Tapping linked to function and structure in premanifest and symptomatic Huntington disease

Abstract

Objective: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy.

Methods: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded.

Results: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes.

Conclusion: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

Figure 1 Data acquisition, variables, and examples (A) Setup of the tapping device and position of hand and index finger in relation to the force-transducer. (B) Definitions of measures for speeded tapping (IOI = interonset interval; IPI = interpeak interval; ITI = intertap interval; TD = tap duration; TF = tap force) and (C) additional measures in metronome tapping (ΔIOI = deviation from IOI = IOI − 0.55 s, ΔIPI = deviation from IPI = IPI − 0.55 s, ΔMTI = midtap interval = [interval time between the arithmetic middles of 2 consecutive taps] − 0.55). (D, E) Finger tapping shows deterioration in advanced stages of Huntington disease. A range of sample recordings from (top to bottom) good to poor performance are given for (D) speeded tapping and (E) metronome tapping—the solid gray lines represent the onset of auditory cues in metronome tapping, the continued dashed lines mark the ideal rate after cues stopped.

Figure 2 Box plots and correlation analysis of selected tapping items by subgroups (A) Unadjusted results of the nondominant hand of tap duration (TD) (speeded tapping [ST]), interonset interval (IOI) (ST), deviation from interonset interval (ΔIOI) (metronome tapping [MT]), and frequency (Freq – ST). Correlations between tapping variables and (B) Unified Huntington's Disease Rating Scale-Total Motor Score and (C) Disease Burden Score (DBS = [CAG repeat – 35.5] × age). Correlations are displayed for TD (ST), IOI (ST), and ΔIOI (MT). For r values, please see table 2. HD = Huntington disease.

Figure 3 Structural brain correlations to tapping performance (A-C) Statistical parametric map showing correlations between tap duration (TD) (speeded tapping [ST]), interonset interval (IOI) (ST), and deviation from interonset interval (ΔIOI) (metronome tapping [MT]) with gray (A) and white matter (B) in voxel-based morphometry (VBM) (results overlaid on a mean image from this dataset are shown, thresholded at p < 0.05, corrected for multiple comparisons using familywise error) and (C) cortical thickness (results are corrected for a false discovery rate at p < 0.01).