Journal article
Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data
Lancet neurology, Vol.12(7), pp.637-649
07/2013
DOI: 10.1016/S1474-4422(13)70088-7
PMID: 23664844
Abstract
TRACK-HD is a multinational prospective observational study of Huntington's disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression.
Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if ≥10·8 years and preHD-B if <10·8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11–13 and HD2 if they had a score of 7–10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis.
At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4·11 points [95% CI 1·49–6·73] greater than controls; p=0·003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0·34 points [95% CI 0·02–0·66] greater than controls; p=0·038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0·01 s [95% CI 0·01–0·02] longer than controls; p=0·0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter-tap interval were particularly sensitive (p=0·013 and 0·002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0·006 and 0·0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p<0·0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD.
We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design.
CHDI Foundation.
Details
- Title: Subtitle
- Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data
- Creators
- Sarah J Tabrizi - UCL Institute of Neurology, University College London, London, UKRachael I Scahill - UCL Institute of Neurology, University College London, London, UKGail Owen - UCL Institute of Neurology, University College London, London, UKAlexandra Durr - Department of Genetics and Cytogenetics, and INSERM UMR S679, APHP, ICM Institute, Hôpital de la Salpêtrière, Paris, FranceBlair R Leavitt - Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, CanadaRaymund A Roos - Department of Neurology, Leiden University Medical Centre, Leiden, NetherlandsBeth Borowsky - CHDI Management/CHDI Foundation, Princeton, NJ, USABernhard Landwehrmeyer - Department of Neurology, Ulm University, Ulm, GermanyChris Frost - London School of Hygiene and Tropical Medicine, London, UKHans Johnson - Department of Psychiatry, University of Iowa, Iowa City, IA, USADavid Craufurd - University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UKRalf Reilmann - Department of Neurology, University of Münster, Münster, GermanyJulie C Stout - School of Psychology and Psychiatry, Monash University, Melbourne, VIC, AustraliaDouglas R Langbehn - Department of Psychiatry, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Lancet neurology, Vol.12(7), pp.637-649
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/S1474-4422(13)70088-7
- PMID
- 23664844
- ISSN
- 1474-4422
- eISSN
- 1474-4465
- Language
- English
- Date published
- 07/2013
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984066392602771
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