John Hardy

UCL Eastman Dental Institute, Londinium, England, United Kingdom

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Publications (764)6775.16 Total impact

  • 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: 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 03/2015; · 10.23 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.
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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.
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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
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    ABSTRACT: During the development of Alzheimer’s disease (AD), changes in gene expression occur at many stages of disease progression. Early changes may be causal, possibly contributing to initial pathology, whereas later changes may be consequential, due to synaptic and neuronal damage. Eventually, amyloid and/or tau deposition and gliosis are thought to result in altered expression of genes including those of the immune system. Although these latter changes have often been thought of as secondary, and therefore of little note, recent analyses have suggested that genetic variability in immune processes, particularly with respect to microglial responses, is important in determining the risk of individuals presenting with the disease. Although mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1) or PSEN2 that lead to raised levels of a range of amyloidβ (Aβ) peptides are sufficient to result in Alzheimer’s disease in humans, phosphorylation of microtubule-associated protein tau (tau) and the development of tangles is an essential step in the course of the disease. The relative contribution of these two elements to different aspects of the disease is still a matter of controversy.
    Cell Reports 01/2015; 5(4). DOI:10.1016/j.celrep.2014.12.041 · 7.21 Impact Factor
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    ABSTRACT: The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
    Nature 01/2015; DOI:10.1038/nature14101 · 42.35 Impact Factor
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    ABSTRACT: The future of genetic diagnostics will see a move toward massively parallel next-generation sequencing of a patient's DNA. Amyotrophic lateral sclerosis (ALS) is one of the diseases that would benefit from this prospect. Exploring this idea, we designed a screening panel to sequence 25 ALS-linked genes and examined samples from 95 patients with both familial and sporadic ALS. Forty-three rare polymorphisms were detected in this cohort. A third of these have already been reported with respect to ALS, leaving 28 novel variants all open for further investigation. This study highlights the potential benefits of next-generation sequencing as a reliable, cost and time efficient, diagnostic, and research tool for ALS. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.12.017 · 4.85 Impact Factor
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    ABSTRACT: BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
    Alzheimer's and Dementia 12/2014; DOI:10.1016/j.jalz.2014.05.1757 · 17.47 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder which predominantly affects the motor neurons in the brain and spinal cord. The death of the motor neurons in ALS causes subsequent muscle atrophy, paralysis and eventual death. Clinical and biological evidence now demonstrates that ALS has many similarities to prion disease in terms of disease onset, phenotype variability and progressive spread. The pathognomonic ubiquitinated inclusions deposited in the neurons and glial cells in brains and spinal cords of patients with ALS and FTLD-U contain aggregated TDP-43 protein, and evidence now suggests that TDP-43 has cellular prion-like properties. The cellular mechanisms of prion protein misfolding and aggregation are thought to be responsible for the characteristics of prion disease. Therefore, there is a strong mechanistic basis for a prion-like behaviour of the TDP-43 protein being responsible for some characteristics of ALS. In this review, we compare the prion-like mechanisms of TDP-43 to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease. This article is protected by copyright. All rights reserved.
    Neuropathology and Applied Neurobiology 12/2014; DOI:10.1111/nan.12206 · 4.97 Impact Factor
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    ABSTRACT: Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 (“hereditary whispering dysphonia”). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 12/2014; DOI:10.1002/mds.26129 · 5.63 Impact Factor
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    ABSTRACT: The introduction of stem cell-associated molecular factors into human patient-derived cells allows for their reprogramming in the laboratory environment. As a result, human induced pluripotent stem cells (hiPSC) can now be reprogrammed epigenetically without disruption of their overall genomic integrity. For patients with neurodegenerative diseases characterized by progressive loss of functional neurons, the ability to reprogram any individual's cells and drive their differentiation toward susceptible neuronal subtypes holds great promise. Apart from applications in regenerative medicine and cell replacement–based therapy, hiPSCs are increasingly used in preclinical research for establishing disease models and screening for drug toxicities. The rapid developments in this field prompted us to review recent progress toward the applications of stem cell technologies for movement disorders. We introduce reprogramming strategies and explain the critical steps in the differentiation of hiPSCs to clinical relevant subtypes of cells in the context of movement disorders. We summarize and discuss recent discoveries in this field, which, based on the rapidly expanding basic science literature as well as upcoming trends in personalized medicine, will strongly influence the future therapeutic options available to practitioners working with patients suffering from such disorders. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 12/2014; DOI:10.1002/mds.26113 · 5.63 Impact Factor

Publication Stats

58k Citations
6,775.16 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