Peter St George-Hyslop

University of Cambridge, Cambridge, England, United Kingdom

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Publications (439)3695.84 Total impact

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    ABSTRACT: Importance: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. Objective: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. Design, setting, and participants: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. Main outcomes and measures: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. Results: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. Conclusions and relevance: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
    JAMA Neurology 09/2015; DOI:10.1001/jamaneurol.2015.1700 · 7.42 Impact Factor
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    ABSTRACT: Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):963-75. DOI:10.1016/j.neuron.2015.08.020 · 15.05 Impact Factor
  • Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2015; DOI:10.1016/j.jalz.2015.06.1887 · 12.41 Impact Factor
  • Kanayo Satoh · Sumiko Abe-Dohmae · Shinji Yokoyama · Peter St George-Hyslop · Paul E Fraser
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    ABSTRACT: The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late-onset Alzheimer's disease (LOAD) in Genome Wide Association Studies (GWAS). ABCA7 has been shown to mediate phagocytosis and affects membrane trafficking. The current study examines the impact of ABCA7 loss-offunction on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knockout mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7 deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared to mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed while Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knockout cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing, which may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to AD have recently been identified which, in some instances, have a great impact than ApoE allelic variants. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated AD susceptibility. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 08/2015; DOI:10.1074/jbc.M115.655076 · 4.57 Impact Factor
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    ABSTRACT: To detect rare coding variants underlying loci detected by genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD). We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A and PICALM in three independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 NIA-LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least two datasets were genotyped in independent groups of ancestry matched controls. Additionally, the Exome Aggregation Consortium (ExAC) was used as a reference dataset for population-based allele frequencies. Overall we detected a statistically significant 3.1-fold enrichment of the non-synonymous mutations in the Caucasian LOAD cases compared with controls (p=0.002) and no difference in synonymous variants. A stopgain mutation in ABCA7 (E1769X) and missense mutation in CD2AP (T374A) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in two of the six Caribbean Hispanic families where the mutations were discovered. Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease related mechanisms and potential therapies. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 06/2015; 78(3). DOI:10.1002/ana.24466 · 9.98 Impact Factor
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    ABSTRACT: The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
    Scientific Reports 06/2015; 5:10934. DOI:10.1038/srep10934 · 5.58 Impact Factor
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    ABSTRACT: Objective In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.Methods About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.ResultsA novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.InterpretationFBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
    06/2015; 2(8):n/a-n/a. DOI:10.1002/acn3.223
  • Brain 03/2015; 138(Pt 9). DOI:10.1093/brain/awv082 · 9.20 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 · 14.50 Impact Factor
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    C Bohm · F Chen · J Sevalle · S Qamar · R Dodd · Y Li · G Schmitt-Ulms · P E Fraser · P H St George-Hyslop
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    ABSTRACT: Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. Copyright © 2015. Published by Elsevier Inc.
    Molecular and Cellular Neuroscience 03/2015; 301(Pt A). DOI:10.1016/j.mcn.2015.02.016 · 3.84 Impact Factor
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    ABSTRACT: Although diverse neurodegenerative diseases cause dementia, they share two important features. First they have long pre-clinical periods with varying disease progression trajectories. Second, their causation is driven by both genetic and environmental factors. Big data approaches will provide opportunities to better understand disease progression and the complex interplay between genes and the environment. Although there are many important biological, clinical and population data sets available, there are key data limitations. Overcoming these limitations and reaping the benefits of linked data will require successful resolution of several challenges including: making existing and newly acquired data available in open access platforms that protect participant privacy; harmonising data so that they can be usefully merged; improving our collection of population-based exposure data; curating databases; and managing expectations. Appropriate funding needs to be set aside for all phases of a big data discovery paradigm as part of a balanced portfolio of research.
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    ABSTRACT: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
    JAMA Neurology 12/2014; 72(2). DOI:10.1001/jamaneurol.2014.2157 · 7.42 Impact Factor
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    ABSTRACT: The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.
    Molecular Neurodegeneration 12/2014; 9(1):59. DOI:10.1186/1750-1326-9-59 · 6.56 Impact Factor
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    ABSTRACT: Background: Inbreeding can be associated with a modification of disease risk due to excess homozygosity of recessive alleles affecting a wide range of phenotypes. We estimated the inbreeding coefficient in Caribbean Hispanics and examined its effects on risk of late-onset Alzheimer disease. Methods: The inbreeding coefficient was calculated in 3,392 subjects (1,451 late-onset Alzheimer disease patients and 1,941 age-matched healthy controls) of Caribbean Hispanic ancestry using 177,997 nearly independent single-nucleotide polymorphisms from genome-wide array. The inbreeding coefficient was estimated using the excess homozygosity method with and without adjusting for admixture. Results: The average inbreeding coefficient in Caribbean Hispanics without accounting for admixture was F = 0.018 (±0.048), suggesting a mating equivalent to that of second cousins or second cousins once removed. Adjusting for admixture from three parent populations, the average inbreeding coefficient was found to be 0.0034 (±0.019) or close to third-cousin mating. Inbreeding coefficient was a significant predictor of Alzheimer disease when age, sex, and APOE genotype were used as adjusting covariates (P = 0.03). Conclusion: The average inbreeding coefficient of this population is significantly higher than that of the general Caucasian populations in North America. The high rate of inbreeding resulting in increased frequency of recessive variants is advantageous for the identification of rare variants associated with late-onset Alzheimer disease.Genet Med 17 8, 639-643.
    Genetics in medicine: official journal of the American College of Medical Genetics 11/2014; 17(8). DOI:10.1038/gim.2014.161 · 7.33 Impact Factor
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    ABSTRACT: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
    Journal of Alzheimer's disease: JAD 10/2014; 44(2). DOI:10.3233/JAD-141902 · 4.15 Impact Factor
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    ABSTRACT: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
    JAMA Neurology 09/2014; DOI:10.1001/jamaneurol.2014.1491 · 7.42 Impact Factor
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    ABSTRACT: Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p.M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.038 · 5.01 Impact Factor
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    Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2014; 10(4):P324. DOI:10.1016/j.jalz.2014.05.293 · 12.41 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P134. DOI:10.1016/j.jalz.2014.04.074 · 12.41 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here, we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wild-type littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid-β protein, may underlie the observed neuronal loss. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 07/2014; 522(10). DOI:10.1002/cne.23536 · 3.23 Impact Factor

Publication Stats

29k Citations
3,695.84 Total Impact Points


  • 2009–2015
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, England, United Kingdom
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1991–2015
    • University of Toronto
      • • Department of Medical Biophysics
      • • Tanz Centre for Research in Neurodegenerative Diseases
      • • Department of Medicine
      • • Division of Neurology
      • • Department of Pharmacology and Toxicology
      Toronto, Ontario, Canada
    • National Institute on Aging
      • Laboratory of Neurosciences (LNS)
      Baltimore, Maryland, United States
  • 2013
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 2012
    • University of Alberta
      • Centre for Prions and Protein Folding Diseases
      Edmonton, Alberta, Canada
  • 2000–2011
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2006
    • University of Nice-Sophia Antipolis
      • Institut de Pharmacologie Moléculaire et Cellulaire (IPMC/UMR6097 CNRS-UNS)
      Nice, Provence-Alpes-Côte d'Azur, France
  • 2004–2006
    • French National Centre for Scientific Research
      • Institut de Pharmacologie Moléculaire et Cellulaire (IPMC)
      Paris, Ile-de-France, France
    • University of Texas at Dallas
      Richardson, Texas, United States
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2001–2006
    • University Health Network
      • • Department of Medicine
      • • Division of Nephrology
      Toronto, Ontario, Canada
  • 1998–2006
    • University of Florence
      Florens, Tuscany, Italy
    • Mount Sinai Hospital, Toronto
      • Department of Medical Imaging
      Toronto, Ontario, Canada
    • University of Guadalajara
      Guadalajara, Jalisco, Mexico
  • 2005
    • University of Ottawa
      Ottawa, Ontario, Canada
  • 2002
    • University of Antwerp
      • VIB Department of Molecular Genetics
      Antwerpen, VLG, Belgium
  • 1992
    • University of California, Los Angeles
      • Department of Neurology
      Los Ángeles, California, United States
  • 1990
    • Medical Neurogenetics
      Atlanta, Georgia, United States
  • 1987–1989
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      • Neuroepigenetics Laboratory
      Boston, MA, United States
  • 1988
    • Harvard Medical School
      • Department of Genetics
      Boston, Massachusetts, United States