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Original Investigation
August 12, 2019

Association of CAG Repeats With Long-term Progression in Huntington Disease

Author Affiliations
  • 1Department of Psychiatry, University of Iowa, Iowa City
  • 2School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia
  • 3Huntington’s Disease Centre, UCL Institute of Neurology, University College London, Queen Square, London, United Kingdom
  • 4Institut du Cerveau et de la Moelle Epinière (ICM), Genetic Department, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale Unité 1127, Le Centre National de la Recherche Scientifique, Unités Mixtes de Recherche 7225, Pitié-Salpêtrière University Hospital, Paris, France
  • 5Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  • 6Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
  • 7Department of Electrical and Computer Engineering, University of Iowa, Iowa City
  • 8Novartis Pharmaceuticals, East Hanover, New Jersey
  • 9Manchester Academic Health Sciences Centre, Central Manchester University Hospitals National Health Service Foundation Trust, University of Manchester, Manchester, United Kingdom
  • 10George-Huntington-Institute, Department of Radiology, University of Münster, Münster, Germany
  • 11Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
  • 12Department of Neurology, Ulm University, Ulm, Germany
JAMA Neurol. 2019;76(11):1375-1385. doi:10.1001/jamaneurol.2019.2368
Key Points

Question  Can summary measures be defined characterizing brain and clinical changes to better understand disease trajectories in Huntington disease?

Findings  Among 2065 visits from 443 participants, this study identifies motor-cognitive and white matter–ventricle summary measures with similar nonlinear trajectories across the disease span and a strong association with CAG. In contrast, the striatum shows a near-linear trajectory with strong CAG dependence, and gray matter has a slow, nonlinear pattern with a weaker dependence on CAG.

Meaning  This work aids understanding of the association between brain changes and clinical manifestation in Huntington disease and their dependence on age and CAG repeat length, which may have utility in disease-modifying clinical trials.


Importance  In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing.

Objective  To succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length.

Design, Setting, and Participants  Prospective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019.

Main Outcomes and Measures  The outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length.

Results  We analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length–dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 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 then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity.

Conclusions and Relevance  Results of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length–dependent association between changes in the brain and clinical manifestations of HD.