Leonard H van den Berg

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (401)2635.87 Total impact

  • 06/2015; 2(4):e119-e119. DOI:10.1212/NXI.0000000000000119
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    ABSTRACT: The objectives of the current study were to provide an overview of the outcome measures (OMs) applied in clinical trials in MMN and to determine the responsiveness of a core set of selected OMs as part of the PeriNomS study. The following OMs were serially applied in 26 patients with newly diagnosed or relapsing MMN, receiving intravenous-immunoglobulin (assessments: T0/T3/T12 months): 14 muscle-pairs MRC scale, the Neuropathy-Impairment-Scale motor-subset, a self-evaluation scale, grip strength, and MMN-RODS(©) . All data, except the grip strength, were subjected to Rasch analyses before determining responsiveness. For grip strength, responsiveness was examined using a combined anchor- (SF-36 question-2) and distribution-based (½xSD) minimum clinically important difference (MCID) techniques, determining the proportion of patients exceeding both identified cut-offs. For the remaining scales, the magnitude of change for each patient on each scale was determined using the MCID related to the individual standard errors (responder definition: MCID-SE≥1.96). Overall, a great assortment of measures has been used in MMN trials with different responsiveness definitions. For the selected OMs, responsiveness was poor and only seen in 1/4-1/3 of the patients, the grip strength being more responsive. Despite the efforts taken to standardize outcome assessment, further clinimetric responsiveness studies are needed in MMN. This article is protected by copyright. All rights reserved.
    Journal of the Peripheral Nervous System 06/2015; DOI:10.1111/jns.12124 · 2.50 Impact Factor
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    ABSTRACT: Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies. To further investigate the pathophysiology of MMN and PMA we determined concentrations of 16 mainly B-cell associated inflammatory markers in serum from 25 patients with MMN, 55 patients with PMA, 25 patients with amyotrophic lateral sclerosis (ALS) and 50 healthy controls. Median serum concentrations of the16 tested cytokines and chemokines were not significantly increased in patients with MMN or patients with PMA, irrespective of the presence of IgM monoclonal gammopathy or high IgM anti-GM1 antibodies. These results argue against a systemic B-cell mediated immune response underlying the pathogenesis of MMN and PMA.
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    ABSTRACT: Our objective was to compare the effects of cognitive behavioural therapy (CBT) and usual care (UC) on quality of life (QoL) in psychologically distressed patients with ALS and their caregivers. We conducted a multicentre randomized controlled trial (RCT). In 16 weeks, patient-carer pairs received five to 10 CBT sessions plus usual care (UC) or UC alone. Outcome measures were SF-36 Mental Component Summary (MCS), ALSAQ-40 Emotional Functioning (EF), Hospital Anxiety and Depression Scale (HADS) and Caregiver Strain Index (CSI). Assessments took place at baseline, four, seven and 10 months. The steering committee decided to stop the trial prematurely and analyse the data due to: 1) slow recruitment (15 patients over 42 months); and 2) the low demand for joint patient-carer CBT sessions. Caregivers, however, expressed an unanticipated demand for individual psychological support. Patients’ ALSAQ-40-EF and caregivers’ SF-36-MCS were significantly better in CBT than UC (p < 0.05). CSI was significantly lower in the CBT than the UC (p < 0.05). In conclusion, CBT might be beneficial to patients and caregivers. The stringent eligibility criteria limited participation rate and consequently the generalizability of results. Future studies should further examine the impact of CBT interventions for patients with ALS and their caregivers.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 06/2015; DOI:10.3109/21678421.2015.1038276 · 2.59 Impact Factor
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    ABSTRACT: How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss-of-function in mice. We generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72(fl/fl) mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization. In addition, motor function and survival were assessed. Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival. Our data suggest that C9orf72 loss-of-function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72-associated ALS. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 06/2015; DOI:10.1002/ana.24453 · 11.91 Impact Factor
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    ABSTRACT: Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.
    Nature Genetics 05/2015; DOI:10.1038/ng.3292 · 29.65 Impact Factor
  • 05/2015; 2(2):157-165. DOI:10.3233/JND-150080
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    ABSTRACT: The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.
    PLoS Genetics 05/2015; 11(5):e1005223. DOI:10.1371/journal.pgen.1005223 · 8.17 Impact Factor
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    ABSTRACT: A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 04/2015; DOI:10.1016/j.jalz.2014.12.009 · 17.47 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, recent histological examinations of Brettschneider and colleagues have proposed four time-sequential stages of neuropathology in ALS based on levels of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) aggregation. What governs dissemination of these aggregates between segregated regions of the brain is unknown. Here, we cross-reference stages of pTDP-43 pathology with in vivo diffusion weighted imaging data of 215 adult healthy control subjects, and reveal that regions involved in pTDP-43 pathology form a strongly interconnected component of the brain network (p = 0.04) likely serving as an anatomical infrastructure facilitating pTDP-43 spread. Furthermore, brain regions of subsequent stages of neuropathology are shown to be more closely interconnected than regions of more distant stages (p = 0.002). Computational simulation of disease spread from first-stage motor regions across the connections of the brain network reveals a pattern of pTDP-43 aggregation that reflects the stages of sequential involvement in neuropathology (p = 0.02), a pattern in favor of the hypothesis of pTDP-43 pathology to spread across the brain along axonal pathways. Our findings thus provide computational evidence of disease spread in ALS to be directed and constrained by the topology of the anatomical brain network. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 04/2015; 64. DOI:10.1016/j.neuroimage.2015.04.005 · 6.13 Impact Factor
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    ABSTRACT: Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.
    Journal of Neurology 03/2015; 262(3). DOI:10.1007/s00415-014-7612-4 · 3.84 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. Copyright © 2015, American Association for the Advancement of Science.
    Science 02/2015; 347(6229). DOI:10.1126/science.aaa3650 · 31.48 Impact Factor
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    ABSTRACT: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1- and T2-weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. Immediate and delayed story recall scores were abnormal in 23% of ALS patients and correlated to bilateral hippocampus grey matter volume (r = 0.52 for both memory tests; P < 0.05; corrected for age, gender and total grey matter volume). This correlation was not found in healthy controls with similar age, education, anxiety and depression levels and white matter changes. Prose memory impairment is a frequent finding in this cohort and is associated with hippocampus volume in ALS patients without dementia. These findings complement previous hippocampus changes in imaging studies in ALS and suggest involvement of the hippocampus in cognitive dysfunction of ALS. © 2014 EAN.
    European Journal of Neurology 12/2014; 22(3). DOI:10.1111/ene.12615 · 3.85 Impact Factor
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    ABSTRACT: Ascertain the incidence of cryptogenic axonal polyneuropathy (CAP) and how this relates to the overall incidence of polyneuropathy. Electronic diagnostic registries of all hospital-based neurologic practices in the province of Utrecht (population 1,224,852 = 7.4% of the Dutch population) were consulted in 2010 to identify incident cases with polyneuropathy. Medical files were reviewed to specify the final diagnosis. Age-adjusted incidence rates for the Netherlands were calculated using national age-specific population figures. The overall incidence of polyneuropathy was 77.0/100,000 person-years (95% confidence interval 71.1-82.8) in persons aged 18 years and older. Diabetic polyneuropathy (32%), CAP (26%), toxic polyneuropathy (14%), and immune-mediated polyneuropathy (9%) were the most frequent diagnoses. The incidence of CAP was 31.6/100,000 person-years (95% confidence interval 27.0-36.3) in persons aged 40 years and older. The incidence of polyneuropathy increased with age, as well as the proportion of patients diagnosed with CAP: 12% (40-49 years), 20% (50-59 years), 28% (60-69 years), 32% (70-79 years), and 35% (≥80 years) (χ(2) test, p = 0.005). The chance of establishing an etiologic diagnosis in patients presenting with a polyneuropathy decreases with age. Given the aging population, polyneuropathy in general and CAP in particular will pose a growing health care problem. © 2014 American Academy of Neurology.
    Neurology 12/2014; 84(3). DOI:10.1212/WNL.0000000000001160 · 8.30 Impact Factor
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    ABSTRACT: The El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis (ALS) were established 20 years ago and have been used as inclusion criteria for clinical trials. However, concerns have been raised concerning their use as diagnostic criteria in clinical practice. Moreover, as modern genetics have shed new light on the heterogeneity of ALS and the close relationship between ALS and frontotemporal dementia (FTD) recognized, the World Federation of Neurology Research Group on ALS/MND has initiated discussions to amend and update the criteria, while preserving the essential components for clinical trial enrolment purposes.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 12/2014; 16(1-2):1-7. DOI:10.3109/21678421.2014.964258 · 2.59 Impact Factor
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    ABSTRACT: The progressive course of amyotrophic lateral sclerosis (ALS) results in an ever-changing spectrum of the care needs of patients with ALS. Knowledge of prognostic factors for the functional course of ALS may enhance clinical prediction and improve the timing of appropriate interventions. Our objective was to systematically review the evidence regarding prognostic factors for the rate of functional decline of patients with ALS, assessed with versions of the ALS Functional Rating Scale (ALSFRS). Two reviewers independently assessed the methodological quality of the thirteen included studies using the Quality in Prognosis Studies (QUIPS) tool. The overall quality of evidence for each prognostic factor was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, considering risk of bias, imprecision, inconsistency, indirectness, and publication bias. The quality of evidence for the prognostic value of age at onset, site of onset, time from symptom onset to diagnosis, and ALSFRS-Revised baseline score was low, mainly due to the limited data and inconsistency of results in the small number of studies included. The prognostic value of initial rate of disease progression, age at diagnosis, forced vital capacity, frontotemporal dementia, body mass index, and comorbidity remains unclear. We conclude that the current evidence on prognostic factors for functional decline in ALS is insufficient to allow the development of a prediction tool that can support clinical decisions. Given the limited data, future prognostic studies may need to focus on factors that have a predictive value for a decline in ALSFRS(-R) domain scores, preferably based on internationally collected and shared data.
    Journal of Neurology 11/2014; DOI:10.1007/s00415-014-7564-8 · 3.84 Impact Factor
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    ABSTRACT: We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M-monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP).
    Neurology 11/2014; DOI:10.1212/WNL.0000000000001044 · 8.30 Impact Factor
  • Brain 10/2014; 137(12). DOI:10.1093/brain/awu299 · 10.23 Impact Factor
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    ABSTRACT: Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
    Neuron 10/2014; 84(2):324-31. DOI:10.1016/j.neuron.2014.09.027 · 15.98 Impact Factor
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    ABSTRACT: Background Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. Methods We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. Findings We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0.95, Ireland r(2)=0.99, Italy r(2)=0.95, the Netherlands r(2)=0.99, and Scotland r(2)=0-97; overall r(2)=0.99. All five registers gave similar estimates of the linear slope ranging from 4.5 to 5.1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4.8 (95% CI 4-5-5-0), with similar estimates for men (4.6, 4.3-4.9) and women (5.0,4.5-5.5). Interpretation A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues.
    The Lancet Neurology 10/2014; 13(11). DOI:10.1016/S1474-4422(14)70219-4 · 21.82 Impact Factor

Publication Stats

9k Citations
2,635.87 Total Impact Points

Institutions

  • 1995–2015
    • University Medical Center Utrecht
      • Department of Neurology
      Utrecht, Utrecht, Netherlands
    • New York Presbyterian Hospital
      New York City, New York, United States
  • 2014
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1993–2013
    • University of Groningen
      • Department of Genetics
      Groningen, Groningen, Netherlands
  • 2012
    • University of Massachusetts Medical School
      • Department of Neurology
      Worcester, MA, United States
  • 2011
    • Radboud University Medical Centre (Radboudumc)
      Nymegen, Gelderland, Netherlands
  • 2010
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2009
    • Umeå University
      Umeå, Västerbotten, Sweden
    • Netherlands Institute for Neuroscience
      Amsterdamo, North Holland, Netherlands
  • 2001–2007
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 2005
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2004
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 1996
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands
  • 1991–1992
    • Columbia University
      • Department of Neurology
      New York City, New York, United States