A systematic review and meta‐analysis of clinical variables used in Huntington disease research

Treatment effect in Huntington disease (HD) clinical trials has relied on primary outcome measures such as total motor score or functional rating scales. However, these measures have limited sensitivity, particularly in pre‐ to early stages of the disease. We performed a systematic review of HD clinical studies to identify endpoints that correlate with disease severity. Using standard HD keywords and terms, we identified 749 published studies from 1993 to 2011 based on the availability of demographic, biochemical, and clinical measures. The average and variability of each measure was abstracted and stratified according to pre‐far, pre‐close, early, mild, moderate, and severe HD stages. A fixed‐effect meta‐analysis on selected variables was conducted at various disease stages. A total of 1,801 different clinical variables and treatment outcomes were identified. Unified Huntington Disease Rating Scale (UHDRS) Motor, UHDRS Independence, and Trail B showed a trend toward separation between HD stages. Other measures, such as UHDRS Apathy, Verbal Fluency, and Symbol Digit, could only distinguish between pre‐ and early stages of disease and later stages, whereas other measures showed little correlation with increasing HD stages. Using cross‐sectional data from published HD clinical trials, we have identified potential endpoints that could be used to track HD disease progression and treatment effect. Longitudinal studies, such as TRACK‐HD, are critical for assessing the value of potential markers of disease progression for use in future HD therapeutic trials. A list of variables, references used in this meta‐analysis, and database is available at http://www.cmmt.ubc.ca/research/investigators/leavitt/publications . © 2013 International Parkinson and Movement Disorder Society     

The unified huntington's disease rating scale for advanced patients: Validation and follow‐up study

The Unified Huntington's Disease Rating Scale (UHDRS) adequately measures decline in patients at early and moderate stages of Huntington's disease (HD). In patients with advanced HD, floor effects hamper the evaluation, thus calling for an adjusted scale. We designed the UHDRS‐For Advanced Patients (UHDRS‐FAP) to improve longitudinal assessment of patients at the advanced disease stage. Sixty‐nine patients with a Total Functional Capacity score ≤ 5 were recruited in France and the Netherlands. Among them, 45 patients were followed longitudinally (mean ± standard deviation, 1.6 ± 1.2 years) with the UHDRS‐FAP; 30 patients also were assessed with the UHDRS. In cross‐sectional analyses, the psychometric properties and inter‐rater reliability of the scale were evaluated. Longitudinal analyses were used to evaluate the sensitivity to decline of the UHDRS‐FAP compared with the UHDRS. Internal consistency was higher for motor (0.84) and cognitive (0.91) scores than for somatic (0.70) and behavioral (0.49) scores. Inter‐rater reliability was ≥ 0.88 for all scores. The somatic score, which was specific to the UHDRS‐FAP, declined over time along with motor and cognitive performance on both scales. Although performance with the two scales was correlated, the UHDRS‐FAP appeared to be more sensitive to change and was the only scale that detected decline in patients with a Total Functional Capacity score ≤ 1. Neither scale detected a significant decline in behavioral scores. The results indicate that the UHDRS‐FAP is reliable and more sensitive to change than the original UHDRS for cognitive and motor domains. It offers items that are relevant for daily care. Behavioral scores tended to decline, but this may reflect the decline in patients' communicative abilities. © 2013 International Parkinson and Movement Disorder Society     

An item response analysis of the motor and behavioral subscales of the unified Huntington's disease rating scale in huntington disease gene expansion carriers

Although the Unified Huntington's Disease Rating Scale (UHDRS) is widely used in the assessment of Huntington disease (HD), the ability of individual items to discriminate individual differences in motor or behavioral manifestations has not been extensively studied in HD gene expansion carriers without a motor‐defined clinical diagnosis (ie, prodromal‐HD or prHD). To elucidate the relationship between scores on individual motor and behavioral UHDRS items and total score for each subscale, a nonparametric item response analysis was performed on retrospective data from 2 multicenter longitudinal studies. Motor and behavioral assessments were supplied for 737 prHD individuals with data from 2114 visits (PREDICT‐HD) and 686 HD individuals with data from 1482 visits (REGISTRY). Option characteristic curves were generated for UHDRS subscale items in relation to their subscale score. In prHD, overall severity of motor signs was low, and participants had scores of 2 or above on very few items. In HD, motor items that assessed ocular pursuit, saccade initiation, finger tapping, tandem walking, and to a lesser extent, saccade velocity, dysarthria, tongue protrusion, pronation/supination, Luria, bradykinesia, choreas, gait, and balance on the retropulsion test were found to discriminate individual differences across a broad range of motor severity. In prHD, depressed mood, anxiety, and irritable behavior demonstrated good discriminative properties. In HD, depressed mood demonstrated a good relationship with the overall behavioral score. These data suggest that at least some UHDRS items appear to have utility across a broad range of severity, although many items demonstrate problematic features. © 2011 Movement Disorder Society     

Tongue force analysis assesses motor phenotype in premanifest and symptomatic Huntington's disease

Motor symptoms in Huntington's Disease (HD) are commonly assessed by the Unified Huntington's Disease Rating Scale‐Total Motor Score (UHDRS‐TMS). However, the UHDRS‐TMS is limited by interrater variability, its categorical nature, and insensitivity in premanifest subjects. More objective and quantitative measures of motor phenotype may complement the use of the UHDRS‐TMS as outcome measure and increase the power and sensitivity of clinical trials. Deficits in tongue protrusion are well acknowledged in HD and constitute a subitem of the UHDRS‐TMS. We, therefore, investigated whether objective and quantitative assessment of tongue protrusion forces (TPF) provides measures that (1) correlate to the severity of motor phenotype detected in the UHDRS‐TMS in symptomatic HD, (2) detect a motor phenotype in premanifest HD gene‐carriers, and (3) exhibit a correlation to the genotype as assessed by a disease burden score (based on CAG‐repeat length and age). Using a precalibrated force transducer, the ability of premanifest gene carriers (n = 15) and subjects with symptomatic HD (n = 20) to generate and maintain isometric TPF at three target force levels (0.25, 0.5, and 1.0 N) was assessed and compared with age‐matched controls (n = 20) in a cross‐sectional study. Measures of variability of TPF and tongue contact time distinguished controls, premanifest, and symptomatic HD groups and correlated to the UHDRS‐TMS and disease burden score, suggesting a strong genotype‐phenotype correlation. Group distinction was most reliable at the lowest target force level. We conclude that assessment of TPF may be a useful objective and quantitative marker of motor dysfunction in premanifest and symptomatic HD. © 2010 Movement Disorder Society     

The relationship between CAG repeat length and clinical progression in Huntington's disease

The objective of this study was to examine the relationship between CAG repeat length (CAGn) and clinical progression in patients with Huntington's disease (HD). There are conflicting reports about the relationship between CAGn and clinical progression of HD. We conducted an analysis of data from the Coenzyme Q10 and Remacemide Evaluation in Huntington's Disease (CARE‐HD) clinical trial. We modeled progression over 30 months on the Unified Huntington's Disease Rating Scale (UHDRS) and supplemental neuropsychological and behavioral tests using multiple linear regression. Mean subject age was 47.9 ± 10.5 years and mean CAGn was 45.0 ± 4.1. Multiple linear regression revealed statistically significant associations between CAGn and worsening on several motor, cognitive, and functional outcomes, but not behavioral outcomes. Many effects were clinically important; 10 additional CAG repeats were associated with an 81% increase in progression on the Independence Scale. These associations were not observed in the absence of age adjustment. Age at the time of assessment confounds the association between CAGn and progression. Adjusting for age shows that longer CAGn is associated with greater clinical progression of HD. This finding may account for the variable results from previous studies examining CAGn and progression. Adjusting for CAGn may be important for clinical trials. © 2008 Movement Disorder Society     

Unified Huntington's disease rating scale for advanced patients: Validation and follow‐up study

The Unified Huntington's Disease Rating Scale (UHDRS) adequately measures decline in patients at early and moderate stages of Huntington's disease (HD). In advanced patients, floor effects hamper the evaluation, thus calling for an adjusted scale. We designed the UHDRS‐For Advanced Patients (UHDRS‐FAP), in order to improve longitudinal assessment of patients at advanced disease stage. Sixty‐nine patients with a Total Functional Capacity (TFC) ≤ 5 were recruited in France and in the Netherlands. Among them, 45 patients were followed longitudinally (mean 1.6 ± 1.2 years) with the UHDRS‐FAP; 30 were also assessed with the UHDRS. Cross‐sectional analyses evaluated psychometric properties and interrater reliability of the scale. Longitudinal analyses evaluated the sensitivity to decline compared to the UHDRS. Internal consistency was higher for motor and cognitive scores than for somatic and behavioral scores (0.84, 0.91, 0.70, and 0.49, respectively). Interrater reliability was ≥ 0.88 in all scores. The somatic score, specific to the UHDRS‐FAP, declined over time, as well as motor and cognitive performance with both scales. Although performance with the 2 scales correlated, the UHDRS‐FAP appeared more sensitive to change and was the only scale that detected decline in patients with a TFC ≤ 1. Neither scale detected a significant decline in behavioral scores. The UHDRS‐FAP is reliable and more sensitive to change than the original UHDRS for cognitive and motor domains. It offers items relevant for daily care. Behavioral scores tended to decline but this may reflect the decline in the communicative abilities of the patients. © 2013 International Parkinson and Movement Disorder Society     

Assessment of simple movements and progression of Huntington's disease

Instrumental measurement of simple motion sequences reflects impairment in patients with Huntington's disease (HD). The objectives were to study the progress of symptoms of HD and tapping results in 42 patients with HD, without symptomatic drug treatment over 3 years. Assessment moments were at baseline, and at years 1, 2 and 3. Unified Huntington's Disease Rating Scale (UHDRS) total score and UHDRS arm score significantly increased. Motor test outcomes considerably worsened. Instrumental test results significantly correlated with both UHDRS scores at each assessment. Assessment of simple movement sequences is an additional simple method to follow impairment in patients with HD in addition to clinical rating.     

Rate of functional decline in Huntington's disease. Huntington Study Group

OBJECTIVE: To determine the rate of functional decline in a large cohort of patients with Huntington's disease (HD) followed at 43 sites by the Huntington Study Group (HSG). METHODS: The annual rate of functional decline was measured using the Total Functional Capacity Scale (TFC) and the Independence Scale (IS) in 960 patients with definite HD followed prospectively for a mean of 18.3 months. All patients were rated with the Unified Huntington's Disease Rating Scale (UHDRS). Sample size calculations for hypothetical clinical trials were calculated. Results: A factor analysis of the UHDRS at baseline yielded 15 factors accounting for 77% of the variance. The TFC score declined at a rate of 0.72 units/year (standard error [SE] 0.04) and the IS score declined at a rate of 4.52 units/year (SE 0.23). Lower TFC score at baseline, indicating more severe impairment, was associated with less rapid annual decline in TFC score, perhaps reflecting the floor effect of the scale. The annual rate of decline for 575 patients with baseline TFC scores of 7 to 13 was 0.97 (SE 0.06), was 0.38 (SE 0.08) for 270 patients with baseline TFC scores of 3 to 6, and was 0.06 (SE 0.1) for 101 patients with TFC scores of 0 to 2. In multivariate analysis (n = 960), longer disease duration and better cognitive status at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology was the only factor associated with more rapid decline on the IS score. Age at onset of HD, sex, weight, and education did not affect decline on either score. CONCLUSIONS: The comparable rates of decline on the TFC and the IS scores with other published studies suggest that these estimates of functional decline are representative of HD patients who are evaluated at HSG research sites. In longitudinal analysis, longer disease duration and better neuropsychological performance at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology at baseline was associated with a more rapid decline in the IS score. These rates of functional decline and the covariates that modify them should be considered in estimating statistical power and designing future therapeutic trials involving HD patients with early or moderately severe disease.     

Internal consistency of a Brazilian version of the unified Huntington's disease rating scale

We evaluated the reliability of a translated Brazilian version of the Unified Huntington's Disease Rating Scale (UHDRS) to establish the reproducibility of the scale in a population that differs substantially from that on which the scale was originally validated. After a training period with the video and guidelines requested from the Huntington Study Group, we applied the UHDRS, except for the cognitive tests, to a group of 21 Brazilian patients with a molecular diagnosis of Huntington's disease (HD). We found a high degree of internal consistency of the motor section of the UHDRS (Cronbach's alpha= 0.841). There was a negative correlation between the total motor score and the functional assessment, the independence scale and the functional capacity. There was a positive correlation between these 3 scales of functional evaluation and a negative correlation between the age of onset of the disease and the number of CAG repeats. The behavioral scale and disease duration were not correlated with any factor. The clinical characteristics of this sample of patients as described by the UHDRS were roughly similar to those reported in the original validation studies and the correlations described were similar to those reported previously. We conclude that the Brazilian version of the UHDRS is reliable and valid to study patients with HD in the Brazilian setting, that this sample of Brazilian patients had clinical characteristics similar to those observed in other world regions, as expected, and that the clinical training method used for the application of the UHDRS was effective to insure a high degree of clinical reproducibility.     

The influence of gender on phenotype and disease progression in patients with Huntington's disease

IntroductionHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The aim of this study is to determine whether gender plays a role in the phenotypic expression and progression of HD.Methods1267 patients with HD (636 women) from the Registry project of the EHDN were included. A cross-sectional analysis (ANCOVA) controlling for differences in age at onset, disease burden, disease duration, smoking status, alcohol abuse, depression and the number of years of education, was performed to evaluate if there were differences between men and women in UHDRS motor, function and cognitive scores. Additionally, analyses on follow-up data using linear mixed models with the same covariates were performed to test for gender-related differences in progression.ResultsBaseline features did not differ between genders, with the exception of a higher frequency of past and current depression among women, and a higher number of years of education as well as more frequent alcohol abuse and smoking among men. In the cross-sectional ANCOVA analyses of patients with a mid-age HD onset, women showed worse scores than men in the functional domain (TFC, P = 0.001; UHDRS functional, P = 0.033), UHDRS motor (P = 0.033). The longitudinal analyses showed a faster rate of progression in women in the functional assessment (P = 0.025), the motor assessment (P = 0.032) and the independence scale (P = 0.008).ConclusionsThese results suggest a complex gender effect on the phenotypical presentation and the rate of disease progression in HD, with slightly more severe phenotype and faster rate of progression in women in especially the motor and functional domains.     

Electrophysiological deterioration over time in patients with Huntington's disease.

In recent studies aimed at assessing the effects of original therapeutic strategies applied to patients with Huntington's disease (HD), we observed informative changes in electrophysiological results that recovered normal values in coherence with clinical improvement. However, longitudinal studies were lacking for determining whether electrophysiological test results evolve in parallel with clinical markers of the natural course of the disease and could consequently provide objective quantifiable markers of disease progression. For this purpose, electrophysiological testing was performed annually in a cohort of 20 patients with HD over a 2-year period (three examinations). The study included the recording of sympathetic skin responses and blink reflexes (BRs) to supraorbital nerve stimulation, long latency reflexes (LLRs) and somatosensory evoked potentials (SEPs) to median nerve stimulation, and cortical silent periods (CSPs) to transcranial magnetic stimulation. Clinical evaluation was based on the Total Functional Capacity scale (TFC) and the Motor part of the Unified Huntington's Disease Rating Scale (UHDRS). A significant deterioration with time was found for BR latency, LLR presence, various SEP parameters (parietal N20 peak amplitude and frontal N30 presence) and CSP duration. Attenuation of the N20 peak and CSP shortening correlated with functional decline, as assessed by the TFC score, whereas delayed BR and LLR abolition correlated with UHDRS Motor score deterioration. This study shows that several electrophysiological parameters are closely associated with dysfunction of various neural circuits in HD and could be useful markers of disease progression.     

Hand tapping: A simple,reproducible, objective marker of motor dysfunction in Huntington’s disease

Huntington’s disease (HD) is a severe neurodegenerative condition in which the impairment in voluntary movement is related to functional disability. Clinical assessment of motor deficit currently relies largely on subjective rating scales without objective measurement. We have developed a quick and easy-to-use hand tapping device that enables measurement of (a) the number of taps in 30 seconds, (b) variability in tapping rhythm and (c) fatigue over the testing period. Initial cross-sectional testing of 178 consecutive HD clinic patients using an early model of the device showed that the total number of taps in 30 seconds correlated with the motor UHDRS (Spearmann’s rho, r_s = –0.81, p < 0.0001) and independence scores (r_s = 0.78, p = 0.01). Longitudinal data from a small cohort followed over 10 years reveals a correlation between total number of taps in 30 seconds and motor UHDRS over time (rs = –0.49, p < 0.001), and suggests the technique may provide an objective measure of disease progression. Further tests on 15 HD patients and 9 controls were repeated three times in a single day using an updated device. The HD group made significantly fewer taps in 30 seconds (median HD = 79, control = 104, p = 0.009) and had greater variability of inter-tap interval (mean interdecile range HD = 148, control = 56, p = 0.016) compared to controls. Both the total number of taps and variability of inter-tap interval correlated with motor UHDRS. Of vital importance for any potential marker of disease progression is that these tapping parameters were reproducible with repeated measurement. Given that hand tapping parameters differ between HD and control populations, they correlate with motor UHDRS over time and are reproducible, we propose that assessment of hand tapping represents a useful objective adjunct to the clinical assessment of HD patients. *contributed equally to this paper     

Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized cross-over trial.

We evaluated tolerability and the efficacy of continuous infusion of apomorphine hydrochloride on involuntary movements and mood disorder in Huntington's disease (HD) patients in a pilot, single center, double-blind, randomized, crossover, and controlled versus placebo study. Nine patients with a molecular diagnosis of HD were screened for response to acute apomorphine injection. Four of them, not ameliorating at the acute test, were discontinued. Five patients, responding to acute apomorphine, received continuous infusion of either apomorphine or placebo for 5 days. After 2 days of washout, the alternative treatment was administered. Primary endpoint measures were scores of the Unified Huntington's Disease Rating Scale (UHDRS "motor section") and of the Abnormal Involuntary Movement Scale (AIMS). Secondary endpoint measures were the Hamilton Depression Rating Scale (HAD) score and safety parameters. Both UHDRS and AIMS scores significantly decreased in all patients after apomorphine. The beneficial effect of apomorphine was recorded throughout the 5 treatment days. The HAD score did not change after infusion of either treatment. No serious adverse events were reported by either group during the study. Our results suggest that continuous infusion of apomorphine might be considered for the treatment of involuntary movements in some HD patients.     

Unified Huntington's disease rating scale: clinical practice and a critical approach

The purpose of this study was to test the usefulness of the Unified Huntington's Disease Rating Scale (UHDRS) in clinical practice. The UHDRS was used to examine 45 persons with genetically diagnosed Huntington's disease (HD) in various stages. The rate of motor involvement, cognitive deficit and reliance on nursing care rose in linear proportion to HD duration. The severity of motor involvement correlated significantly with all UHDRS subscales except for that of behavioral disorders, the rate of these disorders being unrelated to any of the parameters under study. The number of CAG triplets was inversely correlated with the age at onset of HD. Being considerably time consuming, administration of the whole UHDRS calls for interdisciplinary co-operation. For valid data acquisition, the participation of caregivers is also essential. In clinical practice it is advisable regularly to monitor the patient's conditions and the efficacy of treatment using the UHDRS motor, functional and behavioral subscales. Cognitive tests present difficulties but, in view of the progressive cognitive deterioration in HD, they are very useful in the early stage of the disease. The UHDRS does not assess impaired voluntary motor activity, or furnish information relating to therapy, dysphagia, weight loss, sexual problems or drug abuse.     

Grasping premanifest Huntington's disease – shaping new endpoints for new trials

Future clinical trials in subjects with premanifest Huntington's disease (preHD) may depend on the availability of biomarkers. It was previously shown in symptomatic HD that, the grip force variability coefficient‐of‐variation (GFV‐C) in a grasping paradigm was correlated to the Unified‐Huntington's‐Disease‐Rating‐Scale‐Total‐Motor‐Score (UHDRS‐TMS) and increased in a 3 year follow‐up study. To further elucidate its potential as a biomarker, we investigated whether GFV‐C is able to detect a motor phenotype in preHD and is correlated to the genotype assessed by a disease‐burden‐score. The ability of preHD (n = 15) and symptomatic HD subjects (n = 20) to maintain stable grip forces, while holding an object (250 g and 500 g), was measured and compared with the controls (n = 19). GFV‐C was increased in preHD at 500 g, in symptomatic subjects at both weights and was correlated to the disease‐burden‐score and UHDRS‐TMS. GFV‐C may be a useful objective and quantitative marker of motor dysfunction across genetically diagnosed premanifest and symptomatic HD subjects. © 2010 Movement Disorder Society     

A pilot study using nabilone for symptomatic treatment in Huntington's disease

Pilot study of nabilone in Huntington's disease (HD). Double‐blind, placebo‐controlled, cross‐over study of nabilone versus placebo. Primary outcome, Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Secondary measures: UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI). 44 randomized patients received either nabilone (1 or 2 mg) followed by placebo (n = 22), or placebo followed by nabilone (n = 22). Recruiting was straightforward. Nabilone safe and well tolerated, no psychotic episodes. Assessment of either dose of nabilone versus placebo showed a treatment difference of 0.86 (95% CI: ?1.8 to 3.52) for total motor score; 1.68 (95% CI: 0.44 to 2.92) for chorea; 3.57 (95% CI: ?3.41 to 10.55) for UHDRS cognition; 4.01 (95% CI: ?0.11 to 8.13) for UHDRS behavior, and 6.43 (95% CI: 0.2 to 12.66) for the NPI. Larger longer RCT of nabilone in HD is feasible and warranted. © 2009 Movement Disorder Society     

Open-label pilot study of levetiracetam (Keppra) for the treatment of chorea in Huntington's disease.

The objective of this study is to evaluate the tolerability and preliminary efficacy of levetiracetam (LEV) in reducing chorea in Huntington's disease (HD) patients in a prospective open-label pilot study. Nine HD patients with chorea were treated with LEV in doses up to 3,000 mg/day for up to 48 days. The primary endpoint measure was the Unified Huntington's Disease Rating Scale (UHDRS) chorea subscore. The mean dose (+/-SD) of LEV at endpoint was 2,583.3 +/- 1,020.6 mg/day. Mean UHDRS chorea score decreased from 12.6 +/- 3.0 at baseline to 6.7 +/- 4.3 at endpoint (P = 0.01). There was no significant change in UHDRS total motor scores (38.8 +/- 11.4 at baseline and 33.6 +/- 26.7 at endpoint; P = 0.24). Somnolence contributed to a 33% drop-out rate, and 3 patients developed Parkinsonism. Results of this open label study suggest that LEV may be efficacious in reducing chorea in HD patients.     

Clinical and genetic characteristics in patients with Huntington’s disease from China

Huntington’s disease (HD) is a neurodegenerative disease caused by the expansion of unstable CAG repeats in the HTT gene. There are scarce data about HD in China. Fifty-eight HD patients were consecutively recruited and assessed using the Unified HD Rating Scale (UHDRS) motor section and UHDRS behaviour assessment (UHDRS-b). Genetic analyses were also conducted. Thirty-three women and Twenty -five men were diagnosed with a mean age of 46.1 ± 11.2 years and a mean number of CAG triplet repeats 44.6 ± 4.4. CAG triplet repeat number was negatively correlated with age at onset, and positively correlated with UHDRS-b total score, and its subdomains including depressed mood, low self-esteem, anxiety and irritability. On the other hand, negative correlations were identified between age at onset and UHDRS-b total score, and its subdomains include low self-esteem, anxiety, suicidal thought, irritability and apathy. Disease durations were correlated with UHDRS motor scores and anxiety domain of UHDRS-b. This is the largest series of Chinese HD patients with demographic, clinical and genetic data confirms the demographic features of Chinese HD patients are comparable to those in other ethnic backgrounds. CAG triplet repeat number may also predict the severity of behaviour problems in HD patients besides its predication for age of onset.     

Challenges assessing clinical endpoints in early Huntington disease

The basic aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest‐studied HD participants likely to be recruited into clinical trials. As the advent of genetic testing for HD, it is possible to identify gene carriers before the diagnosis of disease, which opens up the possibility of clinical trials of disease‐modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multinational, 32‐site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene‐positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow‐up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real‐life function. © 2010 Movement Disorder Society     

Clinical predictors of driving status in Huntington's disease

The aim of this study was to identify the motor, cognitive, and behavioral determinants of driving status and risk factors for driving cessation in Huntington's disease (HD). Seventy-four patients with HD were evaluated for cognitive, motor, psychiatric, and functional status using a standardized battery (Unified Huntington's Disease Rating Scale [UHDRS] and supplemental neuropsychological testing) during a research clinic visit. Chart review was used to categorize patients into two driving status categories: (1) "currently driving" included those driving and driving but with clinician recommendation to restrict, and (2) "not driving" included those with clinician recommendation to cease driving and those not currently driving because of HD. Multi- and univariate logistic regression was used to identify significant clinical predictors of those driving versus not driving. Global cognitive performance and UHDRS Total Functional Capacity scores provided the best predictive model of driving cessation (Nagelkerke R(2) = 0.65; P < 0.0001). Measures of learning (P = 0.006) and psychomotor speed/attention (P = 0.003) accounted for the overall cognitive finding. In univariate analyses, numerous cognitive, motor, and daily functioning items were significantly associated with driving. Although driving status is associated with many aspects of the disease, results suggest that the strongest association is with cognitive performance. A detailed cognitive evaluation is an important component of multidisciplinary clinical assessment in patients with HD who are driving. ? 2012 Movement Disorder Society.