John Hardy

UCL Eastman Dental Institute, Londinium, England, United Kingdom

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Publications (772)6949.18 Total impact

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    ABSTRACT: Detecting and treating Alzheimer’s disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer’s disease is rising Aβ. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble Aβ peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measured the early rise of different Aβ peptides in a mouse model of increasing Aβ (‘TASTPM’, transgenic for familial Alzheimer’s disease genes APP/PSEN1). In the third postnatal week, several Aβ peptides were above the limit of detection, including Aβ40, Aβ38 and Aβ42 with an intensity ratio of 6:3:2, respectively. By 2 months Aβ levels had only increased by 50% and, although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to WT mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of Aβ40 rose by about seven-fold but Aβ42 rose by 25-fold, increasing Aβ42:Aβ40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice, however synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P<0.001, n=7-9; consistent with the proposed physiological effect of Aβ) and loss of spontaneous action potential-mediated activity in the CA1 and dentate gyrus regions of the hippocampus (P<0.001, n=7). Hence synaptic changes occur when the Aβ levels and Aβ42:Aβ40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising Aβ, the initial deposition of plaques does not occur until several months after the first Aβ becomes detectable but coincides with a rapid acceleration in the rise of Aβ levels and the Aβ42:Aβ40 ratio. Prior to acceleration however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer’s disease.
    Brain 07/2015; · 10.23 Impact Factor
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    ABSTRACT: The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
    Brain 05/2015; DOI:10.1093/brain/awv132 · 10.23 Impact Factor
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    ABSTRACT: It is generally believed that splicing removes introns as single units from precursor messenger RNA transcripts. However, some long Drosophila melanogaster introns contain a cryptic site, known as a recursive splice site (RS-site), that enables a multi-step process of intron removal termed recursive splicing. The extent to which recursive splicing occurs in other species and its mechanistic basis have not been examined. Here we identify highly conserved RS-sites in genes expressed in the mammalian brain that encode proteins functioning in neuronal development. Moreover, the RS-sites are found in some of the longest introns across vertebrates. We find that vertebrate recursive splicing requires initial definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded from the dominant mRNA isoform owing to competition with a reconstituted 5' splice site formed at the RS-site after the first splicing step. Conversely, the RS-exon is included when preceded by cryptic promoters or exons that fail to reconstitute an efficient 5' splice site. Most RS-exons contain a premature stop codon such that their inclusion can decrease mRNA stability. Thus, by establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms emerging from long genes by coupling cryptic elements with inclusion of RS-exons.
    Nature 05/2015; DOI:10.1038/nature14466 · 42.35 Impact Factor
  • Movement Disorders 05/2015; DOI:10.1002/mds.26249 · 5.63 Impact Factor
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    ABSTRACT: Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 05/2015; DOI:10.1016/j.ajhg.2015.04.008 · 10.99 Impact Factor
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    ABSTRACT: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10-8) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10-7) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
    05/2015; DOI:10.1001/jamaneurol.2015.0582
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    ABSTRACT: Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.068 · 7.21 Impact Factor
  • Biological psychiatry 04/2015; 77(8). DOI:10.1016/j.biopsych.2015.03.001 · 9.47 Impact Factor
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    ABSTRACT: -Epidemiological findings suggest a relationship between Alzheimer's disease (AD), inflammation and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. -Using summary statistics (p-values and odds ratios) from genome-wide association studies of over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 x 10(-8)) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 x 10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. -We demonstrate genetic overlap between AD, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
    Circulation 04/2015; DOI:10.1161/CIRCULATIONAHA.115.015489 · 14.95 Impact Factor
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    ABSTRACT: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.
    Molecular Psychiatry 03/2015; DOI:10.1038/mp.2015.23 · 15.15 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) is common in boxing and other contact sports. The long term irreversible and progressive aftermath of TBI in boxers depicted as punch drunk syndrome was described almost a century ago and is now widely referred as chronic traumatic encephalopathy (CTE). The short term sequelae of acute brain injury including subdural haematoma and catastrophic brain injury may lead to death, whereas mild TBI, or concussion, causes functional disturbance and axonal injury rather than gross structural brain damage. Following concussion, symptoms such as dizziness, nausea, reduced attention, amnesia and headache tend to develop acutely but usually resolve within a week or two. Severe concussion can also lead to loss of consciousness. Despite the transient nature of the clinical symptoms, functional neuroimaging, electrophysiological, neuropsychological and neurochemical assessments indicate that the disturbance of concussion takes over a month to return to baseline and neuropathological evaluation shows that concussion-induced axonopathy may persist for years. The developing brains in children and adolescents are more susceptible to concussion than adult brain. The mechanism by which acute TBI may lead to the neurodegenerative process of CTE associated with tau hyperphosphorylation and the development of neurofibrillary tangles (NFTs) remains speculative. Focal tau-positive NFTs and neurites in close proximity to focal axonal injury and foci of microhaemorrhage and the predilection of CTE-tau pathology for perivascular and subcortical regions suggest that acute TBI-related axonal injury, loss of microvascular integrity, breach of the blood brain barrier, resulting inflammatory cascade and microglia and astrocyte activation are likely to be the basis of the mechanistic link of TBI and CTE. This article provides an overview of the acute and long-term neurological consequences of TBI in sports. Clinical, neuropathological and the possible pathophysiological mechanisms are discussed. This article is part of a Special Issue entitled 'Traumatic Brain Injury'. Copyright © 2015. Published by Elsevier Inc.
    Molecular and Cellular Neuroscience 03/2015; 32. DOI:10.1016/j.mcn.2015.03.012 · 3.73 Impact Factor
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    ABSTRACT: Objective We have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.Methods This study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome-wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015
    Annals of Neurology 03/2015; 77(4). DOI:10.1002/ana.24335 · 11.91 Impact Factor
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    ABSTRACT: Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 02/2015; DOI:10.1016/j.ajhg.2015.01.005 · 10.99 Impact Factor
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    ABSTRACT: We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.Molecular Psychiatry advance online publication, 17 February 2015; doi:10.1038/mp.2015.6.
    Molecular Psychiatry 02/2015; DOI:10.1038/mp.2015.6 · 15.15 Impact Factor
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    ABSTRACT: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a spectrum. Clinically, FTD patients present with dementia frequently characterized by behavioral and speech problems. ALS patients exhibit alterations of voluntary movements caused by degeneration of motor neurons. Both syndromes can be present within the same family or even in the same person. The genetic findings for both diseases also support the existence of a continuum, with mutations in the same genes being found in patients with FTD, ALS, or FTD/ALS. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; 160(4):798-798.e1. DOI:10.1016/j.cell.2015.01.052 · 33.12 Impact Factor
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    ABSTRACT: Different types of genetic technologies and approaches allow for the study and identification of different types of genetic variability in a disease. Here represented are the genes and genetic loci independently replicated as being associated with the development of Parkinson's disease (PD)/parkinsonism. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 01/2015; 160(3). DOI:10.1016/j.cell.2015.01.019 · 33.12 Impact Factor
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    ABSTRACT: C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Neurology 01/2015; 14(3). DOI:10.1016/S1474-4422(14)70233-9 · 21.82 Impact Factor

Publication Stats

59k Citations
6,949.18 Total Impact Points

Institutions

  • 2007–2015
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
    • Translational Genomics Research Institute
      • Division of Neurogenomics
      Phoenix, AZ, United States
    • Duke University
      Durham, North Carolina, United States
  • 2001–2015
    • University College London
      • • Department of Molecular Neuroscience
      • • Institute of Neurology
      Londinium, England, United Kingdom
  • 2012–2014
    • WWF United Kingdom
      Londinium, England, United Kingdom
    • University of Thessaly
      • Κλινική Νευρολογίας
      Iolcus, Thessaly, Greece
    • Banner Alzheimer's Institute
      Phoenix, Arizona, United States
  • 2013
    • University of Campinas
      Conceição de Campinas, São Paulo, Brazil
    • L'Institut du Cerveau et de la Moelle Épinière
      Lutetia Parisorum, Île-de-France, France
  • 2011–2012
    • Cardiff University
      • • School of Medicine
      • • Department of Psychological Medicine and Neurology
      Cardiff, Wales, United Kingdom
    • Wellcome Trust
      Londinium, England, United Kingdom
  • 2002–2012
    • National Institute on Aging
      • Laboratory of Neurogenetics (LNG)
      Baltimore, Maryland, United States
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
    • Mayo Clinic - Rochester
      • Department of Neurology
      Рочестер, Minnesota, United States
    • Tehran University of Medical Sciences
      • Department of Biochemistry
      Tehrān, Ostan-e Tehran, Iran
  • 2010
    • University of Geneva
      • Department of Genetic Medicine and Development (GEDEV)
      Genève, GE, Switzerland
  • 2002–2009
    • National Institutes of Health
      • Laboratory of Neurogenetics
      Maryland, United States
  • 1992–2009
    • University of South Florida
      Tampa, Florida, United States
  • 1991–2009
    • Imperial College London
      Londinium, England, United Kingdom
    • Yale University
      New Haven, Connecticut, United States
    • Florida Clinical Research Center
      Florida, United States
  • 2008
    • University of Miami Miller School of Medicine
      • Department of Psychiatry and Behavioral Sciences
      Miami, Florida, United States
    • London Research Institute
      Londinium, England, United Kingdom
  • 1999–2008
    • University of Helsinki
      • • Department of Pathology
      • • Department of Neurology
      Helsinki, Uusimaa, Finland
    • University of California, Los Angeles
      Los Ángeles, California, United States
    • Mater Misericordiae University Hospital
      Dublin, Leinster, Ireland
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Sydney
      Sydney, New South Wales, Australia
  • 2005
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2004
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • Northern Inyo Hospital
      BIH, California, United States
    • Hospital Universitario Fundacion Alcorcon
      Madrid, Madrid, Spain
    • Chang Gung University
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2003
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 1997–2003
    • Mayo Foundation for Medical Education and Research
      • • Department of Neurology
      • • Department of Pharmacology
      Scottsdale, AZ, United States
  • 2000–2001
    • Ludwig-Maximilian-University of Munich
      • Department of Biochemistry
      München, Bavaria, Germany
  • 1998
    • Columbia University
      • Department of Neurology
      New York City, New York, United States
    • Central Institute of Mental Health
      Mannheim, Baden-Württemberg, Germany
  • 1996–1998
    • Washington University in St. Louis
      • Department of Psychiatry
      Saint Louis, MO, United States
    • Washington School of Psychiatry
      Washington, Washington, D.C., United States
  • 1994
    • University of Essex
      Colchester, England, United Kingdom
  • 1989–1993
    • Imperial College Healthcare NHS Trust
      • Division of Biochemistry
      Londinium, England, United Kingdom