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D22 Compensation in preclinical huntington’s disease: evidence from the track-on HD study
  1. Sarah Gregory1,
  2. Stefan Klöppel2,
  3. Elisa Scheller3,
  4. Lora Minkova3,
  5. Adeel Razi4,
  6. Alexandra Durr5,
  7. Raymund AC Roos6,
  8. Blair R Leavitt7,
  9. Marina Papoutsi1,
  10. G Bernhard Landwehrmeyer8,
  11. Ralf Reilmann9,
  12. Beth Borowsky10,
  13. Hans Johnson11,
  14. James A Mills12,
  15. Gail Owen1,
  16. Julie Stout13,
  17. Rachael I Scahill1,
  18. Jeffrey D Long12,14,
  19. Geraint Rees4,
  20. Sarah J Tabrizi1,
  21. the TrackON investigators
  1. 1Huntington’s Disease Research Group, Institute of Neurology, University College London, London, UK
  2. 2Division Freiburg Brain Imaging, Department of Psychiatry and Psychotherapy and Department of Neurology, Albert-Ludwigs-University Freiburg, University Medical Centre, Freiburg, Germany
  3. 3Division Freiburg Brain Imaging, Department of Psychiatry and Psychotherapy and Department of Psychology, Laboratory for Biological and Personality Psychology, Albert-Ludwigs-University Freiburg, University Medical Centre, Freiburg, Germany
  4. 4Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK
  5. 5APHP Department of Genetics, Groupe Hospitalier Pitié-Salpêtrière, and Institut du Cerveau et de la Moelle, INSERM U1127, CNRS UMR7225, UPMC Université Paris VI UMR_S1127, Paris France
  6. 6Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands
  7. 7Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Canada
  8. 8Department of Neurology, Ulm University, Ulm, Germany
  9. 9George-Huntington-Institute, Muenster, Germany
  10. 10CHDI Management/CHDI Foundation, Princeton, NJ, USA
  11. 11Department of Electrical and Computer Engineering, University of Iowa, Iowa City, IA, USA
  12. 12Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa, City, IA, USA
  13. 13School of Psychological Sciences and Institute of Clinical and Cognitive Neuroscience, Monash University, Melbourne, Australia
  14. 14Department of Biostatistics, College of Public Health, University of Iowa, Iowa, City, IA, USA

Abstract

Background Cognitive and motor task performance in premanifest Huntington’s disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been explicitly addressed in statistical models.

Aims Using a new statistical model, which incorporates individual variability related to structural burden (i.e., loss of brain volume) and behaviour, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers.

Methods We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI.

Results Consistent with compensation, higher atrophy was associated with increased performance-related activity of the right parietal cortex during a working memory task. Similarly, higher functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance in individuals with higher disease burden. Such patterns were not detectable for the left hemisphere or for motor tasks.

Conclusion Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy.

  • Compensation
  • Magnetic Resonance Imaging
  • Cognition

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