title: Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study.
abstract: There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.
authors.affiliation: Department of Psychiatry, Carver College of Medicine, The University of Iowa , Iowa City, IA , USA ; Department of Neurology, Carver College of Medicine, The University of Iowa , Iowa City, IA , USA ; Department of Psychology, The University of Iowa , Iowa City, IA , USA.
authors.forename: Jane S
authors.initials: JS
authors.lastname: Paulsen
authors.affiliation: Department of Psychiatry, Carver College of Medicine, The University of Iowa , Iowa City, IA , USA ; Department of Biostatistics, College of Public Health, The University of Iowa , Iowa City, IA , USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Long
authors.affiliation: Department of Psychiatry, Carver College of Medicine, The University of Iowa , Iowa City, IA , USA ; Department of Biomedical Engineering, College of Engineering, The University of Iowa , Iowa City, IA , USA.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Johnson
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, WA , USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Aylward
authors.affiliation: Division of Neurobiology, Johns Hopkins University , Baltimore, MD , USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: College of Nursing, The University of Iowa , Iowa City, IA , USA.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Williams
authors.affiliation: Department of Neurology, College of Medicine, The University of Minnesota , Minneapolis, MN , USA.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Nance
authors.affiliation: Center of Excellence for Ethics, Humanities and Spirituality, Texas Tech University Health Sciences Center School of Medicine , Lubbock, TX , USA.
authors.forename: Cheryl J
authors.initials: CJ
authors.lastname: Erwin
authors.affiliation: Department of Psychiatry and Human Behavior, Division of Biology and Medicine, Brown University , Providence, RI , USA.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Westervelt
authors.affiliation: Department of Radiology, School of Medicine, University of California , San Diego, CA , USA ; Veterans Affairs San Diego Healthcare System , San Diego, CA , USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Harrington
authors.affiliation: Advanced Biomedical Informatics Group, LLC , Iowa City, IA , USA.
authors.forename: H Jeremy
authors.initials: HJ
authors.lastname: Bockholt
authors.affiliation: Department of Biostatistics, Indiana University Fairbanks School of Public Health and Indiana University School of Medicine , Indianapolis, IN , USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Westmead Hospital, The University of Sydney , Sydney, NSW , Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McCusker
authors.affiliation: Department of Psychiatry, The University of Melbourne , Melbourne, VIC , Australia.
authors.forename: Edmond M
authors.initials: EM
authors.lastname: Chiu
authors.affiliation: Neurodegenerative Disorders Research Pty Ltd. , Perth, WA , Australia.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Panegyres
keywords: Huntington disease; PREDICT-HD; clinical trials; natural history; neurodegenerative disorders; outcome measures; premanifest