Search

Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (ND), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the ND gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non- linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials. [ABSTRACT FROM AUTHOR]

Background/aims TRACK-HD is a multinational prospective, observational study of Huntington's disease (HD) that aims to examine longitudinal change in premanifest carriers of the mutant HTT gene and subjects with early stage disease (Tabrizi 2009). New data from the first follow-up assessment are reported here, and build on previous findings from baseline 3T MRI and novel clinical, cognitive, quantitative motor, oculomotor and neuropsychiatric assessments. Of 366 subjects enrolled at baseline, 345 (115 controls, 116 premanifest (preHD) and 114 early HD) completed 12 months of follow-up. Statistical analysis was performed to assess annualised change in all modalities. Methods/techniques Annualised rates of global and regional atrophy were higher in both the pre- and early HD groups than in controls (p≤0.007). Whole brain atrophy rates were 0.3%, 0.5% and 0.9%, and caudate atrophy rates 0.6%, 2.0% and 3.5%, in controls, pre and early HD, respectively, over 1 year. Whole brain image analysis techniques also revealed striking cortical and subcortical grey and white matter atrophy over just 1 year even in subjects furthest from predicted disease onset. Quantitative imaging showed significant associations with disease burden and total functional capacity, a widely used clinical measure of disease severity. Cognitive deterioration was detectable in both HD groups. However, rates of decline in cognitive, quantitative motor and oculomotor tasks were greater after onset of motor signs. Results/outcome HD is characterised by a long premanifest state, slow progression and a disease course of around 20 years. After 1 year, we have identified robust change in a range of measures across modalities in both premanifest and early stage HD. Quantitative imaging showed the greatest differentiation across the spectrum of the disease and a number of functional measures of decline were sensitive in early HD with cognitive impairment also detectable in the pre-HD group. Conclusions TRACK-HD is the first multi-site study to report whole brain, regional and subcortical atrophy in premanifest subjects many years from predicted disease onset using 3T MR imaging; and demonstrates the feasibility of obtaining quantifiable endpoints which show robust change over just 1 year thus showing potential as endpoints for future therapeutic trials. [ABSTRACT FROM PUBLISHER]

Background Huntington's disease (HD) is a progressive, inherited neurodegenerative condition, with onset usually in mid-life, affecting motor, cognitive and neuropsychiatric functions. Not surprisingly, studies have suggested that HD has a detrimental effect on the quality of life (QoL) of individuals with the HD gene expansion and also by association their families. The present literature exploring the impact for spouses predominantly investigates the later stages of HD. This study, however, uses clearly defined groups of both premanifest and early-stage symptomatic gene-carriers and their spouse/partners. Methods/techniques Self-report measures of quality of life and neuropsychiatric domains (SF-36; Quality of Life Index; Frontal Systems Behaviour Inventory (FrSBe)), clinical rating of motor function (UHDRS motor), Cognitive measures (Emotion Recognition, Trails-B) and the Short version of Problem Behaviours Assessment for HD (PBA-s) were completed by 86 participants from the TRACK-HD study. This included 23 pre-manifest gene carriers, 20 early, clinical stage 1 and 2, HD patients and 43 gene-negative spouse controls. Between-group differences and relationships between neuropsychiatric and cognitive data from the premanifest and symptomatic participants and QoL for their spouses were examined. Results/outcomes Largest between-group differences were evident between spouses and their partners with early stage disease; and different QoL domains were impacted in the different participant groups. The data presented shows the QoL domains affected in each group; and the impact of specific neuropsychiatric, cognitive and motor symptoms on spouse partners. Identification of the specific domains impacted in spouse/partners at an early stage of disease is crucial for establishing appropriate and long-term support. [ABSTRACT FROM PUBLISHER]

Background TRACK-HD is a multi-centre, longitudinal study investigating a range of motor, cognitive, neuropsychiatric and imaging measures as potential biomarkers for clinical trials in Huntington's disease (HD). The neuropsychiatric battery includes the Frontal Systems Behaviour Scale (FrSBe), a 46-item scale measuring behaviours associated with damage to the frontal lobes of the brain. In addition to subjects rating their own behaviour on the FrSBe, companions also rated subjects' behaviour. This provided an opportunity to investigate HD patients' insight into their behaviour by studying discrepancies between subject and companion ratings. Method 225 TRACK-HD subjects (62 premanifest gene carriers far from onset, 52 near to onset, 70 stage 1 HD and 41 stage 2 HD) completed the FrSBe. In addition, 164 companions (77 of premanifest subjects and 87 of early HD subjects) rated subjects' behaviour with the FrSBe. Results Companion ratings indicate a worsening of FrSBe scores with disease progression, especially in subjects with manifest HD. In contrast, subjects' self ratings did not show the same deterioration in FrSBe scores across the pre-HD and stage 1 subgroups, with the biggest discrepancy between subject and companion ratings at stage 1 HD. Surprisingly, self-ratings of stage 2 subjects were markedly worse than those at stage 1, almost eliminating this discrepancy between companion and self-ratings. Companion FrSBe ratings correlated more strongly with objective measures of cognitive and behavioural function than did subjects own ratings. Conclusion The existence of a discrepancy between companion and subjects' own ratings using the FrSBe in stage 1 HD but not in those with more advanced disease suggests that denial (as a psychological defence mechanism) is a more likely explanation than a loss of insight secondary to cognitive impairment. [ABSTRACT FROM PUBLISHER]

Background Speeded (ST) and metronome (MT) tapping have been shown to be sensitive in distinguishing premanifest (preHD) and manifest (HD) stages of Huntington's disease (HD) in the cross-sectional analysis of the TRACK-HD study, and to detect an early motor phenotype even more than 14 years before predicted disease manifestation. Aims To investigate whether ST and MT are able to track disease progression within a 12 month follow-up period. Methods Participants from the four TRACK-HD sites (ST/MT: controls: 120/122, preHD: 117/118, HD: 117/121) were instructed to perform two tapping tasks with their non-dominant index finger. In ST, they had to tap at maximal speed for 10s; in MT, they were instructed to continue a given tapping rate of 1.8 Hz for 10s. After one year, the assessments were repeated. The annual change in performance of gene-carriers was compared to controls and to each other. The variability of tapping intervals expressed as logarithmic standard deviations was calculated for the primary outcome measures (ie, inter-onset interval (IOI) & tap duration (TD) in ST, inter-onset intervals (ΔIOI) & mid-tap interval (ΔMTI) in MT). Results The annual change in IOI and TD for ST showed significant results for HD versus controls and HD versus preHD. ΔIOI and ΔMTI, both MT variables, failed to make this distinction. Conclusions ST is able to detect changes in manifest HD within only one year of follow-up and may thus be applicable as an outcome measure for disease modifying clinical trials in early manifest HD. Possible changes in preHD may require longer follow-up periods or larger cohorts. The hypothesis that force-transducer-based MT and ST tasks may track the progression of a premanifest motor phenotype will be tested in the TRACK-HD study. [ABSTRACT FROM PUBLISHER]