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Biomarkers
H01 Significant biological and clinical change detected over 1 year in premanifest and early stage Huntington's disease in the TRACK-HD study
  1. S J Tabrizi1,
  2. A Dürr2,
  3. R A C Roos3,
  4. B R Leavitt4,
  5. R Jones5,
  6. G B Landwehrmeyer6,
  7. H Johnson7,
  8. S L Hicks8,
  9. C Kennard8,
  10. R Reilmann9,
  11. D Craufurd10,
  12. H D Rosas11,
  13. C Frost5,
  14. D R Langbehn12,
  15. R I Scahill1,
  16. J C Stout13,
  17. TRACK-HD Investigators
  1. 1UCL Institute of Neurology, University College London, London, UK
  2. 2Department of Genetics and Cytogenetics and INSERM UMR S679, APHP Hôpital de la Salpêtrière, Paris, France
  3. 3Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  4. 4Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  5. 5London School of Hygiene and Tropical Medicine, London, UK
  6. 6Department of Neurology, Ulm University, Ulm, Germany
  7. 7Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA
  8. 8Department of Clinical Neurology, University of Oxford, Oxford, UK
  9. 9Department of Neurology, University of Münster, Münster, Germany
  10. 10Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK
  11. 11Massachusetts General Hospital Department of Neurology, Harvard, Charlestown, Massachusetts, USA
  12. 12Departments of Psychiatry and Biostatistics (Secondary), University of Iowa, Iowa City, Iowa, USA
  13. 13School of Psychology, Psychiatry, and Psychological Medicine, Monash University, Victoria, Australia

Abstract

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 et al. Lancet Neurology 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.

  • Huntington's disease
  • longitudinal
  • disease progression
  • biological markers
  • cognition
  • motor
  • oculomotor
  • magnetic resonance imaging
  • atrophy
  • VBM
  • cortical thickness

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Footnotes

  • Funding TRACK-HD is supported by the CHDI/High Q Foundation.

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