title: Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data.
abstract: BACKGROUND
  TRACK-HD is a prospective observational biomarker study in premanifest and early Huntington's disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials.
  
  
  METHODS
  We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes.
  
  
  RESULTS
  Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants.
  
  
  CONCLUSIONS
  On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group.
  
  
  BACKGROUND
  CHDI/HighQ Foundation Inc.
authors.affiliation: UCL Institute of Neurology, University College London, Queen Square, London, UK. s.tabrizi@ucl.ac.uk
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Ralf
authors.initials: R
authors.lastname: Reilmann
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Blair
authors.initials: B
authors.lastname: Leavitt
authors.forename: Gail
authors.initials: G
authors.lastname: Owen
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jones
authors.forename: Hans
authors.initials: H
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Craufurd
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hicks
authors.forename: Christopher
authors.initials: C
authors.lastname: Kennard
authors.forename: Bernhard
authors.initials: B
authors.lastname: Landwehrmeyer
authors.forename: Julie C
authors.initials: JC
authors.lastname: Stout
authors.forename: Beth
authors.initials: B
authors.lastname: Borowsky
authors.forename: Rachael I
authors.initials: RI
authors.lastname: Scahill
authors.forename: Chris
authors.initials: C
authors.lastname: Frost
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Langbehn
mesh_terms: D000328:Adult; D001284:Atrophy / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006816:Huntington Disease / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011446:Prospective Studies
chemical_list: D015415:Biomarkers