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JAMA Neurol. 2016 Jan;73(1):102-10. doi: 10.1001/jamaneurol.2015.2736.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

Author information

1
Department of Neurology, University of Rochester, Rochester, New York.
2
Department of Neurology, Georgetown University, Washington, DC.
3
Department of Biostatics, University of Rochester, Rochester, New York.
4
Department of Epidemiology & Biostatistics, Texas A&M, College Station.
5
Department of Statistics, Pennsylvania State University, University Park.
6
Department of Neurology, Massachusetts General Hospital, Charleston.
7
Department of Neurology, Columbia University Medical Center, New York, New York.
8
Department of Psychiatry and Neurology, University of Iowa, Iowa City.
9
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
10
Lilly Corporate Center, Indianapolis, Indiana.
11
The Parkinson's Institute, Sunnyvale, California.
12
Hereditary Neurological Disease Centre, Wichita, Kansas.
13
Department of Neurology, University of Kansas Medical Center, Kansas City.
14
Department of Neurology, Hennepin County Medical Center/Minneapolis, Minneapolis, Minnesota.
15
Department of Neurology, The Ohio State University, Columbus.
16
Wake Forest University School of Medicine, Winston-Salem, North Carolina.
17
Hotel-Dieu Hospital-CHUM, Montreal, Quebec, Canada.
18
Department of Neurology, Emory University School of Medicine, Atlanta, Georgia.
19
Department of Neuroscience, University of California, San Diego, La Jolla.
20
Department of Neurology, University of Washington, Seattle21Veterans Affairs Puget Sound Health Care System, Seattle.
21
Department of Neurology, Medical College of Wisconsin, Milwaukee.
22
Department of Neurology, Mayo Clinic Scottsdale, Scottsdale, Arizona.
23
Department of Neurology, University of California, Davis, Sacramento.
24
Idaho Elks Rehabilitation Hospital, Boise.
25
Department of Neurology, University of Michigan, Ann Arbor.
26
Department of Neurology, Washington University, St Louis, Missouri.
27
Department of Neurology, University of California Los Angeles Medical Center, Los Angeles.
28
Department of Neurology, University of Alberta, Edmonton, Alberta, Canada.
29
Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
30
Department of Neurology, Baylor College of Medicine, Houston, Texas.
31
Department of Neurology, University of South Florida, Tampa.
32
Department of Neurology, University of Calgary, Calgary, Alberta, Canada.
33
Centre for Addiction and Mental Health, Markham, Ontario, Canada.
34
Department of Neurology, North Shore LIJ University Hospital, Manhasset, New York.
35
Department of Neurobiology, University of Alabama at Birmingham.
36
Department of Neurology, University of Virginia, Charlottesville.
37
Department of Neurology, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical Center, Stratford.
38
Department of Neurology, Albany Medical College, Albany, New York.
39
Winnipeg Clinic, Winnipeg, Manitoba, Canada.
40
Department of Neurology, University of Miami, Miami, Florida.
41
Department of Neurological Sciences, Rush University, Chicago, Illinois.
42
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.
43
Department of Neurology, Boston University, Boston, Massachusetts.
44
Department of Neurology, Virginia Commonwealth University, Richmond.
45
Department of Neurology, Oregon Health and Science University, Portland.
46
Department of Neurology, University of Maryland School of Medicine, Baltimore.
47
US Food and Drug Administration, Rockville, Maryland.
48
Department of Neurology, Rocky Mountain Movement Disorders Center, Denver, Colorado.
49
Department of Neurology, Institute for Neurodegenerative Disorders, New Haven, Connecticut.
50
Clinical and Cognitive Neuroscience Laboratory, Monash University, Melbourne, Australia.

Abstract

IMPORTANCE:

Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.

OBJECTIVE:

To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).

DESIGN, SETTING, AND PARTICIPANTS:

A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.

EXPOSURE:

Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.

MAIN OUTCOMES AND MEASURES:

Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.

RESULTS:

Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups.

CONCLUSIONS AND RELEVANCE:

Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

PMID:
26569098
DOI:
10.1001/jamaneurol.2015.2736
[Indexed for MEDLINE]

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