Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy

Abstract

TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD.

Figure 1

Statistical parametric map (SPM) showing correlations between increased variability in tongue force and reduction in (top) GM and (bottom) WM. Results are shown overlaid on a mean customized template at P < 0.05, corrected for multiple comparisons using familywise error. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

SPM showing correlations between decreased precision in metronome tapping and reduction in (top) GM and (bottom) WM. Results are shown overlaid on a mean customised template at P < 0.05, corrected for multiple comparisons using familywise error. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

SPM showing correlations between increased anti‐saccade error rate and reduction in (top) GM and (bottom) WM. Results are shown overlaid on a mean customised template at P < 0.05, corrected for multiple comparisons using familywise error. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

SPM showing correlations between decrease in recognition of negative emotion and reduction in (top) GM and (bottom) WM. Results are shown overlaid on a mean customised template at P < 0.05, corrected for multiple comparisons using familywise error. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]