Late-stage Huntington's Disease Research Articles

Locomotor Behavior and Memory Dysfunction Induced by 3-Nitropropionic Acid in Adult Zebrafish: Modulation of Dopaminergic Signaling.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D2 receptors (D2R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D2R and dopamine D1 receptors (D1R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D2R agonist) and eticlopride (D2R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD.

Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease.

In Huntington's disease (HD), a CAG repeat expansion mutation in the Huntingtin (HTT) gene drives a gain-of-function toxicity that disrupts mRNA processing. Although dysregulation of gene splicing has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes in late-stage HD, limiting the ability to identify dysregulation related to early pathogenesis. To investigate gene splicing changes in early HD, we performed alternative splicing analyses coupled with a proteogenomics approach to identify early CAG length-associated splicing changes in an established isogenic HD cell model. We report widespread neuronal differentiation stage- and CAG length-dependent splicing changes, and find an enrichment of RNA processing, neuronal function, and epigenetic modification-related genes with mutant HTT-associated splicing. When integrated with a proteomics dataset, we identified several of these differential splicing events at the protein level. By comparing with human post-mortem and mouse model data, we identified common patterns of altered splicing from embryonic stem cells through to post-mortem striatal tissue. We show that widespread splicing dysregulation in HD occurs in an early cell model of neuronal development. Importantly, we observe HD-associated splicing changes in our HD cell model that were also identified in human HD striatum and mouse model HD striatum, suggesting that splicing-associated pathogenesis possibly occurs early in neuronal development and persists to later stages of disease. Together, our results highlight splicing dysregulation in HD which may lead to disrupted neuronal function and neuropathology. This research is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Nanyang Assistant Professorship Start-Up Grant, the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (RG23/22), the BC Children's Hospital Research Institute Investigator Grant Award (IGAP), and a Scholar Award from the Michael Smith Health Research BC.

Chorea Severity Change Over Time in Huntington Disease and by Huntington Disease Stage (P1-11.010)

<h3>Objective:</h3> To describe chorea severity over time in individuals with Huntington disease (HD) stratified by Total Functional Capacity (TFC). <h3>Background:</h3> Chorea, the most common motor symptom in HD, negatively affects quality of life and TFC. Addressing chorea is crucial to reduce the burden of motor symptomatology in HD. Chorea has been reported to increase initially, plateau, and potentially decrease over time; however, longitudinal data assessing chorea severity by disease stage are limited. <h3>Design/Methods:</h3> Participants were adults from Enroll-HD, a global, longitudinal, observational registry for individuals with or at risk for HD (data cut 2013–31 October 2020). The manifest population was stratified by baseline TFC score as a proxy for HD stage (TFC 7–13/stage 1–2 [early], 3–6/stage 3 [middle], 0–2/stage 4–5 [late]). Chorea severity was assessed by Total Maximal Chorea (TMC) score at baseline and at annual visits. Patients with ≥4 years of follow-up were selected for estimating chorea progression over time. <h3>Results:</h3> The manifest population was grouped by HD stage: early, n=7441; middle, n=2330; late, n=1120. Baseline TMC scores (mean [SD]) increased as HD stage progressed (early, 8.0 [4.7]; middle, 10.4 [5.8]; late, 10.6 [6.9]). For participants with ≥4 years of follow-up (n=1271), TMC scores increased over time in early-stage HD (n=963; years 1–2, 8.5 [5.0]; years 2–3, 9.1 [5.3]; years 3–4, 9.5 [5.6]), but plateaued at high levels in middle- (n=222; 10.6 [5.3]; 10.6 [6.0]; 10.1 [5.7], respectively) and late-stage HD (n=86; 10.4 [6.6]; 9.8 [6.9]; 9.7 [6.2]). <h3>Conclusions:</h3> Chorea severity increased in early-stage HD, and plateaued in middle- and late-stage HD. Chorea severity did not decrease longitudinally in any stage; however, the limited sample size for the follow-up period should be considered. These results support the need for increased awareness about the potential for persistent chorea in late-stage HD. <b>Disclosure:</b> Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Michael J. Fox Foundation. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. The institution of Dr. Furr-Stimming has received research support from Cures within Reach. The institution of Dr. Furr-Stimming has received research support from Huntington’s Disease Society of America. The institution of Dr. Furr-Stimming has received research support from Roche/Genetech. The institution of Dr. Furr-Stimming has received research support from Uniqure. The institution of Dr. Furr-Stimming has received research support from CHDI. The institution of Dr. Furr-Stimming has received research support from Huntington Study Group/Neurocrine. The institution of Dr. Furr-Stimming has received research support from NIH/University of Iowa. The institution of Dr. Furr-Stimming has received research support from Sage Therapeutics. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Reshef has received personal compensation for serving as an employee of Teva. Ms. Willock has received personal compensation for serving as an employee of HCD Economics. Rinat Ribalov has received personal compensation for serving as an employee of TEVA. Miss Brighton has nothing to disclose. Dr. Leo has received personal compensation for serving as an employee of Teva Pharmaceutical Industries.

Modulation of adenosine signaling reverses 3-nitropropionic acid-induced bradykinesia and memory impairment in adult zebrafish

Huntington's disease (HD) is a neurodegenerative disorder, characterized by motor dysfunction, psychiatric disturbance, and cognitive decline. In the early stage of HD, occurs a decrease in dopamine D2 receptors and adenosine A2A receptors (A2AR), while in the late stage also occurs a decrease in dopamine D1 receptors and adenosine A1 receptors (A1R). Adenosine exhibits neuromodulatory and neuroprotective effects in the brain and is involved in motor control and memory function. 3-Nitropropionic acid (3-NPA), a toxin derived from plants and fungi, may reproduce HD behavioral phenotypes and biochemical characteristics. This study investigated the effects of acute exposure to CPA (A1R agonist), CGS 21680 (A2AR agonist), caffeine (non-selective of A1R and A2AR antagonist), ZM 241385 (A2AR antagonist), DPCPX (A1R antagonist), dipyridamole (inhibitor of nucleoside transporters) and EHNA (inhibitor of adenosine deaminase) in an HD pharmacological model induced by 3-NPA in adult zebrafish. CPA, CGS 21680, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA were acutely administered via i.p. in zebrafish after 3-NPA (at dose 60 mg/kg) chronic treatment. Caffeine and ZM 241385 reversed the bradykinesia induced by 3-NPA, while CGS 21680 potentiated the bradykinesia caused by 3-NPA. Moreover, CPA, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA reversed the 3-NPA-induced memory impairment. Together, these data support the hypothesis that A2AR antagonists have an essential role in modulating locomotor function, whereas the activation of A1R and blockade of A2AR and A1R and modulation of adenosine levels may reduce the memory impairment, which could be a potential pharmacological strategy against late-stage symptoms HD.

Responsiveness to Change Over Time: An Examination of the Neuro-QoL Social Function Measures in Persons with Huntington's Disease.

Social health is an important concern in persons with Huntington's disease (HD); however, there is little literature examining this construct in this population. While cross-sectional data supports the clinical utility of two Neuro-QoL social health measures in persons with HD, data is still needed to establish their longitudinal validity. Participants (N = 358) completed baseline and at least one follow-up (12- and 24-month) assessment that included the completion of Neuro-QoL Social Health computer adaptive tests (CATs) and short forms (for Ability to Participate in Social Roles and Activities [SRA] and Satisfaction with SRA). Test-retest reliability was examined using intra class correlations, and one-way ANOVAs with Bonferroni post-hoc contrasts were used to determine whether there were group differences among premanifest, early- and late-stage HD participants on the Social health measures. In addition, standardized response means were used to examine longitudinal responsiveness, and mixed or general linear models were used to examine change over time (relative to self-reported change on an associated anchor item about social health and clinician-rated change based on Total Functional Capacity scores from the UHDRS). Test-retest reliability of the measures was excellent (ICCs ranged from 0.82 to 0.87 across the different measures) and persons with greater disease burden reported more problems with social health than those at earlier stages in the disease process (all p < 0.0001). Responsiveness was supported for all measures except the Ability to Participate in SRA CAT; participants who had self-reported or clinician-rated declines in health generally had 12- and 24-month declines on the Neuro-QoL measures. Findings indicate that these measures may be useful for studies attempting to assess change in social health over time.

Extending the Phenotypic Spectrum of Huntington Disease: Hypothermia

Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder associated with expanded CAG repeat size in the huntingtin gene and usually presenting with movement disorder, psychiatric symptoms, and cognitive decline. Sleep problems, weight loss, and cachexia are also common. Here, we report a patient presenting with hypothermia in late-stage HD. Although thermoregulatory defects were documented in animal models, this is the first report describing HD with hypothermia in humans.

Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease

Disturbances in motor movement can have similar clinical presentations, albeit having different pathways and temporal onset. Hypokinetic movements present with rigidity, resting tremors, postural instability and bradykinesia, as seen in parkinsonism, while hyperkinetic movements typically present with chorea, ballismus, tic, athetosis and dystonia. Nonetheless, movement disorders are thought to be a continuum. Long-term therapy of parkinsonism with L-DOPA or dopamine (DA) agonists leads to late-onset dyskinesia – a hyperkinetic movement disorder, while patients with late-stage Huntington disease (HD) often develop non-DOPA responsive parkinsonism. In this paper, it is proposed that late-onset parkinsonism is driven by the overactivity of the nigrostriatal dopaminergic pathway. The excessive synthesis, storage, release, reuptake and degradation of dopamine in the presynaptic terminal and synaptic clefts lead to cellular stress and damage, resulting to progressive neuroapoptosis aggravated by pro-parkinsonism drugs used to treat hyperkinesia. Glutamate excitotoxicity may provide initial stress to neurons during early HD – but as the disease advances, lower glutamate levels are observed, making it less likely to cause the hypokinetic shift on its own. Over time, dopaminergic neurons are depleted and cholinergic influence to striatal GABA release is unopposed, leading to late-onset parkinsonism that is unresponsive to DOPA challenge, due to drastic DA neuron loss previously masked by the dominating choreic presentation. This paper thus provides a mechanism of action to a common clinical sequela and complication of long-term choreic diseases, whose pathophysiologic mechanism is presently lacking.

Perceptions of the impact of chorea on health-related quality of life in Huntington disease (HD): A qualitative analysis of individuals across the HD spectrum, family members, and clinicians

ABSTRACTChorea, a hallmark symptom of Huntington’s disease (HD), is characterized by jerky involuntary movements affecting the whole body that can interfere with daily functioning and impact health-related quality of life (HRQOL). To characterize chorea’s impact on everyday functioning and HRQOL and identify patterns of perception and experiences of chorea among patients, caregivers, and providers. Data from focus groups of individuals with manifest HD (n = 8 early-stage HD; n = 16 late-stage HD), individuals at-risk or prodromal HD (n = 16), family HD caregivers (n = 17), and HD clinicians (n = 25). Focus group recordings were transcribed verbatim and analysed via constant comparison to identify meaningful and salient themes of living with chorea. Global themes of chorea’s impact identified included: watching for chorea, experiences of stigma, and constraints on independence and relationships. Themes distinct to specific respondent groups included: Vigilance (at risk, prodromal); adaptation to chorea (early-stage); loss of autonomy and social life (late-stage); monitoring engagement (family caregivers) and safety (clinical providers). Living with chorea significantly constrains daily functioning, interactions, and HRQOL across the HD disease spectrum. Addressing these impacts via appropriate management of chorea can potentially enhance functioning, HRQOL, and overall satisfaction for persons with HD and their families.

Longitudinal assessment of the Unified Huntington's Disease Rating Scale (UHDRS) and UHDRS-For Advanced Patients (UHDRS-FAP) in patients with late stage Huntington's disease.

Symptoms and signs in patients with Huntington's disease are usually assessed with the Unified Huntington's Disease Rating Scale (UHDRS). Ceiling and floor effects hamper the measurement of disease progression in patients with late stage Huntington's disease and therefore the UHDRS-For Advanced Patients (UHDRS-FAP) has been developed. The aim of this longitudinal study was to examine if the UHDRS-FAP and UHDRS are sensitive enough to detect change over time in late stage Huntington's disease. Forty nursing home residents and patients receiving day-care were assessed with the UHDRS, UHDRS-FAP and Care Dependency Scale (CDS). After 6months, the assessment scales were completed again in 29 patients. Changes between baseline and follow-up were calculated using paired t tests. Wilcoxon signed-rank tests were used to calculate longitudinal changes for middle and late stage patients separately. The motor and cognitive score of the UHDRS-FAP deteriorated during 6months' follow-up, whilst the motor and cognitive score of the UHDRS did not show change. Two functional domains of the UHDRS and the CDS also declined. The behavioral score significantly improved with both rating scales in late stage patients. Our results suggest that the UHDRS-FAP motor and cognitive score, the functional domains of the UHDRS, and the CDS can detect disease progression in late stage Huntington's disease. Therefore, the use of these scores in nursing homes is recommended to optimize care by monitoring disease progression and by evaluating the effect of interventions in clinical care. Psychiatric symptoms seem to fade away as the disease progresses.

Assessment Scales for Patients with Advanced Huntington's Disease: Comparison of the UHDRS and UHDRS-FAP.

The standard clinical assessment tool in Huntington's disease is the Unified Huntington's Disease Rating Scale (UHDRS). In patients with advanced Huntington's disease ceiling and floor effects of the UHDRS hamper the detection of changes. Therefore, the UHDRS-For Advanced Patients (UHDRS-FAP) has been designed for patients with late-stage Huntington's disease. This cross-sectional study aims to examine if the UHDRS-FAP can differentiate better between patients with advanced Huntington's disease than the UHDRS. Forty patients, who were institutionalized or received day-care, were assessed with the UHDRS, UHDRS-FAP, and Care Dependency Scale (CDS). The severity of Huntington's disease was defined by the Total Functional Capacity (TFC). Comparisons between consecutive TFC stages were performed for all domains of the UHDRS, UHDRS-FAP, and CDS using Mann-Whitney U tests. The motor scores of the UHDRS-FAP and UHDRS were the only subscales with significantly worse scores in TFC stage 5 compared to stage 4. In TFC stages 4-5, the range of the UHDRS-FAP motor score was broader, the standard error of measurement was lower, and the effect size r was higher than for the UHDRS motor score. The CDS declined significantly across all TFC stages. Our results suggest that the UHDRS-FAP motor score might differentiate better between patients with severe Huntington's disease than the UHDRS motor score. Therefore, the UHDRS-FAP motor score is potentially a better instrument than the UHDRS motor score to improve disease monitoring and, subsequently, care in patients with advanced Huntington's disease in long-term care facilities.

Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability?

Symptom progression in Huntington disease (HD) is associated with cognitive decline which may interfere with the self-report of symptoms. Unfortunately, data to support or refute the psychometric reliability of patient-reported outcomes (PROs) as HD progresses are limited. This is problematic given that PROs are increasingly recognized as important measures of efficacy for new treatments. We examined PRO data from the HDQLIFE Measurement System (Speech Difficulties; Swallowing Difficulties; Chorea) in 509 individuals with premanifest, early-stage, or late-stage HD. Clinician-administered assessments of motor functioning (items from the UHDRS) and standardized objective assessments of cognition (Stroop, Symbol Digit Modalities) were also collected. We examined item bias using differential item functioning (DIF) across HD stage (premanifest, early-, late-) and relative to cognitive performance. We also examined the correlations between self-report and clinician ratings. Regression models that considered total cognitive ability were utilized to determine psychometric reliability of the PROs. Most PRO items were free from DIF for both staging and cognition. There were modest correlations between PROs and clinician report (ranged from - 0.40 to - 0.60). Modeling analyses indicated that psychometric reliability breaks down with poorer cognition and more progressed disease stage; split-half reliability was compromised (i.e., split-half reliability < 0.80) when scores were < 136 for Chorea, < 109 for Speech Difficulties, and < 179 for Swallowing Difficulties. Results indicate that the psychometric reliability of PROs can be compromised as HD symptoms progress and cognition declines. Clinicians should consider PROs in conjunction with other types of assessments when total cognition scores exceed critical thresholds.

Evaluating cognition in individuals with Huntington disease: Neuro-QoL cognitive functioning measures.

Cognitive functioning impacts health-related quality of life (HRQOL) for individuals with Huntington disease (HD). The Neuro-QoL includes two patient-reported outcome (PRO) measures of cognition-Executive Function (EF) and General Concerns (GC). These measures have not previously been validated for use in HD. The purpose of this analysis is to evaluate the reliability and validity of the Neuro-QoL Cognitive Function measures for use in HD. Five hundred ten individuals with prodromal or manifest HD completed the Neuro-QoL Cognition measures, two other PRO measures of HRQOL (WHODAS 2.0 and EQ5D), and a depression measure (PROMIS Depression). Measures of functioning The Total Functional Capacity and behavior (Problem Behaviors Assessment) were completed by clinician interview. Objective measures of cognition were obtained using clinician-administered Symbol Digit Modalities Test and the Stroop Test (Word, Color, and Interference). Self-rated, clinician-rated, and objective composite scores were developed. We examined the Neuro-QoL measures for reliability, convergent validity, discriminant validity, and known-groups validity. Excellent reliabilities (Cronbach's alphas ≥ 0.94) were found. Convergent validity was supported, with strong relationships between self-reported measures of cognition. Discriminant validity was supported by less robust correlations between self-reported cognition and other constructs. Prodromal participants reported fewer cognitive problems than manifest groups, and early-stage HD participants reported fewer problems than late-stage HD participants. The Neuro-QoL Cognition measures provide reliable and valid assessments of self-reported cognitive functioning for individuals with HD. Findings support the utility of these measures for assessing self-reported cognition.

Cognitive decline in Huntington's disease expansion gene carriers

BackgroundIn Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown. ObjectiveThe aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline. MethodsIn the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage. ResultsThere was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset.The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time. ConclusionCognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline.

Varenicline improves motor and cognitive deficits and decreases depressive-like behaviour in late-stage YAC128 mice

ObjectiveStudies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease. MethodThe performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively. ResultsChronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype-independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival. InterpretationOur findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease.

Problem solving, impulse control and planning in patients with early- and late-stage Huntington's disease.

Sub-domains of executive functions, including problems with planning, accuracy, impulsivity, and inhibition, are core features of Huntington’s disease. It is known that the decline of cognitive function in Huntington’s disease is related to the anatomical progression of pathology in the basal ganglia. However, it remains to be determined whether the severity of executive dysfunction depends on the stage of the disease. To examine the severity of sub-domains of executive dysfunction in early- and late-stage Huntington’s disease, we studied performance in the Tower of London task of two groups of Huntington’s disease patients (Group 1: early, n = 23, and Group 2: late stage, n = 29), as well as a third group of age, education, and IQ matched healthy controls (n = 34). During the task, we measured the total number of problems solved, total planning time, and total number of breaks taken. One aspect of executive function indexed by the number of solved problems seems to progress in the course of the disease. Late-stage Huntington’s disease patients scored significantly worse than early-stage patients and controls, and early-stage patients scored significantly worse than controls on this measure of accuracy. In contrast, late- and early-stage HD patients did not differ in terms of planning time and number of breaks. Early- and late-stage HD pathology has a different impact on executive sub-domains. While accuracy differs between early- and late-stage HD patients, other domains like planning time and number of breaks do not. Striatal degeneration, which is a characteristic feature of the disease, might not affect all aspects of executive function in HD.

Fat-free mass and its predictors in Huntington's disease.

The causes of weight loss in Huntington's disease (HD) are not entirely clear. The aim was to identify risk factors that are associated with a loss of metabolically active tissues, i.e. fat-free mass. A consecutive cohort of non-diabetic HD participants (manifest HD, n = 43; CAG: mean 43.6.0 ± 3.6; preHD, n = 10; CAG: mean 41.4 ± 1.4) and 36 healthy controls was recruited. Twenty-five HD participants were early-stage HD (UHDRS Total Functional Capacity [TFC] stages I and II), 12 mid-stage HD (TFC stage III), and 6 participants were in late-stage HD (TFC stages IV and V). Food intake, basic metabolic rate and glucose homeostasis were assessed. In addition, fat-free mass was determined using bioelectric impedance analysis, and leptin, insulin and ghrelin as key metabolic regulators. Sex ratio and age were similar in HD participants (71 % women; age 50.6 ± 10.9) and controls (66 % women; age 46.4 ± 14.5). Body mass index (BMI) was lower in HD participants than controls (median 24.1 vs. 25.9, p = 0.04). However, fat-free mass and basic metabolic rate were not statistically different between groups and showed no association with disease burden. In controls and HD participants, leptin was the most important predictor of fat-free mass. While BMI was lower in HD participants, fat-free mass was similar to controls with leptin as its most important predictor. Leptin levels and fat-free mass measurements using bioelectric impedance analysis may be good screening tools to identify HD patients at risk for weight loss.

Validity of the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) in individuals with Huntington disease (HD).

The reliability and construct validity of the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) were examined in individuals with Huntington disease (HD). We examined factor structure (confirmatory factor analysis), internal consistency reliability (Cronbach's alpha), floor and ceiling effects, convergent validity (Pearson correlations), and known-groups validity (multivariate analysis). Results of a confirmatory factor analysis replicated the six-factor latent model that reflects the six separate scales within the WHODAS 2.0 (understanding and communicating; getting around; self-care; getting along with others; life activities; participation). Cronbach's alpha for the scale was 0.94, suggesting good internal consistency reliability. The WHODAS demonstrated a ceiling effect for 19.5% of participants; there were no floor effects. There was evidence for convergent validity; the WHODAS demonstrated moderate significant correlations with other general measures of health-related quality of life (HRQOL; i.e., RAND-12, EQ5D). Multivariate analyses indicated that late-stage HD participants indicated poorer HRQOL than both early-stage HD and prodromal HD participants for all HRQOL measures. Findings provide support for both the reliability and validity of the WHODAS 2.0 in individuals with HD.

Novel BAC Mouse Model of Huntington's Disease with 225 CAG Repeats Exhibits an Early Widespread and Stable Degenerative Phenotype

Unusually large CAG repeat expansions (>60) in exon one of Huntingtin (HTT) are invariably associated with a juvenile-onset form of Huntington's disease (HD), characterized by a more extensive and rapidly progressing neuropathology than the more prevalent adult-onset form. However, existing mouse models of HD that express the full-length Htt gene with CAG repeat lengths associated with juvenile HD (ranging between ~75 to ~150 repeats in published models) exhibit selective neurodegenerative phenotypes more consistent with adult-onset HD. Objective: To determine if a very large CAG repeat (>200) in full-length Htt elicits neurodegenerative phenotypes consistent with juvenile HD. Using a …bacterial artificial chromosome (BAC) system, we generated mice expressing full-length mouse Htt with ~225 CAG repeats under control of the mouse Htt promoter. Mice were characterized using behavioral, neuropathological, biochemical and brain imaging methods. BAC-225Q mice exhibit phenotypes consistent with a subset of features seen in juvenile-onset HD: very early motor behavior abnormalities, reduced body weight, widespread and progressive increase in Htt aggregates, gliosis, and neurodegeneration. Early striatal pathology was observed, including reactive gliosis and loss of dopamine receptors, prior to detectable volume loss. HD-related blood markers of impaired energy metabolism and systemic inflammation were also increased. Aside from an age-dependent progression of diffuse nuclear aggregates at 6 months of age to abundant neuropil aggregates at 12 months of age, other pathological and motor phenotypes showed little to no progression. The HD phenotypes present in animals 3 to 12 months of age make the BAC-225Q mice a unique and stable model of full-length mutant Htt associated phenotypes, including body weight loss, behavioral impairment and HD-like neurodegenerative phenotypes characteristic of juvenile-onset HD and/or late-stage adult-onset HD.

Feasibility and Safety of an Aquatherapy Program in Mid- to Late-Stage Huntington Disease

Background: The progressive motor dysfunction and cognitive impairment associated with mid- to late-stage Huntington Disease (HD) renders few exercise programs amenable for use in this population. Exercise may slow the symptomatic progression of HD, therefore appropriate programs should be available to those with advanced disease. The pool, with a low risk of falling, boasts an appropriate environment to support choreic limbs. The purpose of this qualitative questionnaire-based study was to assess the feasibility and safety of aquatherapy in mid- to late-stage HD, and program perception by participants/caregivers. Methods: Six participants with manifest HD completed a six-week aquatherapy program comprised of twiceweekly sessions. Participant-tailored aquatherapy sessions involved a warm-up, exercise-set, and a cool-down. Study notes regarding injury and compliance were recorded to track measures of safety and feasibility. Participants (and caregivers where available) gave an interview following the program. Conversations were audio recorded and fully transcribed. Interviews were analyzed to extract themes. Results: Generally, participants reported the aquatherapy to be enjoyable, feasible, and safe, as well described improved mood, sleep, and quality of life. Anecdotal evidence suggests that many participants experienced improved physical conditioning. Conclusions: Twice-weekly aquatherapy is feasible in mid- to late-stage HD, and was perceived to be safe and enjoyable.

A07 Critical consideration of the criteria for the motor diagnosis of huntington disease

Background Huntington disease (HD) is a fatal inherited disorder with typical onset in adulthood. In research studies of HD, it is necessary to characterise the progression of participants in order to validly interpret results. Aims A distinction is often made between gene-positive individuals who are displaying hallmark motor signs (manifest HD) and gene-positive individuals who are not (pre-manifest HD). The conventional threshold for this distinction is the highest rating on the Diagnostic Criterion Level (DCL) scale of the Unified Huntington Disease Rating Scale (UHDRS), which constitutes the motor examiner9s confidence level of ≥99% for an unequivocal movement disorder (DCL=4). Methods A study was undertaken to investigate the empirical support for the use of the DCL for manifest HD classification, and alternatives including cutoffs based on the Total Motor Score (TMS) of the UHDRS. Because a gold standard classification does not exist, extreme case/control differences and extreme of the control distribution were used as a guide to selecting cutoffs. Results The results show that the conventional DCL criteria is too stringent in the sense that (1) cutoffs based on the TMS and the lower DCL confidence level of 90%–99% (DCL=3) both provide a very strong distinction between cases and controls, and (2) the conventional criterion tends to be assigned well after the accelerated deterioration trajectory characteristic of late-stage HD has already commenced. Conclusion The results suggest that alternate criteria, especially the intersection of DCL ≥3 and TMS cutoffs, might be considered in HD research.