The occipital lobe is an important visual processing region of the brain. Following consistent findings of early neural changes in the occipital lobe in Huntington's Disease (HD), we examined ...cortical thickness across four occipital regions in premanifest (preHD) and early HD groups compared with controls. Associations between cortical thickness in gene positive individuals and performance on six cognitive tasks, each with a visual component, were examined. In addition, the association between cortical thickness in gene positive participants and one non-visual motor task was also examined for comparison.
Cortical thickness was determined using FreeSurfer on T1-weighted 3T MR datasets from controls (N=97), preHD (N=109) and HD (N=69) from the TRACK-HD study. Regression models were fitted to assess between-group differences in cortical thickness, and relationships between performance on the cognitive tasks, the motor task and occipital thickness were examined in a subset of gene-positive participants (N=141).
Thickness of the occipital cortex in preHD and early HD participants was reduced compared with controls. Regionally-specific associations between reduced cortical thickness and poorer performance were found for five of the six cognitive tasks, with the strongest associations in lateral occipital and lingual regions. No associations were found with the cuneus. The non-visual motor task was not associated with thickness of any region.
The heterogeneous pattern of associations found in the present study suggests that occipital thickness negatively impacts cognition, but only in regions that are linked to relatively advanced visual processing (e.g., lateral occipital, lingual regions), rather than in basic visual processing regions such as the cuneus. Our results show, for the first time, the functional implications of occipital atrophy highlighted in recent studies in HD.
•Occipital regions performing basic and advanced visual processing examined in HD.•Regionally-specific reductions in cortical thickness found in pre- and symptomatic HD.•Significant associations between occipital thickness and scores on cognitive tasks.•Strongest associations with cognitive scores were for advanced visual processing regions.•Reduced thickness in advanced visual regions affects cognitive performance.
Background
Whole‐brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white ...matter (WM) microstructure across the timecourse of Huntington's disease (HD).
Methods
We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn‐HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24‐month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15‐month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract‐based spatial statistics. An optimized pipeline was employed to generate participant‐specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion‐carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS).
Results
HD expansion‐carriers from TrackOn‐HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion‐carriers.
Conclusion
The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution.
ObjectivesTo evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on ...rapid efficacy readouts for disease-modifying trials.Methods40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies.ResultsLongitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision.ConclusionsTo exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.
Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the ...current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials.
Using a cohort of early Huntington's disease (HD) patients (
= 46) and controls (
= 35), we compared the performance of four automated segmentation tools (FIRST, FreeSurfer, STEPS, MALP-EM) with manual delineation for generating cross-sectional caudate volume, a region known to be vulnerable in HD. We then examined the effect of each of these baseline regions on the ability to detect change over 15 months using the established longitudinal Caudate Boundary Shift Integral (cBSI) method, an automated longitudinal pipeline requiring a baseline caudate region as an input.
All tools, except Freesurfer, generated significantly smaller caudate volumes than the manually derived regions. Jaccard indices showed poorer levels of overlap between each automated segmentation and manual delineation in the HD patients compared with controls. Nevertheless, each method was able to demonstrate significant group differences in volume (
< 0.001). STEPS performed best qualitatively as well as quantitively in the baseline analysis. Caudate atrophy measures generated by the cBSI using automated baseline regions were largely consistent with those derived from a manually segmented baseline, with STEPS providing the most robust cBSI values across both control and HD groups.
Atrophy measures from the cBSI were relatively robust to differences in baseline segmentation technique, suggesting that fully automated pipelines could be used to generate outcome measures for clinical trials.
Background: Recognition of negative emotions is impaired in Huntington's Disease (HD). It is unclear whether these emotion-specific problems are driven by dissociable cognitive deficits, emotion ...complexity, test cue difficulty, or visuoperceptual impairments. This study set out to further characterise emotion recognition in HD by comparing patterns of deficits across stimulus modalities; notably including for the first time in HD, the more ecologically and clinically relevant modality of film clips portraying dynamic facial expressions. Methods: Fifteen early HD and 17 control participants were tested on emotion recognition from static facial photographs, non-verbal vocal expressions and one second dynamic film clips, all depicting different emotions. Results: Statistically significant evidence of impairment of anger, disgust and fear recognition was seen in HD participants compared with healthy controls across multiple stimulus modalities. The extent of the impairment, as measured by the difference in the number of errors made between HD participants and controls, differed according to the combination of emotion and modality (p=0.013, interaction test). The largest between-group difference was seen in the recognition of anger from film clips. Conclusions: Consistent with previous reports, anger, disgust and fear were the most poorly recognised emotions by the HD group. This impairment did not appear to be due to task demands or expression complexity as the pattern of between-group differences did not correspond to the pattern of errors made by either group; implicating emotion-specific cognitive processing pathology. There was however evidence that the extent of emotion recognition deficits significantly differed between stimulus modalities. The implications in terms of designing future tests of emotion recognition and care giving are discussed.
Huntington's disease is marked by progressive neuroanatomical changes, assumed to underlie the development of the disease's characteristic symptoms. Previous work has demonstrated longitudinal ...macrostructural white-matter atrophy, with some evidence of microstructural change focused in the corpus callosum.
To more accurately characterise longitudinal patterns, we examined white matter microstructural change using Diffusion Tensor Imaging (DTI) data from three timepoints over a 15 month period.
In 48 early-stage HD patients and 36 controls from the multi-site PADDINGTON project, diffusion tensor imaging (DTI) was employed to measure changes in fractional anisotropy (FA) and axial (AD) and radial diffusivity (RD) in 24 white matter regions-of-interest (ROIs).
Cross-sectional analysis indicated widespread baseline between-group differences, with significantly decreased FA and increased AD and RD found in HD patients across multiple ROIs. Longitudinal rates of change differed significantly between HD patients and controls in the genu and body of corpus callosum, corona radiata and anterior limb of internal capsule. Change in RD in the body of the corpus callosum was significantly associated with baseline disease burden, but other clinical associations were not significant.
We detected subtle longitudinal white matter changes in early HD patients. Progressive white matter abnormalities in HD may not be uniform throughout the brain, with some areas remaining static in the early symptomatic phase. Longer assessment periods across disease stages will help map this progressive trajectory.
Recognition of negative emotions is impaired in Huntington׳s Disease (HD). It is unclear whether these emotion-specific problems are driven by dissociable cognitive deficits, emotion complexity, test ...cue difficulty, or visuoperceptual impairments. This study set out to further characterise emotion recognition in HD by comparing patterns of deficits across stimulus modalities; notably including for the first time in HD, the more ecologically and clinically relevant modality of film clips portraying dynamic facial expressions.
Fifteen early HD and 17 control participants were tested on emotion recognition from static facial photographs, non-verbal vocal expressions and one second dynamic film clips, all depicting different emotions.
Statistically significant evidence of impairment of anger, disgust and fear recognition was seen in HD participants compared with healthy controls across multiple stimulus modalities. The extent of the impairment, as measured by the difference in the number of errors made between HD participants and controls, differed according to the combination of emotion and modality (p=0.013, interaction test). The largest between-group difference was seen in the recognition of anger from film clips.
Consistent with previous reports, anger, disgust and fear were the most poorly recognised emotions by the HD group. This impairment did not appear to be due to task demands or expression complexity as the pattern of between-group differences did not correspond to the pattern of errors made by either group; implicating emotion-specific cognitive processing pathology. There was however evidence that the extent of emotion recognition deficits significantly differed between stimulus modalities. The implications in terms of designing future tests of emotion recognition and care giving are discussed.
•Recognition of negative emotions is impaired in Huntington׳s Disease.•It is unclear whether this deficit is consistent across stimulus modalities.•Emotion recognition from photo, vocal and film cues was tested in HD and controls.•Varying patterns of impairment were found across modalities.•Emotion recognition deficits are valence and modality specific in HD.
Macro- and micro-structural neuroimaging measures provide valuable information on the pathophysiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of ...microstructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two.
40 controls and 61 early HD subjects underwent 3 T MRI (T1- and diffusion-weighted), as part of the PADDINGTON study. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial- and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others.
Macrostructural measures showed decreased regional and global volume in HD (p < 0.001); except the ventricles which were enlarged (p < 0.01). In HD, FA was increased in the deep grey-matter structures (p < 0.001), and decreased in the WM (CC, p = 0.035; WM, p = 0.053); diffusivity metrics (MD, RD, AD) were increased for all brain regions (p < 0.001). The largest effect sizes were for putamen volume, caudate volume and putamen diffusivity (AD, RD and MD); each was significantly larger than those for all other metrics (p < 0.05).
The highest performing macro- and micro-structural metrics had similar sensitivity to HD pathology quantified via effect sizes. Region-of-interest may be more important than imaging modality, with deep grey-matter regions outperforming the CC and global measures, for both volume and diffusivity. FA appears to be relatively insensitive to disease effects.
Identifying markers able to characterise the progression of Huntington's Disease (HD) is of great importance to the HD research community, as such markers may provide valuable outcome measures in ...future clinical trials. Neuroimaging measures are obvious candidates because of their clear relevance to the neuropathology of the disease. Many also show improved precision and sensitivity compared with standard functional scales. This review summarizes findings from the wealth of longitudinal imaging studies in the literature, focusing on the most widely available imaging modalities: structural MRI (volumetric and diffusion imaging), functional MRI and PET. We discuss the longitudinal sensitivity, reproducibility and feasibility of each imaging modality for use in clinical trials.
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