Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data

• Published in: Lancet neurology 2009-09, Vol.8 (9), p.791-801
• Main Authors: Tabrizi, Sarah J, Langbehn, Douglas R, Leavitt, Blair R, Roos, Raymund AC, Durr, Alexandra, Craufurd, David, Kennard, Christopher, Hicks, Stephen L, Fox, Nick C, Scahill, Rachael I, Borowsky, Beth, Tobin, Allan J, Rosas, H Diana, Johnson, Hans, Reilmann, Ralf, Landwehrmeyer, Bernhard, Stout, Julie C
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Atrophy - diagnosis; Atrophy - pathology; Atrophy - physiopathology; Biomarkers - analysis; Brain - pathology; Brain - physiopathology; Cognition Disorders - diagnosis; Cognition Disorders - etiology; Cognition Disorders - physiopathology; Cohort Studies; Cross-Sectional Studies; Disease Progression; Early Diagnosis; Female; Genetic Carrier Screening - methods; Genetic Predisposition to Disease - genetics; Genetic Testing; Humans; Huntington Disease - diagnosis; Huntington Disease - genetics; Huntington Disease - physiopathology; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neurologic Examination - methods; Neurology; Predictive Value of Tests; Reference Values; Young Adult
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/S1474-4422(09)70170-X

Summary Background Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions. Methods This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD. Findings The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease. Interpretation We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials. Funding CHDI/High Q Foundation.