Showing papers by "Luisa Benussi published in 2014"

Frontotemporal dementia and its subtypes: a genome-wide association study

Abstract: Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles.

Abstract: Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Measurement of the muon charge asymmetry in inclusive pp →w+X production at s =7TeV and an improved determination of light parton distribution functions

Abstract: Measurements of the muon charge asymmetry in inclusive pp to WX production at sqrt(s) = 7 TeV are presented. The data sample corresponds to an integrated luminosity of 4.7 inverse femtobarns recorded with the CMS detector at the LHC. With a sample of more than twenty million W to mu nu events, the statistical precision is greatly improved in comparison to previous measurements. These new results provide additional constraints on the parton distribution functions of the proton in the range of the Bjorken scaling variable x from 10E-3 to 10E-1. These measurements and the recent CMS measurement of associated W + charm production are used together with the cross sections for inclusive deep inelastic ep scattering at HERA in a next-to-leading-order QCD analysis. The determination of the valence quark distributions is improved, and the strange-quark distribution is probed directly through the leading-order process g + s to W + c in proton-proton collisions at the LHC.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Abstract: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease.

Abstract: Objective Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up. Methods The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis—with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates—was applied to predict the conversion from MCI to AD. Results Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03–1.47, p = 0.022); for each additional micromole per liter unit (μmol/l) of non-Cp copper, the hazard increased by ∼20%. Subjects with non-Cp copper levels >1.6μmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ∼3× higher than those with values ≤1.6μmol/l (<20% in 4 years). The rate of conversion was similar between APOE4 carriers and noncarriers (p = 0.321), indicating that the non-Cp copper association was independent of APOE4. Interpretation Non-Cp copper appears to predict conversion from MCI to AD. These results encourage healthy life style choices and dietary intervention to modify this risk. ANN NEUROL 2014;75:574–580

Conformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum

Abstract: Ab oligomers (AbOs) are crucially involved in Alzheimer’s Disease (AD). However, the lack of selective approaches for targeting these polymorphic Ab assemblies represents a major hurdle in understanding their biosynthesis, traffic and actions in living cells. Here, we established a subcellularly localized conformational-selective interference (CSI) approach, based on the expression of a recombinant antibody fragment against AbOs in the endoplasmic reticulum (ER). By CSI, we can control extra- and intracellular pools of AbOs produced in an AD-relevant cell model, without interfering with the maturation and processing of the Ab precursor protein. The anti-AbOs intrabody selectively intercepts critical AbO conformers in the ER, modulating their assembly and controlling their actions in pathways of cellular homeostasis and synaptic signalling. Our results demonstrate that intracellular Ab undergoes pathological oligomerization through critical conformations formed inside the ER. This establishes intracellular AbOs as key targets for AD treatment and presents CSI as a potential targeting strategy.

Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers

Abstract: Background To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin ( GRN ) mutation carriers. Methods Ten cognitively normal subjects (five mutation carriers, GRN +; years to estimated disease onset: 12 ± 7; five mutation noncarriers, GRN −) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. Results GRN + showed smaller cortical thickness than GRN − in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. Conclusion Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.

Search for Jet Extinction in the Inclusive Jet-p[subscript T] Spectrum from Proton-Proton Collisions at √s = 8 TeV

Abstract: The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Search for jet extinction in the inclusive jet-p T spectrum from proton-proton collisions at ffiffi s p ¼ 8 TeV V. Khachatryan et al. The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7 fb −1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale.

Study of the production of charged pions, kaons, and protons in pPb collisions at √s[subscript NN] = 5.02 TeV

Abstract: Spectra of identified charged hadrons are measured in pPb collisions with the CMS detector at the LHC at √ sN N = 5.02 TeV. Charged pions, kaons, and protons in the transverse-momentum range pT ≈ 0.1–1.7 GeV/c and laboratory rapidity |y| < 1 are identified via their energy loss in the silicon tracker. The average pT increases with particle mass and the charged multiplicity of the event. The increase of the average pT with charged multiplicity is greater for heavier hadrons. Comparisons to Monte Carlo event generators reveal that Epos Lhc, which incorporates additional hydrodynamic evolution of the created system, is able to reproduce most of the data features, unlike Hijing and Ampt. The pT spectra and integrated yields are also compared to those measured in pp and PbPb collisions at various energies. The average transverse momentum and particle ratio measurements indicate that particle production at LHC energies is strongly correlated with event particle multiplicity.

Measurement of the t[line over t] production cross section in the dilepton channel in pp collisions at √s = 8 TeV

Abstract: The top-antitop quark (tt̄) production cross section is measured in protonproton collisions at √ s = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb−1. The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239±2 (stat.)±11 (syst.)±6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model.