Showing papers by "Luisa Benussi published in 2015"

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

Abstract: Summary Background Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin ( GRN ), microtubule-associated protein tau ( MAPT ), or chromosome 9 open reading frame 72 ( C9orf72 ). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT , or C9orf72 , or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test −0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all −0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference −0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference −0·2, SE 0·1). Interpretation Structural imaging and cognitive changes can be identified 5–10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Funding Centres of Excellence in Neurodegeneration.

Extracellular Vesicles in Alzheimer's Disease: Friends or Foes? Focus on aβ-vesicle Interaction

Abstract: The intercellular transfer of amyloid-β (Aβ) and tau proteins has received increasing attention in Alzheimer’s disease (AD). Among other transfer modes, Aβ and tau dissemination has been suggested to occur through release of Extracellular Vesicles (EVs), which may facilitate delivery of pathogenic proteins over large distances. Recent evidence indicates that EVs carry on their surface, specific molecules which bind to extracellular Aβ, opening the possibility that EVs may also influence Aβ assembly and synaptotoxicity. In this review we focus on studies which investigated the impact of EVs in Aβ-mediated neurodegeneration and showed either detrimental or protective role for EVs in the pathology.

Measurement of electroweak production of two jets in association with a Z boson in proton–proton collisions at √s = 8 TeV

Abstract: The purely electroweak (EW) cross section for the production of two jets in association with a Z boson, in proton–proton collisions at √ s = 8 TeV, is measured using data recorded by the CMS experiment at the CERN LHC, corresponding to an integrated luminosity of 19.7 fb−1. The electroweak cross section for the jj final state (with = e or μ and j representing the quarks produced in the hard interaction) in the kinematic region defined by M > 50 GeV, Mjj > 120 GeV, transverse momentum pTj > 25 GeV, and pseudorapidity |ηj| < 5, is found to be σEW( jj) = 174 ± 15 (stat) ± 40 (syst) fb, in agreement with the standard model prediction. The associated jet activity of the selected events is studied, in particular in a signalenriched region of phase space, and the measurements are found to be in agreement with QCD predictions.

Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

Abstract: Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.

A study of HFO-1234ze (1,3,3,3-Tetrafluoropropene) as an eco-friendly replacement in RPC detectors

Abstract: The operations of Resistive Plate Chambers in LHC experiments require F-based gases for optimal performance. Recent regulations demand the use of environmentally unfriendly F-based gases to be limited or banned. This report shows results of studies on performance of RPCs operated with a potential eco-friendly gas candidate 1,3,3,3-Tetrafluoropropene, commercially known as HFO-1234ze.

Mirror Image of the Amyloid-β Species in Cerebrospinal Fluid and Cerebral Amyloid in Alzheimer's Disease.

Abstract: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation in brain that is paralleled by Aβ(1-42) reduction in cerebrospinal fluid (CSF). We analyzed the pattern of Aβ peptides, including the N- and C-terminal truncated fragments, in brain and CSF from two familial and one sporadic AD cases. We found that (i) each patient is characterized by a distinct Aβ profile in CSF and brain deposits and (ii) the CSF Aβ pattern mirrors the Aβ profile of cerebral amyloid. These results suggest the existence of different molecular AD subtypes which can be recognized by CSF analysis, enabling patient stratification.

Σ−pemission rates inK−absorptions at rest onLi6,Li7,Be9,C13, andO16

Abstract: An experimental study of the ${K}_{\mathrm{stop}}^{\ensuremath{-}}A\ensuremath{\rightarrow}{\mathrm{\ensuremath{\Sigma}}}^{\ensuremath{-}}p{A}^{\ensuremath{'}}$ reaction on $A=^{6}\mathrm{Li},\phantom{\rule{0.16em}{0ex}}^{7}\mathrm{Li},\phantom{\rule{0.16em}{0ex}}^{9}\mathrm{Be},\phantom{\rule{0.16em}{0ex}}^{13}\mathrm{C}$, and $^{16}\mathrm{O}\phantom{\rule{4pt}{0ex}}p$-shell nuclei is presented. The data were collected by the FINUDA spectrometer operating at the $\mathrm{DA}\mathrm{\ensuremath{\Phi}}\mathrm{NE}\phantom{\rule{4pt}{0ex}}\ensuremath{\phi}$ factory (LNF-INFN, Italy). Emission rates for the reaction in the mentioned nuclei are measured and compared with the few existing data. The spectra of several observables are discussed; indications of quasifree absorptions by a $(np)$ pair embedded in the $A$ nucleus can be obtained from the study of the missing mass distributions.

Angular analysis of the decay B⁰ → K*⁰ μ⁺ μ⁻ from pp collisions at √s = 8 TeV

Abstract: Article history: Received 29 July 2015 Received in revised form 30 November 2015 Accepted 7 December 2015 Available online 11 December 2015 Editor: M. Doser

Study of Z production in PbPb and pp collisions at √s[subscript NN] = 2.76 TeV in the dimuon and dielectron decay channels

Abstract: The production of Z bosons is studied in the dimuon and dielectron decay channels in PbPb and pp collisions at √ sNN = 2.76 TeV, using data collected by the CMS experiment at the LHC. The PbPb data sample corresponds to an integrated luminosity of about 166μb−1, while the pp data sample collected in 2013 at the same nucleon-nucleon centre-of-mass energy has an integrated luminosity of 5.4 pb−1. The Z boson yield is measured as a function of rapidity, transverse momentum, and collision centrality. The ratio of PbPb to pp yields, scaled by the number of inelastic nucleon-nucleon collisions, is found to be 1.06± 0.05 (stat) ± 0.08 (syst) in the dimuon channel and 1.02± 0.08 (stat) ± 0.15 (syst) in the dielectron channel, for centrality-integrated Z boson production. This binary collision scaling is seen to hold in the entire kinematic region studied, as expected for a colourless probe that is unaffected by the hot and dense QCD medium produced in heavy ion collisions.

Candidate eco-friendly gas mixtures for MPGDs

Abstract: Modern gas detectors for detection of particles require F-based gases for optimal performance. Recent regulations demand the use of environmentally unfriendly F-based gases to be limited or banned. This review studies properties of potential eco-friendly gas candidate replacements.

Effect of extracellular vesicles derived from distinct brain cells on Aβ toxicity and assembly: focus on Microglia derived vesicles

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder. The pathohistological features in AD are intracellular accumulation of neurofibrillary tangles and extracellular senile plaques. Plaque deposition leads to recruitment and activation of microglial cells, which induces neuroinflammation and drives neurodegeneration. Recent evidence show that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are highly neurotoxic and correlate with disease severity.Hence, preventing formation of soluble Aβ and its interaction with neurons is a major goal in AD. Despite massive efforts, how extracellular factors regulate assembly of Aβ peptide and neurotoxic activity of Aβ species is still largely undefined. Recent studies indicate that Extracellular Vesicles (EVs), including exosomes and PM-derived microvesicles (MVs), may influence Aβ neurotoxicity. Our findings reveal that production of microglial MVs (m-MVs) is strikingly high in patients with mild cognitive impairment and AD as compared to healthy controls and positively correlates with markers of neurodegeneration and hippocampal atrophy. Furthermore we found that MVs isolated from the CSF of AD patients are toxic to cultured hippocampal neurons. Through in vitro studies we demonstrate that the m-MVs promote generation of neurotoxic soluble species from almost inert Aβ aggregates, which is mediated by lipid components of MVs. Our findings suggest that m-MVs favor formation of neurotoxic Aβ species throughout the brain, possibly representing the mechanism behind transynaptic spread of Aβ in AD. On the other hand, studies conducted by Yuyama et al 2012, 2014 & An et al 2013 suggest that exosomes produced by neurons may exert opposite action by neutralizing neurotoxicity of soluble Aβ. To verify if the overall effect of exosomes and MVs on Aβ neurotoxicity may vary depending on parental cell type we are currently studying the influence of EVs (exosomes & MVs) derived from distinct brain cells on Aβ toxicity and assembly.

Effect of extracellular vesicles derived from distinct brain cells on A beta toxicity and assembly : focus on microglia derived vesicles

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder. The pathohistological features in AD are intracellular accumulation of neurofibrillary tangles and extracellular senile plaques. Plaque deposition leads to recruitment and activation of microglial cells, which induces neuroinflammation and drives neurodegeneration. Recent evidence show that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are highly neurotoxic and correlate with disease severity.Hence, preventing formation of soluble Aβ and its interaction with neurons is a major goal in AD. Despite massive efforts, how extracellular factors regulate assembly of Aβ peptide and neurotoxic activity of Aβ species is still largely undefined. Recent studies indicate that Extracellular Vesicles (EVs), including exosomes and PM-derived microvesicles (MVs), may influence Aβ neurotoxicity. Our findings reveal that production of microglial MVs (m-MVs) is strikingly high in patients with mild cognitive impairment and AD as compared to healthy controls and positively correlates with markers of neurodegeneration and hippocampal atrophy. Furthermore we found that MVs isolated from the CSF of AD patients are toxic to cultured hippocampal neurons. Through in vitro studies we demonstrate that the m-MVs promote generation of neurotoxic soluble species from almost inert Aβ aggregates, which is mediated by lipid components of MVs. Our findings suggest that m-MVs favor formation of neurotoxic Aβ species throughout the brain, possibly representing the mechanism behind transynaptic spread of Aβ in AD. On the other hand, studies conducted by Yuyama et al 2012, 2014 & An et al 2013 suggest that exosomes produced by neurons may exert opposite action by neutralizing neurotoxicity of soluble Aβ. To verify if the overall effect of exosomes and MVs on Aβ neurotoxicity may vary depending on parental cell type we are currently studying the influence of EVs (exosomes & MVs) derived from distinct brain cells on Aβ toxicity and assembly.