Raymund A C Roos

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (171)704.65 Total impact

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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; DOI:10.1176/appi.neuropsych.14030051 · 2.77 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 · 5.58 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 designFrom 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 observationsHigher 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. Hum Brain Mapp, 2015. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 02/2015; DOI:10.1002/hbm.22756 · 6.92 Impact Factor
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    ABSTRACT: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. This study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality.To this end, salivary cortisol concentrations at 7 time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers, and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses.There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi) compared with motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early, and advanced disease stages, betas differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse non-significant association in advanced disease stage mutation carriers.The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early, and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study.This article is protected by copyright. All rights reserved.
    Journal of Neuroendocrinology 01/2015; 27(3). DOI:10.1111/jne.12255 · 3.51 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 01/2015; 27(1):59-64. DOI:10.1176/appi.neuropsych.13070169 · 2.77 Impact Factor
  • Joseph Jankovic, Raymund A.C. Roos
    Movement Disorders 09/2014; 29(11). DOI:10.1002/mds.25996 · 5.63 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 · 3.84 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 · 5.63 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. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 08/2014; 36(1). DOI:10.1002/hbm.22616 · 6.92 Impact Factor
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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 · 3.51 Impact Factor
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    ABSTRACT: The clinical diagnosis of Huntington's disease (HD) is based on the motor symptoms, although these can be preceded by cognitive and behavioral changes. Biomarker studies have shown that structural imaging modalities are useful biomarkers of HD onset, while functional imaging measures have been studied less often for this purpose. Our aim was to investigate the combined value of 18-fluorodesoxyglucose (FDG)-PET and cognitive measures as biomarkers of HD onset. Twenty-two premanifest mutation carriers of HD (PMCs) and 11 healthy controls were assessed twice with FDG-PET scan, neurological and neuropsychological assessments over a 2-year interval. Seventeen PMCs had an additional third neurological evaluation, 10 years after baseline. Disease load was defined as the probability of motor onset within 5 years. Metabolism in putamen, caudate and pallidum of PMCs was significantly lower than that of controls, at both assessments. Almost half of the PMCs had converted to manifest HD 10 years later and all converters had low average or abnormal putaminal metabolism at 2 year follow-up. In contrast, all PMCs with normal putaminal metabolism at 2 year follow-up remained premanifest during the following 8 years. Furthermore, glucose metabolism of putamen explained a substantial part of the variance in disease load. A composite score of psychomotor tests contributed significantly to the prediction model as well, while cognitive performance was comparable for PMCs and controls. We conclude that in future clinical trials a combination of psychomotor tests and putaminal glucose metabolism may be used to identify PMCs close to motor onset of HD.
    Journal of Neurology 04/2014; 261(7). DOI:10.1007/s00415-014-7350-7 · 3.84 Impact Factor
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    ABSTRACT: Automated analysis of structural magnetic resonance images is a promising way to improve early detection of neurodegenerative brain diseases. Clinical applications of such methods involve multiple scanners with potentially different hardware and/or acquisition sequences and demographically heterogeneous groups. To improve classification performance, we propose to correct effects of subject-specific covariates (such as age, total intracranial volume, and sex) as well as effects of scanner by using a non-linear Gaussian process model. To test the efficacy of the correction, we performed classification of carriers of the genetic mutation leading to Huntington's disease (HD) versus healthy controls. Half of the HD carriers were free of typical HD symptoms and had an estimated 5 to 20 years before onset of clinical symptoms, thus providing a model for preclinical diagnosis of a neurodegenerative disease.
    NeuroImage 04/2014; 98. DOI:10.1016/j.neuroimage.2014.04.057 · 6.13 Impact Factor
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    ABSTRACT: Motor disturbances can be present in both manifest and premanifest Huntington's 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. © International Parkinson and Movement Disorder Society © 2014 International Parkinson and Movement Disorder Society.
    Movement Disorders 03/2014; 29(3). DOI:10.1002/mds.25806 · 5.63 Impact Factor
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    ABSTRACT: PURPOSE: To develop a framework for quantitative detection of between-group textural differences in ultrahigh field T2 *-weighted MR images of the brain. MATERIALS AND METHODS: MR images were acquired using a three-dimensional (3D) T2 *-weighted gradient echo sequence on a 7 Tesla MRI system. The phase images were high-pass filtered to remove phase wraps. Thirteen textural features were computed for both the magnitude and phase images of a region of interest based on 3D Gray-Level Co-occurrence Matrix, and subsequently evaluated to detect between-group differences using a Mann-Whitney U-test. We applied the framework to study textural differences in subcortical structures between premanifest Huntington's disease (HD), manifest HD patients, and controls. RESULTS: In premanifest HD, four phase-based features showed a difference in the caudate nucleus. In manifest HD, 7 magnitude-based features showed a difference in the pallidum, 6 phase-based features in the caudate nucleus, and 10 phase-based features in the putamen. After multiple comparison correction, significant differences were shown in the putamen in manifest HD by two phase-based features (both adjusted P values = 0.04). CONCLUSION: This study provides the first evidence of textural heterogeneity of subcortical structures in HD. Texture analysis of ultrahigh field T2 *-weighted MR images can be useful for noninvasive monitoring of neurodegenerative diseases. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 03/2014; 39(3). DOI:10.1002/jmri.24199 · 2.79 Impact Factor
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    ABSTRACT: Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients. The length of the CAG repeat is inversely correlated with age of onset (AO) in HD patients, while environmental and genetic factors can further modulate this parameter. Here, we explored whether the recently described copy-number variation (CNV) of the gene SLC2A3-which encodes the neuronal glucose transporter GLUT3-could modulate AO in HD. Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells. To our knowledge this is the first time that CNV of a candidate gene has been found to modulate HD pathogenesis. Furthermore, we found that increasing dosage of Glut1-the Drosophila melanogaster homologue of this glucose transporter-ameliorated HD-relevant phenotypes in fruit flies, including neurodegeneration and life expectancy. As alterations in glucose metabolism have been implicated in HD pathogenesis, this study may have important therapeutic relevance for HD.
    Human Molecular Genetics 02/2014; 23(12). DOI:10.1093/hmg/ddu022 · 6.68 Impact Factor
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    ABSTRACT: 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 Huntington's 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.
    Journal of Neurology Neurosurgery & Psychiatry 01/2014; 3(2):197-207. DOI:10.3233/JHD-140101 · 5.58 Impact Factor

Publication Stats

3k Citations
704.65 Total Impact Points


  • 1983–2015
    • Leiden University Medical Centre
      • • Department of Neurology
      • • Department of Radiology
      • • Department of Psychiatry
      • • Department of Clinical Genetics
      Leyden, South Holland, Netherlands
  • 1991–2014
    • Leiden University
      • Molecular Cell Biology Group
      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
  • 1996
    • University of California, Davis
      • Department of Neurology
      Davis, California, United States
  • 1992
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands