Reliability and Validity of the HD-PRO-TriadTM, a Health-Related Quality of Life Measure Designed to Assess the Symptom Triad of Huntington\u27s Disease.

BACKGROUND: Huntington\u27s disease (HD), is a neurodegenerative disorder that is associated with cognitive, behavioral, and motor impairments that diminish health related quality of life (HRQOL). The HD-PRO-TRIADTM is a quality of life measure that assesses health concerns specific to individuals with HD. Preliminary psychometric characterization was limited to a convenience sample of HD participants who completed measures at home so clinician-ratings were unavailable. OBJECTIVES: The current study evaluates the reliability and validity of the HD-PRO-TRIADTM in a well-characterized sample of individuals with HD. METHODS: Four-hundred and eighty-two individuals with HD (n = 192 prodromal, n = 193 early, and n = 97 late) completed the HD-PRO-TRIADTM questionnaire. Clinician-rated assessments from the Unified Huntington Disease Rating Scales, the short Problem Behaviors Assessment, and three generic measures of HRQOL (WHODAS 2.0, RAND-12, and EQ-5D) were also examined. RESULTS: Internal reliability for all domains and the total HD-PRO-TRIADTM was excellent (all Cronbach\u27s α \u3e0.93). Convergent and discriminant validity were supported by significant associations between the HD-PRO-TRIADTM domains, and other patient reported outcome measures as well as clinician-rated measures. Known groups validity was supported as the HD-PRO-TRIADTM differentiated between stages of the disease. Floor and ceiling effects were generally within acceptable limits. There were small effect sizes for 12-month change over time and moderate effect sizes for 24-month change over time. CONCLUSIONS: Findings support excellent internal reliability, convergent and discriminant validity, known groups validity, and responsiveness to change over time. The current study supports the clinical efficacy of the HD-PRO-TRIADTM. Future research is needed to assess the test-retest reliability of this measure

Relationships Among Apathy, Health-Related Quality of Life, and Function in Huntington\u27s Disease.

Up to 90% of individuals with Huntington\u27s disease (HD)-a progressive, inherited neurodegenerative disorder-experience apathy. Apathy is particularly debilitating because it is marked by a reduction in goal-directed behaviors, including self-care, social interactions, and mobility. The objective of this study was to examine relationships between variables of apathy, functional status, physical function, cognitive function, behavioral status/emotional function, and health-related quality of life. Clinician-rated measures of physical, cognitive, and behavioral function, including one clinician-rated item on apathy, and self-reported measures of physical function, health-related quality of life, and emotional, cognitive, and social function were collected in a single session from 487 persons with the HD mutation (prodromal, N=193; early-stage manifest, N=186; late-stage manifest, N=108). Multiple linear regression models were used to examine which outcomes best predicted clinician-rated apathy after controlling for disease stage. Greater apathy related to less independence, increased motor impairment, and more clinician-rated behavioral problems (i.e., anger, irritability, depression). Similarly, poorer self-reported health-related quality of life; greater chorea; greater upper- and lower-extremity dysfunction; greater speech and swallowing dysfunction; worse anxiety, depression, and behavioral dyscontrol; worse cognitive function; and less satisfaction with social roles related to greater apathy. In conclusion, apathy related to physical, cognitive, and behavioral dysfunction across disease stages. Future work should explore whether clinical interventions targeting different functional domains may have the potential to reduce apathy in this patient population

Agreement Between Clinician-Rated Versus Patient-Reported Outcomes in Huntington Disease

BACKGROUND: Clinician-rated measures of functioning are often used as primary endpoints in clinical trials and other behavioral research in Huntington disease. As study costs for clinician-rated assessments are not always feasible, there is a question of whether patient self-report of commonly used clinician-rated measures may serve as acceptable alternatives in low risk behavioral trials. AIM: The purpose of this paper was to determine the level of agreement between self-report and clinician-ratings of commonly used functional assessment measures in Huntington disease. DESIGN: 486 participants with premanifest or manifest Huntington disease were examined. Total Functional Capacity, Functional Assessment, and Independence Scale assessments from the Unified Huntington Disease Rating scale were completed by clinicians; a self-report version was also completed by individuals with Huntington disease. Cronbach\u27s α was used to examine internal consistency, one-way analysis of variance was used to examine group differences, and paired t tests, kappa agreement coefficients, and intra-class correlations were calculated to determine agreement between raters. RESULTS: Internal consistency for self-reported ratings of functional capacity and ability were good. There were significant differences between those with premanifest, early-, and late-stage disease; those with later-stage disease reported less ability and independence than the other clinical groups. Although self-report ratings were not a perfect match with associated clinician-rated measures, differences were small. Cutoffs for achieving specified levels of agreement are provided. CONCLUSIONS: Depending on the acceptable margin of error in a study, self-reported administration of these functional assessments may be appropriate when clinician-related assessments are not feasible

Evaluating Cognition in Individuals with Huntington Disease: NeuroQoL Cognitive Functioning Measures

PURPOSE: 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. METHODS: 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. RESULTS: Excellent reliabilities (Cronbach\u27s 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. CONCLUSIONS: 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

Transplant Acceptance Following Anti-CD4 Versus Anti-CD40L Therapy: Evidence for Differential Maintenance of Graft-Reactive T Cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73145/1/j.1600-6143.2008.02372.x.pd

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure

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

Background 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. Methods 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. Findings 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 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 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. Interpretation 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