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Motor onset and diagnosis in Huntington disease using the diagnostic confidence level

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Abstract

Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine–adenine–guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington’s Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11 % (95 % CI 7–15 %) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47 % (95 % CI 27–69 %). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.

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Acknowledgments

This research is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (5R01NS040068) awarded to Jane Paulsen; CHDI Foundation, Inc (A6266; A2015) awarded to Jane Paulsen; and Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (HD) (5R01NS054893) awarded to Jane Paulsen. We thank the PREDICT-HD sites, the study participants, the National Research Roster for Huntington Disease Patients and Families, the Huntington’s Disease Society of America, and the Huntington Study Group. This publication was supported by the National Center for Advancing Translational Sciences, and the National Institutes of Health (NIH), through Grant 2 UL1 TR000442-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

PREDICT-HD Investigators, Coordinators, Motor Raters, Cognitive Raters

Isabella De Soriano, Courtney Shadrick, and Amanda Miller (University of Iowa, Iowa City, IA, USA); Edmond Chiu, Joy Preston, Anita Goh, Stephanie Antonopoulos, and Samantha Loi (St. Vincent’s Hospital, The University of Melbourne, Kew, VIC, Australia); Phyllis Chua and Angela Komiti (The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia); Lynn Raymond, Joji Decolongon, Mannie Fan, and Allison Coleman (University of British Columbia, Vancouver, BC, Canada); Christopher A. Ross, Mark Varvaris, Maryjane Ong, and Nadine Yoritomo (Johns Hopkins University, Baltimore, MD, USA); William M. Mallonee and Greg Suter (Hereditary Neurological Disease Centre, Wichita, KS, USA); Ali Samii, Emily P. Freney, and Alma Macaraeg (University of Washington and VA Puget Sound Health Care System, Seattle, WA, USA); Randi Jones, Cathy Wood-Siverio, and Stewart A. Factor (Emory University School of Medicine, Atlanta, GA, USA); Roger A. Barker, Sarah Mason, and Natalie Valle Guzman (John van Geest Centre for Brain Repair, Cambridge, UK); Elizabeth McCusker, Jane Griffith, Clement Loy, Jillian McMillan, and David Gunn (Westmead Hospital, Sydney, NSW, Australia); Michael Orth, Sigurd Süβmuth, Katrin Barth, Sonja Trautmann, Daniela Schwenk, and Carolin Eschenbach (University of Ulm, Ulm, Germany); Kimberly Quaid, Melissa Wesson, and Joanne Wojcieszek (Indiana University School of Medicine, Indianapolis, IN, USA); Mark Guttman, Alanna Sheinberg, Albie Law, and Irita Karmalkar (Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada); Susan Perlman and Brian Clemente (UCLA Medical Center, Los Angeles, CA, USA); Michael D. Geschwind, Sharon Sha, Joseph Winer, and Gabriela Satris (University of California, San Francisco, San Francisco, CA, USA); Tom Warner and Maggie Burrows (National Hospital for Neurology and Neurosurgery, London, UK); Anne Rosser, Kathy Price, and Sarah Hunt (Cardiff University, Cardiff, Wales, UK); Frederick Marshall, Amy Chesire, Mary Wodarski, and Charlyne Hickey (University of Rochester, Rochester, NY, USA); Peter Panegyres, Joseph Lee, Maria Tedesco, and Brenton Maxwell (Neurosciences Unit, Graylands, Selby-Lemnos & Special Care Health Services, Perth, WA, Australia); Joel Perlmutter, Stacey Barton, and Shineeka Smith (Washington University, St. Louis, MO, USA); Zosia Miedzybrodzka, Daniela Rae, Vivien Vaughan, and Mariella D’Alessandro (Clinical Genetics Centre, Aberdeen, Scotland, UK); David Craufurd, Judith Bek, and Elizabeth Howard (University of Manchester, Manchester, UK); Pietro Mazzoni, Karen Marder, and Paula Wasserman (Columbia University Medical Center, New York, NY, USA); Rajeev Kumar, Diane Erickson, Christina Reeves, and Breanna Nickels (Colorado Neurological Institute, Englewood, CO, USA); Vicki Wheelock, Lisa Kjer, Amanda Martin, and Sarah Farias (University of California, Davis, Sacramento, CA, USA); Wayne Martin, Oksana Suchowersky, Pamela King, Marguerite Wieler, and Satwinder Sran (University of Alberta, Edmonton, AB, Canada); and Anwar Ahmed, Stephen Rao, Christine Reece, Alex Bura, and Lyla Mourany (Cleveland Clinic Foundation, Cleveland, OH, USA).

Executive Committee

Principal Investigator Jane S. Paulsen, Jeffrey D. Long, Hans J. Johnson, Thomas Brashers-Krug, Phil Danzer, Amanda Miller, H. Jeremy Bockholt, and Kelsey Montross.

Scientific Consultants

Deborah Harrington (University of California, San Diego); Holly Westervelt (Rhode Island Hospital/Alpert Medical School of Brown University); Elizabeth Aylward (Seattle Children’s Research Institute); Stephen Rao (Cleveland Clinic); David J. Moser, Janet Williams, Nancy Downing, Vincent A. Magnotta, Hans J. Johnson, Thomas Brashers-Krug, Jatin Vaidya, Daniel O’Leary, and Eun Young Kim (University of Iowa).

Core Sections

Biostatistics: Jeffrey D. Long, Ji-In Kim, Spencer Lourens (University of Iowa); Ying Zhang and Wenjing Lu (University of Indiana).

Ethics: Cheryl Erwin (Texas Tech University Health Sciences Center); Thomas Brashers-Krug, Janet Williams (University of Iowa); and Martha Nance (University of Minnesota).

Biomedical Informatics: H. Jeremy Bockholt, Jason Evans, and Roland Zschiegner (University of Iowa).

Author information

Author notes

  1. Dawei Liu

    Present address: Biogen, 300 Binney Street, Cambridge, MA, 02142, USA

Authors and Affiliations

  1. Department of Psychiatry, Carver College of Medicine, The University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Dawei Liu, Jeffrey D. Long, James A. Mills & Jane S. Paulsen

  2. Department of Biostatistics, College of Public Health, The University of Iowa, S160 CPHB, 145 N. Riverside Drive, Iowa City, IA, 52242, USA

    Jeffrey D. Long

  3. Department of Biostatistics, Indiana University Fairbanks School of Public Health, 410 W. Tenth Street, Suite 3000, Indianapolis, IN, 46202, USA

    Ying Zhang

  4. Department of Psychiatry and Brain Research Centre, University of British Columbia, Detwiller Pavilion, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada

    Lynn A. Raymond

  5. Department of Neurology, Gertrude H. Sergievsky Center, Taub Institute on Alzheimers Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, 710 West 168th Street, New York, NY, 10032, USA

    Karen Marder

  6. Department of Psychiatry, Columbia University Medical Center, 622 West 168th Street, New York, NY, 10032, USA

    Karen Marder

  7. Institute for Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK

    Anne Rosser

  8. School of Biosciences, Cardiff University, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK

    Anne Rosser

  9. Department of Neurology, Westmead Hospital, The University of Sydney, Cnr Hawkesbury and Darcy Roads, Westmead, NSW, 2145, Australia

    Elizabeth A. McCusker

  10. Department of Neurology, Carver College of Medicine, The University of Iowa, 2007 Roy Carver Pavilion, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Jane S. Paulsen

  11. Department of Psychology, The University of Iowa, E11 Seashore Hall, Iowa City, IA, 52242, USA

    Jane S. Paulsen

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  1. Dawei Liu
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  3. Ying Zhang
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The PREDICT-HD Investigators and Coordinators of the Huntington Study Group

Corresponding author

Correspondence to Jane S. Paulsen.

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Conflicts of interest

J. Paulsen is the principal investigator for PREDICT-HD and has therefore received grant funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke as detailed above. J. Paulsen has also served on an advisory board for Lundbeck, LLC, and has a consulting agreement with ProPhase, LLC. J. Long has a consulting agreement with NeuroPhage, LLC. All other authors declare no conflicts of interest.

Ethical standards

PREDICT-HD was approved by the institutional review boards at the University of Iowa and each participating site, and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from each participant.

Additional information

The members of the PREDICT-HD Investigators and Coordinators of the Huntington Study Group are listed in Acknowledgments.

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Liu, D., Long, J.D., Zhang, Y. et al. Motor onset and diagnosis in Huntington disease using the diagnostic confidence level. J Neurol 262, 2691–2698 (2015). https://doi.org/10.1007/s00415-015-7900-7

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  • DOI: https://doi.org/10.1007/s00415-015-7900-7

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