Force-transducer-based tapping objectively quantified motor deficits in premanifest and symptomatic HD gene carriers and distinguished between all groups and subgroups. Correlations to disease burden, UHDRS-TMS, and the reduction of brain volume in VBM and cortical thickness were demonstrated, suggesting a link between structure and function. Our results extend earlier findings on tapping deficits in HD. Paulsen et al.6
reported timing deficits in a tapping task up to a decade before predicted disease onset in a premanifest cohort. Tapping deficiencies in manifest HD and their correlation to the UHDRS-TMS have been described in smaller cohorts.18,19
Deficits are reproducible in repeated measurements19
and progress over time in manifest HD.10,19
TRACK-HD assessed a large cohort of premanifest and symptomatic gene carriers and controls. The UHDRS-TMS commonly serves as a primary or secondary outcome measure in clinical trials. However, the UHDRS-TMS is a categorical scale with limited sensitivity. It is susceptible to subjective error and interrater variability20,21
and was designed for manifest HD.22
Many studies define premanifest HD by a UHDRS-Diagnostic Confidence Level of 3 or lower. Subjects with up to 98% diagnostic certainty for manifest HD—based on the presence of characteristic motor signs—are thus considered premanifest. Accordingly, premanifest subjects may show noticeable motor signs with an impact on motor task performance. Study requirements in TRACK-HD limited clinical motor signs to a marginally noticeable level. Minor signs (UHDRS-TMS ≤5) were tolerated since instilled behavior has been reported in gene-negative offspring of HD families.20
Accordingly, gene-negative family members in the PREDICT-HD study exhibited a mean UHDRS-TMS of 2.41 (SD 3.06).23
The index finger is crucial for many fine motor tasks and thus well-trained, minimizing the potential impact of motor learning. Variability of motor task execution has been observed in several tasks, e.g., grasping,24,25
Accordingly, variability of motor coordination appears to be a characteristic sign of HD.
Motor timing is another substantial component of motor coordination and thus precise motor functioning. There is also evidence for increased timing variability in HD,27
even in a premanifest state.28
Higher variability of isometric contraction duration was interpreted as an impairment of the speed control system in manifest HD.29
Impaired time estimation in premanifest gene carriers correlated with the estimated years until onset.30
Both speeded and metronome tapping assessments require motor timing efforts. However, the tasks were designed to be relatively simple, not only to be easily applicable in various settings, but also minimizing the impact of working memory dysfunction, which occurs in HD.31
Demanding more attention, the metronome tapping task could be more influenced by memory dysfunction and cognitive deficits than the speeded tapping task. Nevertheless, both tasks detected deficits in tapping across all subgroups.
TRACK-HD provides the unique opportunity to correlate motor performance with structural brain changes employing 2 complementary imaging techniques under standardized, blinded conditions. We acknowledge that cortical thickness data were limited to 2 sites using Siemens scanners to avoid differing image contrast and variation in segmentation routines. Also, different methods for multiple comparison correction were used for the 2 techniques, which may partially account for lacking cortical correlations in VBM. However, the parameters were optimized for each technique.
The results suggest a strong link between structure and motor function that has not yet been demonstrated in a comparable cohort in HD. Nevertheless, we acknowledge that these correlations may reflect a common association with overall HD progression rather than a direct functional association. We are aware that etiologic conclusions may only be derived from functional imaging techniques.32
The use of fMRI in multicenter studies remains a challenge for future developments, however, the literature provides us with ample evidence for an overlap between affected brain regions and tapping tasks.
Several brain regions predominantly affected in HD play an important role in internal time-keeping processes. Timing processes in self-paced tapping involve the SMA,33
dorsolateral prefrontal cortex,35
and basal ganglia.36,37
Functional compensation mechanisms have been postulated in premanifest HD.38,39
White matter changes were suggested to represent the earliest measurable changes in HD and precede cell death.3
Information processing speed assessed by intraindividual variability in a reaction time task was associated with decreased white matter volume.40
As a repetitive task, speeded tapping requires rapid execution of extension-flexion movements and thus rapid cerebral processing. Accordingly, we found speeded tapping measures to distinguish better between preHD-A and controls. Additionally, IOI (speeded tapping) correlated more strongly with internal capsule volume than ΔIOI (metronome tapping). Thus initial changes may be partially due to processes underlying movement preparation and execution, possibly white matter changes. Speeded tapping may therefore be of particular interest in the assessment of earliest changes. In contrast, the speeded tapping frequency showed the greatest contrast between preHD-B and HD1, and may serve as disease onset marker.
TD shows a distinct character with higher effect sizes in between-group and subgroup comparisons in speeded tapping; TD best distinguishes between preHD-A and controls among the metronome tapping variables. Interestingly, TD (speeded tapping) shows markedly stronger cortical thickness correlations than the other investigated variables; its specific distribution may thus be due to a stronger impact of cortical pathology.
In this cross-sectional study, force-transducer-based speeded and metronome tapping tasks provided sensitive, objective measures of motor dysfunction. Motor deficits in premanifest and premotor HD gene carriers were measurable in a subgroup of gene carriers with a median of 14 years (preHD-A) before estimated disease onset; earliest changes seem to be more sensitively detectable in speeded tapping, whereas some later stages of disease are more reliably distinguished by the metronome task. Tapping interval variability was the most robust quantitative motor measure and correlated with disease genotype and phenotype as well as structural changes within the brain. Although evidence for pathophysiologic changes underlying tapping impairment in HD is ample, distinct processes are diverse and remain speculative. Tapping devices are portable and can be easily applied in an outpatient setting by trained technicians. They may increase the sensitivity and reliability of motor measurements in clinical trials and supplement or even ultimately substitute categorical rating scales. Their sensitivity in detecting disease progression will be investigated prospectively in the TRACK-HD study.