L.H. van den Berg

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (221)811.68 Total impact

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    ABSTRACT: In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM.
    Journal of neurology, neurosurgery, and psychiatry. 07/2014;
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    ABSTRACT: Objective: Executive dysfunction occurs in 30-50% of amyotrophic lateral sclerosis (ALS) patients and is most frequently assessed with the verbal fluency test. The verbal fluency index (VFI) has been developed to correct for slowness of speech in ALS, and reflects the average thinking time per word. However, its use as a marker of cognitive impairment is hindered by the absence of valid norm scores. Therefore, we provide normative data for the VFI. Methods: Dutch volunteers were demographically matched to the Dutch ALS population and completed the verbal fluency index (one-minute and three-minute spoken letter fluency). Multiple stepwise linear regression was performed to assess the influence of demographic variables, past medical history and medication use. Results: 273 volunteers participated in this study. Educational level was negatively correlated to one-minute and three-minute VFI performance (r = -0.3 and r = -0.4, p < 0.001, respectively). No correlations for age, gender, medication and past medical history were found. A formula for standardized z-scores, corrected for educational level, for the one-minute and three-minute VFI was calculated. Conclusions: We provide Dutch normative data for the spoken verbal fluency index, which can be used internationally, but validation in other languages is recommended. The findings illustrate the importance of valid disease-specific norm scores for time-dependent cognitive tests in ALS.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 05/2014; · 2.37 Impact Factor
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    ABSTRACT: Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.157.
    Molecular Psychiatry 01/2014; 19:108-114. · 15.15 Impact Factor
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    ABSTRACT: Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
    PLoS Pathogens 07/2013; 9(7):e1003515. · 8.14 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: We assessed the first evaluation at a large ventilation clinic in the Netherlands to: (i) determine what proportion of patients with motor neuron disease would benefit from earlier referral; and (ii) examine the patient preferences regarding ventilatory support. METHODS: Observational study at a single centre with a catchment area of 7.6 million inhabitants. Data on disease status, the referral process and patients' preferences regarding ventilatory support were collected during the first home ventilation services (HVS) assessment and analysed for correlation with the presence of daytime hypercapnia and suspected nocturnal hypoventilation. The latter conditions require immediate (within 48 h) or subacute (within 3 weeks) initiation of ventilatory support. RESULTS: Vital capacity (in percentage of predicted value, VC%pred) was assessed by referring physicians in 84% of the 217 referred patients; the mean VC%pred was 69% (SD 16). One-hundred and ninety-one patients attended the first HVS assessment without ventilatory support, at a median of 21 days following referral: 18% had respiratory failure (daytime hypercapnia), 19% had normocapnia but were suspected of nocturnal hypoventilation, and 63% had normocapnia without symptoms. Following the HVS assessment, 25 patients (13%) declined home mechanical ventilation; this occurred more often in patients with (14/70) compared with patients without respiratory impairment (11/121; P < 0.05). CONCLUSION: A meaningful proportion of patients who desire ventilatory support are referred to a ventilation clinic after already developing respiratory failure. Future studies could examine means, including more sensitive respiratory measures, to detect those patients who could benefit from earlier referral.
    European Journal of Neurology 02/2013; · 4.16 Impact Factor
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    ABSTRACT: SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.
    Journal of Neurology 10/2012; · 3.58 Impact Factor
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    ABSTRACT: The pathogenesis of amyotrophic lateral sclerosis (ALS) is considered to be multifactorial. Several epidemiological studies showed a lower incidence of ALS in women than in men. This suggests a possible protective effect of female reproductive hormones. The aim of this study was to investigate the association between female reproductive hormones and ALS. We performed a population-based, case-control study in the Netherlands between 1st January 2006 and 1st December 2009. Only women with a natural menopause were included in the analysis. A total of 209 (85 %) of 246 female patients and 672 (93 %) of 719 controls returned a questionnaire on reproductive history to calculate the reproductive time-span and lifetime endogenous estrogen exposure (calculated by subtracting the duration of pregnancies and of oral contraceptive use, and the number of post-ovulatory weeks from the reproductive time-span). 131 (63 %) patients and 430 (64 %) age-matched, population-based controls had experienced a natural menopause. Multivariate analysis showed that increasing the reproductive time-span by a year decreases the risk of ALS with an OR of 0.95 (p = 0.005). Each year longer reproductive time-span [HR 0.90 (p = 0.01)] and lifetime endogenous estrogen exposure [HR 0.96 (p = 0.025)] were associated with a longer survival of ALS patients. The positive association of a longer reproductive time-span and susceptibility and survival of ALS might imply that longer exposure to female reproductive hormones has a neuroprotective effect on motor neurons.
    Journal of Neurology 09/2012; · 3.58 Impact Factor
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    ABSTRACT: A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.European Journal of Human Genetics advance online publication, 13 June 2012; doi:10.1038/ejhg.2012.98.
    European journal of human genetics: EJHG 06/2012; · 3.56 Impact Factor
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    ABSTRACT: To investigate the role of SMN1 and SMN2 copy number variation and point mutations in amyotrophic lateral sclerosis (ALS) pathogenesis in a large population. We conducted a genetic association study including 847 patients with ALS and 984 controls. We used multiplexed ligation-dependent probe amplification (MLPA) assays to determine SMN1 and SMN2 copy numbers and examined effects on disease susceptibility and disease course. Furthermore, we sequenced SMN genes to determine if SMN mutations were more prevalent in patients with ALS. A meta-analysis was performed with results from previous studies. SMN1 duplications were associated with ALS susceptibility (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.34-3.20, p = 0.001). A meta-analysis with previous data including 3,469 individuals showed a similar effect: OR 1.85, 95% CI 1.18-2.90, p = 0.008). SMN1 deletions and SMN2 copy number status were not associated with ALS. SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. We found no enrichment of SMN point mutations in patients with ALS. Our data provide firm evidence for a role of common SMN1 duplications in ALS, and raise new questions regarding the disease mechanisms involved.
    Neurology 02/2012; 78(11):776-80. · 8.30 Impact Factor
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    ABSTRACT: Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p<0.005 were included in a follow-up study in 202 cases and 892 controls. Of the total cohort, ~50% showed a clear-cut primary VUR phenotype and ~25% had both a duplex collecting system and VUR. We also looked for association in these two extreme phenotype groups. None of the SNPs reached a significant p-value. Common genetic variants in four genes (GREM1, EYA1, ROBO2 and UPK3A) show a trend towards association with the development of primary VUR (GREM1, EYA1, ROBO2) or duplex collecting system (EYA1 and UPK3A). SNPs in three genes (TGFB1, GNB3 and VEGFA) have been shown to be associated with VUR in other populations. Only the result of rs1800469 in TGFB1 hinted at association in our study. This is the first extensive study of common variants in the genes of the ureteric budding pathway and the genetic susceptibility to primary VUR
    PLoS.One. 01/2012; 7(4):e31327-.
  • Neurology 10/2011; 77(17):e102-3; author reply e103-4. · 8.30 Impact Factor
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    ABSTRACT: To determine whether the frequency of Parkinson disease (PD), dementia, and vascular diseases in relatives of patients with amyotrophic lateral sclerosis (ALS) differs from the frequency of those diseases in relatives of controls, providing further information about the association between these diseases. We studied the occurrence of neurodegenerative and vascular diseases in families of patients with ALS in a prospective, population-based, case-control study in the Netherlands between 2006 and 2009, using the recurrence risk λ. Family history data were obtained by asking participants to fill in questionnaires. A total of 635 patients and 1,616 controls were included. The frequency of dementia was mildly increased only among parents and siblings of patients with sporadic ALS (λ1.32; 95 confidence interval [CI] 1.10-1.59), not among grandparents, or aunts and uncles. The risk of PD was not elevated (any relative: λ 0.91; 95% CI 0.70-1.17). Among relatives of patients with familial ALS, no significantly increased risk of neurodegenerative diseases was found. A reduced risk of vascular diseases was found in relatives of patients with sporadic ALS (stroke: λ 0.90; 95% CI 0.80-1.01 and myocardial infarction: λ 0.86; 95% CI 0.79-0.94), and in relatives of patients with familial ALS (stroke: λ 0.88; 95% CI 0.61-1.27 and myocardial infarction: λ 0.61; 95% CI 0.43-0.86). This large, prospective, population-based study showed that familial aggregation of ALS, dementia, and PD is substantially lower than previously thought. The lowered risk of vascular diseases in relatives of patients with ALS supports the view that a beneficial vascular risk profile increases ALS susceptibility.
    Neurology 09/2011; 77(14):1363-9. · 8.30 Impact Factor
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    ABSTRACT: Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).
    Human Molecular Genetics 08/2011; 20(20):4076-81. · 7.69 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons that results in progressive muscle weakness and limits survival to 2-5 years after disease onset. Intermediate CAG repeat expansions in ataxin 2 (ATXN2), the causative gene of spinocerebellar ataxia type 2 (SCA2), have been implicated in sporadic ALS. We studied ATXN2 in a large cohort of patients with sporadic and familial ALS. We determined ATXN2 CAG repeat size in 1,948 sporadic and familial ALS cases and 2,002 controls from Belgium and the Netherlands. In controls, the maximal ATXN2 repeat size was 31. In sporadic ALS, a significant amount of longer repeat sizes (≥ 32, range 32-39) were encountered (in 0.5% or 10/1,845 ALS cases, vs 0% in controls, p = 0.0006). Receiver operating characteristic analysis showed that a cutoff of ≥ 29 appeared optimal to discriminate ALS from control (p = 0.036, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.04-3.64). A meta-analysis with the previously published results from the United States showed that the association between a repeat length of ≥ 29 and ALS became stronger (p < 0.0001, OR 2.93, 95% CI 1.73-4.98). In unexplained familial ALS, we found an intermediate repeat expansion of 31 and a homozygous repeat expansion of 33 each in 1.1% of families. The phenotype of patients with ALS with expanded repeat sizes ranged from rapidly progressive typical ALS to slowly progressive ALS with reduced sensory nerve action potentials. Our data reveal a novel genetic overlap between ALS and SCA2.
    Neurology 06/2011; 76(24):2066-72. · 8.30 Impact Factor
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    ABSTRACT: Reports of increased amyotrophic lateral sclerosis (ALS) with hyperlipidaemia and elevated plasma homocysteine levels as well as cigarette-smoking and polymorphisms in angiogenic genes suggest a role for altered vascular homeostasis in ALS pathogenesis. The authors assessed the association between vascular risk factors and ALS. Traditional cardiovascular risk factors (smoking, hypertension, hypercholesterolaemia, diabetes and body mass index (BMI)) and cardiovascular disease prior to ALS onset established by a questionnaire were compared in 334 patients and 538 age- and sex-matched controls. Biochemical assessments (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), hs-CRP, and homocysteine) at diagnosis were measured in blood samples of 303 patients with ALS and compared with prospectively collected data from 2100 population-based controls. Patients with ALS used cholesterol-lowering agents less frequently (OR=0.6, p=0.008) and had a lower BMI (OR=0.9, p=0.001), a lower LDL/HDL ratio (women: OR=0.5, p<0.001; men: OR=0.4, p<0.001) and lower homocysteine levels (women: OR=0.9, p=0.02; men: OR=0.9, p<0.001). The mean LDL and TC levels were significantly lower among patients with a lower functional vital capacity percentage of predicted (FVC). In the univariate analysis, a higher LDL/HDL ratio correlated with increased survival (HR=0.9, p=0.04); after adjusting for the confounders age, site and FVC, no difference was observed. Vascular risk factors, measured clinically and biochemically, were not associated with increased ALS. Instead, patients reported less use of cholesterol-lowering medication and had a lower premorbid BMI and favourable lipid profile-all findings consistent with the hypothesis that a higher metabolic rate plays a role in ALS.
    Journal of neurology, neurosurgery, and psychiatry 04/2011; 82(6):638-42. · 4.87 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. Optimal management requires a palliative approach from diagnosis with emphasis on patient autonomy, dignity and quality of life. To conduct a systematic analysis of the type, level and timing of specialist palliative care intervention in ALS. Despite an international consensus that ALS management should adopt a multidisciplinary approach, integration of palliative care into ALS management varies considerably across health care systems. Late referral to palliative services in ALS is not uncommon and may impact negatively on the quality of life of ALS patients and their caregivers. However, common themes and principles of engagement can be identified across different jurisdictions, and measurement systems have been established that can assess the impact of palliative care intervention. There is considerable evidence that palliative care intervention improves quality of life in patients and carers. International consensus guidelines would assist in the development of a framework for active palliative care engagement in ALS and other neurodegenerative diseases.
    Journal of neurology, neurosurgery, and psychiatry 02/2011; 82(4):413-8. · 4.87 Impact Factor
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    ABSTRACT: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
    Nat Genet. 01/2011;
  • L. H. van den Berg, W. L. van der Pol
    Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2011; 21(9):683-684.
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    ABSTRACT: Different preparations of intravenous immunoglobulin (IVIg) are considered to have comparable clinical efficacy but this has never been formally investigated. Some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report that some IVIg brands are more effective than others. A liquid IVIg preparation is more user friendly and potentially can be infused at a faster rate. The primary objective was to compare the efficacy of two different IVIg brands in CIDP. The secondary objective was to compare their safety. This was an investigator-initiated multi-centre randomised controlled double-blind trial. Twenty-seven patients with active but stable CIDP treated with their individual stable IVIg (Gammagard S/D) maintenance dose and interval were randomised to receive four infusions of freeze-dried 5% IVIg (Gammagard S/D) or the new liquid 10% IVIg (Kiovig). The overall disability sum score (ODSS) was used as the primary outcome scale. The equivalence margin was defined as a difference of ≤1 point in mean ΔODSS between treatment groups. Main secondary outcome scales were the MRC sum score and the Vigorimeter. Repeated measurements analysis of variance, adjusted for baseline ODSS, showed a clinically insignificant treatment difference of 0.004 (95% CI -0.4 to 0.4). We also found no significant differences in any of the other outcome measures. Besides a lower occurrence of cold shivers in patients randomised to Kiovig (p=0.03), no significant differences were found in the occurrence of adverse events. This trial demonstrated equal clinical efficacy between a freeze-dried and a liquid IVIg preparation for maintenance treatment of CIDP.
    Journal of neurology, neurosurgery, and psychiatry 12/2010; 81(12):1374-9. · 4.87 Impact Factor

Publication Stats

4k Citations
811.68 Total Impact Points

Institutions

  • 1993–2014
    • University Medical Center Utrecht
      • • Department of Neurology
      • • Department of Radiology
      Utrecht, Utrecht, Netherlands
  • 2004–2010
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
    • King's College London
      • Institute of Psychiatry
      London, ENG, United Kingdom
  • 2002–2008
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
  • 2007
    • Netherlands Institute for Neuroscience
      Amsterdamo, North Holland, Netherlands
  • 2001
    • University of Bergen
      Bergen, Hordaland, Norway
  • 1996
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands
  • 1995–1996
    • New York Presbyterian Hospital
      New York City, New York, United States
  • 1991–1996
    • Columbia University
      • Department of Neurology
      New York City, New York, United States
  • 1992
    • University of Groningen
      • Department of Neurology
      Groningen, Province of Groningen, Netherlands
  • 1990
    • CUNY Graduate Center
      New York City, New York, United States