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F21 Cag-dependent huntington’s disease patterns over decades: the track-hd and track-on studies
  1. Douglas Langbehn1,
  2. Rachael Scahill2,
  3. James Mills1,
  4. Alexandra Durr3,
  5. Blair Leavitt4,
  6. Raymund Roos5,
  7. Jeffrey Long1,
  8. Sarah Gregory2,
  9. Gail Owen2,
  10. Hans Johnson1,
  11. Beth Borowsky6,
  12. David Craufurd7,
  13. Ralf Reilmann8,
  14. Julie C Stout9,
  15. Bernhard Landwehrmeyer10,
  16. Sarah J Tabrizi2
  1. 1University of Iowa, Iowa City, Iowa, USA
  2. 2University College London, Queen Square, London, UK
  3. 3Sorbonne Université, Inserm U 1127, CNRS UMR 7225, Pitié-Salpêtrière University Hospital, Paris, France
  4. 4University of British Columbia, Vancouver, British Columbia, Canada
  5. 5Leiden University Medical Centre, RC Leiden, The Netherlands
  6. 6Teva Pharmaceuticals, Clinical Development, Neurodegenerative Diseases, Malvern, PA, USA
  7. 7University of Manchester, Manchester, UK
  8. 8George-Huntington-Institute, Muenster, Germany
  9. 9Monash University, VIC, Australia
  10. 10Ulm University, Ulm, Germany


Background In HD, the dependency of onset-age of overt disease on CAG expansion length is well-studied. However, the relationship between CAG length and lifetime trajectory is less well characterized.

Aims To capture the decades-long early progression of Huntington’s Disease (HD), its dependence on CAG expansion length, and to evaluate whether progression could be well-represented by clinical and imaging summary measures.

Methods Using the combined longitudinal TRACK-HD and Track-On studies (n=290 CAG-expanded, 153 controls), we used principal component analysis to assess common patterns among CAG-expanded participants, who ranged at study entry from presymptomatic adults to those with stage II disease. We modelled these patterns’ interrelationships, dependencies on CAG repeat-length and age, and association with total functional capacity decline.

Results Nominally cognitive and motor measures are highly correlated and have similar CAG- dependent relationships to age; a composite summary score accounted for 67.6% of the combined variance. This score was well-approximated by combining just three items (Total Motor Score, Symbol Digit Modalities Test, and Stroop Word-Reading) from the Unified Huntington’s Disease Rating Scale. For either score, initial progression age and later acceleration were highly CAG-dependent, with accelerating beginning in the pre-diagnostic years and continuing through stage II disease. In contrast, we observed three distinct patterns among brain measure changes. A basal ganglia pattern showed considerable change in even the youngest participants, but minimal acceleration with aging. Each clinical and brain summary score strongly predicted the onset and rate of TFC decline.

Conclusions Summary measures of function and brain loss characterize HD progression across the disease span. Similar to HD clinical onset, we show that CAG length strongly predicts the rate of decline throughout late pre-diagnosis and early diagnosis.

  • Huntington Disease
  • Trinucleotide Repeat Expansion
  • Neuroimaging
  • Statistical Models
  • Longitudinal Studies

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