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Journal of Neurology

, Volume 262, Issue 12, pp 2691–2698 | Cite as

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

  • Dawei Liu
  • Jeffrey D. Long
  • Ying Zhang
  • Lynn A. Raymond
  • Karen Marder
  • Anne Rosser
  • Elizabeth A. McCusker
  • James A. Mills
  • Jane S. Paulsen
  • The PREDICT-HD Investigators and Coordinators of the Huntington Study Group
Original Communication

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.

Keywords

Huntington disease Hidden Markov model Diagnostic confidence level Prediction Diagnosis Onset 

Notes

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).

Compliance with ethical standards

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.

Supplementary material

415_2015_7900_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Dawei Liu
    • 1
    • 2
  • Jeffrey D. Long
    • 1
    • 3
  • Ying Zhang
    • 4
  • Lynn A. Raymond
    • 5
  • Karen Marder
    • 6
    • 7
  • Anne Rosser
    • 8
    • 9
  • Elizabeth A. McCusker
    • 10
  • James A. Mills
    • 1
  • Jane S. Paulsen
    • 1
    • 11
    • 12
  • The PREDICT-HD Investigators and Coordinators of the Huntington Study Group
  1. 1.Department of PsychiatryCarver College of Medicine, The University of IowaIowa CityUSA
  2. 2.BiogenCambridgeUSA
  3. 3.Department of BiostatisticsCollege of Public Health, The University of Iowa, S160 CPHBIowa CityUSA
  4. 4.Department of BiostatisticsIndiana University Fairbanks School of Public HealthIndianapolisUSA
  5. 5.Department of Psychiatry and Brain Research CentreUniversity of British ColumbiaVancouverCanada
  6. 6.Department of Neurology, Gertrude H. Sergievsky Center, Taub Institute on Alzheimers Disease and the Aging BrainColumbia University College of Physicians and SurgeonsNew YorkUSA
  7. 7.Department of PsychiatryColumbia University Medical CenterNew YorkUSA
  8. 8.Institute for Psychological Medicine and Clinical NeurosciencesCardiff University School of MedicineCardiffUK
  9. 9.School of BiosciencesCardiff UniversityCardiffUK
  10. 10.Department of NeurologyWestmead Hospital, The University of SydneyWestmeadAustralia
  11. 11.Department of Neurology, Carver College of MedicineThe University of IowaIowa CityUSA
  12. 12.Department of PsychologyThe University of IowaIowa CityUSA

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