Ellen P. Hart

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.

Reduced functional brain connectivity prior to and after disease onset in Huntington's disease.

Background Huntingtons disease (HD) is characterised by both regional and generalised neuronal cell loss in the brain. Investigating functional brain connectivity patterns in rest in HD has the potential to broaden the understanding of brain functionality in relation to disease progression. This study aims to establish whether brain connectivity during rest is different in premanifest and manifest HD as compared to controls. Methods At the Leiden University Medical Centre study site of the TRACK-HD study, 20 early HD patients (disease stages 1 and 2), 28 premanifest gene carriers and 28 healthy controls underwent 3 T MRI scanning. Standard and high-resolution T1-weighted images and a resting state fMRI scan were acquired. Using FSL, group differences in resting state connectivity were examined for eight networks of interest using a dual regression method. With a voxelwise correction for localised atrophy, group differences in functional connectivity were examined. Results Brain connectivity of the left middle frontal and pre-central gyrus, and right post central gyrus with the medial visual network was reduced in premanifest and manifest HD as compared to controls (0.05 > p > 0.0001). In manifest HD connectivity of numerous widespread brain regions with the default mode network and the executive control network were reduced (0.05 > p > 0.0001). Discussion Brain regions that show reduced intrinsic functional connectivity are present in premanifest gene carriers and to a much larger extent in manifest HD patients. These differences are present even when the potential influence of atrophy is taken into account. Resting state fMRI could potentially be used for early disease detection in the premanifest phase of HD and for monitoring of disease modifying compounds.

Elevated brain iron is independent from atrophy in Huntington's Disease

Increased iron in subcortical structures in patients with Huntingtons Disease (HD) has been suggested as a causal factor of neuronal degeneration. The present study examines iron accumulation, measured using magnetic resonance imaging (MRI), in premanifest gene carriers and in early HD patients as compared to healthy controls. In total 27 early HD patients, 22 premanifest gene carriers and 25 healthy controls, from the Leiden site of the TRACK-HD study, underwent 3T MRI including high resolution 3D T(1)- and T(2)-weighted and asymmetric spin echo (ASE) sequences. Magnetic Field Correlation (MFC) maps of iron levels were constructed to assess magnetic field inhomogeneities and compared between groups in the caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, accumbens nucleus, and thalamus. Subsequently the relationship of MFC value to volumetric data and disease state was examined. Higher MFC values were found in the caudate nucleus (p<0.05) and putamen (p<0.005) of early HD compared to controls and premanifest gene carriers. No differences in MFC were found between premanifest gene carriers and controls. MFC in the caudate nucleus and putamen is a predictor of disease state in HD. No correlation was found between the MFC value and volume of these subcortical structures. We conclude that Huntingtons disease patients in the early stages of the disease, but not premanifest gene carriers, have higher iron concentrations in the caudate nucleus and putamen. We have demonstrated that the iron content of these structures relates to disease state in gene carriers, independently of the measured volume of these structures.

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.

Longitudinal resting state fMRI analysis in healthy controls and premanifest Huntington's disease gene carriers: a three-year follow-up study.

Background: We previously demonstrated that in the premanifest stage of Huntingtons disease (preHD), a reduced functional connectivity exists compared to healthy controls. In the current study, we look at possible changes in functional connectivity occurring longitudinally over a period of 3 years, with the aim of assessing the potential usefulness of this technique as a biomarker for disease progression in preHD.

Better global and cognitive functioning in choreatic versus hypokinetic-rigid Huntington's disease

Understanding the relation between predominantly choreatic and hypokinetic‐rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntingtons disease.

Magnetization transfer imaging in premanifest and manifest huntington disease: a 2-year follow-up.

BACKGROUND AND PURPOSE: MTI is a quantitative MR imaging technique that has recently demonstrated structural integrity differences between controls and patients with HD. Potentially, MTI can be used as a biomarker for monitoring disease progression. To establish the value of MTI as a biomarker, we aimed to examine the change in these measures during the course of HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 25 controls, 21 premanifest gene carriers, and 21 patients with manifest HD participated at baseline and during a 2-year follow-up visit. Brain segmentation of the cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed by using the automated tools FAST and FIRST in FSL. Individual MTR values were calculated from these regions, and MTR histograms were constructed. RESULTS: In the premanifest HD group stage “far from disease onset,” a significant increase in MTR peak height of the putamen was observed with time. During the manifest HD stage, neither the mean MTR nor the MTR peak height showed a significant change during a 2-year follow-up. CONCLUSIONS: MTI-derived measures are not suitable for monitoring in Huntington disease during a 2-year period because there was no decrease in structural integrity detected in any of the manifest HD groups longitudinally. The finding of increased putaminal MTR peak height in the premanifest far from disease onset group could relate to a predegenerative process, compensatory mechanisms, or aberrant development but should be interpreted with caution until future studies confirm this finding.

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.

Longitudinal pilot‐study of Sustained Attention to Response Task and P300 in manifest and pre‐manifest Huntington's disease

BACKGROUND Earlier research has found cross-sectional attentional control deficits in manifest Huntingtons disease (HD) using neuropsychological testing combined with simultaneous P300 registration. In the current pilot-study, we investigate attentional control in pre-manifest and manifest HD over a 3-year follow-up period. METHOD Five manifest HD (MHD), 9 pre-manifest HD (PMHD), and 12 control subjects were included. Sustained Attention to Response task (SART) and P300 registration resulted in number of errors, reaction time (RT), and P300 amplitude and latency. RT change patterns surrounding No-go trials were also investigated. Within-subject differences were tested using paired-samples t-tests and between-group results with ANCOVA on delta scores (follow-up--baseline scores). RESULTS Manifest HD made more errors and were slower than controls and PMHD. Longitudinally, MHD showed an overall RT increase and a specific slowing on trials preceding a correct No-go trial (within-group effects). The latter was also seen in PMHD. P300 latency prolongation was found for controls on No-go and for MHD on Go trials. On specific trials surrounding both correct and incorrect No-go trials, MHD became significantly slower over time than controls and PMHD (between-group effects). CONCLUSIONS Over 3-years, MHD subjects became slower on the SART and showed a prolongation of P300 latency on specific SART trials. Specific slowing of performance over time was also seen in PMHD, suggestive of compensatory mechanisms in this group.

Motor dysfunction influence on executive functioning in manifest and premanifest Huntington's disease

Motor disturbances can be present in both manifest and premanifest Huntingtons disease (HD). We aimed to investigate the role of motor functioning on executive functioning to better understand the progression of cognitive dysfunction in HD. Forty patients with manifest HD, 21 patients with premanifest HD, and a group of 28 controls were tested twice with a 1‐year interval. For the Symbol Digit Modalities Test and the Figure Fluency Test, extra conditions were designed to measure motor involvement. Subtraction of this motor score from the original test score resulted in isolation of the cognitive component. Groups were compared on motor, cognitive, and original test scores using multilevel regression analysis. Manifest patients had lower baseline scores of 0.53 standard deviations (SD) on the original Symbol Digit Modalities Test (P = 0.03) and 0.71 SD on the motor isolation part (P = 0.006), and they showed a deterioration of 0.47 SD over 1 year of follow‐up on the original Symbol Digit Modalities Test (P = 0.001) compared with controls. Premanifest patients had lower baseline scores of 0.67 SD on the Symbol Digit Modalities motor part (P = 0.008) and deterioration of 0.48 SD on the original (P = 0.001) and cognitive isolation (P = 0.02) parts. Secondary analyses revealed that the premanifest deterioration resulted from the close‐to‐predicted‐onset group. Motor disturbances have a negative influence on performance on the Symbol Digit Modalities Test. Isolation of the cognitive component of this test revealed cognitive deterioration in the premanifest group only, caused by deteriorating scores for patients who were close to their predicted clinical disease onset. The Figure Fluency Test did not prove sensitive to cognitive change.