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

Abstract

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.

Conflict of interest statement

Conflicts of interest

We have no conflicts of interest.

Figures

Figure 1. Whole brain and regional atrophy in the controls, premanifest, and early Huntington’s disease groups

(A) 3T volumetric MRI scan in a 50-year-old control, a 55-year-old individual with preHD, and a 49-year-old with early Huntington’s disease. Brain volumes are corrected for intracranial volume. (B) Brain volume as a percentage of intracranial volume across all groups (horizontal lines are median; boxes are upper and lower quartiles; bars are range; dots are outliers) and scatter plot of brain volume as a percentage of intracranial volume against disease burden. (C) Cortical thinning in the Huntington’s disease groups compared with controls. The top panel shows statistical maps corrected with the false discovery rate; magnitude maps are shown below. All results are adjusted for age and sex. ICV=intracranial volume. LH=left hemisphere. RH=right hemisphere.

Figure 2. Voxel-based morphometry

Statistical parametric maps of grey and white matter differences among groups compared with controls. Data adjusted for age, sex, study site, and intracranial volume. Results are corrected for multiple comparisons using familywise error at the p

Figure 3. Quantitative and oculomotor measures

(A) Antisaccade error rate. (B) Static tongue force variability. (C) Self-paced tapping. (D) Gait as normal speed stance. Box plots: horizontal lines are median; boxes are upper and lower quartiles; bars are range; and dots are outliers. CV=coefficient of variance.

Figure 4. Cognitive measures

(A) Recognition of facial expressions of negative emotions, scored as number correct out of 50. (B) Spot the change visual working memory Set Size 5 condition; “K” is the number correct, corrected for guessing (calculated as 5 [for the set size]×[the number of hits plus the number of correct rejections –1]. (C) University of Pennsylvania Smell Identification Test (number correct out of 20). Box plots: horizontal lines are median; boxes are upper and lower quartiles; bars are range; and dots are outliers.

Figure 5. Problem behaviour assessment

(A) PBA apathy score (frequency×severity). (B) PBA irritability score (frequency×severity; sum of irritability, anger/aggression and perseverative thinking/behaviour items). (C) PBA affect score (frequency×severity; sum of depressed mood, suicidal ideation, and anxiety items). Box plots: horizontal lines are median; boxes are upper and lower quartiles; bars are range; dots are outliers. PBA=problem behaviour assessment.