Elsevier

Psychiatry Research

Volume 178, Issue 2, 30 July 2010, Pages 414-418
Psychiatry Research

Earliest functional declines in Huntington disease

https://doi.org/10.1016/j.psychres.2010.04.030Get rights and content

Abstract

We examined the gold standard for Huntington disease (HD) functional assessment, the Unified Huntington's Disease Rating Scale (UHDRS), in a group of at-risk participants not yet diagnosed but who later phenoconverted to manifest HD. We also sought to determine which skill domains first weaken and the clinical correlates of declines. Using the UHDRS Total Functional Capacity (TFC) and Functional Assessment Scale (FAS), we examined participants from Huntington Study Group clinics who were not diagnosed at their baseline visit but were diagnosed at a later visit (N = 265). Occupational decline was the most common with 65.1% (TFC) and 55.6% (FAS) reporting some loss of ability to engage in their typical work. Inability to manage finances independently (TFC 49.2%, FAS 35.1%) and drive safely (FAS 33.5%) were also found. Functional decline was significantly predicted by motor, cognitive, and depressive symptoms. The UHDRS captured early functional losses in individuals with HD prior to formal diagnosis, however, fruitful areas for expanded assessment of early functional changes are performance at work, ability to manage finances, and driving. These are also important areas for clinical monitoring and treatment planning as up to 65% experienced loss in at least one area prior to diagnosis.

Introduction

Huntington Disease (HD) is an autosomal-dominant genetic disease that results in progressive deterioration of motor and cognitive abilities and the emergence of psychiatric symptoms (Huntington Study Group (HSG), 1993, Paulsen et al., 2001a, Shoulson, 1990). The combination of these symptoms eventually contributes to significant declines in functional capacity that affect both activities of daily living (ADLs, e.g., eating, bathing) and instrumental activities of daily living (IADLs, e.g., managing medications and finances). The assessment of functional capacity is a key component of a clinical or research exam because it has traditionally been viewed as the closest proxy of “real world” functioning and has immediately discernable practical value (e.g., what tasks is the patient capable of independently completing). The importance of functional level in HD is also apparent in recent drug trials; the FDA has mandated the use of patient-reported outcomes (Bren, 2006). Thus, the sensitive assessment of functional status has significance not only in the clinical monitoring of patients, but also in the advancement of therapies for this disease.

The Total Functional Capacity (TFC) scale (Shoulson and Fahn, 1979), which is a component of the Unified Huntington's Disease Rating Scale (HSG, 1996), is the main assessment tool of functional status in HD clinical care and research. It has been used as the primary outcome measure in several clinical trials in manifest HD. However, the scale was designed to assess progression of HD in patients with manifest disease and accordingly emphasizes self-care, mobility, and independence. Thus the usefulness of the TFC in detecting very early changes in functional capacity is unknown. Clinical experience and research strongly suggest that many gene-expanded individuals experience declines in their functional status and other clinical domains even before formal HD diagnosis (Lawrence et al., 1998, Paulsen et al., 2008). Recent research in other neurodegenerative disorders has also shown that poor performance in IADLs predicts conversion to dementia 10 years later (Peres et al., 2008).

Clinical trials are currently underway in pre-diagnosed and early-stage HD individuals. It would be helpful for selection of outcomes to know whether the current UHDRS functional assessment scales are capable of detecting early functional changes. Additionally, examination of current brief measures may guide the development of more detailed measures by informing us about which aspects of functioning decline as the early disease-related changes manifest. We examined the functional declines in a sample of at-risk participants who were identified as “phenoconverters” (i.e., those who were not yet diagnosed with HD at their baseline visit but were later rated at a follow-up visit as having “unquestionable” HD based on motor signs) on two measures of functional capacity: the UHDRS TFC scale and the Functional Assessment Scale (FAS). We also determined which aspects of disease (motor score, cognitive performance, depression) were associated with these early declines.

Section snippets

Participants

Participants were seen for a clinical research evaluation at one of 55 sites affiliated with the Huntington Study Group (HSG) in North America, Europe, or Australia. All HSG sites who had contributed de-identified data during the 1990s were included, regardless of specific ongoing studies individuals may have been participating in at the time of their visit. The total number of participants available for analysis was all HSG participants at visit 1 (N = 4423). Selection criteria for this analysis

Participant demographics and functional descriptive results

Participants were included if they had a DCL less than 3 at their first visit and converted to a DCL of 3 at a subsequent visit. In our sample, the majority of participants meeting these criteria had a DCL of 2 at the first visit (n = 185, 69.8%; DCL 1 n = 58, 21.9%; DCL 0 n = 22, 8.3%), which indicates that they were nearing diagnosis. The sample had an equal gender distribution (50.4% male), an average age of 44.47 years (SD = 12.37), and 13 years of education. Participants had baseline clinical scores

Discussion

The current analysis is the first attempt to evaluate which aspects of functional capacity show early decline in patients with HD and whether the UHDRS functional scales may be extended downward to participants who do not yet meet diagnostic criteria. On both the TFC and FAS, declines in occupational performance were the most commonly endorsed functional problems by participants. Up to 65% (TFC) and 55% (FAS) of participants reported some loss of ability to engage in work. Inability to manage

Acknowledgment

This research is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NS40068), and CHDI Foundation. We also wish to acknowledge the Huntington Study Group investigators and coordinators that participated in data collection for this study (please see footnote 1). Finally, we thank the HD families who volunteer their time to assist in clinical research; without their commitment, progress in HD research would not be possible.

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1

HSG Participating investigators and coordinators: Phillipa Hedges, Elizabeth McCusker, MD, Samantha Pearce, and Ronald Trent, PhD, Westmead Hospital, Sydney, NSW Australia; David Abwender, PhD, Peter Como, PhD, Irenita Gardiner, RN, Charlyne Hickey, RN, Elise Kayson, RN, Karl Kieburtz, MD, Frederick Marshall, MD, Nancy Pearson, RN, Ira Shoulson, MD, and Carol Zimmerman, RN, University of Rochester, NY; Elan Louis, MD, Karen Marder, MD, Carol Moskowitz, RN, Carmen Polanco, BA, Stuart Taylor, MD, and Naomi Zubin, BA, Columbia Presbyterian Medical Center, New York, NY; Catherine Brown, RN, Jill Burkeholder, Mark Guttman, MD, Sandra Russell, Dwight Stewart, MD, and Jackie Thomson, RN, Markham Health Center, Toronto, ONT; Daniel S. Sax, MD, and Marie Saint-Hilaire, MD, Boston University, Boston, MA; Jackie Gray, Cindy Hunter, MS, Nanette Mercado, PhD, Eric Siemers, MD, and Joanne Wojcieszek, MD, Indiana University School of Medicine, Indianapolis, IN; Ted Dawson, MD, Elizabeth Leritz, BS, Adam Rosenblatt, MD, Meeia Sherr, RN, and Candace Young, RN, Johns Hopkins University, Baltimore, MD; Tetsuo Ashizawa, MD, Jenny Beach, RN, and Joseph Jankovic, MD, Baylor College of Medicine, Houston, TX; Jeana Jaglin, RN, and Kathleen Shannon, MD, Rush Presbyterian/St. Luke's Medical Center, Chicago, IL; Anders Lundin, MD, Karolinska Hospital, Stockholm, Sweden; Kathleen Francis, MD, and Kim Lane, UMDNJ Robert Wood Johnson Medical School, Camden, NJ; Alexander Auchus, MD, J. Timothy Greenamyre, MD, Steven Hersch, MD, Randi Jones, PhD, David Olson, MD, and Janet Cellar, RN, Emory University, Atlanta, GA; Jang-Ho John Cha, MD, Merit Cudkowicz, MD, Walter Koroshetz, MD, John Penney (deceased), Greg Rudolf, Paula Sexton, MA, and Anne B. Young, MD, Massachusetts General Hospital, Boston, MA; Roger Albin, MD, and Kristine Wernette, RN, University of Michigan, Ann Arbor, MI; Donald S. Higgins, MD, and Carson Reider, MS, Ohio State University, Columbus, OH; Vicki Hunt, RN, and Francis Walker, MD, Bowman Gray School of Medicine, Winston-Salem, NC; Robert Hauser, MD, Juan Sanchez-Ramos, MD, and Audrey Walker, RN, University of South Florida, Tampa, FL; Martha Nance, MD, Minneapolis Veterans Administration Medical Center, Minneapolis, MN; Susan Cleary, RN, Gina Rohs, and Oksana Suchowersky, MD, University of Calgary Medical Center, Calgary AB; Kerry Duncan and Lauren Seeberger, MD, Colorado Neurologic Institute, Englewood, CO; Jody Corey-Bloom, MD, Michael Swenson, MD, and Neal Swerdlow, MD, University of California, San Diego, CA; Henry Paulson, MD, PhD, Robert Rodnitzky, MD, Lynn Vining, RN, and Jane Paulsen, PhD, University of Iowa, Iowa City, IA; Wayne Martin, MD, and Marguerite Wieler, BSC, PT, University of Alberta, Edmonton, AB; Alicia Facca, MD, Gustavo Rey, PhD, and William Weiner, MD, University of Miami, FL; Charles Adler, MD, John Caviness, MD, Cindy Lied, RN, and Stephanie Newman, RN Mayo Clinic, Scottsdale, AZ; Andrew Feigin, MD, and Jennifer Mazurkiewicz, BA, North Shore University Hospital, Manhasset, NY; Karen Caplan, MSW, and Kenneth Marek, MD, Yale University School of Medicine, New Haven, CT; Michael Hayden, MD, Lynn Raymond, and MD University of British Columbia, Vancouver, BC; Leon S. Dure, MD, and Jane Lane, RN, Children's Hospital of Alabama, Birmingham, AL; Diane Brown, RN (deceased), Stewart Factor, DO, and Eric Molho, MD, Albany Medical College, Albany, NY; Madeline Harrison, MD, Carol Manning, PhD, and Elke Rost-Ruffner, RN, University of Virginia, Charlottesville, VA; Jonelle Adams, Ruth Cummings, RN, and Vicki Wheelock, MD, University of California Davis, CA; Richard Dubinsky, MD, and Carolyn Gray, RN, University of Kansas Medical Center, Kansas City, KS; Ann Catherine Bachoud-Levi, MD, Hopital Henri Mondor, Creteil, France; Hartmut Meierkord, MD, Universitatsklinikum Charite, Berlin, Germany; Joseph Friedman, MD, and Margaret Lannon, RN, Memorial Hospital of Rhode Island, Pawtucket, RI; Joan Lawrence, MD, Royal Brisbane Hospital, Brisbane, Queensland, Australia; and Allen Rubin, MD, and Rose Schwarz, RN, Allegheny University, Philadelphia, PA; William M. Mallonee, MD, David Palmer, MD (deceased), and Greg Suter, BA, Hereditary Neurological Disease Centre. Biostatistics and Coordination Center Staff: Alicia Brocht, BA, Kathy Claude, MS, Joshua Goldstein, Connie Orme, BA, Michael McDermott, PhD, and David Oakes, PhD, University of Rochester, Rochester, NY.

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