J.S. Paulsen

CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695

COHORT study oft the HSG. CAG repeat expansion in Huntington disease determines age at onset in al fully dominant fashion

Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695

The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

Age of onset for Huntingtons disease (HD) varies inversely with the length of the disease‐causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R‐squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two‐segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log‐transformed age of onset against CAG repeat length reveals this segmental relationship. This two‐segment exponential regression on age of onset data increases the adjusted R‐squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two‐segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P= 2 × 10−5] and in the HD MAPS cohort [F(2, 688) = 38.27, P= 2 × 10−16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult‐onset range of CAG repeats than in the juvenile‐onset range.

Interrater agreement in the assessment of motor manifestations of Huntington's disease

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntingtons disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy‐five clinicians experienced in the evaluation of patients with early HD and six non‐clinicians were shown a videotape compiled from the film archives of the United States–Venezuela Collaborative HD Research Project. Observers were asked to rate a 2–3‐minute segment of the motor examination for each of 17 at‐risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted κ statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted κ = 0.67; standard error (SE) = 0.09). Agreement among the non‐clinicians was only fair (weighted κ = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.

H03 Rate of progression is associated with age of disease onset for all HD

Background Understanding the rate of progression in HD is a key component for the design of clinical trials. Previous research has shown a significant positive relationship between the rate of disease progression and the length of the CAG repeat length and/or the age of disease onset. Much of this research has been criticised as driven by outliers and/or accounted for by the most extreme cases. For instance, CAG lengths greater than 60 often manifest as juvenile onset and demonstrate a more rapid decline. Aims A large collaborative dataset from the Huntington Study Group was analysed to examine whether the relationship between progression rate and onset age was consistent regardless of outliers. Methods 4607 participants were included in the analyses although complete data were available for 2960. Years of longitudinal study varied from 1 to 15 years. Age at onset ranged from 2 to 81 years old. Growth curve analysis using linear mixed effects regression were used to examine possible outcomes controlling for gender, age of onset and all interactions. Results Results show that total motor score, symbol digit, Stroop colour naming and general functioning have more rapid progression with earlier age of onset. Conclusion Comparison curves will be shown for various subgroups with onset ages of 18, 30, 45, 60 and 80 demonstrating varying rates of progression. Implications for clinical trial design will be addressed.

I01 Unawareness of motor phenoconversion in huntington disease

Background Unawareness of disease manifestations in neurodegenerative diseases has been defined by Flashman et al 2002 as “pathological unawareness of a neurological or functional deficit” and by Antoine et al 2004 as “the discrepancy between the patients self report and the report of a natural caregiver or the clinical rating of a health professional”. Affected patients may have no complaints (symptoms) in contrast with a carers or examiners observations. Unawareness of movements and impairments in cognitive, emotional and functional capacity are documented in diagnosed Huntington Disease (HD). The PREDICT-HD study of mutation carriers allows a study of unawareness in the HD prodrome to phenoconversion. Aims Determine if PREDICT-HD participants have motor complaints at the time motor phenoconversion and document differences between groups with and without awareness on cognitive, functional and behavioural measures. Methods The PREDICT-HD database cross sectional information recorded at the third annual study visit for participants was reviewed. Demographics, motor, functional, cognitive and behavioural scores were analysed. Unawareness was identified as lack of agreement between participant report of symptoms and the trained examiners rating of a diagnosis of unequivocal signs of HD. The groups with and without self-reported symptoms and an examiner rating of motor onset were compared on a range of cognitive, functional and behavioural measures, accounting for CAG repeat length and age. Results Of 550 participants at the third annual PREDICT—HD visit, motor phenoconversion was recorded in 38 (6.91%). Of those, 18 (47.36 %) reported that they had no motor symptoms but were given a similar motor rating to those who reported having symptoms. The groups with and without reported motor symptoms but with signs were similar on measures of executive dysfunction and motor score. Phenoconverters without symptoms reported less depression. Conclusions Poor awareness may occur in the prodromal stage and at phenoconversion to early HD or “HD onset”, as well as in later stages. Unawareness should be considered in assessment and provision of care.

K01 Behaviour assessments in children at risk for huntington's disease

Background Although the primary neuropathology of HD is that of neurodegeneration, mutant Huntingtin (mHTT), which is present throughout the life span, may also affect normal brain development. Therefore, subtle differences in behaviour, cognition, and motor skills may be present life-long (ie, functional “traits”) with significant worsening of these functions as disease onset approaches. The KidsHD program evaluates children (ages 6–18 years) who are at risk for HD (no children manifesting symptoms, no JHD included). For research purposes only, participants are genotyped and separated into gene-expanded (GE) and those that are non gene-expanded (GNE). A group of normal healthy control (HC) children are also assessed. Aims To evaluate effects of gene-expansion on quantitative measures of behaviour in GE, GNE, and HC children. Methods Parents completed ratings on two standardised questionnaires, Paediatric Behaviour Scale (PBS) and Behaviour Rating Inventory of Executive Function (BRIEF). GE children (n=29) and GNE children (n=30) were each matched by sex and age to three HC children. Multiple Analysis of Covariance (MANCOVA) was used to compare behaviour ratings across groups controlling for age sex and social class. The higher the scores, the more problematic the behaviour. Results GE children had significantly elevated scores compared to HC: opposition, explosiveness, impulsivity, hyperactivity, and inattention within PBS. Depression/anxiety scores were not elevated. Within the BRIEF, the GE group had elevations in shifting, initiation, working memory, planning/organizing and monitoring scores. GNE had no significant differences in scores compared to HC. Conclusions Subtle but significant differences in behaviour in children who are estimated to be decades ahead of HD diagnosis may reflect early influence of mHTT on normal neural developmental process, manifesting in specific patterns of behavioural traits.

F08 The functional rating taskforce for pre-huntington's disease: results so far

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

F09 Progression of motor symptoms prior to diagnosis in HD-gene carriers

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