Author
Giuliano Binetti
Other affiliations: Massachusetts Institute of Technology
Bio: Giuliano Binetti is an academic researcher from Sacred Heart Hospital. The author has contributed to research in topics: Frontotemporal dementia & Frontotemporal lobar degeneration. The author has an hindex of 60, co-authored 234 publications receiving 11295 citations. Previous affiliations of Giuliano Binetti include Massachusetts Institute of Technology.
Papers published on a yearly basis
Papers
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TL;DR: Data will ameliorate the overall reliability of MMSE as a screening test for cognitive impairment in elderly people and reduce the influence of demographic variables on the MMSE raw scores.
Abstract: The Mini-Mental State Examination (MMSE), a brief test to assess cognitive status, is heavily influenced by age and education. It was administered to 1019 elderly subjects (aged 65-89 years) living in three different Italian cities. A statistical non-linear regression model was built up in order to obtain adjustment coefficients to reduce the influence of demographic variables on the MMSE raw scores. Age and educational level were significantly and independently associated with the MMSE score. Results of a multiple linear regression with transformation of age and education provided adjustment coefficients of the MMSE raw scores. Data from this study will ameliorate the overall reliability of MMSE as a screening test for cognitive impairment in elderly people.
553 citations
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University College London1, University of London2, Erasmus University Rotterdam3, Leiden University Medical Center4, Sunnybrook Health Sciences Centre5, University of Toronto6, University Health Network7, Laval University8, University of Brescia9, University of Milan10, University of Cambridge11, Karolinska Institutet12, Karolinska University Hospital13, University of Geneva14, University of Western Ontario15, University of Florence16
TL;DR: 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, which could help to define biomarkers that can stage presymPTomatic disease and track disease progression.
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.
448 citations
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TL;DR: This paper performed a two-stage genome-wide association study with 111,326 clinically diagnosed/proxy AD cases and 677,663 controls and found 75 risk loci, of which 42 were new at the time of analysis.
Abstract: Abstract Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
403 citations
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TL;DR: Individual analysis of the alpha frequency and power can discriminate mild AD from VaD and normal elderly subjects, and may probe pathophysiological mechanisms causing AD and VaD.
310 citations
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Raffaele Ferrari1, Raffaele Ferrari2, Dena G. Hernandez3, Dena G. Hernandez1 +178 more•Institutions (54)
TL;DR: The findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways ( link to 11q14) are potentially involved in FTD.
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.
282 citations
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9,362 citations
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Rutgers University1, New York University2, University of Oxford3, Harvard University4, Bangor University5, University of Copenhagen6, National Institutes of Health7, Oregon Health & Science University8, Yale University9, Nathan Kline Institute for Psychiatric Research10, Medical College of Wisconsin11, University of Oulu12, Radboud University Nijmegen13, National Yang-Ming University14, Cleveland Clinic15, Duke University16, Max Planck Society17, Emory University18, University of Queensland19, University of Michigan20, Kennedy Krieger Institute21, Washington University in St. Louis22, Technische Universität München23, Leiden University24, University of Texas at Dallas25, Charité26, University of Pittsburgh27, Southeast University28, Otto-von-Guericke University Magdeburg29, Massachusetts Institute of Technology30, University of Western Ontario31, Medical University of Vienna32, Beijing Normal University33
TL;DR: The 1000 Functional Connectomes Project (Fcon_1000) as discussed by the authors is a large-scale collection of functional connectome data from 1,414 volunteers collected independently at 35 international centers.
Abstract: Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.
2,787 citations
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01 Jan 2016
TL;DR: In this paper, a study suggests that there are sex differences in vocational attitude maturity, with the relationship being higher for males than for females, and the self-concept variables of self-satisfaction, family, and moral-ethical self were found to contribute to the attitude maturity of males.
Abstract: This study suggests that there are sex differences in vocational attitude maturity. In the four-school stratified sample of eleventh grade boys and girls studied, the girls scored significantly higher than the boys in vocational attitude. No sex differences in overall level of self-esteem, as measured by the Tennessee Self-Concept Scale, were found. For both sexes a significant relationship between the over all level of self-esteem and vocational attitude maturity was indicated, with the relationship being higher for males than for females. The self-concept variables of self-satisfaction, family, and moral-ethical self were found to contribute to the vocational attitude maturity of males. For females, the self-concept variables of identity and moral-ethical self contributed to their vocational attitude maturity.
2,376 citations
01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.
2,187 citations
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TL;DR: Screening different groups of elderly individuals in a general or specialty practice would be beneficial in detecting dementia and persons with memory impairment who were not demented were characterized in the literature as having mild cognitive impairment.
Abstract: Article abstract—Objective: The goal of this project was to determine whether screening different groups of elderly individuals in a general or specialty practice would be beneficial in detecting dementia. Background: Epidemiologic studies of aging and dementia have demonstrated that the use of research criteria for the classification of dementia has yielded three groups of subjects: those who are demented, those who are not demented, and a third group of individuals who cannot be classified as normal or demented but who are cognitively (usually memory) impaired. Methods: The authors conducted computerized literature searches and generated a set of abstracts based on text and index words selected to reflect the key issues to be addressed. Articles were abstracted to determine whether there were sufficient data to recommend the screening of asymptomatic individuals. Other research studies were evaluated to determine whether there was value in identifying individuals who were memory-impaired beyond what one would expect for age but who were not demented. Finally, screening instruments and evaluation techniques for the identification of cognitive impairment were reviewed. Results: There were insufficient data to make any recommendations regarding cognitive screening of asymptomatic individuals. Persons with memory impairment who were not demented were characterized in the literature as having mild cognitive impairment. These subjects were at increased risk for developing dementia or AD when compared with similarly aged individuals in the general population. Recommendations: There were sufficient data to recommend the evaluation and clinical monitoring of persons with mild cognitive impairment due to their increased risk for developing dementia (Guideline). Screening instruments, e.g., Mini-Mental State Examination, were found to be useful to the clinician for assessing the degree of cognitive impairment (Guideline), as were neuropsychologic batteries (Guideline), brief focused cognitive instruments (Option), and certain structured informant interviews (Option). Increasing attention is being paid to persons with mild cognitive impairment for whom treatment options are being evaluated that may alter the rate of progression to dementia.
2,081 citations