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1. A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia.

Author

Fernando Palluzzi, Raffaele Ferrari, Francesca Graziano, Valeria Novelli, Giacomina Rossi, Daniela Galimberti, Innocenzo Rainero, Luisa Benussi, Benedetta Nacmias, Amalia C Bruni, Daniele Cusi, Erika Salvi, Barbara Borroni, and Mario Grassi

Subjects
Medicine, Science
Abstract

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.

Published
2017
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2. PML nuclear bodies and neuronal intranuclear inclusion in polyglutamine diseases

Author

Junko Takahashi, Hiroto Fujigasaki, Kiyoshi Iwabuchi, Amalia C Bruni, Toshiki Uchihara, Khalid H El Hachimi, Giovanni Stevanin, Alexandra Dürr, Anne-Sophie Lebre, Yvon Trottier, Hugues de Thé, Junichi Tanaka, Jean-Jacques Hauw, Charles Duyckaerts, and Alexis Brice

Subjects
Polyglutamine diseases, Neuronal intranuclear inclusions, Nuclear bodies, Promyelocytic leukemia protein, mSin3A, Ubiquitin, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

In polyglutamine diseases, accumulation in the nucleus of mutant proteins induces the formation of neuronal intranuclear inclusions (NIIs). The nucleus is compartmentalized into structural and functional domains, which are involved in NII formation. Promyelocytic leukemia protein (PML), a major component of nuclear bodies, and mSin3A, a component of the transcription co-repressor complex, were used to investigate how the intranuclear domains/sites relate to NII formation in SCA2, SCA3, SCA7, SCA17 and DRPLA brains. We demonstrate that the size of PML-positive intranuclear structures was larger in pathological brains than in control ones and that these structures contained mutant proteins. PML colocalized only with small NIIs, which maintained the ring-like structure of normal nuclear bodies. Enlarged ring-like PML-positive structures, devoid of mutant proteins, were also found and might represent structures where mutant polyglutamine proteins have been successfully processed. These data suggest that NIIs originate from nuclear bodies, where mutant proteins accumulate for degradation.

Published
2003
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3. Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study.

Author

Giuseppina Rose, Giuseppe Romeo, Serena Dato, Paolina Crocco, Amalia C Bruni, Antti Hervonen, Kari Majamaa, Federica Sevini, Claudio Franceschi, Giuseppe Passarino, and GEnetics of Healthy Ageing Project Consortium

Subjects
Medicine, Science
Abstract

Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions.

Published
2010
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4. Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population

Author

Paolina Crocco, Francesco De Rango, Francesco Bruno, Antonio Malvaso, Raffaele Maletta, Amalia C. Bruni, Giuseppe Passarino, Giuseppina Rose, and Serena Dato

Subjects
Frontotemporal dementia, FTD, FOXP2, PRNP, CNTNAP2, SNPs, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Published
2024
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5. Using the Theory of Planned Behavior and Past Behavior to Explain the Intention to Receive a Seasonal Influenza Vaccine among Family Caregivers of People with Dementia

Author

Francesco Bruno, Paolo Abondio, Valentina Laganà, Rosanna Colao, Sabrina M. Curcio, Francesca Frangipane, Gianfranco Puccio, Raffaele Di Lorenzo, Amalia C. Bruni, and Raffaele Maletta

Subjects
family caregivers, dementia, theory of planned behavior, seasonal influenza, vaccine hesitancy, vaccination intentions, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Older adults with dementia present an increased risk of mortality due to seasonal influenza. Despite concerning evidence, the influenza vaccination program has been unsuccessful, with low rates of uptake in Italian people ≥65 years. In addition, being vaccinated does not eliminate the risk of contracting a virus, especially by coming into close contact with other possibly unvaccinated people, such as family caregivers in the home environment. Therefore, the refusal of family caregivers to get vaccinated for seasonal influenza could have dire consequences for their relatives with dementia. The aims of this study were to investigate the predictive role of the Theory of Planned Behavior model (TPB) and past vaccination behavior on the intention to receive a seasonal influenza vaccine among family caregivers of people with dementia. Data were collected from seventy-one respondents during July–September 2021 using a cross-sectional web-based survey design. Results of hierarchical binary logistic regression showed that TPB (i.e., attitudes towards vaccination, subjective norms, and perceived behavioral control) explained 51.6% of the variance in intention to receive a seasonal influenza vaccine; past vaccination behavior increased this to 58.8%. In conclusion, past vaccination behavior and the theory of planned behavior variables effectively predict influenza vaccine willingness of family caregivers of people with dementia and should be targeted in vaccination campaigns.

Published
2023
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6. Calabria as a Genetic Isolate: A Model for the Study of Neurodegenerative Diseases

Author

Francesco Bruno, Valentina Laganà, Raffaele Di Lorenzo, Amalia C. Bruni, and Raffaele Maletta

Subjects
Calabria, Italy, neurodegenerative diseases, Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Biology (General), QH301-705.5
Abstract

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology—ranging from clinical activity to the genealogical reconstruction of families/populations across the centuries, the creation of databases, and molecular/genetic research—was modelled on the characteristics of the Calabrian population for more than three decades. This methodology allowed the identification of several novel genetic mutations or variants associated with neurodegenerative diseases. In addition, a higher prevalence of several hereditary neurodegenerative diseases has been reported in this population, such as Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Niemann–Pick type C disease, spinocerebellar ataxia, Creutzfeldt–Jakob disease, and Gerstmann–Straussler–Scheinker disease. Here, we summarize and discuss the results of research data supporting the view that Calabria could be considered as a genetic isolate and could represent a model, a sort of outdoor laboratory—similar to very few places in the world—useful for the advancement of knowledge on neurodegenerative diseases.

Published
2022
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7. Neurodegenerative clinical records analyzer: detection of recurrent patterns within clinical records towards the identification of typical signs of neurodegenerative disease history

Author

Erika Pasceri, Mérième Bouhandi, Claudia Lanza, Anna Perri, Valentina Laganà, Raffaele Maletta, Raffaele Di Lorenzo, and Amalia C. Bruni

Subjects
Conservation, Library and Information Sciences, Computer Science Applications
Abstract

When treating structured health-system-related knowledge, the establishment of an over-dimension to guide the separation of entities becomes essential. This is consistent with the information retrieval processes aimed at defining a coherent and dynamic way – meaning by that the multilevel integration of medical textual inputs and computational interpretation – to replicate the flow of data inserted in the clinical records. This study presents a strategic technique to categorize the clinical entities related to patients affected by neurodegenerative diseases. After a pre-processing range of tasks over paper-based and handwritten medical records, and through subsequent machine learning and, more specifically, natural language processing operations over the digitized clinical records, the research activity provides a semantic support system to detect the main symptoms and locate them in the appropriate clusters. Finally, the supervision of the experts proved to be essential in the correspondence sequence configuration aimed at providing an automatic reading of the clinical records according to the clinical data that is needed to predict the detection of neurodegenerative disease symptoms.

Published
2023
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8. Table S3 from Tau Mutations Serve as a Novel Risk Factor for Cancer

Author

Fabrizio Tagliavini, Raffaele Ferrari, Claudia Manzoni, Simona Buiatiotis, Giorgio Giaccone, Mariangela Farinotti, Graziella Filippini, Amalia C. Bruni, Luisa Benussi, Paola Perego, Giovanna Tagliabue, Sabrina Fabiano, Paolo Contiero, Veronica Redaelli, and Giacomina Rossi

Abstract

Table S3 shows all cancer types found in tau-mutated and reference families

Published
2023
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9. Data from Tau Mutations Serve as a Novel Risk Factor for Cancer

Author

Fabrizio Tagliavini, Raffaele Ferrari, Claudia Manzoni, Simona Buiatiotis, Giorgio Giaccone, Mariangela Farinotti, Graziella Filippini, Amalia C. Bruni, Luisa Benussi, Paola Perego, Giovanna Tagliabue, Sabrina Fabiano, Paolo Contiero, Veronica Redaelli, and Giacomina Rossi

Abstract

In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731–9. ©2018 AACR.

Published
2023
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10. A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer’s Disease

Author

Francesca Frangipane, Valentina Laganà, Raffaele Maletta, Sabrina A.M. Curcio, Amalia C. Bruni, Raffaele Di Lorenzo, Nicoletta Smirne, Rosanna Colao, Francesco Bruno, Gianfranco Puccio, and Natalia Altomari

Subjects
Male, Pediatrics, medicine.medical_specialty, Apathy, Late onset, Behavioral Symptoms, Disease, Neuropsychological Tests, Severity of Illness Index, Alzheimer Disease, medicine, Humans, Dementia, Affective Symptoms, Age of Onset, Psychomotor Agitation, Aged, Early onset, Aged, 80 and over, Psychiatric Status Rating Scales, business.industry, General Neuroscience, General Medicine, Middle Aged, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Italy, Psychotic Disorders, Female, Geriatrics and Gerontology, business
Abstract

Background: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer’s disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results. Objective: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1. Methods: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period. Results: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences. Conclusion: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.

Published
2022
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11. The Nerve Growth Factor Receptor (NGFR/p75NTR): A Major Player in Alzheimer’s Disease

Author

Francesco Bruno, Paolo Abondio, Alberto Montesanto, Donata Luiselli, Amalia C. Bruni, and Raffaele Maletta

Subjects
Inorganic Chemistry, Organic Chemistry, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract

Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., proNGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. In addition to pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

Published
2023
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12. A Novel Mutation (D395A) in Valosin-Containing Protein Gene Is Associated With Early Onset Frontotemporal Dementia in an Italian Family

Author

Rosanna Colao, Sabrina A.M. Curcio, Nicoletta Smirne, Livia Bernardi, Francesco Bruno, Raffaele Maletta, Raffaele Di Lorenzo, Francesca Frangipane, Valentina Laganà, Maria Elena Conidi, Amalia C. Bruni, Gianfranco Puccio, and Maria Mirabelli

Subjects
Hereditary spastic paraplegia, Neurological examination, QH426-470, frontotemporal dementia, Exon, VCP gene, medicine, Genetics, Missense mutation, Neuropsychological assessment, body myopathy, Amyotrophic lateral sclerosis, Genetics (clinical), Original Research, medicine.diagnostic_test, business.industry, D395A, Paget’s disease of bone, medicine.disease, bvFTD, Paget's disease of bone, Valosin-Containing Protein, Molecular Medicine, novel mutation, business, Frontotemporal dementia
Abstract

Inclusion body myopathy (IBM) with Paget’s disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain’s morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.

Published
2021

13. Evolution of genetic testing supports precision medicine for caring Alzheimer's disease patients

Author

Raffaele Maletta, Amalia C. Bruni, and Livia Bernardi

Subjects
Pharmacology, medicine.diagnostic_test, business.industry, High-Throughput Nucleotide Sequencing, Computational biology, Disease, Gene mutation, Precision medicine, Clinical trial, Alzheimer Disease, Pharmacogenetics, Pharmacogenomics, Drug Discovery, Genotype, medicine, Humans, Genetic Testing, Precision Medicine, business, Gene, Genetic testing
Abstract

Genetic testing for Alzheimer's disease offers a molecular diagnosis to patients and their relatives and provides information on personal risk, reproductive choices, clinical trial eligibility, and treatment options. In the past, molecular testing was limited to detecting single variations in single genes. Currently, with the advent of next-generation sequencing, simultaneous analysis of more than 100 genes using the same DNA sample is possible. This approach allows the determination of gene mutations, genetic risk factors, genotypes at many pharmacogenomic loci, and the determination of a polygenic risk scores for stratification of risk. This article reviews the diagnostic genetic testing of Alzheimer’s disease, from the first molecular approaches to recent advances in NGS, focusing on a precision medicine approach.

Published
2021

14. Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Author

Eliecer Coto, Pau Pastor, Maria Serpente, Sandro Sorbi, Benedetta Nacmias, Victoria Alvarez, Raffaele Maletta, Livia Bernardi, Sergio Pérez-Oliveira, Paola Caroppo, Roberta Ghidoni, Manuel Menéndez-González, Irene Piaceri, Raffaele Ferrari, Beatriz De la Casa-Fages, Daniela Galimberti, Raquel Sánchez-Valle, Monica Diez-Fairen, Oriol Dols-Icardo, Ignacio Illán-Gala, Ifgc, Daniel Queimaliños-Perez, Elio Scarpini, Julie van der Zee, Amalia C. Bruni, Christine Van Broeckhoven, Maria Rosário Almeida, Giacomina Rossi, Irene Rosas, Carmen Martínez, Silvia Bagnoli, Francisco Grandas, Barbara Borroni, Jordi Clarimón, Alberto Lleó, Giuliano Binetti, Luisa Benussi, Anna Antonell, Maria Anfossi, and EU EOD Consortium

Subjects
0301 basic medicine, Apolipoprotein E, Male, Aging, Heterozygote, Biology, 03 medical and health sciences, 0302 clinical medicine, Apolipoproteins E, Progranulins, C9orf72, mental disorders, Genetic variation, medicine, Humans, TP53, Gene, Genetic Association Studies, Genetics, Heterogeneous group, C9orf72 Protein, Age at onset, APOE, Frontotemporal dementia, GRN, Survival probability, General Neuroscience, Genetic Variation, medicine.disease, Phenotype, 030104 developmental biology, Disease risk, Female, Human medicine, Neurology (clinical), Geriatrics and Gerontology, Tumor Suppressor Protein p53, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Published
2021

15. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author

Lianne M. Reus, Bogdan Pasaniuc, Danielle Posthuma, Toni Boltz, Yolande A.L. Pijnenburg, Roel A. Ophoff, Raffaele Ferrari, Dena G. Hernandez, Michael A. Nalls, Jonathan D. Rohrer, Adaikalavan Ramasamy, John B.J. Kwok, Carol Dobson-Stone, William S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J. Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R.A. Mackenzie, Ging-Yuek R. Hsiung, David M.A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan J. Thomas, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Atik Baborie, Evelyn Jaros, Michael C. Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St. George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B. Rowe, Johannes C.M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Julie van der Zee, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, Lena E. Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C. Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, David Knopman, Keith A. Josephs, Bradley F. Boeve, Joseph E. Parisi, William W. Seeley, Bruce L. Miller, Anna M. Karydas, Howard Rosen, John C. van Swieten, Elise G.P. Dopper, Harro Seelaar, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A. Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B. Singleton, John Hardy, Parastoo Momeni, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Neurology, Psychiatry, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Candidate gene, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci (eQTL), Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Semantic dementia, Gene Expression, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, Progressive nonfluent aphasia, mental disorders, medicine, Humans, Gene, Biological Psychiatry, Genetics, nutritional and metabolic diseases, medicine.disease, Genetic architecture, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, Frontotemporal Dementia, 030217 neurology & neurosurgery
Abstract

Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Published
2021
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16. The Impact of COVID-19 Quarantine on Patients With Dementia and Family Caregivers: A Nation-Wide Survey

Author

Innocenzo Rainero, Amalia C. Bruni, Camillo Marra, Annachiara Cagnin, Laura Bonanni, Chiara Cupidi, Valentina Laganà, Elisa Rubino, Alessandro Vacca, Raffaele Di Lorenzo, Paolo Provero, Valeria Isella, Nicola Vanacore, Federica Agosta, Ildebrando Appollonio, Paolo Caffarra, Cinzia Bussè, Renato Sambati, Davide Quaranta, Valeria Guglielmi, Giancarlo Logroscino, Massimo Filippi, Gioacchino Tedeschi, Carlo Ferrarese, the SINdem COVID-19 Study Group, Erica Gallo, Alberto Grassini, Andrea Marcinnò, Fausto Roveta, Paola De Martino, Francesca Frangipane, Gianfranco Puccio, Rosanna Colao, Maria Mirabelli, Chiara Terracciano, Federica Lino, Stefano Mozzetta, Gianmarco Gazzola, Giulia Camporese, Simona Sacco, Maria Carmela Lechiara, Claudia Carrarini, Mirella Russo, Alfonsina Casa lena, Patrizia Sucapane, Pietro Tiraboschi, Paola Caroppo, Veronica Redaelli, Giuseppe Di Fede, Daniela Coppa, Lenino Peluso, Pasqualina Insarda, Matteo De Bartolo, Sabrina Esposito, Alessandro Iavarone, Carmine Fuschillo, Elena Salvatore, Chiara Criscuolo, Luisa Sambati, Rossella Santoro, Daniela Gragnaniello, Ilaria Pedriali, Livia Ludovico, Annalisa Chiari, Andrea Fabbo, Petra Bevilacqua, Chiara Galli, Silvia Magarelli, Gianfranco Spalletta, Nerisa Banaj, Giulia Caruso, Desirée Estela Porcari, Franco Giubilei, Anna Rosa Casini, Francesca Ursini, Giuseppe Bruno, Stefano Boffelli, Michela Brambilla, Giuseppe Magnani, Francesca Caso, Edoardo G. Spinelli, Elena Sinforiani, Alfredo Costa, Simona Luzzi, Gabriella Cacchiò, A.I.M.A. –sez Parma, Marta Perini, Rossano Angeloni, Cinzia Giuli, Katia Fabi, Marco Guidi, Cristina Paci, Annaelisa Castellano, Elena Carapelle, Rossella Petrucci, Miriam Accogli, Giovanna Nicoletta Trevisi, Serena Renna, Antonella Vasquez Giuliano, Fulvio Da Re, Antonio Milia, Giuseppina Pilia, Maria Giuseppina Mascia, Valeria Putzu, Tommaso Piccoli, Luca Cuffaro, Roberto Monastero, Antonella Battaglia, Valeria Blandino, Federica Lupo, Eduardo Cumbo, Antonina Luca, Giuseppe Caravaglios, Annalisa Vezzosi, Valentina Bessi, Gloria Tognoni, Valeria Calsolaro, Giulia Lucarelli, Serena Amici, Alberto Trequattrini, Salvatore Pezzuto, Patrizia Mecocci, Giulia Caironi, Barbara Boselli, Marino Formilan, Alessandra Coin, Laura De Togni, Francesca Sala, Giulia Sandri, Maurizio Gallucci, Anna Paola Mazzarolo, Cristina Bergamelli, Serena Passoni, Rainero, I., Bruni, A. C., Marra, C., Cagnin, A., Bonanni, L., Cupidi, C., Lagana, V., Rubino, E., Vacca, A., Di Lorenzo, R., Provero, P., Isella, V., Vanacore, N., Agosta, F., Appollonio, I., Caffarra, P., Busse, C., Sambati, R., Quaranta, D., Guglielmi, V., Logroscino, G., Filippi, M., Tedeschi, G., Ferrarese, C., Rainero, I, Bruni, A, Marra, C, Cagnin, A, Bonanni, L, Cupidi, C, Lagana, V, Rubino, E, Vacca, A, Di Lorenzo, R, Provero, P, Isella, V, Vanacore, N, Agosta, F, Appollonio, I, Caffarra, P, Busse, C, Sambati, R, Quaranta, D, Guglielmi, V, Logroscino, G, Filippi, M, Tedeschi, G, Ferrarese, C, Gallo, E, Grassini, A, Marcinnò, A, Roveta, F, De Martino, P, Frangipane, F, Puccio, G, Colao, R, Mirabelli, M, Terracciano, C, Lino, F, Mozzetta, S, Gazzola, G, Camporese, G, Sacco, S, Lechiara, M, Carrarini, C, Russo, M, Casa Lena, A, Sucapane, P, Tiraboschi, P, Caroppo, P, Redaelli, V, Di Fede, G, Coppa, D, Peluso, L, Insarda, P, De Bartolo, M, Esposito, S, Iavarone, A, Fuschillo, C, Salvatore, E, Criscuolo, C, Sambati, L, Santoro, R, Gragnaniello, D, Pedriali, I, Ludovico, L, Chiari, A, Fabbo, A, Bevilacqua, P, Galli, C, Magarelli, S, Spalletta, G, Banaj, N, Caruso, G, Porcari, E, Giubilei, F, Casini, A, Ursini, F, Bruno, G, Boffelli, S, Brambilla, M, Magnani, G, Caso, F, Spinelli, E, Sinforiani, E, Costa, A, Luzzi, S, Cacchiò, G, Perini, M, Angeloni, R, Giuli, C, Fabi, K, Guidi, M, Paci, C, Castellano, A, Carapelle, E, Petrucci, R, Accogli, M, Trevisi, G, Renna, S, Vasquez Giuliano, A, Da Re, F, Milia, A, Pilia, G, Mascia, M, Putzu, V, Piccoli, T, Cuffaro, L, Monastero, R, Battaglia, A, Blandino, V, Lupo, F, Cumbo, E, Luca, A, Caravaglios, G, Vezzosi, A, Bessi, V, Tognoni, G, Calsolaro, V, Lucarelli, G, Amici, S, Trequattrini, A, Pezzuto, S, Mecocci, P, Caironi, G, Boselli, B, Formilan, M, Coin, A, De Togni, L, Sala, F, Sandri, G, Gallucci, M, Mazzarolo, A, Bergamelli, C, Passoni, S, Rainero I., Bruni A.C., Marra C., Cagnin A., Bonanni L., Cupidi C., Lagana V., Rubino E., Vacca A., Lorenzo R.D., Provero P., Isella V., Vanacore N., Agosta F., Appollonio I., Caffarra P., Busse C., Sambati R., Quaranta D., Guglielmi V., Logroscino G., Filippi M., Tedeschi G., Ferrarese C., Gallo E., Grassini A., Marcinno A., Roveta F., De Martino P., Frangipane F., Puccio G., Colao R., Mirabelli M., Terracciano C., Lino F., Mozzetta S., Gazzola G., Camporese G., Sacco S., Lechiara M.C., Carrarini C., Russo M., Casa Lena A., Sucapane P., Tiraboschi P., Caroppo P., Redaelli V., Di Fede G., Coppa D., Peluso L., Insarda P., De Bartolo M., Esposito S., Iavarone A., Fuschillo C., Salvatore E., Criscuolo C., Sambati L., Santoro R., Gragnaniello D., Pedriali I., Ludovico L., Chiari A., Fabbo A., Bevilacqua P., Galli C., Magarelli S., Spalletta G., Banaj N., Caruso G., Estela Porcari D., Giubilei F., Casini A.R., Ursini F., Bruno G., Boffelli S., Brambilla M., Magnani G., Caso F., Spinelli E.G., Sinforiani E., Costa A., Luzzi S., Cacchio G., Perini M., Angeloni R., Giuli C., Fabi K., Guidi M., Paci C., Castellano A., Carapelle E., Petrucci R., Accogli M., Nicoletta Trevisi G., Renna S., Giuliano A.V., Da Re F., Milia A., Pilia G., Mascia M.G., Putzu V., Piccoli T., Cuffaro L., Monastero R., Battaglia A., Blandino V., Lupo F., Cumbo E., Luca A., Caravaglios G., Vezzosi A., Bessi V., Tognoni G., Calsolaro V., Lucarelli G., Amici S., Trequattrini A., Pezzuto S., Mecocci P., Caironi G., Boselli B., Formilan M., Coin A., De Togni L., Sala F., Sandri G., Gallucci M., Mazzarolo A.P., Bergamelli C., Passoni S., Lorenzo, R. D., Gallo, E., Grassini, A., Marcinno, A., Roveta, F., De Martino, P., Frangipane, F., Puccio, G., Colao, R., Mirabelli, M., Terracciano, C., Lino, F., Mozzetta, S., Gazzola, G., Camporese, G., Sacco, S., Lechiara, M. C., Carrarini, C., Russo, M., Casa Lena, A., Sucapane, P., Tiraboschi, P., Caroppo, P., Redaelli, V., Di Fede, G., Coppa, D., Peluso, L., Insarda, P., De Bartolo, M., Esposito, S., Iavarone, A., Fuschillo, C., Salvatore, E., Criscuolo, C., Sambati, L., Santoro, R., Gragnaniello, D., Pedriali, I., Ludovico, L., Chiari, A., Fabbo, A., Bevilacqua, P., Galli, C., Magarelli, S., Spalletta, G., Banaj, N., Caruso, G., Estela Porcari, D., Giubilei, F., Casini, A. R., Ursini, F., Bruno, G., Boffelli, S., Brambilla, M., Magnani, G., Caso, F., Spinelli, E. G., Sinforiani, E., Costa, A., Luzzi, S., Cacchio, G., Perini, M., Angeloni, R., Giuli, C., Fabi, K., Guidi, M., Paci, C., Castellano, A., Carapelle, E., Petrucci, R., Accogli, M., Nicoletta Trevisi, G., Renna, S., Giuliano, A. V., Da Re, F., Milia, A., Pilia, G., Mascia, M. G., Putzu, V., Piccoli, T., Cuffaro, L., Monastero, R., Battaglia, A., Blandino, V., Lupo, F., Cumbo, E., Luca, A., Caravaglios, G., Vezzosi, A., Bessi, V., Tognoni, G., Calsolaro, V., Lucarelli, G., Amici, S., Trequattrini, A., Pezzuto, S., Mecocci, P., Caironi, G., Boselli, B., Formilan, M., Coin, A., De Togni, L., Sala, F., Sandri, G., Gallucci, M., Mazzarolo, A. P., Bergamelli, C., and Passoni, S.

Subjects
Aging, Pediatrics, medicine.medical_specialty, Cognitive Neuroscience, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Alzheimer’s disease, BPSD, caregiver burden, COVID-19, dementia, quarantine, medicine, Dementia, BPSD, 030212 general & internal medicine, Vascular dementia, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Alzheimer’s disease, caregiver burden, COVID-19, dementia, quarantine, Depression (differential diagnoses), Original Research, M-PSI/05 - PSICOLOGIA SOCIALE, MED/26 - NEUROLOGIA, Dementia with Lewy bodies, Family caregivers, business.industry, Odds ratio, medicine.disease, Settore MED/26 - NEUROLOGIA, Distress, MED/17 - MALATTIE INFETTIVE, business, 030217 neurology & neurosurgery, Neuroscience, Frontotemporal dementia
Abstract

IntroductionPrevious studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine.MethodsThe study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features.Results4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress.ConclusionOur study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.

Published
2021

17. IP6K3 and IPMK variations in LOAD and longevity: Evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival

Author

Giuseppe Passarino, Paolina Crocco, Francesca Iannone, Giuseppina Rose, Serena Dato, Adolfo Saiardi, Francesco De Rango, Amalia C. Bruni, and Raffaele Maletta

Subjects
0301 basic medicine, Male, Linkage disequilibrium, Aging, media_common.quotation_subject, Longevity, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Alzheimer Disease, Protein Interaction Mapping, medicine, SNP, Humans, Genetic Predisposition to Disease, Allele, media_common, Aged, Genetics, Phosphotransferases (Phosphate Group Acceptor), Neurodegeneration, medicine.disease, Mitochondria, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, Italy, Expression quantitative trait loci, Female, 030217 neurology & neurosurgery, Developmental Biology, Signal Transduction
Abstract

Several studies reported that genetic variants predisposing to neurodegeneration were at higher frequencies in centenarians than in younger controls, suggesting they might favor also longevity. IP6K3 and IPMK regulate many crucial biological functions by mediating synthesis of inositol poly- and pyrophosphates and by acting non-enzymatically via protein-protein interactions. Our previous studies suggested they affect Late Onset Alzheimer Disease (LOAD) and longevity, respectively. Here, in the same sample groups, we investigated whether variants of IP6K3 also affect longevity, and variants of IPMK also influence LOAD susceptibility. We found that: i) a SNP of IP6K3 previously associated with increased risk of LOAD increased the chance to become long-lived, ii) SNPs of IPMK, previously associated with decreased longevity, were protective factors for LOAD, as previously observed for UCP4. SNP-SNP interaction analysis, including our previous data, highlighted phenotype-specific interactions between sets of alleles. Moreover, linkage disequilibrium and eQTL data associated to analyzed variants suggested mitochondria as crossroad of interconnected pathways crucial for susceptibility to neurodegeneration and/or longevity. Overall, data support the view that in these traits interactions may be more important than single polymorphisms. This phenomenon may contribute to the non-additive heritability of neurodegeneration and longevity and be part of the missing heritability of these traits.

Published
2020

18. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Author

Manuel Mayhaus, Sandro Sorbi, Peter R. Schofield, A. Rollin, A. Karydas, Alessandro Padovani, Gilles Gasparoni, Peter St George-Hyslop, Carol Dobson-Stone, Stefano F. Cappa, D. S. Knopman, John Hardy, John R. Hodges, Graziella Milan, Florence Pasquier, Christopher Morris, Edward D. Huey, Marc Cruts, Y.A.L. Pijnenburg, R. C. Petersen, Elisa Rubino, P. Scheltens, Vincent Deramecourt, Neil Graff-Radford, Elio Scarpini, Ting Wang, Panagiotis Alexopoulos, Peter Heutink, Lena E. Hjermind, AB Singleton, Jordan Grafman, Elizabeth Thompson, Adrian Danek, Pietro Pietrini, Raffaele Ferrari, Innocenzo Rainero, C. Van Broeckhoven, Rosa Capozzo, Adaikalavan Ramasamy, J. van der Zee, Eric M. Wassermann, Karin Nilsson, Ging-Yuek Robin Hsiung, J. C. van Swieten, Ping Zeng, Rosa Rademakers, Siro Bagnoli, Amalia C. Bruni, Anna Richardson, Dimitrios Kapogiannis, Ian R. A. Mackenzie, Martin N. Rossor, Bruce L. Miller, Roberta Ghidoni, Raffaele Maletta, Massimo Franceschi, Rafael Blesa, Vivianna M. Van Deerlin, Christer Nilsson, Glenda M. Halliday, Jordi Clarimón, John Q. Trojanowski, Michael Tierney, Valeria Novelli, Agustín Ruiz, Didier Hannequin, Giorgio Giaccone, Elise G.P. Dopper, Nicoletta Smirne, F Tagliavini, I. Leber, Julie S. Snowden, Sara Rollinson, Alexis Brice, Ian G. McKeith, John E. Nielsen, Paolo Sorrentino, Véronique Golfier, Maura Gallo, Lauren Bartley, B. F. Boeve, Giancarlo Logroscino, Elena Alonso, Lorenzo Pinessi, Matt Baker, Nigel J. Cairns, Matthias Riemenschneider, William S. Brooks, Alexander Gerhard, Mark Kristiansen, Eric Haan, Israel Hernandez, Ekaterina Rogaeva, Jason D. Warren, Thibaud Lebouvier, Nick C. Fox, Stuart Pickering-Brown, Giacomina Rossi, Carlos Cruchaga, G. Binetti, Maria Landqvist Waldö, William W. Seeley, Jonathan D. Rohrer, Keith A. Josephs, Diego Albani, Wei Gu, Huei-Hsin Chiang, Luigi Ferrucci, H. Zhao, Howie Rosen, Pau Pastor, Alfredo Postiglione, Evelyn Jaros, Livia Bernardi, Dena G. Hernandez, Alberto Lleó, James B. Rowe, Parastoo Momeni, Maria Serpente, Huw R. Morris, Timothy D. Griffiths, Maria Grazia Spillantini, Alan J. Thomas, Maria Elena Conidi, M. Anfossi, Sabrina Pichler, Martine Vercelletto, Murray Grossman, Johannes C. M. Schlachetzki, Gianluigi Forloni, Dennis W. Dickson, Chiara Fenoglio, Olivier Piguet, John B.J. Kwok, Benedetta Nacmias, Harro Seelaar, Robert Perneczky, A. Baborie, Patrizia Rizzu, Y. Gao, Simon Mead, Janine Diehl-Schmid, Sara Ortega-Cubero, Mike A. Nalls, Daniela Galimberti, Annibale Alessandro Puca, Cristina Razquin, Mercè Boada, Johannes Attems, Luisa Benussi, Chiara Cupidi, Irene Piaceri, Xinghao Yu, Joseph E. Parisi, Alexander Kurz, John Collinge, James Uphill, Barbara Borroni, Francesca Frangipane, Caroline Graff, Bernd Ibach, D. M. A. Mann, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Neurology, Apollo - University of Cambridge Repository, and Int FTD-Genomics Consortium IFGC

Subjects
0301 basic medicine, Oncology, lcsh:Medicine, Genome-wide association study, Neurodegenerative, 631/208, 0302 clinical medicine, Leukocytes, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, Amyotrophic lateral sclerosis, lcsh:Science, Telomerase, Telomere Shortening, education.field_of_study, Multidisciplinary, 692/617, article, Mendelian Randomization Analysis, Amyotrophic Lateral Sclerosis, Asian Continental Ancestry Group, Cholesterol, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, LDL, Polymorphism, Single Nucleotide, Proportional Hazards Models, Telomere, Frontotemporal Dementia, Single Nucleotide, Neurology, Engineering sciences. Technology, 692/499, medicine.medical_specialty, Lipoproteins, 692/308, Population, White People, LDL, Mendelian randomization (MR) , leukocyte telomere length (LTL) , amyotrophic lateral sclerosis (ALS), 03 medical and health sciences, Medical research, Rare Diseases, Asian People, Internal medicine, Mendelian randomization, Genetics, medicine, Polymorphism, education, Genetic association, business.industry, Proportional hazards model, International FTD-Genomics Consortium, lcsh:R, Neurosciences, Odds ratio, medicine.disease, Computational biology and bioinformatics, Brain Disorders, 030104 developmental biology, Risk factors, lcsh:Q, 631/114, ALS, business, ddc:600, 030217 neurology & neurosurgery
Abstract

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Published
2020
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19. Prevalence of heterozygous mutations in Niemann-Pick type C genes in a cohort of progressive supranuclear palsy

Author

Raffaele Maletta, Paolo Barone, Marina Picillo, Amalia C. Bruni, and Marianna Amboni

Subjects
Pathology, medicine.medical_specialty, Heterozygote, Heterozygosity, business.industry, Progressive supranuclear palsy, Niemann-Pick, Niemann-Pick Disease, Type C, medicine.disease, Loss of heterozygosity, Genetics, Neurology, Cohort, Mutation, medicine, Prevalence, Humans, Neurology (clinical), Supranuclear Palsy, Progressive, Geriatrics and Gerontology, business, Gene
Published
2020

20. The Italian dementia with lewy bodies study group (DLB-SINDEM): A multicenter survey on the accuracy and the prevalence of DLB diagnosis

Author

Vincenzo Silani, Laura Ferri, Cristina Muscio, Pietro Tiraboschi, Federica Agosta, Daniela Galimberti, Claudia Carrarini, Laura Serra, Barbara Borroni, Massimo Filippi, Annachiara Cagnin, Mirella Russo, Alessandro Padovani, Matteo De Rosa, Angelo Di Iorio, Amalia C. Bruni, Dario Calisi, Marco Bozzali, Marco Onofrj, Daniela Perani, Laura Bonanni, Lucilla Parnetti, Stefano Consoli, Fedele Dono, Roberto Monastero, and Claudio Babiloni

Subjects
Pediatrics, medicine.medical_specialty, Neurology, business.industry, Dementia with Lewy bodies, Multicenter survey, Medicine, Neurology (clinical), business, medicine.disease
Published
2021
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21. Prevalence of Delirium in a Population of Elderly Outpatients with Dementia: A Retrospective Study

Author

Chiara Cupidi, Natalia Altomari, Valentina Laganà, Rosanna Colao, Amalia C. Bruni, Desirée Addesi, Francesco Perticone, Raffaele Maio, Gianfranco Puccio, and Nicoletta Smirne

Subjects
Male, Pediatrics, medicine.medical_specialty, Population, Severity of Illness Index, behavioral disciplines and activities, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Outpatients, mental disorders, Prevalence, medicine, Humans, Dementia, Medical history, 030212 general & internal medicine, education, Geriatric Assessment, Aged, Aged, 80 and over, education.field_of_study, business.industry, General Neuroscience, Medical record, Delirium, Retrospective cohort study, General Medicine, medicine.disease, nervous system diseases, Psychiatry and Mental health, Clinical Psychology, Cohort, Population study, Female, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract

Background Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia. Objective The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population. Methods We randomly selected 650 medical records of outpatients referred to the "Neurogenetic Regional Centre" (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument. Results The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed. Conclusions In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients.

Published
2017
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22. Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts

Author

F. Miraglia, P.M. Rossini, Maria Anfossi, F. Vecchio, Bahar Güntekin, Marco Bozzali, Stefano F. Cappa, Camillo Marra, Franca Tecchio, Francisco J. Fraga, Panteleimon Giannakopoulos, Amalia C. Bruni, Claudio Babiloni, Bruno Dubois, Alvaro Pascual-Leone, F. Panza, R. Di Iorio, Giancarlo Logroscino, and Javier Escudero

Subjects
medicine.medical_specialty, AD biomarkers, Disease, EEG analysis, Electroencephalography, Sensitivity and Specificity, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Alzheimer Disease, Physiology (medical), medicine, Dementia, Humans, 0501 psychology and cognitive sciences, Cognitive decline, Intensive care medicine, EEG rhythms, Alzheimer's disease, dementia, early diagnosis, event-related responses, mild cognitive impairment, medicine.diagnostic_test, business.industry, 05 social sciences, Neuropsychology, Brain, Mild cognitive impairment, Signal Processing, Computer-Assisted, medicine.disease, Early diagnosis, Sensory Systems, Settore MED/26 - NEUROLOGIA, Event-related responses, Neurology, Neurology (clinical), Functional magnetic resonance imaging, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Published
2020

23. Behavioral and psychological effects of coronavirus disease-19 quarantine in patients with dementia

Author

Annachiara Cagnin, Raffaele Di Lorenzo, Camillo Marra, Laura Bonanni, Chiara Cupidi, Valentina Laganà, Elisa Rubino, Alessandro Vacca, Paolo Provero, Valeria Isella, Nicola Vanacore, Federica Agosta, Ildebrando Appollonio, Paolo Caffarra, Ilaria Pettenuzzo, Renato Sambati, Davide Quaranta, Valeria Guglielmi, Giancarlo Logroscino, Massimo Filippi, Gioacchino Tedeschi, Carlo Ferrarese, Innocenzo Rainero, Amalia C. Bruni, SINdem COVID-19 Study Group, Erica Gallo, Alberto Grassini, Andrea Marcinnò, Fausto Roveta, Paola De Martino, Francesca Frangipane, Gianfranco Puccio, Rosanna Colao, Maria Mirabelli, Noemi Martellacci, Federica Lino, Stefano Mozzetta, Cinzia Bussè, Giulia Camporese, Simona Sacco, Maria Carmela Lechiara, Claudia Carrarini, Mirella Russo, Alfonsina Casalena, Patrizia Sucapane, Pietro Tiraboschi, Paola Caroppo, Veronica Redaelli, Giuseppe Di Fede, Daniela Coppa, Lenino Peluso, Pasqualina Insarda, Matteo De Bartolo, Sabrina Esposito, Alessandro Iavarone, Anna Vittoria Marta Orsini, Elena Salvatore, Chiara Criscuolo, Luisa Sambati, Rossella Santoro, Daniela Gragnaniello, Ilaria Pedriali, Livia Ludovico, Annalisa Chiari, Andrea Fabbo, Petra Bevilacqua, Chiara Galli, Silvia Magarelli, Marta Perini, Gianfranco Spalletta, Nerisa Banaj, Desirée Estela Porcari, Giulia Caruso, Virginia Cipollini, Anna Rosa Casini, Francesca Ursini, Giuseppe Bruno, Renzo Rozzini, Michela Brambilla, Giuseppe Magnani, Francesca Caso, Edoardo G. Spinelli, Matteo Cotta Ramusino, Giulia Perini, Simona Luzzi, Gabriella Cacchiò, Rossano Angeloni, Cinzia Giuli, Katia Fabi, Marco Guidi, Cristina Paci, Annaelisa Castellano, Elena Carapelle, Rossella Petrucci, Miriam Accogli, Gianluigi Calabrese, Giovanna Nicoletta Trevisi, Brigida Coluccia, Antonella Vasquez Giuliano, Marcella Caggiula, Fulvio Da Re, Antonio Milia, Giuseppina Pilia, Maria Giuseppina Mascia, Valeria Putzu, Tommaso Piccoli, Luca Cuffaro, Roberto Monastero, Antonella Battaglia, Valeria Blandino, Federica Lupo, Eduardo Cumbo, Luca Antonina, Giuseppe Caravaglios, Annalisa Vezzosi, Valentina Bessi, Gloria Tognoni, Valeria Calsolaro, Enrico Mossello, Serena Amici, Alberto Trequattrini, Salvatore Pezzuto, Patrizia Mecocci, Giulia Fichera, Samantha Pradelli, Marino Formilan, Alessandra Coin, Laura Detogni, Francesca Sala, Giulia Sandri, Maurizio Gallucci, Anna Paola Mazzarolo, Cristina Bergamelli, Cagnin, A., Di Lorenzo, R., Marra, C., Bonanni, L., Cupidi, C., Lagana, V., Rubino, E., Vacca, A., Provero, P., Isella, V., Vanacore, N., Agosta, F., Appollonio, I., Caffarra, P., Pettenuzzo, I., Sambati, R., Quaranta, D., Guglielmi, V., Logroscino, G., Filippi, M., Tedeschi, G., Ferrarese, C., Rainero, I., Bruni, A. C., Cagnin A., Di Lorenzo R., Marra C., Bonanni L., Cupidi C., Lagana V., Rubino E., Vacca A., Provero P., Isella V., Vanacore N., Agosta F., Appollonio I., Caffarra P., Pettenuzzo I., Sambati R., Quaranta D., Guglielmi V., Logroscino G., Filippi M., Tedeschi G., Ferrarese C., Rainero I., Bruni A.C., Gallo E., Grassini A., Marcinno A., Roveta F., De Martino P., Frangipane F., Puccio G., Colao R., Mirabelli M., Martellacci N., Lino F., Mozzetta S., Busse C., Camporese G., Sacco S., Lechiara M.C., Carrarini C., Russo M., Casalena A., Sucapane P., Tiraboschi P., Caroppo P., Redaelli V., Di Fede G., Coppa D., Peluso L., Insarda P., De Bartolo M., Esposito S., Iavarone A., Orsini A.V.M., Salvatore E., Criscuolo C., Sambati L., Santoro R., Gragnaniello D., Pedriali I., Ludovico L., Chiari A., Fabbo A., Bevilacqua P., Galli C., Magarelli S., Perini M., Spalletta G., Banaj N., Porcari D.E., Caruso G., Cipollini V., Casini A.R., Ursini F., Bruno G., Rozzini R., Brambilla M., Magnani G., Caso F., Spinelli E.G., Ramusino M.C., Perini G., Luzzi S., Cacchio G., Angeloni R., Giuli C., Fabi K., Guidi M., Paci C., Castellano A., Carapelle E., Petrucci R., Accogli M., Calabrese G., Trevisi G.N., Coluccia B., Giuliano A.V., Caggiula M., Da Re F., Milia A., Pilia G., Mascia M.G., Putzu V., Piccoli T., Cuffaro L., Monastero R., Battaglia A., Blandino V., Lupo F., Cumbo E., Antonina L., Caravaglios G., Vezzosi A., Bessi V., Tognoni G., Calsolaro V., Mossello E., Amici S., Trequattrini A., Pezzuto S., Mecocci P., Fichera G., Pradelli S., Formilan M., Coin A., Detogni L., Sala F., Sandri G., Gallucci M., Mazzarolo A.P., Bergamelli C., Gallo, E., Grassini, A., Marcinno, A., Roveta, F., De Martino, P., Frangipane, F., Puccio, G., Colao, R., Mirabelli, M., Martellacci, N., Lino, F., Mozzetta, S., Busse, C., Camporese, G., Sacco, S., Lechiara, M. C., Carrarini, C., Russo, M., Casalena, A., Sucapane, P., Tiraboschi, P., Caroppo, P., Redaelli, V., Di Fede, G., Coppa, D., Peluso, L., Insarda, P., De Bartolo, M., Esposito, S., Iavarone, A., Orsini, A. V. M., Salvatore, E., Criscuolo, C., Sambati, L., Santoro, R., Gragnaniello, D., Pedriali, I., Ludovico, L., Chiari, A., Fabbo, A., Bevilacqua, P., Galli, C., Magarelli, S., Perini, M., Spalletta, G., Banaj, N., Porcari, D. E., Caruso, G., Cipollini, V., Casini, A. R., Ursini, F., Bruno, G., Rozzini, R., Brambilla, M., Magnani, G., Caso, F., Spinelli, E. G., Ramusino, M. C., Perini, G., Luzzi, S., Cacchio, G., Angeloni, R., Giuli, C., Fabi, K., Guidi, M., Paci, C., Castellano, A., Carapelle, E., Petrucci, R., Accogli, M., Calabrese, G., Trevisi, G. N., Coluccia, B., Giuliano, A. V., Caggiula, M., Da Re, F., Milia, A., Pilia, G., Mascia, M. G., Putzu, V., Piccoli, T., Cuffaro, L., Monastero, R., Battaglia, A., Blandino, V., Lupo, F., Cumbo, E., Antonina, L., Caravaglios, G., Vezzosi, A., Bessi, V., Tognoni, G., Calsolaro, V., Mossello, E., Amici, S., Trequattrini, A., Pezzuto, S., Mecocci, P., Fichera, G., Pradelli, S., Formilan, M., Coin, A., Detogni, L., Sala, F., Sandri, G., Gallucci, M., Mazzarolo, A. P., Bergamelli, C., Cagnin, A, Di Lorenzo, R, Marra, C, Bonanni, L, Cupidi, C, Lagana, V, Rubino, E, Vacca, A, Provero, P, Isella, V, Vanacore, N, Agosta, F, Appollonio, I, Caffarra, P, Pettenuzzo, I, Sambati, R, Quaranta, D, Guglielmi, V, Logroscino, G, Filippi, M, Tedeschi, G, Ferrarese, C, Rainero, I, and Bruni, A

Subjects
Pediatrics, medicine.medical_specialty, lcsh:RC435-571, Irritability, Behavioral symptoms, 03 medical and health sciences, 0302 clinical medicine, lcsh:Psychiatry, Psychological symptoms, medicine, Dementia, Apathy, Vascular dementia, Behavioral and psychological symptoms, Behavioral symptoms, Caregiver, Coronavirus disease, Dementia, Gender, Psychological symptoms, Quarantine, Original Research, MED/26 - NEUROLOGIA, Psychiatry, Behavioral symptom, Dementia with Lewy bodies, Family caregivers, business.industry, Behavioral and psychological symptoms, Gender, Behavioral and psychological symptom, Caregiver burden, medicine.disease, Multiinfarct dementia, Caregiver, 030227 psychiatry, Coronavirus disease, Quarantine, Psychiatry and Mental health, Settore MED/26 - NEUROLOGIA, MED/17 - MALATTIE INFETTIVE, MED/25 - PSICHIATRIA, M-PSI/08 - PSICOLOGIA CLINICA, Psychological symptom, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background: In March 2020, the World Health Organization declared a global pandemic due to the novel coronavirus SARS-CoV-2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of neuropsychiatric symptoms during quarantine in patients with dementia and their caregivers. Methods: This is a sub-study of a multicenter nation-wide survey. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VD), followed regularly at 87 Italian memory clinics. Variations in behavioral and psychological symptoms (BPSD) were collected after 1 month since quarantine declaration and associations with disease type, severity, gender, and caregiver’s stress burden were analyzed. Results: A total of 4,913 caregivers participated in the survey. Increased BPSD was reported in 59.6% of patients as worsening of preexisting symptoms (51.9%) or as new onset (26%), and requested drug modifications in 27.6% of these cases. Irritability, apathy, agitation, and anxiety were the most frequently reported worsening symptoms and sleep disorder and irritability the most frequent new symptoms. Profile of BPSD varied according to dementia type, disease severity, and patients’ gender. Anxiety and depression were associated with a diagnosis of AD (OR 1.35, CI: 1.12–1.62), mild to moderate disease severity and female gender. DLB was significantly associated with a higher risk of worsening hallucinations (OR 5.29, CI 3.66–7.64) and sleep disorder (OR 1.69, CI 1.25–2.29), FTD with wandering (OR 1.62, CI 1.12–2.35), and change of appetite (OR 1.52, CI 1.03–2.25). Stress-related symptoms were experienced by two-thirds of caregivers and were associated with increased patients’ neuropsychiatric burden (p

Published
2020

24. Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

Author

Jordi Clarimón, Giuliano Binetti, Maria Rosário Almeida, Pau Pastor, Daniela Galimberti, Maria Serpente, Ignacio Illán-Gala, Silvia Bagnoli, Raquel Sánchez-Valle, Barbara Borroni, Livia Bernardi, Beatriz De la Casa-Fages, Elio Scarpini, Francisco Grandas, Alberto Lleó, Roberta Ghidoni, Anna Antonell, Sandro Sorbi, Raffaele Maletta, Irene Rosas, Paola Caroppo, Irene Piaceri, Benedetta Nacmias, Carmen Martínez, Monica Diez-Fairen, Victoria Alvarez, Maria Anfossi, Oriol Dols-Icardo, Luisa Benussi, Julie van der Zee, Christine Van Broeckhoven, Raffaele Ferrari, Manuel Menéndez-González, Amalia C. Bruni, and Giacomina Rossi

Subjects
0301 basic medicine, Male, Aging, medicine.medical_specialty, ATXN2 gene, Genotype, CAG repeats, Disease, Gastroenterology, Pathogenesis, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Progressive nonfluent aphasia, Gene Frequency, Trinucleotide Repeats, C9orf72, Alzheimer Disease, Internal medicine, mental disorders, Medicine, Humans, Tauopathie, Allele, Neurodegeneration, Ataxin-1, Ataxin-2, Huntingtin Protein, C9orf72 Protein, business.industry, General Neuroscience, Parkinson Disease, medicine.disease, nervous system diseases, 030104 developmental biology, Frontotemporal Dementia, Cohort, Intermediate alleles, Female, Neurology (clinical), Human medicine, Geriatrics and Gerontology, business, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HIT CAG repeats. The frequency of HIT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD. (C) 2019 Elsevier Inc. All rights reserved.

Published
2019

25. Role of Niemann-Pick Type C Disease Mutations in Dementia

Author

Sabrina A.M. Curcio, Raffaele Maletta, Maria Mirabelli, Livia Bernardi, Nicoletta Smirne, Francesca Frangipane, Alessandra Clodomiro, Maura Gallo, Franca Vasso, Gianfranco Puccio, Amalia C. Bruni, Maria Gabriella Muraca, Chiara Cupidi, Raffaele Di Lorenzo, Maria Elena Conidi, Andrea Dardis, Milena Romanello, Maria Anfossi, Giusi Torchia, Rosanna Colao, and Stefania Zampieri

Subjects
Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, DNA Mutational Analysis, Vesicular Transport Proteins, Disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Niemann-Pick C1 Protein, hemic and lymphatic diseases, medicine, Animals, Humans, Dementia, Missense mutation, Gene, Aged, Glycoproteins, Tomography, Emission-Computed, Single-Photon, Mutation, Membrane Glycoproteins, business.industry, General Neuroscience, Neurodegeneration, Intracellular Signaling Peptides and Proteins, Brain, nutritional and metabolic diseases, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Phenotype, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Immunology, Female, Geriatrics and Gerontology, NPC1, Carrier Proteins, business, 030217 neurology & neurosurgery
Abstract

Background Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. Objective To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. Methods We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. Results Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. Conclusions Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

Published
2016
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27. The largest caucasian kindred with dentatorubral-pallidoluysian atrophy: A founder mutation in italy

Author

Silvia Grimaldi, Livia Bernardi, Chiara Cupidi, Giuseppe Donato Mangano, Giuseppina Piccione, Raffaele Maletta, Salvatore Basiricò, Nicoletta Smirne, Enrico Grosso, Valentina Laganà, Amalia C. Bruni, Laura Orsi, Rosaria Nardello, Micaela Mitolo, Fabio Giacalone, Grimaldi S., Cupidi C., Smirne N., Bernardi L., Giacalone F., Piccione G., Basirico S., Mangano G.D., Nardello R., Orsi L., Grosso E., Lagana V., Mitolo M., Maletta R.G., Bruni A.C., Grimaldi S, Cupidi C, Smirne N, Bernardi L, Giacalone F, Piccione G, Basiricò S, Mangano GD, Nardello R, Orsi L, Grosso E, Laganà V, Mitolo M, Maletta RG, and Bruni AC

Subjects
0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Disease, Neuropsychological Tests, White People, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Atrophy, Trinucleotide Repeats, dentatorubral-pallidoluysian atrophy, medicine, Humans, Family, ATN1 gene, Child, Founder mutation, Aged, Dentatorubral-pallidoluysian atrophy, business.industry, genealogical method, Middle Aged, medicine.disease, Myoclonic Epilepsies, Progressive, Pedigree, 030104 developmental biology, founder effect, Neurology, Cerebellar cognitive affective syndrome, Italy, cerebellar cognitive-affective syndrome, Mutation, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Founder effect
Abstract

BACKGROUND: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. METHODS: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. RESULTS: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. CONCLUSIONS: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

28. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Author

Jiang, Shan, Wen, Natalie, Zeran, Li, Dube, Umber, Del Aguila, Jorge, Budde, John, Martinez, Rita, Hsu, Simon, Fernandez, Maria V, Cairns, Nigel J, Harari, Oscar, Cruchaga, Carlos, Karch, Celeste MRaffaele Ferrari, Dena, G Hernandez, Michael, A Nalls, Jonathan, D Rohrer, Adaikalavan, Ramasamy, John B, J Kwok, Carol, Dobson-Stone, William, S Brooks, Peter, R Schofield, Glenda, M Halliday, John, R Hodges, Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Eric, Haan, Isabel, Hernández, Agustín, Ruiz, Mercè, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Nigel, J Cairns, Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, Jordi, Clarimón, Alberto, Lleó, Rafael, Blesa, Maria Landqvist Waldö, Karin, Nilsson, Christer, Nilsson, Ian R, A Mackenzie, Ging-Yuek, R Hsiung, David M, A Mann, Jordan, Grafman, Christopher, M Morris, Johannes, Attems, Timothy, D Griffiths, Ian, G McKeith, Alan, J Thomas, Pietrini, P, Edward, D Huey, Eric, M Wassermann, Atik, Baborie, Evelyn, Jaros, Michael, C Tierney, Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Lorenzo, Pinessi, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, James, B Rowe, Johannes C, M Schlachetzki, James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Vivianna, M Van Deerlin, Murray, Grossman, John, Q Trojanowski, Julie van der Zee, William, Deschamps, Tim Van Langenhove, Marc, Cruts, Christine Van Broeckhoven, Stefano, F Cappa, Isabelle Le Ber, Didier, Hannequin, Véronique, Golfier, Martine, Vercelletto, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Jørgen, E Nielsen, Lena, E Hjermind, Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Martin, N Rossor, Nick, C Fox, Jason, D Warren, Maria Grazia Spillantini, Huw, R Morris, Patrizia, Rizzu, Peter, Heutink, Julie, S Snowden, Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Amalia, C Bruni, Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dennis, W Dickson, Neill, R Graff-Radford, Ronald, C Petersen, David, Knopman, Keith, A Josephs, Bradley, F Boeve, Joseph, E Parisi, William, W Seeley, Bruce, L Miller, Anna, M Karydas, Howard, Rosen, John, C van Swieten, Elise G, P Dopper, Harro, Seelaar, Yolande A, L Pijnenburg, Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Annibale, A Puca, Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Florence, Pasquier, Adeline, Rollin, Vincent, Deramecourt, Florence, Lebert, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Andrew, B Singleton, John, Hardy, and Parastoo, Momeni

Subjects
0301 basic medicine, Male, Tau protein, Induced Pluripotent Stem Cells, tau Proteins, medicine.disease_cause, Article, lcsh:RC321-571, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, Receptors, GABA, medicine, Animals, Humans, Induced pluripotent stem cell, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Aged, Aged, 80 and over, Neurons, Mutation, biology, Brain, Frontotemporal lobar degeneration, Human brain, medicine.disease, 3. Good health, Cell biology, Mice, Inbred C57BL, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Female, Tauopathy, Supranuclear Palsy, Progressive, CRISPR-Cas Systems, Frontotemporal Lobar Degeneration, Transcriptome, Frontotemporal dementia, Signal Transduction
Abstract

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

Published
2018

29. Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

Author

Nicoletta Smirne, Maura Gallo, Livia Bernardi, Maria Anfossi, Annamaria Confaloni, Giusi Torchia, Paola Piscopo, Maria Elena Conidi, Francesca Frangipane, Chiara Cupidi, Raffaele Di Lorenzo, Alessandra Clodomiro, Raffaele Maletta, Amalia C Bruni, Maria Gabriella Muraca, Sabrina A.M. Curcio, Maria Mirabelli, Gianfranco Puccio, Paola Mandich, Rosanna Colao, and Franca Vasso

Subjects
Male, Apolipoprotein E, Heterozygote, Disease, Biology, Asymptomatic, Article, Amyloid beta-Protein Precursor, Alzheimer Disease, medicine, Humans, Aged, Dominance (genetics), Genetics, TREM2, Homozygote, Heterozygote advantage, Middle Aged, medicine.disease, Phenotype, Pedigree, Mutation, Female, Neurology (clinical), Alzheimer's disease, medicine.symptom
Abstract

Objective: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions. Methods: The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma β-amyloid peptide was measured. Sequencing of causative AD genes was performed. Results: Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected). Conclusions: Our findings, also supported by the β-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE , TOMM40 , and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance.

Published
2015
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30. Influence of controlled encoding and retrieval facilitation on memory performance in patients with different profiles of mild cognitive impairment

Author

Marco Monaco, Laura Serra, Lucia Fadda, Roberta Perri, Amalia C. Bruni, Carlo Caltagirone, Camillo Marra, Giovanni Augusto Carlesimo, Marco Bozzali, and Sabrina A.M. Curcio

Subjects
Male, Mild Cognitive Impairment, medicine.medical_specialty, Neurology, FCRST, Neuropsychological Tests, Audiology, Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Female, Humans, Magnetic Resonance Imaging, Memory Disorders, Mental Recall, Middle Aged, Psychiatric Status Rating Scales, Cues, Text mining, Atrophy, Encoding (memory), 80 and over, medicine, Cognitive Dysfunction, Cerebral atrophy, business.industry, Cognition, medicine.disease, Facilitation, Settore MED/26 - Neurologia, Neurology (clinical), Analysis of variance, business, Psychology, Cognitive psychology
Abstract

Memory tests able to differentiate encoding and retrieval processes from the memoranda storing ones should be used to differentiate patients in a very early phase of AD. In fact, individuals with mild cognitive impairment (MCI) can be characterized by two different memory profiles: a pure amnestic one (with poor learning and retrieval and poor improvement when encoding is assisted and retrieval is facilitated) and a dysexecutive one (with inefficient encoding and/or poor retrieval strategies and improvement with assisted encoding and retrieval). The amnestic profile characterizes subjects affected by medio-temporal atrophy typical of AD. In this study, a Grober-Buschke memory procedure was used to evaluate normal controls and MCI patients with different cognitive profiles: pure amnestic (aMCIsd), amnestic plus other cognitive impairments (aMCImd) and non-amnestic (naMCI). An index of sensitivity of cueing (ISC) measured the advantage passing from free to cued recall. Results showed that both strategic and consolidation abilities were impaired in the aMCIsd and aMCImd groups and were preserved in the naMCI group. aMCImd, however, compensated the memory deficit with assisted encoding and retrieval, but aMCIsd performed very poorly. When MCI subjects were defined according to the ISC value, subjects with poor ISC were primarily in the aMCIsd group and, to a lesser extent, in the aMCImd group and the naMCI group. Finally, patients with a poor ISC showed cerebral atrophy documented in the precocious phase of AD and the retrosplenial cerebral areas seemed to be the most useful areas for identifying patients in the early phase of AD.

Published
2015
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31. Frequency of Cardiovascular Genetic Risk Factors in a Calabrian Population and Their Effects on Dementia

Author

Maria Gabriella Muraca, Livia Bernardi, Franca Vasso, Giuseppe Passarino, Raffaele Maletta, Alberto Montesanto, Giusi Torchia, Maria Elena Conidi, Rosanna Colao, Amalia C. Bruni, Nicoletta Smirne, Chiara Cupidi, Raffaele Di Lorenzo, Maura Gallo, Valentina Laganà, Sabrina A.M. Curcio, Francesca Frangipane, Gianfranco Puccio, Maria Anfossi, Giuseppina Rose, and Maria Mirabelli

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Population, Apolipoprotein E4, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Alzheimer Disease, Risk Factors, Internal medicine, medicine, Dementia, Humans, Risk factor, Vascular dementia, education, Allele frequency, Aged, Aged, 80 and over, education.field_of_study, Polymorphism, Genetic, business.industry, General Neuroscience, Dementia, Vascular, Case-control study, General Medicine, Middle Aged, medicine.disease, Cholesterol Ester Transfer Proteins, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Italy, Case-Control Studies, Frontotemporal Dementia, Female, Geriatrics and Gerontology, Alzheimer's disease, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Background Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. Objectives To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. Methods The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. Results Carriers of at least one APOEɛ4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477-5.011)] and VaD [OR(95% CI) = 6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364-4.319)] and VaD [OR(95% CI) = 3.649(1.455-9.152)] compared to subjects with the II-VV genotypes. Conclusion CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEɛ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.

Published
2018

32. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author

David J. Irwin, Nilufer Ertekin-Taner, Sara Rollinson, Mads Kjolby, John Hardy, Julia Kofler, Robert A. Rissman, Bernardino Ghetti, Stuart Pickering-Brown, Jonathan Glass, Carlos Cruchaga, Jonathan D. Rohrer, Keith A. Josephs, Maura Gallo, Parastoo Momeni, Emilia J. Sitek, Matthis Synofzik, Sandro Sorbi, Carlo Wilke, Oscar L. Lopez, Nigel J. Cairns, Miren Zulaica, Peter Heutink, Leonard Petrucelli, Bret M. Evers, Luisa Benussi, Jeroen van Rooij, Olivier Piguet, Sandra E. Black, Bradley F. Boeve, Cyril Pottier, Eric M. Reiman, Melissa E. Murray, Ralph B. Perkerson, Daniela Galimberti, Thomas G. Beach, Giorgio G. Fumagalli, Giacomina Rossi, David M. A. Mann, John B.J. Kwok, Harro Seelaar, Edward B. Lee, Jean-Paul Vonsattel, Didier Hannequin, Rosa Rademakers, John R. Hodges, Nicole A. Finch, John Q. Trojanowski, David S. Knopman, Yingxue Ren, Albert Lladó, Anders Nykjaer, Claire Troakes, Linn Öijerstedt, EunRan Suh, Isabelle Le Ber, Juliane Winkelmann, Ian R. Mackenzie, Glenda M. Halliday, William W. Seeley, Salvatore Spina, Simon Mead, Elio Scarpini, Fabrizio Tagliavini, Bruce L. Miller, Mariely DeJesus-Hernandez, Dennis W. Dickson, Elizabeth Christopher, Mario Masellis, Florence Pasquier, Roberta Ghidoni, Janine Diehl-Schmid, Silvia Bagnoli, Barbara Borroni, Adam L. Boxer, Adrian L. Oblak, Elizabeth Finger, Carol F. Lippa, Giuliano Binetti, Eileen H. Bigio, Vivianna M. Van Deerlin, Anna Karydas, William S. Brooks, Julie S. Snowden, Anna Richardson, Lea T. Grinberg, Manuela Neumann, Jordan Grafman, Zbigniew K. Wszolek, Edward D. Huey, Caroline Graff, John C. van Swieten, Sandra Weintraub, Raffaele Maletta, Ekaterina Rogaeva, Fermin Moreno, Raffaele Ferrari, Charles L. White, Adolfo López de Munain, Neill R. Graff-Radford, Camilla Ferrari, Jill R. Murell, Marwan N. Sabbagh, Raquel Sánchez-Valle, Marka van Blitterswijk, Alessandro Padovani, Peter Johannsen, Daniel J. Serie, Francesca Frangipane, Safa Al-Sarraj, Anna Antonell, Kevin F. Bieniek, Tsz H. Wong, Ging-Yuek Robin Hsiung, Jarosław Sławek, Matthew B. Baker, Gregory D. Jenkins, Ronald C. Petersen, Murray Grossman, Benedetta Nacmias, Tammee M. Parsons, Lawrence S. Honig, Maria Anfossi, Richard J. Caselli, Changiz Geula, Marla Gearing, M.-Marsel Mesulam, Xiaolai Zhou, Joanna M. Biernacka, Joseph E. Parisi, Irene Piaceri, Jorgen E. Nielsen, Amalia C. Bruni, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Erasmus MC other, and Neurology

Subjects
0301 basic medicine, Oncology, Male, RNA, Messenger/metabolism, Genome-wide association study, Disease, Gene mutation, genetics [Progranulins], 0302 clinical medicine, Progranulins, Cerebellum, GFRA2 protein, human, Medicine, Age of Onset, genetics [Genetic Predisposition to Disease], Genetic Predisposition to Disease/genetics, Frontotemporal lobar degeneration, metabolism [Cerebellum], Middle Aged, 3. Good health, Frontotemporal Dementia, Female, genetics [Frontotemporal Lobar Degeneration], Frontotemporal dementia, medicine.medical_specialty, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mutation/genetics, Genetic counseling, genetics [Mutation], Progranulins/genetics, metabolism [RNA, Messenger], Article, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, ddc:610, RNA, Messenger, Cerebellum/metabolism, Aged, business.industry, metabolism [Progranulins], Case-control study, genetics [Glial Cell Line-Derived Neurotrophic Factor Receptors], Odds ratio, medicine.disease, metabolism [Frontotemporal Lobar Degeneration], metabolism [Glial Cell Line-Derived Neurotrophic Factor Receptors], 030104 developmental biology, Case-Control Studies, Mutation, GRN protein, human, Frontotemporal Lobar Degeneration/genetics, Neurology (clinical), Human medicine, Frontotemporal Lobar Degeneration, business, Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Published
2018
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33. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD

Subjects
0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract

International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017
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34. Brain-derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons

Author

Aldo Donizetti, Amalia C. Bruni, Vincenza Aliperti, Luisa Cigliano, Chiara Cupidi, Maria Stefania Spagnuolo, Lucia Iannotta, Spagnuolo, MARIA STEFANIA, Donizetti, Aldo, Iannotta, Lucia, Aliperti, Vincenza, Chiara, Cupidi, Amalia Cecilia Bruni, and Cigliano, Luisa

Subjects
0301 basic medicine, Apolipoprotein E, Physiology, MAP Kinase Signaling System, Clinical Biochemistry, astrocytes, neuron, Prefrontal Cortex, Apoptosis, Models, Biological, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Apolipoproteins E, Neurotrophic factors, Cell Line, Tumor, medicine, Homeostasis, Humans, Liver X receptor, Liver X Receptors, Brain-derived neurotrophic factor, Neurons, biology, Cholesterol, Brain-Derived Neurotrophic Factor, Cell Biology, Middle Aged, Cell biology, 030104 developmental biology, medicine.anatomical_structure, nervous system, chemistry, ABCA1, Astrocytes, biology.protein, lipids (amino acids, peptides, and proteins), Neuron, 030217 neurology & neurosurgery, Neurotrophin, ATP Binding Cassette Transporter 1
Abstract

In the central nervous system, cholesterol is critical to maintain membrane plasticity, cellular function, and synaptic integrity. In recent years, much attention was focused on the role of cholesterol in brain since a breakdown of cholesterol metabolism has been associated with different diseases. Brain-derived neurotrophic factor (BDNF) was previously reported to elicit cholesterol biosynthesis and promote the accumulation of presynaptic proteins in cholesterol-rich lipid rafts, but no data are available on its ability to modulate physiological mechanisms involved in cholesterol homeostasis. Major aim of this research was to investigate whether BDNF influences cholesterol homeostasis, focusing on the effect of the neurotrophin on Apolipoprotein E (ApoE) synthesis, cholesterol efflux from astrocytes and cholesterol incorporation into neurons. Our results show that BDNF significantly stimulates cholesterol efflux by astrocytes, as well as ATP binding cassette A1 (ABCA1) transporter and ApoE expression. Conversely, cholesterol uptake in neurons was downregulated by BDNF. This effect was associated with the increase of Liver X Receptor (LXR)-beta expression in neuron exposed to BDNF. The level of apoptosis markers, that is, cleaved caspase 3 and poly ADP ribose polymerase (PARP), was found increased in neurons treated with high cholesterol, but significantly lower when the cells were exposed to cholesterol in the presence of BDNF, thus suggesting a neuroprotective role of the neurotrophin, likely through its reducing effect of neuronal cholesterol uptake. Interestingly, cholesterol stimulates BDNF production by neurons. Overall, our findings evidenced a novel role of BDNF in the modulation of ApoE and cholesterol homeostasis in glial and neuronal cells.

Published
2017
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36. [O4–03–06]: SHORT‐TERM RESPONSE IS NOT PREDICTIVE OF LONG‐TERM RESPONSE TO ACETYLCHOLINESTERASE INHIBITORS IN OLD AGE SUBJECTS WITH ALZHEIMER's DISEASE: A ‘REAL WORLD’ STUDY

Author

Alessandra Clodomiro, Marta Baroni, Patrizia Mecocci, Sara Ercolani, Carmelinda Ruggiero, Amalia C Bruni, Virginia Boccardi, Annalisa Longo, and Nicoletta Smirne

Subjects
Pediatrics, medicine.medical_specialty, education.field_of_study, Longitudinal study, Activities of daily living, Epidemiology, business.industry, Health Policy, Population, Cognition, Disease, Response to treatment, Developmental psychology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Long term response, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, education, business
Abstract

BACKGROUND Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population. OBJECTIVE We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting. METHODS This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively. RESULTS In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p

Published
2017
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37. Genetics in Degenerative Dementia

Author

Amalia C. Bruni, Livia Bernardi, and Maria Elena Conidi

Subjects
medicine.medical_specialty, Genetic counseling, MEDLINE, Genetic Counseling, Genotype, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Degenerative dementia, Psychiatry, Genetic testing, Genetics, medicine.diagnostic_test, business.industry, Neurodegenerative Diseases, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Dementia, Identification (biology), Geriatrics and Gerontology, Alzheimer's disease, business, Gerontology, Frontotemporal dementia
Abstract

An increasing number of hereditary neurodegenerative diseases, including autosomal-dominant Alzheimer disease (AD), familial autosomal-dominant frontotemporal dementia (FTD), and heritable Lewy body disease (LBD) have been defined at the molecular level in recent years, making it possible to determine the genotype before the onset of symptoms. The identification of deterministic genes for these common adult-onset genetic diseases is moving the field of genetic counseling toward a new and challenging direction. With the identification of genes associated with AD and FTD, there is considerable interest in the clinical application of genetic information in genetic counseling and testing. Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians therefore increases the need for a better understanding of the multifaceted issues associated with genetic testing. The aims of this systematic review are: (1) to underline the need to consider a genetic etiology of AD, FTD, and LBD; (2) to provide clinicians with information necessary to effectively translate genetic diagnosis into clinical practice; and (3) to highlight gaps and uncertainties in the field which will need to be addressed by future research.

Published
2014
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38. Association of the Variant Cys139Arg at GRN Gene to the Clinical Spectrum of Frontotemporal Lobar Degeneration

Author

Silvia Pradella, Irene Piaceri, Chiara Cupidi, Livia Bernardi, Cristina Polito, Maura Gallo, Amalia C. Bruni, Andrea Tedde, Benedetta Nacmias, Rosanna Colao, Silvia Bagnoli, Maria Anfossi, Sandro Sorbi, Raffaele Maletta, Serena Nannucci, and Nicoletta Smirne

Subjects
Male, DNA Mutational Analysis, Semantic dementia, Biology, Arginine, medicine.disease_cause, Genetic analysis, Progranulins, mental disorders, Genetic variation, medicine, Humans, Cysteine, Gene, Aged, Aged, 80 and over, Family Health, Genetics, Mutation, General Neuroscience, General Medicine, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Null allele, Psychiatry and Mental health, Clinical Psychology, Intercellular Signaling Peptides and Proteins, Female, Frontotemporal Lobar Degeneration, Geriatrics and Gerontology, Frontotemporal dementia
Abstract

Background Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer's disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. Objective Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. Methods The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. Results The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. Conclusion We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD.

Published
2014
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39. Role of TOMM40 rs10524523 Polymorphism in Onset of Alzheimer's Disease Caused by the PSEN1 M146L Mutation

Author

Maria Elena Conidi, Maria Anfossi, Franca Vasso, Francesca Frangipane, Sabrina A.M. Curcio, Alessandra Clodomiro, Maura Gallo, Nicoletta Smirne, Raffaele Maletta, Gianfranco Puccio, Raffaele Di Lorenzo, Maria Mirabelli, Livia Bernardi, Amalia C. Bruni, and Rosanna Colao

Subjects
Adult, Male, Apolipoprotein E, medicine.medical_specialty, Pathology, Psen1 mutation, Genotype, Disease, Neuropsychological Tests, Memory performance, Gastroenterology, Methionine, Alzheimer Disease, Leucine, Internal medicine, Mitochondrial Precursor Protein Import Complex Proteins, Presenilin-1, medicine, PSEN1, Humans, Genetic Predisposition to Disease, In patient, Age of Onset, Memory Disorders, Polymorphism, Genetic, business.industry, General Neuroscience, Membrane Transport Proteins, General Medicine, Middle Aged, Psychiatry and Mental health, Clinical Psychology, Mutation, Female, Geriatrics and Gerontology, Age of onset, business
Abstract

We investigated the association between TOMM40 rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE. APOE33/TOMM40VL/VL patients showed a tendency for an earlier age at onset compared to those with APOE33/TOMM40VL/S and APOE33/TOMM40S/S. Moreover, TOMM40VL/VL patients had better memory performance, when compared to TOMM40S/S but not to TOMM40VL/S patients, so there is not a dose-dependent effect. Our results suggest that, in the presence of the PSEN1 mutation, the slight difference in age of onset together with memory performance could be influenced by TOMM40 genotypes.

Published
2013
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40. Somatic comorbidities and Alzheimer’s disease treatment

Author

Gianfranco Puccio, Rosanna Colao, Roberto Lacava, Valeria Graziella Laura Manfredi, Francesca Frangipane, Amalia C. Bruni, Alessandra Clodomiro, Pietro Gareri, and Alberto Castagna

Subjects
Male, medicine.medical_specialty, Frail Elderly, Clinical Neurology, Comorbidity, Dermatology, Disease, Somatic comorbidities, Efficacy, Drug treatment, Elderly, Alzheimer Disease, Side effects/adverse events, medicine, Humans, Dementia, Cognitive decline, Intensive care medicine, Adverse effect, Aged, Aged, 80 and over, business.industry, Memantine, General Medicine, medicine.disease, Psychiatry and Mental health, Tolerability, Physical therapy, Female, Original Article, Cholinesterase Inhibitors, Neurology (clinical), business, Alzheimer’s disease, medicine.drug
Abstract

Therapeutic strategies in Alzheimer’s disease (AD) must take into account the characteristics of elderly people, who often have somatic comorbidities. Moreover, demented patients are more frequently frailer than older people. They have a higher number of admissions to hospital, a greater prevalence of complications and an increased risk of death. Therapeutic decisions for these patients have to be approached cautiously: aging, a more elevated comorbidity/polytherapy index and frailty contribute to enhance the risk of pharmacological adverse events and drug interactions. The aim of the present study was to focus on risk–benefit profile of pharmacological therapy for AD in relation to somatic comorbidities that often affect these patients. A Medline search (from 2001 to 2012) was performed using as key words dementia, Alzheimer’s disease, drug treatment, somatic comorbidities, side effects/adverse events and elderly. Cholinesterase inhibitors (ChEIs) and memantine represent the main pharmacological strategies effective in reducing the progression of cognitive decline and functional loss in AD. Many conditions very common in the elderly may restrict the use of ChEIs and/or treatment efficacy in AD patients. Memantine has a good efficacy and tolerability profile with better safety in pulmonary, cardiovascular and central nervous system comorbidities compared to ChEIs. Drug interactions with memantine are also more favorable since they concern mostly drugs not commonly used in the elderly. Only a careful evaluation of the associated somatic diseases, taking into account different drugs safety indexes and tolerability, can lead to personalized treatment management, in order to maximize drug efficacy and optimize quality of life.

Published
2013
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41. Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Author

Elisa Rubino, Daniela Galimberti, Amalia C. Bruni, Fernando Palluzzi, Elisa Bonomi, Irene Piaceri, Innocenzo Rainero, Maria Serpente, Giacomina Rossi, Lorenzo Pinessi, Rosanna Colao, Silvia Bagnoli, Alessandro Padovani, Barbara Borroni, Benedetta Nacmias, Raffaele Ferrari, Elio Scarpini, Giuliano Binetti, Parastoo Momeni, Andrew B. Singleton, Raffaele Maletta, Chiara Cupidi, Giorgio Giaccone, John Hardy, Francesca Graziano, Mario Grassi, Luisa Benussi, Roberta Ghidoni, Livia Bernardi, Fabrizio Tagliavini, Silvana Archetti, Ferrari, R, Grassi, M, Graziano, F, Palluzzi, F, Archetti, S, Bonomi, E, Bruni, A, Maletta, R, Bernardi, L, Cupidi, C, Colao, R, Rainero, I, Rubino, E, Pinessi, L, Galimberti, D, Scarpini, E, Serpente, M, Nacmias, B, Piaceri, I, Bagnoli, S, Rossi, G, Giaccone, G, Tagliavini, F, Benussi, L, Binetti, G, Ghidoni, R, Singleton, A, Hardy, J, Momeni, P, Padovani, A, and Borroni, B

Subjects
0301 basic medicine, Genome-wide association study, Cohort Studies, 0302 clinical medicine, Principal Component Analysi, Polymorphism (computer science), Age at onset, Frontotemporal dementia, GWAS, Polymorphism, Adult, Age of Onset, Aged, Aged, 80 and over, Frontotemporal Dementia, Genetic Association Studies, Humans, Italy, Linear Models, Middle Aged, Polymorphism, Single Nucleotide, Principal Component Analysis, Genetic Loci, Clinical Psychology, Geriatrics and Gerontology, Psychiatry and Mental Health, 80 and over, Genetics, General Neuroscience, General Medicine, Single Nucleotide, Linear Model, Alzheimer's disease, Psychology, Human, Single-nucleotide polymorphism, Genetic Association Studie, Article, 03 medical and health sciences, Genetic variation, mental disorders, medicine, Genetic association, Neuroscience (all), medicine.disease, 030104 developmental biology, Cohort Studie, Age of onset, Neuroscience, 030217 neurology & neurosurgery
Abstract

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by −3.86 (95%CI: −4.64 to −3.07, p < 2 × 10−16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

Published
2017

42. Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer's Disease: A 'Real World' Study

Author

Sara Ercolani, Alessandra Clodomiro, Patrizia Mecocci, Marta Baroni, Annalisa Longo, Amalia C Bruni, Nicoletta Smirne, Carmelinda Ruggiero, and Virginia Boccardi

Subjects
Male, cognition, Pediatrics, medicine.medical_specialty, Longitudinal study, Activities of daily living, Time Factors, Population, Disease, 03 medical and health sciences, Age groups, Alzheimer’s disease, aged, therapeutics, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Cognitive decline, education, Psychiatry, Retrospective Studies, Aged, 80 and over, education.field_of_study, Analysis of Variance, General Neuroscience, Cognition, General Medicine, Mental Status and Dementia Tests, Response to treatment, Psychiatry and Mental health, Clinical Psychology, Long term response, Treatment Outcome, Female, Cholinesterase Inhibitors, Geriatrics and Gerontology, Psychology, Cognition Disorders, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract

BACKGROUND Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population. OBJECTIVE We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting. METHODS This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively. RESULTS In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p

Published
2017

43. A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia

Author

Daniele Cusi, Barbara Borroni, Benedetta Nacmias, Amalia C. Bruni, Innocenzo Rainero, Francesca Graziano, Daniela Galimberti, Valeria Novelli, Mario Grassi, Luisa Benussi, Fernando Palluzzi, Giacomina Rossi, Raffaele Ferrari, Erika Salvi, Palluzzi, F, Ferrari, R, Graziano, F, Novelli, V, Rossi, G, Galimberti, D, Rainero, I, Benussi, L, Nacmias, B, Bruni, A, Cusi, D, Salvi, E, Borroni, B, and Grassi, M

Subjects
0301 basic medicine, Genetics and Molecular Biology (all), Pathology, Physiology, Gene Identification and Analysis, lcsh:Medicine, Genetic Networks, Biochemistry, Cell Signaling, C9orf72, Animal Cells, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Medicine and Health Sciences, Cyclic AMP, Homeostasis, Heuristics, lcsh:Science, WNT Signaling Cascade, Neurons, Neuronal Death, Multidisciplinary, Cell Death, Kinase, Neurodegeneration, Long-term potentiation, Genomics, Phenotype, Signaling Cascades, 3. Good health, Neurology, Cell Processes, Frontotemporal Dementia, Cellular Types, Network Analysis, Algorithms, Frontotemporal dementia, Research Article, Signal Transduction, medicine.medical_specialty, Computer and Information Sciences, DNA damage, MAP Kinase Signaling System, Biology, Neuroprotection, 03 medical and health sciences, mental disorders, Mental Health and Psychiatry, medicine, Genetics, Genome-Wide Association Studies, network analysi, Humans, Biomarkers, Calcium, DNA Damage, Oxidative Stress, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, medicine.disease, Genome Analysis, 030104 developmental biology, Cellular Neuroscience, lcsh:Q, Dementia, Physiological Processes, Neuroscience
Abstract

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer’s disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.

Published
2017
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44. Early onset versus late onset in Alzheimer’s disease: What is the reliable cut-off?

Author

Carlo Caltagirone, Alessandro Padovani, Maria Donata Orfei, Gianfranco Spalletta, Amalia C. Bruni, Vincenzo De Luca, Vincenzo Canonico, L. Rozzini, Giuseppe Bellelli, Carla Pettenati, Roberta Perri, Floriana Pazzelli, Alberto Trequattrini, Spalletta, G, De Luca, V, Padovani, A, Rozzini, L, Perri, R, Bruni, A, Canonico, V, Trequattrini, A, Bellelli, G, Pettenati, C, Pazzelli, F, Caltagirone, C, and Orfei, M

Subjects
Onset, Neuropsychiatric Symptom, Pediatrics, medicine.medical_specialty, Mini–Mental State Examination, Activities of daily living, medicine.diagnostic_test, medicine.medical_treatment, Late onset, General Medicine, Disease, Cognitive Reserve, Delusion, Pathogenesi, Admixture Analysi, medicine, Alzheimer’s Disease, medicine.symptom, Antipsychotic, Psychology, Early onset, Clinical psychology, Cognitive reserve
Abstract

Objective: As the literature on conventional cri- teria for discriminating early-onset (EO) from late-onset (LO) Alzheimer’s disease (AD) is sparse and controversial, the aim of this study was to establish a precise age at onset (AAO) criterion, by using a specific statistical proce- dure, and to describe the clinical characteristics of the two sub-groups. Methods: Admixture analysis was performed to establish the AAO cut-off in a multi-center study including 2000 AD patients consecutively recruited in eight Italian Memory Clinics. None of the patients were tak- ing acetylcholinesterase inhibitors, antipsychotic or anti-depressant drugs. At the first diagnostic visit, they were administered the Mini Mental State Examination, the Basic and Instrumental Activi- ties of Daily Living and the Neuropsychiatric Inventory to assess clinical phenomenology. Results: Using a specific statistical procedure, we established that AAO that discriminated EO- from LO-AD was 66. Compared with the LO-AD group, the EO-AD group showed longer duration of illness and a higher educational level as well as less severe functional impairment and delu- sions. Conclusions: Differences in sociodemo- graphic and clinical characteristics, such as duration of illness, education and delusion se-verity, suggested the involvement of different pathogenic processes. Additional studies are needed to further investigate the mechanisms underlying the disorder in the two sub-groups of AD patients.

Published
2013
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45. NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

Author

Nadia Canu, Viviana Triaca, Robert Nisticò, Amalia C. Bruni, Giulia Bolasco, Pietro Calissano, Valentina Sposato, Marco Feligioni, Raffaele Maletta, Maria Teresa Ciotti, Chiara Cupidi, and Pier Giuseppe Pelicci

Subjects
0301 basic medicine, Male, Aging, Golgi Apparatus, Tropomyosin receptor kinase A, TrkA–APP interaction, Hippocampus, PC12 Cells, Amyloid beta-Protein Precursor, 0302 clinical medicine, Nerve Growth Factor, Amyloid precursor protein, Aspartic Acid Endopeptidases, Phosphorylation, APP pT668, NGF, Neurons, biology, Kinase, Settore BIO/14, Phosphothreonine, Original Article, Protein Binding, Adult, medicine.medical_specialty, Src Homology 2 Domain-Containing, Transforming Protein 3, ShcC, Down-Regulation, Neuroprotection, Settore BIO/09, 03 medical and health sciences, Alzheimer Disease, Internal medicine, mental disorders, medicine, Animals, Humans, BACE, Receptor, trkA, JNK Mitogen-Activated Protein Kinases, AD, Cell Biology, Original Articles, Rats, Enzyme Activation, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Nerve growth factor, nervous system, Forebrain, biology.protein, Amyloid Precursor Protein Secretases, Amyloid precursor protein secretase, 030217 neurology & neurosurgery, Gene Deletion
Abstract

Summary NGF has been implicated in forebrain neuroprotection from amyloidogenesis and Alzheimer's disease (AD). However, the underlying molecular mechanisms are still poorly understood. Here, we investigated the role of NGF signalling in the metabolism of amyloid precursor protein (APP) in forebrain neurons using primary cultures of septal neurons and acute septo‐hippocampal brain slices. In this study, we show that NGF controls the basal level of APP phosphorylation at Thr668 (T668) by downregulating the activity of the Ser/Thr kinase JNK(p54) through the Tyr kinase signalling adaptor SH2‐containing sequence C (ShcC). We also found that the specific NGF receptor, Tyr kinase A (TrkA), which is known to bind to APP, fails to interact with the fraction of APP molecules phosphorylated at T668 (APPpT668). Accordingly, the amount of TrkA bound to APP is significantly reduced in the hippocampus of ShcC KO mice and of patients with AD in which elevated APPpT668 levels are detected. NGF promotes TrkA binding to APP and APP trafficking to the Golgi, where APP–BACE interaction is hindered, finally resulting in reduced generation of sAPPβ, CTFβ and amyloid‐beta (1‐42). These results demonstrate that NGF signalling directly controls basal APP phosphorylation, subcellular localization and BACE cleavage, and pave the way for novel approaches specifically targeting ShcC signalling and/or the APP–TrkA interaction in AD therapy.

Published
2016

46. Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease

Author

Raffaele Maletta, Paolina Crocco, Giuseppina Rose, Giuseppe Passarino, Amalia C. Bruni, Miranda S. C. Wilson, and Adolfo Saiardi

Subjects
0301 basic medicine, Male, 5' Flanking Region, Single-nucleotide polymorphism, Biology, In Vitro Techniques, Pyrophosphate, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Downregulation and upregulation, Alzheimer Disease, Humans, Glycolysis, Inositol, Genetic Predisposition to Disease, Allele, Promoter Regions, Genetic, Molecular Biology, Gene, Genetic Association Studies, Aged, Genetics, Aged, 80 and over, Phosphotransferases (Phosphate Group Acceptor), Promoter, 030104 developmental biology, HEK293 Cells, chemistry, Case-Control Studies, Molecular Medicine, Female
Abstract

Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis.

Published
2016

47. Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer's disease

Author

Cristina Cereda, Roberta Ghidoni, Raffaele Maletta, Enzo Emanuele, Simone Lista, Pierluigi Politi, Amalia C. Bruni, Giuliano Binetti, and Luisa Benussi

Subjects
Male, Aging, medicine.medical_specialty, Pathology, Genotype, Polymorphism, Single Nucleotide, Gastroenterology, Cohort Studies, Central nervous system disease, Pathogenesis, Alzheimer Disease, Risk Factors, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Risk factor, Allele, Vascular dementia, Alleles, Aged, Aged, 80 and over, business.industry, Vascular disease, Dementia, Vascular, General Neuroscience, medicine.disease, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Chromosomes, Human, Pair 9, business, Developmental Biology
Abstract

Vascular risk factors have been implicated in the pathogenesis of vascular dementia and Alzheimer's disease. The identification of a novel vascular disease susceptibility locus at 9p21.3 has recently generated great interest. In the present study, we sought to determine whether a common genetic variant (tagged by rs1333049, G/C) in the 9p21.3 locus-that has been previously linked to an increased vascular risk-might influence the susceptibility to vascular dementia (VaD) and late-onset Alzheimer's disease (LOAD). A cohort of 200 VaD patients, 407 LOAD patients and 405 cognitively healthy controls were genotyped for rs1333049 using a fluorogenic 5' nuclease assay. The frequency of the C allele of rs1333049 was significantly higher in VaD (62.2%, P=0.005) and LOAD (60.7%, P=0.004) patients than in controls (53.6%). After adjustment for the APOE ε4 carrier status and other vascular risk factors, the C allele of rs1333049 remained significantly associated with both VaD (OR 1.31, 95% CI 1.07-1.77, P0.01) and LOAD (OR 1.28, 95% CI 1.04-1.55, P0.01). Altogether, our data indicate for the first time that the C allele of rs1333049 in the vascular disease susceptibility locus is associated with VaD and LOAD, independent of traditional risk factors and the APOE ε4 genotype.

Published
2011
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48. AβPP A713T Mutation in Late Onset Alzheimer's Disease with Cerebrovascular Lesions

Author

Livia Bernardi, Carmine Tomaino, Nicoletta Smirne, Sabrina A.M. Curcio, Franca Vasso, Raffaele Maletta, Maria Anfossi, Rosanna Colao, Maria Mirabelli, Francesca Frangipane, Gianfranco Puccio, Amalia C. Bruni, Maura Gallo, and Silvana Geracitano

Subjects
Male, Pathology, medicine.medical_specialty, Apolipoprotein E4, DNA Mutational Analysis, Neuropathology, Neuropsychological Tests, Gene mutation, Amyloid beta-Protein Precursor, Alzheimer Disease, Risk Factors, Activities of Daily Living, medicine, Humans, Dementia, Family history, Stroke, Aged, Aged, 80 and over, Family Health, business.industry, General Neuroscience, Exons, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Cerebrovascular Disorders, Psychiatry and Mental health, Clinical Psychology, Italy, Genetic epidemiology, Mutation, Female, Cerebral amyloid angiopathy, Geriatrics and Gerontology, Alzheimer's disease, Mental Status Schedule, Tomography, X-Ray Computed, business
Abstract

Mutations in the amyloid-beta protein precursor (AbetaPP) gene can cause autosomal dominant early-onset Alzheimer's disease, or Alzheimer's disease (AD) associated with cerebral amyloid angiopathy (CAA), cerebral hemorrhage, or both. We have previously reported that the AbetaPP A713T mutation is associated with AD and subcortical ischemic lesions at magnetic resonance imaging in a large family which neuropathology confirmed CAA, stroke, and AD lesions. The objective of this clinical and molecular study was to investigate AbetaPP gene mutations in 59 patients affected by AD with cerebrovascular lesions (CVLs) and a family history of dementia. We identified three affected subjects with the AbetaPP A713T mutation. Since the prevalence of this mutation worldwide is very low, a common founder could exist in southern Italy. The pathogenicity of this mutation was confirmed and the clinical AD phenotype with CVLs seems to be a distinctive feature in the southern Italian population. The identification of these patients suggests that genetic epidemiology in large cohorts of familial late onset AD with CVLs would increase the probability of identifying AbetaPP mutations.

Published
2009
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49. The Added Value of Neuropsychologic Tests and Structural Imaging for the Etiologic Diagnosis of Dementia in Italian Expert Centers

Author

Gloria Dal Forno, David Iapaolo, Osvaldo Scarpino, Cristina Geroldi, Carlo Gabelli, Giovanni B. Frisoni, Elisa Canu, Raffaele Ferri, Orazio Zanetti, Elena Sinforiani, Amalia C. Bruni, and Roberta Perri

Subjects
Male, Pediatrics, medicine.medical_specialty, Neuropsychological Tests, Neuroimaging, medicine, Humans, Dementia, Medical diagnosis, Medical History Taking, Psychiatry, Vascular dementia, Aged, Neurologic Examination, business.industry, Cognitive disorder, Memory clinic, Neuropsychology, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, Clinical Psychology, Italy, Female, Geriatrics and Gerontology, Alzheimer's disease, Tomography, X-Ray Computed, business, Gerontology
Abstract

Aim of the study was to assess the added diagnostic value of neuropsychologic tests and structural neuroimaging (computed tomography or magnetic resonance) in the routine clinical assessment of demented patients in Italian expert centers. Nine centers were involved, located across the whole country (3 in Northern, 3 in Central, and 3 in Southern Italy). Diagnostic pathways were tracked for 474 patients with an expert diagnosis of neurodegenerative or vascular dementia (age 76+/-8; 62% females; Mini-Mental State Examination 17.70+/-5.7). The contribution of neuropsychology and structural neuroimaging to diagnosis was estimated as "number needed to test" (NNT), denoting the number of patients who need to undergo such procedures to improve expert diagnosis of 1 unit. Expert physicians reached their diagnosis without resorting to structural imaging examinations and neuropsychologic tests in 93% of Alzheimer disease (AD) and 76% of non-AD dementias. The completion of the extended assessment led to improvement of diagnostic accuracy in both cases: the NNT was 15.3 (95% confidence interval: 10.4-29.1) and 4.1 (3.0 to 6.5) for AD and non-AD diagnoses. The added value of structural imaging and neuropsychologic testing in the routine clinical assessment of demented patients is substantial in both AD and non-AD cases.

Published
2008
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50. Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations

Author

Andrea Dardis, Agata Fiumara, Stefania Zampieri, Francesco Brancati, Milena Romanello, Annalisa Sechi, Rossella Parini, Laura Deroma, Bruno Bembi, Barbara Borroni, Amalia C. Bruni, Nadia Bortolotti, Cinzia Valeria Russo, Andrea Bordugo, Romanello, M., Zampieri, S., Bortolotti, N., Deroma, L., Sechi, A., Fiumara, A., Parini, R., Borroni, B., Brancati, F., Bruni, A., Russo, C. V., Bordugo, A., Bembi, B., and Dardis, A.

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Clinical Biochemistry, Hepatosplenomegaly, Liquid chromatography-tandem-mass spectrometry, Niemann-Pick, Oxysterols, Variant biochemical phenotype, Calibration, Carrier Proteins, Cholestanes, Cohort Studies, Humans, Italy, Ketocholesterols, Membrane Glycoproteins, Niemann-Pick Diseases, Reproducibility of Results, Sphingomyelin Phosphodiesterase, Mutation, Biochemistry, Biochemistry (medical), Context (language use), Disease, Liquid chromatography-tandem–mass spectrometry, 03 medical and health sciences, Oxysterol, 0302 clinical medicine, Oxysterols Niemann-Pick, Niemann-Pick C1 Protein, Internal medicine, medicine, Chemistry, Intracellular Signaling Peptides and Proteins, General Medicine, medicine.disease, Phenotype, 030104 developmental biology, Immunology, Cohort, lipids (amino acids, peptides, and proteins), Differential diagnosis, medicine.symptom, NPC1, Niemann–Pick disease, 030217 neurology & neurosurgery
Abstract

Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3β,5α,6β-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3β,5α,6β-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD.

Published
2016

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