Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis.
BACKGROUND
TRACK-HD is a prospective observational study of Huntington's disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings.


METHODS
we did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups.


RESULTS
116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05-0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44-0·76; p<0·0001) in early HD patients, and caudate atrophy rates were 1·37% (0·99-1·75; p<0·0001) per year higher in preHD and 2·86% (2·34-3·39; p<0·0001) in early HD. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. Quantitative imaging showed statistically significant associations with disease burden, an indicator of disease pathology, and total functional capacity, a widely-used clinical measure of disease severity. Relative to controls, decline in cognition and quantitative motor function was detectable in both pre- and early HD, as was deterioration in oculomotor function in early HD.


CONCLUSIONS
quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials.
UCL Institute of Neurology, University College London, Department of Neurodegenerative Disease, Queen Square, London, UK. sarah.tabrizi@prion.ucl.ac.uk
Sarah J
SJ
Tabrizi
Rachael I
RI
Scahill
Alexandra
A
Durr
Raymund Ac
RA
Roos
Blair R
BR
Leavitt
Rebecca
R
Jones
G Bernhard
GB
Landwehrmeyer
Nick C
NC
Fox
Hans
H
Johnson
Stephen L
SL
Hicks
Christopher
C
Kennard
David
D
Craufurd
Chris
C
Frost
Douglas R
DR
Langbehn
Ralf
R
Reilmann
Julie C
JC
Stout
D000328:Adult; D000368:Aged; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D001931:Brain Mapping; D002170:Canada; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology*; D018450:Disease Progression; D005260:Female; D005602:France; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D021621:Imaging, Three-Dimensional / Q000379:methods; D007391:International Cooperation; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009068:Movement / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009426:Netherlands; D009687:Nuclear Proteins / Q000235:genetics; D019370:Observation; D055815:Young Adult
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins