M Say

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

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 Huntingtons 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.

Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease

Background Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntingtons disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. Methods There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. Results 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. Conclusions The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.

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

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 Huntingtons 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. Hum Brain Mapp, 2013.

The structural involvement of the cingulate cortex in premanifest and early Huntington's disease†‡§

The impact of Huntingtons disease neuropathology on the structure of the cingulate is uncertain, with evidence of both cortical enlargement and atrophy in this structure in early clinical disease. We sought to determine differences in cingulate volume between premanifest Huntingtons disease and early Huntingtons disease groups compared with controls using detailed manual measurements. Thirty controls, 30 subjects with premanifest Huntingtons disease, and 30 subjects with early Huntingtons disease were selected from the Vancouver site of the TRACK‐HD study. Subjects underwent 3 Tesla magnetic resonance imaging and motor, cognitive, and neuropsychiatric assessment. The cingulate was manually delineated and subdivided into rostral, caudal, and posterior segments. Group differences in volume and associations with performance on 4 tasks thought to utilize cingulate function were examined, with adjustment for appropriate covariates. Cingulate volumes were, on average, 1.7 mL smaller in early Huntingtons disease (P = .001) and 0.9 mL smaller in premanifest Huntingtons disease (P = .1) compared with controls. Smaller volumes in subsections of the cingulate were associated with impaired recognition of negative emotions (P = .04), heightened depression (P = .009), and worse visual working memory performance (P = .01). There was no evidence of associations between volume and ability on a performance‐monitoring task. This study disputes previous findings of enlargement of the cingulate cortex in Huntingtons disease and instead suggests that the cingulate undergoes structural degeneration during early Huntingtons disease with directionally consistent, nonsignificant differences seen in premanifest Huntingtons disease. Cingulate atrophy may contribute to deficits in mood, emotional processing, and visual working memory in Huntingtons disease.

Reliability and Factor Structure of the Short Problem Behaviors Assessment for Huntington’s Disease (PBA-s) in the TRACK-HD and REGISTRY studies

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntingtons disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohens kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Stability of white matter changes related to Huntington's disease in the presence of imaging noise: a DTI study

Movement artifacts and other sources of noise are a matter of concern particularly in the neuroimaging research of movement disorders such as Huntington’s disease (HD). Using diffusion weighted imaging (DWI) and fractional anisotropy (FA) as a compound marker of white matter integrity, we investigated the effect of movement on HD specific changes in magnetic resonance imaging (MRI) data and how post hoc compensation for it affects the MRI results. To this end, we studied by 3T MRI: 18 early affected, 22 premanifest gene-positive subjects, 23 healthy controls (50 slices of 2.3 mm thickness per volume, 64 diffusion-weighted directions (b = 1000 s/mm2), 8 minimal diffusion-weighting (b = 100 s/mm2)); and by 1.5 T imaging: 29 premanifest HD, 30 controls (40 axial slices of 2.3 mm thickness per volume, 61 diffusion-weighted directions (b = 1000 s/mm2), minimal diffusion-weighting (b = 100 s/mm2)). An outlier based method was developed to identify movement and other sources of noise by comparing the index DWI direction against a weighted average computed from all other directions of the same subject. No significant differences were observed when separately comparing each group of patients with and without removal of DWI volumes that contained artifacts. In line with previous DWI-based studies, decreased FA in the corpus callosum and increased FA around the basal ganglia were observed when premanifest mutation carriers and early affected patients were compared with healthy controls. These findings demonstrate the robustness of the FA value in the presence of movement and thus encourage multi-center imaging studies in HD.

The potential of composite cognitive scores for tracking progression in Huntington's disease

BACKGROUND Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. OBJECTIVE We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntingtons disease (HD) from natural decline in healthy controls. METHODS Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. RESULTS In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. CONCLUSIONS Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.

J03 The potential of a composite cognitive score for tracking progression in Huntington's disease

Background/Aims We investigated the ability of composite scores developed using statistical models to differentiate progressive cognitive deterioration in Huntingtons disease (HD) from natural decline in healthy controls. Methods Using data from TRACK-HD the optimal combination of 24-month changes in quantitative cognitive measures to differentiate early stage HD individuals from controls was determined using logistic regression. Composite scores were calculated from the parameters of the model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change in the composite over 24 months between premanifest and early stage HD groups and controls respectively. This ES was compared with those for individual cognitive outcomes and other measures used in HD research. 0.632 bootstrap methodology was used to allow for biases which result from developing and testing models in the same sample. Results The composite score gave an ES for the difference in rate of 24-month change between early HD and controls of 1.14 (95% CI 0.90 to 1.39): larger than that for any of the individual cognitive outcomes and those for the UHDRS TFC and TMS. Additionally the composite gave a statistically significant difference in the rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI 0.04 to 0.44), despite none of the individual cognitive outcomes having statistically significant ES over this period. Conclusions Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.

G03 Visuomotor integration deficits in premanifest and early manifest Huntington's disease in the TRACK-HD study

Background/aims Visuomotor integration deficits have been documented in manifest Huntingtons disease, with disproportionate impairments when indirect visual cues are relied upon. Visuomotor integration in premanifest gene expansion carriers has not been studied under such conditions. Methods 239 gene expansion carriers spanning over a decade before predicted onset until early stage disease and 122 control subjects were administered a circle tracing task. Performance was guided by direct or indirect visual cues. Outcome measures targeted accuracy, speed and speed of error detection and correction. Predictor variables included disease group and disease burden (age×(CAG−35.5)). Correlations with 3T MRI voxel based morphometry of grey and white matter volume reduction were computed. Results Increased HD disease burden was associated with reduced accuracy and slowed performance in both direct and indirect circle tracing conditions. Expansion carriers who were more than a decade before predicted clinical onset showed deficits in performance compared with controls. Comparing performance in the indirect with the direct condition, expansion carriers had a disproportionate increase in errors than controls. Expansion carriers showed greater latencies in detecting an error when heading away from target, and in correcting an error when heading back to target. Slowed performance in the indirect circle tracing condition was associated with grey matter volume reduction within the left somatosensory cortex in voxel based morphometry analyses. Conclusions Visuomotor integration deficits appear in expansion carriers many years before onset with the use of indirect visual cues especially appearing to impact adversely on accuracy. Slowed performance under indirect visual cues appears to be associated with atrophy of the left hemisphere somatosensory cortex, which likely reflects the proprioceptive demands of the task.

F14 Speeded tapping assesses progression of huntington's disease within one year—results from the track-HD study

Background Speeded (ST) and metronome (MT) tapping have been shown to be sensitive in distinguishing premanifest (preHD) and manifest (HD) stages of Huntingtons disease (HD) in the cross-sectional analysis of the TRACK-HD study, and to detect an early motor phenotype even more than 14 years before predicted disease manifestation. Aims To investigate whether ST and MT are able to track disease progression within a 12 month follow-up period. Methods Participants from the four TRACK-HD sites (ST/MT: controls: 120/122, preHD: 117/118, HD: 117/121) were instructed to perform two tapping tasks with their non-dominant index finger. In ST, they had to tap at maximal speed for 10s; in MT, they were instructed to continue a given tapping rate of 1.8 Hz for 10s. After one year, the assessments were repeated. The annual change in performance of gene-carriers was compared to controls and to each other. The variability of tapping intervals expressed as logarithmic standard deviations was calculated for the primary outcome measures (ie, inter-onset interval (IOI) & tap duration (TD) in ST, inter-onset intervals (ΔIOI) & mid-tap interval (ΔMTI) in MT). Results The annual change in IOI and TD for ST showed significant results for HD versus controls and HD versus preHD. ΔIOI and ΔMTI, both MT variables, failed to make this distinction. Conclusions ST is able to detect changes in manifest HD within only one year of follow-up and may thus be applicable as an outcome measure for disease modifying clinical trials in early manifest HD. Possible changes in preHD may require longer follow-up periods or larger cohorts. The hypothesis that force-transducer-based MT and ST tasks may track the progression of a premanifest motor phenotype will be tested in the TRACK-HD study.