifying mechanisms. They may supplement the UHDRS-TMS, increase the sensitivity and reliability in proof-of-concept studies, and open the door for phenotype assessments in clinical trials in prodromal and premanifest HD.

Striatal hypometabolism in premanifest and manifest Huntington's disease patients.

To assess metabolic changes in cerebral 18F-FDG PET/CT in premanifest and manifest Huntington's disease (HD) subjects compared to a control group and to correlate 18F-FDG uptake patterns with different disease stages. Thirty-three gene-expanded carriers (Eight males; mean age: 43y/o; CAG > 39) were prospectively included. Based on the Unified Huntington's Disease Rating Scale Total Motor Score and the Total Functional Capacity, subjects were classified as premanifest (preHD = 15) and manifest (mHD = 18). Estimated time disease-onset was calculated using the Langbehn formula, which allowed classifying preHD as far-to (preHD-A) and close-to (PreHD-B) disease-onset. Eighteen properly matched participants were included as a control group (CG). All subjects underwent brain 18F-FDG PET/CT and MRI. 18F-FDG PET/CT were initially assessed by two nuclear medicine physicians identifying qualitative metabolic changes in the striatum. Quantitative analysis was performed using SPM8 with gray matter atrophy correction using the BPM toolbox. Visual analysis showed a marked striatal hypometabolism in mHD. A normal striatal distribution of 18F-FDG uptake was observed for most of the preHD subjects. Quantitative analysis showed a significant striatal hypometabolism in mHD subjects compared to CG (p < 0.001 uncorrected, k = 50voxels). In both preHD groups we observed a significant striatal hypometabolism with respect to CG (p < 0.001 uncorrected, k = 50voxels). In mHD subjects we observed a significant striatal hypometabolism with respect to both preHD groups (p < 0.001 uncorrected, k = 50voxels). 18F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. 18F-FDG PET/CT appears as a promising method to monitor the response to disease-modifying therapies even if applied in premanifest subjects.

Change in PDE10 across early Huntington disease assessed by [18F]MNI-659 and PET imaging.

To evaluate whether striatal [(18)F]MNI-659 PET imaging of phosphodiesterase 10A (PDE10) serves as a sensitive and reliable biomarker of striatal neurodegeneration in a longitudinal cohort of participants with early Huntington disease (HD). A cohort of participants with HD, including both participants premanifest or manifest with motor signs, underwent clinical assessments, genetic determination, and 2 [(18)F]MNI-659 PET imaging sessions approximately 1 year apart. Eleven healthy control (HC) participants underwent clinical assessments and [(18)F]MNI-659 PET imaging once. Striatal binding potentials (BPnd) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between baseline and follow-up imaging. Clinical measures of HD severity were assessed at each visit. Eight participants with HD (6 manifest; 2 premanifest) participated. Of those with manifest HD, all had relatively early stage disease (stage 1, n = 2; stage 2, n = 4) and a Unified Huntington's Disease Rating Scale total motor score <45. As expected, the HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of that seen in HC. On follow-up scans, [(18)F]MNI-659 uptake declined in the putamen and caudate nucleus in all 8 participants. The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%. Longitudinal data in this small cohort of participants with early HD support [(18)F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression.

Is There an Association of Physical Activity with Brain Volume, Behavior, and Day-to-day Functioning? A Cross Sectional Design in Prodromal and Early Huntington Disease.

Background: Huntington disease (HD) is a genetic neurodegenerative disease leading to progressive motor, cognitive, and behavioral decline. Subtle changes in these domains are detectable up to 15 years before a definitive motor diagnosis is made. This period, called prodromal HD, provides an opportunity to examine lifestyle behaviors that may impact disease progression. Theoretical Framework: Physical activity relates to decreased rates of brain atrophy and improved cognitive and day-to-day functioning in Alzheimer disease and healthy aging populations. Previous research has yielded mixed results regarding the impact of physical activity on disease progression in HD and paid little attention to the prodromal phase.Methods: We conducted analyses of associations among current physical activity level, current and retrospective rate of change for hippocampus and striatum volume, and cognitive, motor, and day-to-day functioning variables. Participants were 48 gene-expanded cases with prodromal and early-diagnosed HD and 27 nongene-expanded control participants. Participants wore Fitbit Ultra activity monitors for three days and completed the self-reported International Physical Activity Questionnaire (IPAQ). Hippocampal and striatal white matter volumes were measured using magnetic resonance imaging. Cognitive tests included the Stroop Color and Word Test, and the Symbol Digit Modalities Test (SDMT). Motor function was assessed using the Unified Huntington’s Disease Rating Scale total motor score (TMS). Day-to-day functioning was measured using the World Health Organization Disability Assessment Schedule (WHODAS) version 2.0.Results: Higher Fitbit activity scores were significantly related to better scores on the SDMT and WHODAS in case participants but not in controls. Fitbit activity scores tracked better with TMS scores in the group as a whole, though the association did not reach statistical significance in the case participants. Higher Fitbit activity scores related to less day-to-day functioning decline in retrospective slope analyses. Fitbit activity scores did not differ significantly between cases and controls.Conclusions: This is the first known study examining the associations between activity level and imaging, motor, cognitive, and day-to-day functioning outcomes in prodromal and early HD. Preliminary results suggest physical activity positively correlates with improved cognitive and day-to-day functioning and possibly motor function in individuals in the prodromal and early phase of the condition.

A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease.

This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation.

N02 Safety And Tolerability Of Selisistat For The Treatment Of Huntington's Disease: Results From A Randomised, Double-blind, Placebo-controlled Phase Ii Trial

Background Selisistat is a first-in-class SirT1 inhibitor shown to be safe and well tolerated in healthy volunteers and HD patients in short-term studies. Objective To evaluate safety and tolerability of selisistat over 12 weeks in patients with Huntington’s disease (HD). Design/methods This was a double-blind, placebo-controlled, international multi-centre study of selisistat in individuals with Stage I-III HD. Participants (30–70 yrs) with genetically confirmed HD, a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of ≥ 5 and a Total Functional Capacity ≥ 5 were randomised (1:1:1) to selisistat 50 or 200 mg or placebo once daily for 12 weeks. Safety and tolerability were evaluated by monitoring adverse events, vital signs, ECG and laboratory safety data throughout the study. Blood sampling for pharmacokinetics and soluble mutant huntingtin levels were collected throughout. Results/outcome A total of 144 patients were randomised and 125 patients (87%) completed the study. There were 9 serious adverse events, three in each treatment group, including one death in the placebo group. The most common adverse events were reversible increases in liver function tests without accompanying increases in bilirubin. All of these occurred in the selisistat groups; while most of these increases were Conclusions Apart from increases in liver function tests in a subset of patients, selisistat was safe and well tolerated, and a trend for modulation of the levels of soluble mutant huntingtin was observed. Acknowledgement Supported by Siena Biotech SpA.

Optimising mobility outcome measures in Huntington's disease.

Many of the performance-based mobility measures that are currently used in Huntington's disease (HD) were developed for assessment in other neurological conditions such as stroke. We aimed to assess the individual item-response of commonly used performance-based mobility measures, with a view to optimizing the scales for specific application in Huntington's Disease (HD). Data from a larger multicentre, observational study were used. Seventy-five people with HD (11 pre-manifest & 64 manifest) were assessed on the Six-Minute Walk Test, 10-Meter Walk Test, Timed "Up & Go" Test (TUG), Berg Balance Scale (BBS), Physical Performance Test (PPT), Four Square Step Test, and Tinetti Mobility Test (TMT). The Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, Functional Assessment Scale and Total Functional Capacity scores were recorded, alongside cognitive measures. Standard regression analysis was used to assess predictive validity. Individual item responses were investigated using a sequence of approaches to allow for gradual removal of items and the subsequent creation of shortened versions. Psychometric properties (reliability and discriminant ability) of the shortened scales were assessed. TUG (β 0.46, CI 0.20-3.47), BBS (β -0.35, CI -2.10-0.14), and TMT (β -0.45, CI -3.14-0.64) were good disease-specific mobility measures. PPT was the best measure of functional performance (β 0.42, CI 0.00-0.43 for TFC & β 0.57 CI 0.15-0.81 for FAS). Shortened versions of BBS and TMT were developed based on item analysis. The resultant BBS and TMT shortened scales were reliable for use in manifest HD. ROC analysis showed that shortened scales were able to discriminate between manifest and pre-manifest disease states. Our data suggests that the PPT is appropriate as a general measure of function in individuals with HD, and we have identified shortened versions of the BBS and TMT that measure the unique gait and balance impairments in HD. These scales, alongside the TUG, may therefore be important measures to consider in future clinical trials.

Pharmacological treatment of chorea in Huntington's disease–good clinical practice versus evidence‐based guideline

Recently, the American Academy of Neurology published an evidence-based guideline for the pharmacological treatment of chorea in Huntington’s disease. Although the progress in medical care because of the implementation of criteria of evidence-based medicine is undisputed, the guideline classifies the level of evidence for drugs to reduce chorea based on anchors in the Unified Huntington’s Disease Rating Scale-Total Motor Score chorea sum score, which were chosen arbitrarily and do not reflect validated or generally accepted levels of clinical relevance. Thus, the guideline faces several serious limitations and delivers clinical recommendations that do not represent current clinical practice; these are reviewed in detail, and arguments are presented why these recommendations should not be followed. To remedy the lack of evidence-based recommendations and provide guidance to a pragmatic symptomatic therapy of chorea in HD, a flow-chart pathway that follows currently established clinical standards based on expert opinion is presented. © 2013 Movement Disorder Society

A randomized, double‐blind, placebo‐controlled trial of pridopidine in Huntington's disease

We examined the effects of 3 dosages of pridopidine, a dopamine-stabilizing compound, on motor function and other features of Huntington's disease, with additional evaluation of its safety and tolerability. This was a randomized, double-blind, placebo-controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty-seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntington's Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was -1.2 points (95% confidence interval [CI], -2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was -2.8 points (95% CI, -5.4 to -0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntington's disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated.

K04 Incidence and course of irritability in huntington's disease

BackgroundIrritability is a common neuropsychiatric symptom in patients with Huntington's disease (HD).AimThe objective is to examine incidence, course and predictors of irritablity in subjects with HD.MethodsAt baseline, irritability was measured...

I07 Impaired isometric force coordination in Huntington's disease

<h3>Background</h3> Assessment of motor phenotype and diagnosis of Huntington9s Disease (HD) are based on the Unified HD Rating Scale-Total Motor Score, a categorical scale. We have previously shown that impairments in tongue protrusion forces can be seen in premanifest and manifest HD and correlate with clinical severity as assessed by the Unified HD Rating Scale-Total Motor Score and the disease burden score (Reilmann <i>et al.</i> 2010). In this study we aimed to investigate whether similar impairments of force coordination can be found in different force matching tasks. <h3>Objective</h3> To assess whether impairments in isometric force coordination of the upper and lower extremities can be detected in manifest HD gene carriers compared to controls. <h3>Methods</h3> Using a precalibrated force transducer, the ability of subjects with symptomatic HD (n=31) to generate and maintain isometric TPF at different target force levels (1.5, and 5.0 N for thumb, 1.0, 5.0 and 10.0 N for big toe) was assessed and compared with age-matched controls (n=22) in a cross-sectional pilot study. <h3>Results</h3> All paradigms distinguish controls from symptomatic subjects. The static coefficient of variability (%), assessing the degree of deviation from the target force normalised to the mean force, was the most robust measure in all matching trials. Comparisons between tasks and correlations with clinical measures such as the TMS, DBS and TFC will be presented. <h3>Conclusions</h3> Assessment of force matching tasks by hand and feet may provide quantitative objective measures for severity of motor phenotype in symptomatic HD.

Physical therapy in Huntington's disease – toward objective assessments?

Physical therapy is recommended for the treatment of Huntington's disease, but reliable studies investigating its efficacy are almost non-existent. This may in part be due to the lack of suitable outcome measures. Therefore, we investigated the applicability of novel quantitative and objective assessments of motor dysfunction in the evaluation of physical therapy interventions aimed at improving gait and posture. Twelve patients with Huntington disease received a predefined twice-weekly intervention focusing on posture and gait over 6 weeks. The GAITRite mat and a force plate were used for objective and quantitative assessments. The Unified Huntingtons Disease Rating Scale Total Motor Score, the timed Up &Go test, and the Berg Balance Scale were used as clinical outcome measures. Significant improvements were seen in GAITRite measures after therapy. Improvements were also seen in the Up & Go test and Berg Balance Scale, whereas force plate measures and Total Motor Scores did not change. The results suggest that physical therapy has a positive effect on gait in Huntington's disease. The study shows that objective and quantitative measures of gait and posture may serve as endpoints in trials assessing the efficacy of physical therapy. They should be explored further in larger trials applying a randomized controlled setting.

Assessment of involuntary choreatic movements in Huntington's disease—Toward objective and quantitative measures

Objective measures of motor impairment may improve the sensitivity and reliability of motor end points in clinical trials. In Huntington's disease, involuntary choreatic movements are one of the hallmarks of motor dysfunction. Chorea is commonly assessed by subitems of the Unified-Huntington's Disease Rating Scale. However, clinical rating scales are limited by inter- and intrarater variability, subjective error, and categorical design. We hypothesized that assessment of position and orientation changes interfering with a static upper extremity holding task may provide objective and quantitative measures of involuntary movements in patients with Huntington's disease. Subjects with symptomatic Huntington's disease (n = 19), premanifest gene carriers (n = 15; Unified-Huntington's Disease Rating Scale total motor score ≤ 3), and matched controls (n = 19) were asked to grasp and lift a device (250 and 500 g) equipped with an electromagnetic sensor. While subjects were instructed to hold the device as stable as possible, changes in position (x, y, z) and orientation (roll, pitch, yaw) were recorded. These were used to calculate a position index and an orientation index, both depicting the amount of choreatic movement interfering with task performance. Both indices were increased in patients with symptomatic Huntington's disease compared with controls and premanifest gene carriers for both weights, whereas only the position index with 500 g was increased in premanifest gene carriers compared with controls. Correlations were observed with the Disease Burden Score based on CAG-repeat length and age and with the Unified-Huntington's Disease Rating Scale. We conclude that quantitative assessment of chorea is feasible in Huntington's disease. The method is safe, noninvasive, and easily applicable and can be used repeatedly in outpatient settings. A use in clinical trials should be further explored in larger cohorts and follow-up studies.