Raymund A.C. Roos

Leiden University, Leyden, South Holland, Netherlands

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Publications (187)748.85 Total impact

  • Journal of Huntington's disease 09/2015; 4(3):239-249. DOI:10.3233/JHD-150160
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    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.
    Brain 09/2015; DOI:10.1093/brain/awv259 · 9.20 Impact Factor
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    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.
    Clinical neuroimaging 07/2015; 9. DOI:10.1016/j.nicl.2015.07.003 · 2.53 Impact Factor
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    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
  • 07/2015; 3(7):499-500. DOI:10.1016/S2213-8587(15)00217-X
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    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. Results: 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. Conclusion: 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
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    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. Methods: 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. Results: 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. Conclusions: 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
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    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
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    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
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    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.
    Journal of Neurology Neurosurgery & Psychiatry 02/2015; DOI:10.1136/jnnp-2014-309768 · 6.81 Impact Factor
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    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. Experimental design: 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. Principle observations: 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. Conclusions: 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
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    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
  • Suzanne J Booij · Aad Tibben · Dick P Engberts · Raymund A C Roos
    Journal of Huntington's disease 10/2014; 3(3):229-32. DOI:10.3233/JHD-140098
  • Joseph Jankovic · Raymund A.C. Roos
    Movement Disorders 09/2014; 29(11). DOI:10.1002/mds.25996 · 5.68 Impact Factor
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    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
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    ABSTRACT: Background Little is known about the swallowing disturbances of patients with Huntington's disease; therefore, we developed the Huntington's Disease Dysphagia Scale.Methods The scale was developed in four stages: (1) item generation, (2) comprehension testing, (3) evaluation of reliability, (4) item reduction and validity testing. The questionnaire was presented twice to 50 Huntington's disease patients and their caregivers. The Kruskal-Wallis test was used to evaluate whether the severity of swallowing difficulties increased with advancing disease. Pearson's correlation coefficient was used to examine the construct validity with the Swallowing Disturbance Questionnaire.ResultsThe final version contained 11 items with five response options and exhibited a Cronbach's alpha coefficient of 0.728. The severity of swallowing difficulties was significantly higher in more advanced Huntington's disease. The correlation with the Swallowing Disturbance Questionnaire was 0.734.Conclusion We developed a valid and reliable 11-item scale to measure the severity of dysphagia in Huntington's disease. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 09/2014; 29(10). DOI:10.1002/mds.25922 · 5.68 Impact Factor
  • Practical Neurology 08/2014; 15(1). DOI:10.1136/practneurol-2013-000790
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    ABSTRACT: Background: We previously demonstrated that in the premanifest stage of Huntington's 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. Methods: Twenty-two preHD and 17 healthy control subjects completed resting state functional magnetic resonance imaging (fMRI) scans in two visits with 3 years in between. Differences in resting state connectivity were examined for eight networks of interest using FSL with three different analysis types: a dual regression method, region of interest approach, and an independent component analysis. To evaluate a possible combined effect of gray matter volume change and the change in blood oxygenation level dependent signal, the analysis was performed with and without voxel-wise correction for gray matter volume. To evaluate possible correlations between functional connectivity change and the predicted time to disease onset, the preHD group was classed as preHD-A if ≥10.9 years and preHD-B if <10.9 years from predicted disease onset. Possible correlations between burden of pathology score and functional connectivity change in preHD were also assessed. Finally, longitudinal change in whole brain and striatal volumetric measures was assessed in the studied cohort. Results: Longitudinal analysis of the resting state-fMRI (RS-fMRI) data revealed no differences in the degree of connectivity change between the groups over a period of 3 years, though a significantly higher rate of striatal atrophy was found in the preHD group compared to controls in the same period. Discussion: Based on the results found in this study, the provisional conclusion is that RS-fMRI lacks sensitivity in detecting changes in functional connectivity in HD gene carriers prior to disease manifestation over a 3-year follow-up period.
    Human Brain Mapping 08/2014; 36(1). DOI:10.1002/hbm.22616 · 5.97 Impact Factor
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    Daniel J. Wamelen · N. Ahmad Aziz · Raymund A.C. Roos · Dick F. Swaab
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    ABSTRACT: Unintended weight loss, sleep and circadian disturbances and autonomic dysfunction are prevalent features of Huntington's disease (HD), an autosomal dominantly inherited neurodegenerative disorder caused by an expanded CAG repeat sequence in the HTT gene. These features form a substantial contribution to disease burden in HD patients and seem to be accompanied by a number of neuroendocrine and metabolic changes, pointing towards hypothalamic pathology as a likely underlying mechanism. Neuronal inclusion bodies of mutant huntingtin, hallmarks of the disease, occur throughout the hypothalamus, and indicate local mutant huntingtin expression which could interfere with hypothalamic neuropeptide production. Also, several genetic rodent models of HD show features which could be related to hypothalamic pathology, such as weight loss and circadian rhythm disturbances. In these rodents several hypothalamic neuropeptide populations are affected. In the present review we will summarize the changes in genetic rodent models of HD for individual hypothalamic nuclei, compare these observations to the hypothalamic changes that occur in HD patients, and make an inventory of the work that still needs to be done. Surprisingly, there is only limited overlap in the hypothalamic changes reported in HD patients and genetic rodent models. At present, the only similarity between the hypothalamic alterations in HD patients and genetic rodent models is the decrease in the number of orexin-expressing neurones in the lateral hypothalamus. Possible reasons for these discrepancies, as well as potential consequences for the development of novel therapeutic strategies will be discussed.This article is protected by copyright. All rights reserved.
    Journal of Neuroendocrinology 07/2014; 26(11). DOI:10.1111/jne.12190 · 3.14 Impact Factor
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Publication Stats

4k Citations
748.85 Total Impact Points


  • 1991–2015
    • Leiden University
      • Molecular Cell Biology Group
      Leyden, South Holland, Netherlands
  • 1983–2015
    • Leiden University Medical Centre
      • • Department of Neurology
      • • Department of Radiology
      • • Department of Psychiatry
      Leyden, South Holland, Netherlands
  • 2013
    • Netherlands Institute for Neuroscience
      Amsterdamo, North Holland, Netherlands
  • 2010–2011
    • University of Pittsburgh
      • Department of Physical Medicine and Rehabilitation
      Pittsburgh, PA, United States
    • Bronovo Hospital
      's-Gravenhage, South Holland, Netherlands
  • 2005
    • University of Kuopio
      Kuopio, Northern Savo, Finland
  • 2004
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 2002
    • Erasmus Universiteit Rotterdam
      • Department of Clinical Genetics
      Rotterdam, South Holland, Netherlands
  • 1996
    • University of California, Davis
      • Department of Neurology
      Davis, California, United States
  • 1992
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands