[Show abstract][Hide abstract] ABSTRACT: Background:
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 cognitive tasks, the motor task and occipital thickness was 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.
[Show abstract][Hide abstract] ABSTRACT: Background:
Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population.
We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD.
DTI data were collected from 39 premanifest and 45 early-HD participants in the TrackHD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO).
For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain.
We demonstrate that white matter changes associated with both depression and irritability in HD occur at different stages of disease progression concomitant with their clinical presentation.
Journal of Huntington's disease 09/2015; 4(3):239-249. DOI:10.3233/JHD-150160
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease can be predicted many years before symptom onset, and thus makes an ideal model for studying the earliest mechanisms of neurodegeneration. Diffuse patterns of structural connectivity loss occur in the basal ganglia and cortex early in the disease. However, the organizational principles that underlie these changes are unclear. By understanding such principles we can gain insight into the link between the cellular pathology caused by mutant huntingtin and its downstream effect at the macroscopic level. The 'rich club' is a pattern of organization established in healthy human brains, where specific hub 'rich club' brain regions are more highly connected to each other than other brain regions. We hypothesized that selective loss of rich club connectivity might represent an organizing principle underlying the distributed pattern of structural connectivity loss seen in Huntington's disease. To test this hypothesis we performed diffusion tractography and graph theoretical analysis in a pseudo-longitudinal study of 50 premanifest and 38 manifest Huntington's disease participants compared with 47 healthy controls. Consistent with our hypothesis we found that structural connectivity loss selectively affected rich club brain regions in premanifest and manifest Huntington's disease participants compared with controls. We found progressive network changes across controls, premanifest Huntington's disease and manifest Huntington's disease characterized by increased network segregation in the premanifest stage and loss of network integration in manifest disease. These regional and whole brain network differences were highly correlated with cognitive and motor deficits suggesting they have pathophysiological relevance. We also observed greater reductions in the connectivity of brain regions that have higher network traffic and lower clustering of neighbouring regions. This provides a potential mechanism that results in a characteristic pattern of structural connectivity loss targeting highly connected brain regions with high network traffic and low clustering of neighbouring regions. Our findings highlight the role of the rich club as a substrate for the structural connectivity loss seen in Huntington's disease and have broader implications for understanding the connection between molecular and systems level pathology in neurodegenerative disease.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To longitudinally investigate the connectome in different stages of Huntington's disease (HD) by applying graph theoretical analysis to diffusion MRI data.
Experimental design: We constructed weighted structural networks and calculated their topological properties. Twenty-two premanifest (preHD), 10 early manifest HD and 24 healthy controls completed baseline and 2 year follow-up scans. We stratified the preHD group based on their predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. We collected clinical and behavioural measures per assessment time point.
Principle observations: We found a significant reduction over time in nodal betweenness centrality both in the early manifest HD and preHD-B groups as compared to the preHD-A and control groups, suggesting a decrease of importance of specific nodes to overall network organization in these groups (FDR adjusted ps b 0.05). Additionally , we found a significant longitudinal decrease of the clustering coefficient in preHD when compared to healthy controls (FDR adjusted ps 0.05), which can be interpreted as a reduced capacity for internodal information processing at the local level. Furthermore, we demonstrated dynamic changes to hub-status loss and gain both in preHD and early manifest HD. Finally, we found significant cross-sectional as well as longitudinal relationships between graph metrics and clinical and neurocognitive measures.
Conclusions: This study demonstrates divergent longitudinal changes to the connectome in (pre) HD compared to healthy controls. This provides novel insights into structural correlates associated with clinical and cognitive functions in HD and possible compensatory mechanisms at play in preHD.
[Show abstract][Hide abstract] ABSTRACT: Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.
PLoS ONE 07/2015; 10(7):e0131573. DOI:10.1371/journal.pone.0131573 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Methods:
Previously published case reports on HTT intermediate repeat sizes and all cases from the Netherlands with an IA were reviewed for clinical symptoms and signs.
Four patients had a clinical presentation of Huntington's disease and an IA out of ten reported cases in literature. Between 2001 and 2012, 1,690 patients were tested for HD in the Netherlands. One case out of 60 with an IA had a phenotype resembling HD, but had already been published in a case report.
Given the high background frequency of intermediate alleles in several populations, the possibility of developing HD would have huge implications for 1-7% of the normal population. It is possible that IAs present as an endophenotype with the potential of subsequent clinical manifestations. However, given the scarcity of convincing cases, the lack of convincing biological evidence for pathogenicity of intermediate alleles, and many genes still to be discovered for HD mimics, we find that it is premature to claim that IAs can cause HD. We recommend systematic follow up of this group of individuals and if possible brain pathology for confirmation or exclusion of HD.
Journal of Huntington's disease 07/2015; 4(2):141-148. DOI:10.3233/JHD-140120
[Show abstract][Hide abstract] ABSTRACT: Objective:
We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration.
Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age.
Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug naïve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors.
The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies.
Journal of Huntington's disease 07/2015; 4(2):131-140. DOI:10.3233/JHD-150143
[Show abstract][Hide abstract] ABSTRACT: A key neuropsychiatric symptom of Huntington's disease, irritability, contributes to a decline in functioning and to great distress in both patients and their caregivers. To identify mutation carriers prone to the development of irritability, this study aimed to investigate the course and temporal relationships between irritability and other neuropsychiatric symptoms. A cohort of 90 mutation carriers was followed for 2 years. Using the Irritability Scale, the incidence of irritability was 23%, whereas irritability persisted in 70% of the mutation carriers with irritability at baseline. An increase in irritability was strongly associated with an increase in apathy.
The Journal of Neuropsychiatry and Clinical Neurosciences 06/2015; 27(3):appineuropsych14030051. DOI:10.1176/appi.neuropsych.14030051 · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's 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.
The Journal of Neuropsychiatry and Clinical Neurosciences 02/2015; 27(1):59-64. DOI:10.1176/appi.neuropsych.13070169 · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To 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.
40 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.
Longitudinal 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.
To 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.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To investigate both cross-sectional and time-related changes of striatal and whole-brain microstructural properties in different stages of Huntington's disease (HD) using diffusion tensor imaging.
From the TRACK-HD study, premanifest gene carriers (preHD), early manifest HD and controls were scanned at baseline and 2-year follow-up. Stratification of the preHD group into a far (preHD-A) and near (preHD-B) to predicted disease onset was performed. Age-corrected histograms of whole-brain white matter (WM), gray matter (GM) and striatal diffusion measures were computed and normalised by the number of voxels in each subject's data set.
Higher cross-sectional mean, axial and radial diffusivities were found in both WM (P ≤ 0.001) and GM (P ≤ 0.001) of the manifest HD compared to the preHD and control groups. In preHD, only WM axial diffusivity (AD) was higher than in controls (P ≤ 0.01). This finding remained valid only in preHD-B (P ≤ 0.001). AD was also higher in the striatum of preHD-B compared to controls and preHD-A (P ≤ 0.01). Fractional anisotropy (FA) lacked sensitivity in differentiating between the groups. Histogram peak heights were generally lower in manifest HD compared to the preHD and control groups. No longitudinal differences were found in the degree of diffusivity change between the groups in the two year follow-up. There was a significant relationship between diffusivity and neurocognitive measures.
Alterations in cross-sectional diffusion profiles between manifest HD subjects and controls were evident, both in whole-brain and striatum. In the preHD stage, only AD alterations were found, a finding suggesting that this metric is a sensitive marker for early change in HD prior to disease manifestation. The individual diffusivities were superior to FA in revealing pathologic microstructural brain alterations. Diffusion measures were well related to clinical functioning and disease stage.
Human Brain Mapping 02/2015; 36(6). DOI:10.1002/hbm.22756 · 5.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington’s disease (HD) mutation carriers. In non-HD populations, alterations in HPA axis activity have been associated with the presence of depression and suicidality.
Aims To compare HPA axis activity between HD mutation carriers and controls and to investigate its association with depressive symptoms and suicidality.
Methods Salivary cortisol levels at seven timepoints, and both depressive symptoms and suicidality according to the Problem Behaviours Assessment were determined in 48 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in basal and post-dexamethasone parameters of HPA axis activity between these groups and its associations with depressive symptoms and suicidality were analysed by multilevel regression analysis.
Results Pre-motor symptomatic mutation carriers had a significantly higher area under the ground to the increase (AUCi) compared with motor symptomatic mutation carriers, while none of the parameters of HPA axis activity were significantly different between mutation carriers and controls. In the entire HD group, there was no association between parameters of HPA axis activity and depressive symptoms or suicidality. When stratifying mutation carriers in pre-, early (Total Functional Capacity (TFC) stage 1 and 2) and late (TFC stage 3–5) motor symptomatic stages, there was a significant association between a higher AUCi and depressive symptoms in both pre- and early motor symptomatic mutation carriers and between a lower cortisol suppression ratio and suicidality in pre-motor symptomatic mutation carriers.
Conclusions Exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity might explain the lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-, early and late symptomatic mutation carriers.
Journal of Neuroendocrinology 01/2015; 27(3). DOI:10.1111/jne.12255 · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the presence of thoughts or wishes for the end of life in patients with Huntington's disease (HD) or identified gene carriers (further mentioned together as patients). A custom-made questionnaire, based on previous qualitative research, was sent out to 242 patients with HD and identified gene carriers. Presence of wishes was investigated and correlated to demographic and clinical characteristics. A total of 134 patients (55 %) returned the questionnaire. 101 respondents (75 %) reported to have some kind of thoughts or wishes for the end of life. For 15 respondents (11 %) these thoughts concerned care; 86 respondents (64 %) reported to have also thoughts about euthanasia or physician-assisted suicide (PAS). The presence of any thoughts about the end of life was significantly related to being familiar with HD in the family, but not related to any other demographic or clinical variable. Participants with thoughts specifically about euthanasia or PAS were of higher education and in earlier stages of the disease than participants without such thoughts. Thoughts or wishes for the end of life are present amongst patients with HD. These thoughts include euthanasia or PAS in a majority of the respondents. It is suggested that prudential addressing of these issues may enhance the doctor-patient relationship.
Journal of Neurology 09/2014; 261(11). DOI:10.1007/s00415-014-7479-4 · 3.38 Impact Factor