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1. Optimizing electrical efficacy of leadless cardiac resynchronization therapy and leadless left ventricular septal pacing: Insights on left and right ventricular activation from electrocardiographic imaging

Author

Nadeev Wijesuriya, MBBS, Marina Strocchi, PhD, Mark Elliott, MBBS, PhD, Vishal Mehta, MBBS, Felicity De Vere, MBBS, Sandra Howell, MBBS, Nilanka Mannakkara, MBBS, Baldeep S. Sidhu, MBBS, PhD, Jane Kwan, MSc, Paolo Bosco, MBBS, Steven A. Niederer, DPhil, and Christopher A. Rinaldi, MBBS, MD, FHRS

Subjects
Cardiac resynchronization therapy, Heart failure, Leadless pacing, Endocardial pacing, Electrocardiographic imaging, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Leadless cardiac resynchronization therapy (CRT) is an emerging heart failure treatment. An implanted electrode delivers lateral or septal endocardial left ventricular (LV) pacing (LVP) upon detection of a right ventricular (RV) pacing stimulus from a coimplanted device, thus generating biventricular pacing (BiVP). Electrical efficacy data regarding this therapy, particularly leadless LV septal pacing (LVSP) for potential conduction system capture, are limited. Objectives: The purpose of this study was to evaluate the acute performance of leadless CRT using electrocardiographic imaging (ECGi) and assess the optimal pacing modality (OPM) of LVSP on the basis of RV and LV activation. Methods: Ten WiSE-CRT recipients underwent an ECGi study testing: RV pacing, BiVP, LVP only, and LVP with an optimized atrioventricular delay (LV-OPT). BiV, LV, and RV activation times (shortest time taken to activate 90% of the ventricles [BIVAT-90], shortest time taken to activate 95% of the LV, and shortest time taken to activate 90% of the RV) plus LV and BiV dyssynchrony index (standard deviation of LV activation times and standard deviation of all activation times) were calculated from reconstructed epicardial electrograms. The individual OPM yielding the greatest improvement from baseline was determined. Results: BiVP generated a 23.7% improvement in BiVAT-90 (P = .002). An improvement of 43.3% was observed at the OPM (P = .0001), primarily through reductions in shortest time taken to activate 90% of the RV. At the OPM, BiVAT-90 improved in patients with lateral (43.3%; P = .0001; n = 5) and septal (42.4%; P = .009; n = 5) LV implants. The OPM varied by individual. LVP and LV-OPT were mostly superior in patients with LVSP, and in those with sinus rhythm and left bundle branch block (n = 4). Conclusion: Leadless CRT significantly improves acute ECGi-derived activation and dyssynchrony metrics. Using an individualized OPM improves efficacy in selected patients. Effective LVSP is feasible, with fusion pacing at LV-OPT mitigating the potential deleterious effects on RV activation.

Published
2024
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2. Time-of-flight MRA of intracranial vessels at 7 T

Author

Mirco Cosottini, Tommaso Calzoni, Guido Andrea Lazzarotti, Alessandro Grigolini, Paolo Bosco, Paolo Cecchi, Michela Tosetti, Laura Biagi, and Graziella Donatelli

Subjects
Angiography (digital subtraction), Central nervous system vascular malformations, Magnetic fields, Magnetic resonance angiography, Primary angiitis of the central nervous system, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Three-dimensional time-of-flight magnetic resonance angiography (TOF-MRA) is a largely adopted non-invasive technique for assessing cerebrovascular diseases. We aimed to optimize the 7-T TOF-MRA acquisition protocol, confirm that it outperforms conventional 3-T TOF-MRA, and compare 7-T TOF-MRA with digital subtraction angiography (DSA) in patients with different vascular pathologies. Methods Seven-tesla TOF-MRA sequences with different spatial resolutions acquired in four healthy subjects were compared with 3-T TOF-MRA for signal-to-noise and contrast-to-noise ratios as well as using a qualitative scale for vessel visibility and the quantitative Canny algorithm. Four patients with cerebrovascular disease (primary arteritis of the central nervous system, saccular aneurism, arteriovenous malformation, and dural arteriovenous fistula) underwent optimized 7-T TOF-MRA and DSA as reference. Images were compared visually and using the complex-wavelet structural similarity index. Results Contrast-to-noise ratio was higher at 7 T (4.5 ± 0.8 (mean ± standard deviation)) than at 3 T (2.7 ± 0.9). The mean quality score for all intracranial vessels was higher at 7 T (2.89) than at 3 T (2.28). Angiogram quality demonstrated a better vessel border detection at 7 T than at 3 T (44,166 versus 28,720 pixels). Of 32 parameters used for diagnosing cerebrovascular diseases on DSA, 27 (84%) were detected on 7-T TOF-MRA; the similarity index ranged from 0.52 (dural arteriovenous fistula) to 0.90 (saccular aneurysm). Conclusions Seven-tesla TOF-MRA outperformed conventional 3-T TOF-MRA in evaluating intracranial vessels and exhibited an excellent image quality when compared to DSA. Seven-tesla TOF-MRA might improve the non-invasive diagnostic approach to several cerebrovascular diseases. Relevance statement An optimized TOF-MRA sequence at 7 T outperforms 3-T TOF-MRA, opening perspectives to its clinical use for noninvasive diagnosis of paradigmatic pathologies of intracranial vessels. Key points • An optimized 7-T TOF-MRA protocol was selected for comparison with clinical 3-T TOF-MRA for assessing intracranial vessels. • Seven-tesla TOF-MRA outperformed 3-T TOF-MRA in both quantitative and qualitative evaluation. • Seven-tesla TOF-MRA is comparable to DSA for the diagnosis and characterization of intracranial vascular pathologies. Graphical Abstract

Published
2024
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3. Predictors of Outcome in Patients with Pulmonary Hypertension Undergoing Mitral and Tricuspid Valve Surgery

Author

Ee Phui Kew, Vincenzo Caruso, Julia Grapsa, Paolo Bosco, and Gianluca Lucchese

Subjects
cardiac surgery, echocardiography, pulmonary hypertension, mitral valve, tricuspid valve, Medicine (General), R5-920
Abstract

Background and Objectives: Pulmonary hypertension (PH) secondary to left-sided valvular heart disease is associated with poor cardiac surgical outcome compared with patients without PH. Our objective was to investigate the prognostic factors of surgical outcome in patients with PH undergoing mitral valve (MV) and tricuspid valve (TV) surgery, in order to risk stratify their management. Materials and Methods: This is a retrospective observational study on patients with PH who underwent MV and TV surgery from 2011 to 2019. The primary outcome was all-cause mortality. The secondary outcomes were post-op respiratory and renal complications, length of intensive care unit stay and length of hospital stay. Results: Seventy-six patients were included in this study. The all-cause mortality was 13% (n = 10), with mean survival of 92.6 months. Among the patients, 9.2% (n = 7) had post-op renal failure requiring renal replacement therapy and 6.6% (n = 5) had post-op respiratory failure requiring intubation. Univariate analysis demonstrated that pre-operative left ventricular ejection fraction (LVEF), peak systolic tissue velocity at the tricuspid annulus (S’) and etiology of MV disease were associated with respiratory and renal failure. Tricuspid annular plane systolic excursion (TAPSE) was associated with respiratory failure only. S’, type of operation, LVEF, urgency of surgery, and etiology of MV disease were found to be predictive of mortality. After excluding redo mitral surgery, all statistically significant findings remain unchanged, with the addition of right ventricular (RV) size being associated with respiratory failure. In the subgroup analysis of routine cases (n = 56), patients with primary mitral regurgitation who underwent mitral valve repair had better survival outcome. Conclusions: Urgency of surgery, etiology of MV disease, type of operation (replacement or repair), S’ and pre-op LVEF are prognostic indicators in this small cohort of patients with PH undergoing MV and TV surgery. A larger prospective study is warranted to validate our findings.

Published
2023
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4. Quantitative MRI Harmonization to Maximize Clinical Impact: The RIN–Neuroimaging Network

Author

Anna Nigri, Stefania Ferraro, Claudia A. M. Gandini Wheeler-Kingshott, Michela Tosetti, Alberto Redolfi, Gianluigi Forloni, Egidio D'Angelo, Domenico Aquino, Laura Biagi, Paolo Bosco, Irene Carne, Silvia De Francesco, Greta Demichelis, Ruben Gianeri, Maria Marcella Lagana, Edoardo Micotti, Antonio Napolitano, Fulvia Palesi, Alice Pirastru, Giovanni Savini, Elisa Alberici, Carmelo Amato, Filippo Arrigoni, Francesca Baglio, Marco Bozzali, Antonella Castellano, Carlo Cavaliere, Valeria Elisa Contarino, Giulio Ferrazzi, Simona Gaudino, Silvia Marino, Vittorio Manzo, Luigi Pavone, Letterio S. Politi, Luca Roccatagliata, Elisa Rognone, Andrea Rossi, Caterina Tonon, Raffaele Lodi, Fabrizio Tagliavini, Maria Grazia Bruzzone, and The RIN–Neuroimaging

Subjects
harmonization, multisite, quantitative MRI, QSM, diffusion MRI, fMRI, Neurology. Diseases of the nervous system, RC346-429
Abstract

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures.

Published
2022
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5. Relationship among Connectivity of the Frontal Aslant Tract, Executive Functions, and Speech and Language Impairment in Children with Childhood Apraxia of Speech

Author

Clara Bombonato, Emilio Cipriano, Chiara Pecini, Claudia Casalini, Paolo Bosco, Irina Podda, Michela Tosetti, Laura Biagi, and Anna Maria Chilosi

Subjects
childhood apraxia of speech, executive functions, frontal aslant tract, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Childhood apraxia of speech (CAS) is a subtype of motor speech disorder usually co-occurring with language impairment. A supramodal processing difficulty, involving executive functions (EFs), might contribute to the cognitive endophenotypes and behavioral manifestations. The present study aimed to profile the EFs in CAS, investigating the relationship between EFs, speech and language severity, and the connectivity of the frontal aslant tract (FAT), a white matter tract involved in both speech and EFs. A total of 30 preschool children with CAS underwent speech, language, and EF assessments and brain MRIs. Their FAT connectivity metrics were compared to those of 30 children without other neurodevelopmental disorders (NoNDs), who also underwent brain MRIs. Alterations in some basic EF components were found. Inhibition and working memory correlated with speech and language severity. Compared to NoND children, a weak, significant reduction in fractional anisotropy (FA) in the left presupplementary motor area (preSMA) FAT component was found. Only speech severity correlated and predicted FA values along with the FAT in both of its components, and visual-spatial working memory moderated the relationship between speech severity and FA in the left SMA. Our study supports the conceptualization of a composite and complex picture of CAS, not limited to the speech core deficit, but also involving high-order cognitive skills.

Published
2022
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7. Identification of human D lactate dehydrogenase deficiency

Author

Glen R. Monroe, Albertien M. van Eerde, Federico Tessadori, Karen J. Duran, Sanne M. C. Savelberg, Johanna C. van Alfen, Paulien A. Terhal, Saskia N. van der Crabben, Klaske D. Lichtenbelt, Sabine A. Fuchs, Johan Gerrits, Markus J. van Roosmalen, Koen L. van Gassen, Mirjam van Aalderen, Bart G. Koot, Marlies Oostendorp, Marinus Duran, Gepke Visser, Tom J. de Koning, Francesco Calì, Paolo Bosco, Karin Geleijns, Monique G. M. de Sain-van der Velden, Nine V. Knoers, Jeroen Bakkers, Nanda M. Verhoeven-Duif, Gijs van Haaften, and Judith J. Jans

Subjects
Science
Abstract

D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.

Published
2019
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8. Distribution Indices of Magnetic Susceptibility Values in the Primary Motor Cortex Enable to Classify Patients with Amyotrophic Lateral Sclerosis

Author

Mauro Costagli, Graziella Donatelli, Paolo Cecchi, Paolo Bosco, Gianmichele Migaleddu, Gabriele Siciliano, and Mirco Cosottini

Subjects
Amyotrophic Lateral Sclerosis, Magnetic Resonance Imaging, Quantitative Susceptibility Mapping, motor cortex, radiological biomarker, diagnostic accuracy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Quantitative Susceptibility Mapping (QSM) can measure iron concentration increase in the primary motor cortex (M1) of patients with Amyotrophic Lateral Sclerosis (ALS). However, such alteration is confined to only specific regions interested by upper motor neuron pathology; therefore, mean QSM values in the entire M1 have limited diagnostic accuracy in discriminating between ALS patients and control subjects. This study investigates the diagnostic accuracy of a broader set of M1 QSM distribution indices in classifying ALS patients and controls. Mean, standard deviation, skewness and kurtosis of M1 QSM values were used either individually or as combined predictors in support vector machines. The classification performance was compared to that obtained by the radiological assessment of T2* signal hypo-intensity of M1 in susceptibility-weighted MRI. The least informative index for the classification of ALS patients and controls was the subject’s mean QSM value in M1. The highest diagnostic performance was obtained when all the distribution indices of positive QSM values in M1 were considered, which yielded a diagnostic accuracy of 0.90, with sensitivity = 0.89 and specificity = 1. The radiological assessment of M1 yielded a diagnostic accuracy of 0.79, with sensitivity = 0.76 and specificity = 0.90. The joint evaluation of QSM distribution indices could support the clinical examination in ALS diagnosis and patient monitoring.

Published
2022
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9. Neural substrates of neuropsychological profiles in dystrophynopathies: A pilot study of diffusion tractography imaging.

Author

Laura Biagi, Sara Lenzi, Emilio Cipriano, Simona Fiori, Paolo Bosco, Paola Cristofani, Guia Astrea, Antonella Pini, Giovanni Cioni, Eugenio Mercuri, Michela Tosetti, and Roberta Battini

Subjects
Medicine, Science
Abstract

IntroductionCognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures.Materials and methodsThis pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract.ResultsRegarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949).Discussion and conclusionIn this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.

Published
2021
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10. Evaluation of Altered Functional Connections in Male Children With Autism Spectrum Disorders on Multiple-Site Data Optimized With Machine Learning

Author

Giovanna Spera, Alessandra Retico, Paolo Bosco, Elisa Ferrari, Letizia Palumbo, Piernicola Oliva, Filippo Muratori, and Sara Calderoni

Subjects
autism spectrum disorders, children, resting-state fMRI, functional connectivity, machine learning, ABIDE, Psychiatry, RC435-571
Abstract

No univocal and reliable brain-based biomarkers have been detected to date in Autism Spectrum Disorders (ASD). Neuroimaging studies have consistently revealed alterations in brain structure and function of individuals with ASD; however, it remains difficult to ascertain the extent and localization of affected brain networks. In this context, the application of Machine Learning (ML) classification methods to neuroimaging data has the potential to contribute to a better distinction between subjects with ASD and typical development controls (TD). This study is focused on the analysis of resting-state fMRI data of individuals with ASD and matched TD, available within the ABIDE collection. To reduce the multiple sources of heterogeneity that impact on understanding the neural underpinnings of autistic condition, we selected a subgroup of 190 subjects (102 with ASD and 88 TD) according to the following criteria: male children (age range: 6.5–13 years); rs-fMRI data acquired with open eyes; data from the University sites that provided the largest number of scans (KKI, NYU, UCLA, UM). Connectivity values were evaluated as the linear correlation between pairs of time series of brain areas; then, a Linear kernel Support Vector Machine (L-SVM) classification, with an inter-site cross-validation scheme, was carried out. A permutation test was conducted to identify over-connectivity and under-connectivity alterations in the ASD group. The mean L-SVM classification performance, in terms of the area under the ROC curve (AUC), was 0.75 ± 0.05. The highest performance was obtained using data from KKI, NYU and UCLA sites in training and data from UM as testing set (AUC = 0.83). Specifically, stronger functional connectivity (FC) in ASD with respect to TD involve (p < 0.001) the angular gyrus with the precuneus in the right (R) hemisphere, and the R frontal operculum cortex with the pars opercularis of the left (L) inferior frontal gyrus. Weaker connections in ASD group with respect to TD are the intra-hemispheric R temporal fusiform cortex with the R hippocampus, and the L supramarginal gyrus with L planum polare. The results indicate that both under- and over-FC occurred in a selected cohort of ASD children relative to TD controls, and that these functional alterations are spread in different brain networks.

Published
2019
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12. TGF-β1 protects against Aβ-neurotoxicity via the phosphatidylinositol-3-kinase pathway

Author

Filippo Caraci, Giuseppe Battaglia, Carla Busceti, Francesca Biagioni, Federica Mastroiacovo, Paolo Bosco, Filippo Drago, Ferdinando Nicoletti, Maria Angela Sortino, and Agata Copani

Subjects
Amyloid, TGF-β1, SB431542, Hippocampus, Neurons, PI-3-K, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

β-Amyloid (Aβ) injection into the rat dorsal hippocampus had a small neurotoxic effect that was amplified by i.c.v. injection of SB431542, a selective inhibitor of transforming growth factor-β (TGF-β) receptor. This suggested that TGF-β acts as a factor limiting Aβ toxicity. We examined the neuroprotective activity of TGF-β1 in pure cultures of rat cortical neurons challenged with Aβ. Neuronal death triggered by Aβ is known to proceed along an aberrant re-activation of the cell cycle, and involves late β-catenin degradation and tau hyperphosphorylation. TGF-β1 was equally protective when added either in combination with, or 6 h after Aβ. Co-added TGF-β1 prevented Aβ-induced cell cycle reactivation, whereas lately added TGF-β1 had no effect on the cell cycle, but rescued the late β-catenin degradation and tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K) inhibitor, LY294402, abrogated all effects. Thus, TGF-β1 blocks the whole cascade of events leading to Aβ neurotoxicity by activating the PI-3-K pathway.

Published
2008
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13. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Author

Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L DeStefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, United Kingdom Brain Expression Consortium, Andrew D Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, and Cardiovascular Health Study (CHS)

Subjects
Medicine, Science
Abstract

BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Published
2014
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16. Predictors of Outcome in Patients with Pulmonary Hypertension Undergoing Mitral and Tricuspid Valve Surgery

Author

Lucchese, Ee Phui Kew, Vincenzo Caruso, Julia Grapsa, Paolo Bosco, and Gianluca

Subjects
cardiac surgery, echocardiography, pulmonary hypertension, mitral valve, tricuspid valve
Abstract

Background and Objectives: Pulmonary hypertension (PH) secondary to left-sided valvular heart disease is associated with poor cardiac surgical outcome compared with patients without PH. Our objective was to investigate the prognostic factors of surgical outcome in patients with PH undergoing mitral valve (MV) and tricuspid valve (TV) surgery, in order to risk stratify their management. Materials and Methods: This is a retrospective observational study on patients with PH who underwent MV and TV surgery from 2011 to 2019. The primary outcome was all-cause mortality. The secondary outcomes were post-op respiratory and renal complications, length of intensive care unit stay and length of hospital stay. Results: Seventy-six patients were included in this study. The all-cause mortality was 13% (n = 10), with mean survival of 92.6 months. Among the patients, 9.2% (n = 7) had post-op renal failure requiring renal replacement therapy and 6.6% (n = 5) had post-op respiratory failure requiring intubation. Univariate analysis demonstrated that pre-operative left ventricular ejection fraction (LVEF), peak systolic tissue velocity at the tricuspid annulus (S’) and etiology of MV disease were associated with respiratory and renal failure. Tricuspid annular plane systolic excursion (TAPSE) was associated with respiratory failure only. S’, type of operation, LVEF, urgency of surgery, and etiology of MV disease were found to be predictive of mortality. After excluding redo mitral surgery, all statistically significant findings remain unchanged, with the addition of right ventricular (RV) size being associated with respiratory failure. In the subgroup analysis of routine cases (n = 56), patients with primary mitral regurgitation who underwent mitral valve repair had better survival outcome. Conclusions: Urgency of surgery, etiology of MV disease, type of operation (replacement or repair), S’ and pre-op LVEF are prognostic indicators in this small cohort of patients with PH undergoing MV and TV surgery. A larger prospective study is warranted to validate our findings.

Published
2023
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17. Simulated and experimental phantom data for multi-center quality assurance of quantitative susceptibility maps at 3 T, 7 T and 9.4 T

Author

Enrique Gustavo Cuña, Hildegard Schulz, Elisa Tuzzi, Laura Biagi, Paolo Bosco, Margarita García-Fontes, Javier Mattos, Michela Tosetti, Jörn Engelmann, Klaus Scheffler, and Gisela E. Hagberg

Subjects
Biophysics, General Physics and Astronomy, Radiology, Nuclear Medicine and imaging, General Medicine
Abstract

Purpose: To develop methods for quality assurance of quantitative susceptibility mapping (QSM) using MRI at different magnetic field strengths, and scanners, using different MR-sequence protocols, and post-processing pipelines.Methods: We built a custom phantom based on iron in two forms: homogeneous susceptibility ('free iron') and with fine-scaled variations in susceptibility ('clustered iron') at different iron concentrations. The phantom was measured at 3.0 T (two scanners), 7.0 T and 9.4 T using multi-echo, gradient echo acquisition sequences. A digital phantom analogue to the iron-phantom, tailored to obtain similar results as in experimentation was developed, with similar geometry and susceptibility values. Morphology enabled dipole inversion was applied to the phase images to obtain QSM for experimental and simulated data using the MEDI + 0 approach for background regularization.Results: Across all scanners, QSM-values showed a linear increase with iron concentrations. The QSM-relaxivity was 0.231 ± 0.047 ppm/mM for free and 0.054 ± 0.013 ppm/mM for clustered iron, with adjusted determination coefficients (DoC) ≥ 0.87. Similarly, the simulations yielded linear increases (DoC ≥ 0.99). In both the experimental and digital phantoms, the estimated molar susceptibility was lower with clustered iron, because clustering led to highly localized field effects.Conclusion: Our iron phantom can be used to evaluate the capability of QSM to detect local variations in susceptibility across different field strengths, when using different MR-sequence protocols. The devised simulation method captures the effect of iron clustering in QSM as seen experimentally and could be used in the future to optimize QSM processing pipelines and achieve higher accuracy for local field effects, as also seen in Alzheimer's beta-amyloid plaques.

Published
2023

19. Long-term survival following transvenous lead extraction: Importance of indication and comorbidities

Author

Paolo Bosco, Suraj Kadiwar, Justin Gould, Christopher A. Rinaldi, Christopher Blauth, Anoop Shetty, Vittoria Vergani, Jaswinder Gill, Tiffany Kemp, Vishal Mehta, Baldeep S. Sidhu, and Mark K. Elliott

Subjects
Male, Pacemaker, Artificial, medicine.medical_specialty, Prosthesis-Related Infections, Long Term Adverse Effects, Comorbidity, Kaplan-Meier Estimate, Infection group, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Physiology (medical), Internal medicine, Catheterization, Peripheral, Long term survival, medicine, Humans, In patient, Multiple Chronic Conditions, 030212 general & internal medicine, Major complication, Renal Insufficiency, Chronic, Device Removal, Aged, business.industry, Hazard ratio, Stroke Volume, Prognosis, Confidence interval, Defibrillators, Implantable, Transvenous lead, Cohort, Female, Cardiology and Cardiovascular Medicine, business
Abstract

Long-term outcomes are poorly understood, and data in patients undergoing transvenous lead extraction (TLE) are lacking.The purpose of this study was to evaluate factors influencing survival in patients undergoing TLE depending on extraction indication.Clinical data from consecutive patients undergoing TLE in the reference center between 2000 and 2019 were prospectively collected. The total cohort was divided into groups depending on whether there was an infective or noninfective indication for TLE. We evaluated the association of demographic, clinical, and device-related and procedure-related factors on mortality.A total of 1151 patients were included. Mean follow-up was 66 months, and mortality was 34.2% (n = 392). Of these patients, 632 (54.9%) and 519 (45.1%) were for infective and noninfective indications, respectively. A higher proportion in the infection group died (38.6% vs 28.5%; P.001). In the total cohort, multivariable analysis demonstrated increased mortality risk with age75 years (hazard ratio [HR] 2.98; 95% confidence interval [CI] 2.35-3.78; P.001), estimated glomerular filtration rate60 mL/min/1.73 mLong-term mortality for patients undergoing TLE remains high. Consensus guidelines recommend evaluating risk for major complications when determining whether to proceed with TLE. This study suggests also assessing longer-term outcomes when considering TLE in those with a high risk of medium- and long-term mortality, particularly for noninfective indications.

Published
2021
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20. Quality assessment, variability and reproducibility of anatomical measurements derived from T1-weighted brain imaging: The RIN–Neuroimaging Network case study

Author

Paolo Bosco, Marta Lancione, Alessandra Retico, Anna Nigri, Domenico Aquino, Francesca Baglio, Irene Carne, Stefania Ferraro, Giovanni Giulietti, Antonio Napolitano, Fulvia Palesi, Luigi Pavone, Giovanni Savini, Fabrizio Tagliavini, Maria Grazia Bruzzone, Claudia A.M. Gandini Wheeler-Kingshott, Michela Tosetti, and Laura Biagi

Subjects
Biophysics, General Physics and Astronomy, Radiology, Nuclear Medicine and imaging, General Medicine
Published
2023
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21. Feasibility of leadless left ventricular septal pacing with the WiSE-CRT system to target the left bundle branch area: A porcine model and multicenter patient experience

Author

Mark K. Elliott, Pasquale Vergara, Nadeev Wijesuriya, Vishal S. Mehta, Paolo Bosco, Peggy Jacon, Michael Lee, Silvia Taloni, Steven Niederer, Jeffrey Alison, Olivier Piot, Paul R. Roberts, John Paisey, Pascal Defaye, Andrew Shute, and Christopher A. Rinaldi

Subjects
Cardiac Resynchronization Therapy, Heart Failure, Patient Outcome Assessment, Electrocardiography, Treatment Outcome, Swine, Physiology (medical), Animals, Feasibility Studies, Cardiology and Cardiovascular Medicine, Ventricular Function, Left
Abstract

The WiSE-CRT system delivers leadless endocardial left ventricular (LV) pacing to achieve cardiac resynchronization therapy. The electrode is conventionally placed on the lateral wall, but implanting on the LV septum may have advantages, including capture of the left bundle branch, and improved battery longevity owing to reduced distance from the transmitter.The purpose of this study was to assess the feasibility of leadless LV septal pacing via the WiSE-CRT system.Two pigs underwent electrode implantation on the LV septum with subsequent anatomical and histological examination. Eight patients underwent implantation of the WiSE-CRT system with deployment of the electrode on the LV septum via an interatrial transseptal approach.Deployment of the electrode on the LV septum was successful in both animals. Histological examination demonstrated electrode tines in close proximity to Purkinje tissue. WiSE-CRT implantation with an LV septal electrode was successful in all patients. Biventricular capture was confirmed, with a significant reduction in QRS duration (187.1 ± 33.8 ms vs 149.5 ± 15.7 ms; P = .009). Temporary LV pacing achieved further QRS reduction (139.8 ± 12.4 ms), and in 4 patients the peak LV activation time in lead VLeadless LV septal pacing with the WiSE-CRT system to target the left bundle branch appears feasible. Further study is required to assess the efficacy and safety of this technique.

Published
2022

22. A comparison of two statistical mapping tools for automated brain fdg-pet analysis in predicting conversion to alzheimer’s disease in subjects with mild cognitive impairment

Author

Paolo Bosco, Osman Ratib, Robert Perneczky, Giovanni B. Frisoni, Mira Didic, Gabriel Gold, Alexander Drzezga, Sara Trombella, Alberto Redolfi, Panteleimon Giannakopoulos, Valentina Garibotto, Silvia Morbelli, Flavio Nobili, Olivier Rager, Luigi Antelmi, Rik Ossenkoppele, Bart N.M. van Berckel, Claire Tabouret-Viaud, Eric Guedj, Université de Genève = University of Geneva (UNIGE), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria), IRCCS Fondazione Stella Maris [Pisa], IRCCS Fatebenefratelli - Brescia, IRCCS Istituto Giannina Gaslini [Genoa, Italy], Technische Universität München = Technical University of Munich (TUM), Imperial College London, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut FRESNEL (FRESNEL), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, VU University Medical Center [Amsterdam], Otten, Lisa, Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Neurology, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Male, hypometabolic pattern, Concordance, [SDV]Life Sciences [q-bio], Disease, computer.software_genre, 030218 nuclear medicine & medical imaging, Correlation, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Alzheimer Disease, Fluorodeoxyglucose F18, Voxel, medicine, Humans, Dementia, Cognitive Dysfunction, Alzheimer’s disease, Automated analysis, FDG-PET, Hypometabolic pattern, MCI, Tatistical parametric mapping, Aged, Sweden, Brain Mapping, Models, Statistical, tatistical parametric mapping, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Statistical mapping, Brain, Gold standard (test), Alzheimer's disease, medicine.disease, Neurology, Positron-Emission Tomography, Disease Progression, Female, Neurology (clinical), Radiopharmaceuticals, business, Nuclear medicine, computer, 030217 neurology & neurosurgery
Abstract

Objective: Automated voxel-based analysis methods are used to detect cortical hypometabolism typical of Alzheimer’s Disease (AD) on FDG-PET brain scans. We compared the accuracy of two clinically validated tools for their ability to identify those MCI subjects progressing to AD at followup, to evaluate the impact of the analysis method on FDG-PET diagnostic performance. Methods: SPMGrid and BRASS (Hermes Medical Solutions, Stockholm, Sweden) were tested on 131 MCI and elderly healthy controls from the EADC PET dataset. The concordance between the tools was tested by correlating the quantitative parameters (z- and t-values), calculated by the two software tools, and by measuring the topographical overlap of the abnormal regions (Dice score). Three independent expert readers blindly assigned a diagnosis based on the two map sets. We used conversion to AD dementia as the gold standard. Results: The t-map and z-map calculated with SPMGrid and BRASS, respectively, showed a good correlation (R > .50) for the majority of individual cases (128/131) and for the majority of selected regions of interest (ROIs) (98/116). The overlap of the hypometabolic patterns from the two tools was, however, poor (Dice score .36). The diagnostic performance was comparable, with BRASS showing significantly higher sensitivity (.82 versus .59) and SPMGrid showing higher specificity (.87 versus .52). Conclusion: Despite similar diagnostic performance in predicting conversion to AD in MCI subjects, the two tools showed significant differences, and the maps provided by the tools showed limited overlap. These results underline the urgency for standardization across FDG-PET analysis methods for their use in clinical practice.

Published
2020
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23. Multi-centre and multi-vendor reproducibility of a standardized protocol for quantitative susceptibility Mapping of the human brain at 3T

Author

Marta Lancione, Paolo Bosco, Mauro Costagli, Anna Nigri, Domenico Aquino, Irene Carne, Stefania Ferraro, Giovanni Giulietti, Antonio Napolitano, Fulvia Palesi, Luigi Pavone, Alice Pirastru, Giovanni Savini, Fabrizio Tagliavini, Maria Grazia Bruzzone, Claudia A.M. Gandini Wheeler-Kingshott, Michela Tosetti, and Laura Biagi

Subjects
Brain Mapping, quantitative susceptibility mapping, multicentric study, Biophysics, General Physics and Astronomy, Reproducibility of Results, Brain, General Medicine, magnetic resonance imaging, protocol harmonization, reproducibility, Humans, Radiology, Nuclear Medicine and imaging, Gray Matter
Abstract

Quantitative Susceptibility Mapping (QSM) is an MRI-based technique allowing the non-invasive quantification of iron content and myelination in the brain. The RIN - Neuroimaging Network established an optimized and harmonized protocol for QSM across ten sites with 3T MRI systems from three different vendors to enable multicentric studies. The assessment of the reproducibility of this protocol is crucial to establish susceptibility as a quantitative biomarker. In this work, we evaluated cross-vendor reproducibility in a group of six traveling brains. Then, we recruited fifty-one volunteers and measured the variability of QSM values in a cohort of healthy subjects scanned at different sites, simulating a multicentric study. Both voxelwise and Region of Interest (ROI)-based analysis on cortical and subcortical gray matter were performed. The traveling brain study yielded high structural similarity (∼0.8) and excellent reproducibility comparing maps acquired on scanners from two different vendors. Depending on the ROI, we reported a quantification error ranging from 0.001 to 0.017 ppm for the traveling brains. In the cohort of fifty-one healthy subjects scanned at nine different sites, the ROI-dependent variability of susceptibility values, of the order of 0.005-0.025 ppm, was comparable to the result of the traveling brain experiment. The harmonized QSM protocol of the RIN - Neuroimaging Network provides a reliable quantification of susceptibility in both cortical and subcortical gray matter regions and it is ready for multicentric and longitudinal clinical studies in neurological and pychiatric diseases.

Published
2022

24. Prolonged lead dwell time and lead burden predict bailout transfemoral lead extraction

Author

Jaswinder Gill, Christopher A. Rinaldi, Anoop Shetty, Bradley Porter, Baldeep S. Sidhu, Benjamin Sieniewicz, Justin Gould, Steven Williams, Paolo Bosco, Thomas Teall, and Christopher Blauth

Subjects
Pacemaker, Artificial, medicine.medical_specialty, Time Factors, medicine.medical_treatment, 030204 cardiovascular system & hematology, bailout femoral extraction, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Medicine, Prospective Studies, Registries, 030212 general & internal medicine, Major complication, Thoracotomy, Lead (electronics), Vein, Device Removal, Aged, business.industry, Mortality rate, transvenous lead extraction, Equipment Design, General Medicine, Femoral Vein, Middle Aged, Defibrillators, Implantable, Surgery, Dwell time, medicine.anatomical_structure, Equipment Failure, Implant, Cardiology and Cardiovascular Medicine, business, femoral lead extraction, Lead extraction
Abstract

Background: Transvenous lead extraction (TLE) may be performed by superior approach using the original implant vein or via a femoral approach; however, limited comparative data exists. We compare outcomes between femoral versus nonfemoral TLE approaches and determine predictors of bailout transfemoral lead extraction in patients undergoing initial TLE via the original implant vein by a superior approach. Methods: All consecutive TLEs between October 2000 and March 2018 were prospectively collected (n = 1052). Patients were dichotomized into femoral (n = 118) and nonfemoral (n = 934) groups. Results: Demographics were balanced between femoral vs nonfemoral groups. Patients in the femoral group had significantly higher mean lead dwell times (11.6 ± 9.7 vs 6.6 ± 6.6 years, P

Published
2019
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25. Probing the Role of a Regional Quantitative Assessment of Amyloid PET

Author

Paolo Bosco, Dario Arnaldi, Matteo Pardini, Flavio Nobili, Francesco Sensi, Silvia Morbelli, Andrea Chincarini, Enrico Peira, Matteo Bauckneht, and Matteo Grazzini

Subjects
0301 basic medicine, Male, Amyloid, Trail Making Test, Standardized uptake value, Neuropsychological Tests, Verbal learning, Brain mapping, standardized uptake value ratio, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Image Processing, Computer-Assisted, Verbal fluency test, Medicine, Humans, semi-quantification, Neuropsychological assessment, Gray Matter, ELBA, Aged, Amyloid PET, regional amyloid, Aged, 80 and over, Brain Mapping, medicine.diagnostic_test, business.industry, Verbal Behavior, General Neuroscience, Cognition, General Medicine, Amyloidosis, Middle Aged, Verbal Learning, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Positron-Emission Tomography, Stroop Test, Female, Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery, Stroop effect
Abstract

Background: In clinical practice, the amy-PET is globally inspected to provide a binary outcome, but the role of a regional assessment has not been fully investigated yet. Objective: To deepen the role of regional amyloid burden and its implication on clinical-neuropsychological features. Materials: Amy-PET and a complete neuropsychological assessment (Trail Making Test, Rey Auditory Verbal Learning Test, semantic verbal fluency, Symbol Digit, Stroop, visuoconstruction) were available in 109 patients with clinical suspicion of Alzheimer’s disease. By averaging the standardized uptake value ratio and ELBA, a regional quantification was calculated for each scan. Patients were grouped according to their overall amyloid load: correlation maps, based on regional quantification, were calculated and compared. A regression analysis between neuropsychological assessment and the regional amyloid-β (Aβ) load was carried out. Results: Significant differences were observed between the correlation maps of patients at increasing levels of Aβ and the overall dataset. The Aβ uptake of the subcortical gray matter resulted not related to other brain regions independently of the global Aβ level. A significant association of semantic verbal fluency was observed with ratios of cortical and subcortical distribution of Aβ which represent a coarse measure of differences in regional distribution of Aβ. Conclusion: Our observations confirmed the different susceptibility to Aβ accumulation among brain regions. The association between cognition and Aβ distribution deserves further investigations: it is possibly due to a direct local effect or it represents a proxy marker of a more aggressive disease subtype. Regional Aβ assessment represents an available resource on amy-PET scan with possibly clinical and prognostic implications.

Published
2021

26. Residual Convolutional Neural Networks for Breast Density Classification

Author

Paolo Bosco, Giacomo Aringhieri, Davide Caramella, Stefano Atzori, Carolina Marini, A. C. Traino, Alessandra Retico, Francesca Lizzi, Maria Evelina Fantacci, Francesca Lizzi , Stefano Atzori , Giacomo Aringhieri , Paolo Bosco , Carolina Marini , Alessandra Retico , Antonio Traino , Davide Caramella and M. Fantacci, elisabetta De Maria, Ana Fred, Hugo Gamboa, Fantacci, M., Caramella, Davide, Traino, Antonio, Retico, Alessandra, Marini, Carolina, Bosco, Paolo, Aringhieri, Giacomo, Atzori, Stefano, and Lizzi, Francesca

Subjects
Residual Neural Networks, BI-RADS, Computer science, business.industry, Convolutional Neural Networks, Pattern recognition, Residual, Convolutional neural network, Breast Density, Artificial intelligence, Breast density, business
Published
2019
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27. 'Thunderball': Oscillating ball thrombus within a giant sinus of Valsalva aneurysm

Author

Julia Grapsa, Paolo Bosco, Daniela Silva, Ronak Rajani, and Thomas D. Gossios

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Computed tomography, Thrombosis, Sinus of Valsalva, medicine.disease, Aneurysm, Ball thrombus, Aortic Aneurysm, medicine.anatomical_structure, Echocardiography, RC666-701, Medicine, Diseases of the circulatory (Cardiovascular) system, Humans, Radiology, Thrombus, Cardiology and Cardiovascular Medicine, business, Sinus (anatomy)
Published
2020

30. Otological Planning Software—OTOPLAN: A Narrative Literature Review

Author

Annalisa Gatto, Margherita Tofanelli, Ludovica Costariol, Serena Rizzo, Daniele Borsetto, Nicoletta Gardenal, Francesco Uderzo, Paolo Boscolo-Rizzo, and Giancarlo Tirelli

Subjects
cochlear implant, OTOPLAN, otological planning software, otosurgery, Otorhinolaryngology, RF1-547
Abstract

The cochlear implant (CI) is a widely accepted option in patients with severe to profound hearing loss receiving limited benefit from traditional hearing aids. CI surgery uses a default setting for frequency allocation aiming to reproduce tonotopicity, thus mimicking the normal cochlea. One emerging instrument that may substantially help the surgeon before, during, and after the surgery is a surgical planning software product developed in collaboration by CASCINATION AG (Bern, Switzerland) and MED-EL (Innsbruck Austria). The aim of this narrative review is to present an overview of the main features of this otological planning software, called OTOPLAN®. The literature was searched on the PubMed and Web of Science databases. The search terms used were “OTOPLAN”, “cochlear planning software” “three-dimensional imaging”, “3D segmentation”, and “cochlear implant” combined into different queries. This strategy yielded 52 publications, and a total of 31 studies were included. The review of the literature revealed that OTOPLAN is a useful tool for otologists and audiologists as it improves preoperative surgical planning both in adults and in children, guides the intraoperative procedure and allows postoperative evaluation of the CI.

Published
2023
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32. Identification of human D lactate dehydrogenase deficiency

Author

Karen Duran, Johanna C. van Alfen, Paolo Bosco, Judith J.M. Jans, Paulien A Terhal, Saskia N. van der Crabben, Gepke Visser, Koen L.I. van Gassen, Markus J. van Roosmalen, Karin Geleijns, Tom J. de Koning, Nanda M. Verhoeven-Duif, Marinus Duran, Francesco Calì, Monique G.M. de Sain-van der Velden, Glen R. Monroe, Klaske D. Lichtenbelt, Bart G. Koot, Sabine A. Fuchs, Marlies Oostendorp, Johan Gerrits, Nine V A M Knoers, Albertien M. van Eerde, Mirjam van Aalderen, Sanne M C Savelberg, Federico Tessadori, Jeroen Bakkers, Gijs van Haaften, Human genetics, Pediatric surgery, Hubrecht Institute for Developmental Biology and Stem Cell Research, Human Genetics, Paediatric Gastroenterology, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, ARD - Amsterdam Reproduction and Development, and Movement Disorder (MD)

Subjects
Male, 0301 basic medicine, General Physics and Astronomy, 02 engineering and technology, Consanguinity, Loss of Function Mutation, Non-U.S. Gov't, lcsh:Science, Zebrafish, Acidosis, Multidisciplinary, ABNORMALITIES, Research Support, Non-U.S. Gov't, Homozygote, ANIRIDIA, 021001 nanoscience & nanotechnology, Short bowel syndrome, Phenotype, D-lactate dehydrogenase, Medical genetics, Acidosis, Lactic, medicine.symptom, 0210 nano-technology, Spasms, Infantile, Adult, Short Bowel Syndrome, EXPRESSION, medicine.medical_specialty, DISORDERS, Science, Biology, METABOLISM, Research Support, DIAGNOSIS, Article, General Biochemistry, Genetics and Molecular Biology, Diagnosis, Differential, 03 medical and health sciences, Internal medicine, Journal Article, medicine, Animals, Humans, Lactic Acid, Lactate Dehydrogenases, Gene, D-LACTIC ACIDOSIS, PURIFICATION, Wild type, Infant, General Chemistry, medicine.disease, biology.organism_classification, ACIDS, GENE, 030104 developmental biology, Endocrinology, lcsh:Q
Abstract

Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients’ variant LDHD, confirming these variants’ loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis., D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.

Published
2019
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33. The necessity of immediate cardio-thoracic surgical cover for high-risk transvenous lead extraction procedures: the Art of lead extraction

Author

Paolo Bosco and Christopher A. Rinaldi

Subjects
Surgeons, medicine.medical_specialty, Shoulder, business.industry, Extraction (chemistry), Thoracic Surgical Procedures, Transvenous lead, Surgery, Defibrillators, Implantable, medicine, Humans, Cover (algebra), Cardiology and Cardiovascular Medicine, business, Device Removal, Lead extraction
Published
2019

34. Brainstem enlargement in preschool children with autism: Results from an intermethod agreement study of segmentation algorithms

Author

Filippo Muratori, Alessia Giuliano, Paolo Bosco, Sara Calderoni, Stefania Bargagna, Jonathan Delafield-Butt, and Alessandra Retico

Subjects
Normalization (statistics), Male, Autism Spectrum Disorder, autism spectrum disorders, Population, Neuroimaging, T1-weighted MRI, brainstem, brainstem volume, segmentation, Multiple methods, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Segmentation, education, Child, Research Articles, education.field_of_study, Radiological and Ultrasound Technology, 05 social sciences, medicine.disease, Magnetic Resonance Imaging, Neurology, Child, Preschool, RC0321, Autism, Female, Neurology (clinical), Brainstem, Anatomy, Psychology, Algorithm, 030217 neurology & neurosurgery, Brain Stem
Abstract

The intermethod agreement between automated algorithms for brainstem segmentation is investigated, focusing on the potential involvement of this structure in Autism Spectrum Disorders (ASD). Inconsistencies highlighted in previous studies on brainstem in the population with ASD may in part be a result of poor agreement in the extraction of structural features between different methods. A sample of 76 children with ASD and 76 age-, gender-, and intelligence-matched controls was considered. Volumetric analyses were performed using common tools for brain structures segmentation, namely FSL-FIRST, FreeSurfer (FS), and Advanced Normalization Tools (ANTs). For shape analysis SPHARM-MAT was employed. Intermethod agreement was quantified in terms of Pearson correlations between pairs of volumes obtained by the different methods. The degree of overlap between segmented masks was quantified in terms of the Dice index. Both Pearson correlations and Dice indices, showed poor agreement between FSL-FIRST and the other methods (ANTs and FS), which by contrast, yielded Pearson correlations greater than 0.93 and average Dice indices greater than 0.76 when compared with each other. As with volume, shape analyses exhibited discrepancies between segmentation methods, with particular differences noted between FSL-FIRST and the others (ANT and FS), with under- and over-segmentation in specific brainstem regions. These data suggest that research on brain structure alterations should cross-validate findings across multiple methods. We consistently detected an enlargement of brainstem volume in the whole sample and in the male cohort across multiple segmentation methods, a feature particularly driven by the subgroup of children with idiopathic intellectual disability associated with ASD.

Published
2019

35. Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease

Author

Florentino Sanchez-Garcia, Jean-Charles Lambert, Horacio Scaro, Zulma Sevillano, Paolo Bosco, Wolfgang Maier, Silvia Kochen, Alfredo Ramirez, Laura Morelli, Julieta Lisso, Mariana Soledad Sanchez Avalos, Carlos A Mangone, Cynthia Liberczuk, Paolo Caffarra, Frank Jessen, Daniel Gustavo Politis, Eduardo M. Castaño, Guillermo Jemar, Eliecer Coto, Claudia Kairiyama, Daniela Galimberti, Cristina Fezza, Patrizia Mecocci, Per Hoffmann, Jordi Clarimón, Luis I. Brusco, Claudia Hanses, Paola Bossù, Sandro Sorbi, Benedetta Nacmias, Nancy Medel, Mariana Estela Carulla, Michelangelo Mancuso, Federico A. Prestia, Maria Carolina Dalmasso, Pascual Sánchez-Juan, Pablo Galeano, María J. Bullido, Carolina Muchnik, Martin Ingelsson, Luis Eduardo Martinez, Pablo Javier Azurmendi, Caroline Graff, J Becker, Alberto Pilotto, Marcelo Sampaño, Céline Bellenguez, Maria Fierens, Francesco Panza, Natividad Olivar, Esther Milz, Stefanie Heilmann-Heimbach, Gianfranco Spalletta, Patricia Solís, International Society for Neurochemistry, Alexander von Humboldt Foundation, Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Universidad de Cantabria, and UAM. Departamento de Biología Molecular

Subjects
0301 basic medicine, Male, Neurologi, Genome-wide association study, genetics [Alzheimer Disease], Disease, 0302 clinical medicine, genetics [Membrane Glycoproteins], genetics [Adaptor Proteins, Signal Transducing], purl.org/becyt/ford/3.2 [https], genetics [Black People], TREM2, ethnology [Argentina], genetics [Receptors, Immunologic], Receptors, Immunologic, ABI3 protein, human, Genetics, Aged, 80 and over, Membrane Glycoproteins, Genomics, genetics [African Continental Ancestry Group], Middle Aged, Biología y Biomedicina / Biología, genetics [European Continental Ancestry Group], Neurology, genetics [Phospholipase C gamma], Psychiatry and Mental Health, genetics [Indians, North American], purl.org/becyt/ford/3 [https], Female, Alzheimer's disease, Genotype, ABI3, GENETIC, Argentina, genetics [White People], Black People, Single-nucleotide polymorphism, Biology, DIAGNOSIS, White People, Article, lcsh:RC321-571, PLCG2, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, ddc:610, Allele frequency, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Genetic association, Aged, Adaptor Proteins, Signal Transducing, ethnology [Alzheimer Disease], TREM2 protein, human, Phospholipase C gamma, Genetic Variation, medicine.disease, 030104 developmental biology, PLCG2, ABI3, TREM2, Indians, North American, Alzheimer, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage., International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.)

Published
2019
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36. Evaluation of the intra- and inter-method agreement of brain MRI segmentation software packages: A comparison between SPM12 and FreeSurfer v6.0

Author

Elisa Ferrari, Letizia Palumbo, Paolo Bosco, Piernicola Oliva, Giovanna Spera, Maria Evelina Fantacci, and Alessandra Retico

Subjects
Male, Biophysics, General Physics and Astronomy, Statistical parametric mapping, 030218 nuclear medicine & medical imaging, Correlation, White matter, 03 medical and health sciences, 0302 clinical medicine, Segmentation, Neuroimaging, medicine, Image Processing, Computer-Assisted, Brain MRI, Repeatability, Reproducibility, Humans, Radiology, Nuclear Medicine and imaging, Mathematics, business.industry, Brain, Pattern recognition, General Medicine, Magnetic Resonance Imaging, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Brain size, Female, Artificial intelligence, business, Software
Abstract

Purpose The lack of inter-method agreement can produce inconsistent results in neuroimaging studies. We evaluated the intra-method repeatability and the inter-method reproducibility of two widely-used automatic segmentation methods for brain MRI: the FreeSurfer (FS) and the Statistical Parametric Mapping (SPM) software packages. Methods We segmented the gray matter (GM), the white matter (WM) and subcortical structures in test-retest MRI data of healthy volunteers from Kirby-21 and OASIS datasets. We used Pearson’s correlation (r), Bland-Altman plot and Dice index to study intra-method repeatability and inter-method reproducibility. In order to test whether different processing methods affect the results of a neuroimaging-based group study, we carried out a statistical comparison between male and female volume measures. Results A high correlation was found between test-retest volume measures for both SPM (r in the 0.98–0.99 range) and FS (r in the 0.95–0.99 range). A non-null bias between test-retest FS volumes was detected for GM and WM in the OASIS dataset. The inter-method reproducibility analysis measured volume correlation values in the 0.72–0.98 range and the overlap between the segmented structures assessed by the Dice index was in the 0.76–0.83 range. SPM systematically provided significantly greater GM volumes and lower WM and subcortical volumes with respect to FS. In the male vs. female brain volume comparisons, inconsistencies arose for the OASIS dataset, where the gender-related differences appear subtler with respect to the Kirby dataset. Conclusions The inter-method reproducibility should be evaluated before interpreting the results of neuroimaging studies.

Published
2019

38. Evaluation of Mild Cognitive Impairment through Perientorhinal/Hippocampal Imaging and Comprehensive Neuropsychological and Psychophysical Assessment

Author

Sara Invitto, Paolo Boscolo-Rizzo, Giacomo Spinato, Giuseppe Trinchera, Giuseppe Accogli, Vincenzo Ciccarese, Luca Saba, Marcella Caggiula, Gaetano Barbagallo, Alfredo Pauciulo, and Marina de Tommaso

Subjects
olfactory perception, mild cognitive impairment, enthorinal cortex, anxiety, neurodegenerative processes, biomarkers, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Mild cognitive impairment (MCI) is a significant concern as it is a risk factor for AD progression, and early detection is vital in order to delay dementia onset and enable potential therapeutic interventions. Olfactory impairment is recognized as a predictive biomarker in neurodegenerative processes. The aims of this study were to explore the degree of entorhinal cortical atrophy (ERICA) and the severity of MCI symptoms; to analyze magnetic resonance imaging (MRI) results for the entorhinal cortex, parahippocampal gyrus, peri entorhinal cortex, and the cerebellar tentorium; and to perform a comprehensive neuropsychological and psychophysical assessment. The main results highlighted that in our sample—multidomain amnesic MCI patients with hyposmic symptomatology—we found that ERICA scores were associated with the severity of anxiety symptomatology. One possible hypothesis to explain this observation is that anxiety may contribute to neurodegenerative processes by inducing chronic stress and inflammation. Future research should consider the longitudinal development of neuropsychological scores, anxiety disorders, and brain atrophy to determine their potential predictive value for MCI progression. These findings suggest the importance of psychological factors in MCI progression and the utility of neuropsychological assessment alongside neuroimaging techniques for early detection and follow-up in MCI patients.

Published
2024
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39. Autism Spectrum Disorder and Childhood Apraxia of Speech: Early Language-Related Hallmarks across Structural MRI Study

Author

Eugenia Conti, Sara Calderoni, Alessandra Retico, Paola Cipriani, Anna Maria Chilosi, Michela Tosetti, Giovanni Cioni, Paolo Bosco, Letizia Palumbo, Giovanna Spera, Laura Biagi, Filippo Muratori, and Simona Fiori

Subjects
medicine.medical_specialty, genetic structures, neuroanatomy, Neural substrate, Magnetic Resonance Imaging (MRI), FreeSurfer, lcsh:Medicine, Medicine (miscellaneous), childhood apraxia of speech, Audiology, Autism Spectrum Disorders (ASD), behavioral disciplines and activities, Article, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, children, mental disorders, Basal ganglia, medicine, 0501 psychology and cognitive sciences, Early language, medicine.diagnostic_test, business.industry, lcsh:R, 05 social sciences, Magnetic resonance imaging, medicine.disease, medicine.anatomical_structure, Autism spectrum disorder, Childhood apraxia of speech, Differential diagnosis, business, human activities, 030217 neurology & neurosurgery, Neuroanatomy
Abstract

Autism Spectrum Disorder (ASD) and Childhood Apraxia of Speech (CAS) are developmental disorders with distinct diagnostic criteria and different epidemiology. However, a common genetic background as well as overlapping clinical features between ASD and CAS have been recently reported. To date, brain structural language-related abnormalities have been detected in both the conditions, but no study directly compared young children with ASD, CAS and typical development (TD). In the current work, we aim: (i) to test the hypothesis that ASD and CAS display neurostructural differences in comparison with TD through morphometric Magnetic Resonance Imaging (MRI)-based measures (ASD vs. TD and CAS vs. TD), (ii) to investigate early possible disease-specific brain structural patterns in the two clinical groups (ASD vs. CAS), (iii) to evaluate predictive power of machine-learning (ML) techniques in differentiating the three samples (ASD, CAS, TD). We retrospectively analyzed the T1-weighted brain MRI scans of 68 children (age range: 34&ndash, 74 months) grouped into three cohorts: (1) 26 children with ASD (mean age &plusmn, standard deviation: 56 &plusmn, 11 months), (2) 24 children with CAS (57 &plusmn, 10 months), (3) 18 children with TD (55 &plusmn, 13 months). Furthermore, a ML analysis based on a linear-kernel Support Vector Machine (SVM) was performed. All but one brain structures displayed significant higher volumes in both ASD and CAS children than TD peers. Specifically, ASD alterations involved fronto-temporal regions together with basal ganglia and cerebellum, while CAS alterations are more focused and shifted to frontal regions, suggesting a possible speech-related anomalies distribution. Caudate, superior temporal and hippocampus volumes directly distinguished the two conditions in terms of greater values in ASD compared to CAS. The ML analysis identified significant differences in brain features between ASD and TD children, whereas only some trends in the ML classification capability were detected in CAS as compared to TD peers. Similarly, the MRI structural underpinnings of two clinical groups were not significantly different when evaluated with linear-kernel SVM. Our results may represent the first step towards understanding shared and specific neural substrate in ASD and CAS conditions, which subsequently may contribute to early differential diagnosis and tailoring specific early intervention.

Published
2020
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40. Reproducibility of hippocampal atrophy rates measured with manual, FreeSurfer, AdaBoost, FSL/FIRST and the MAPS-HBSI methods in Alzheimer's disease

Author

Hugo Vrenken, Paolo Bosco, Giovanni B. Frisoni, Baptiste Grenier, Frederik Barkhof, Adriaan Versteeg, Alberto Redolfi, Ronald A. van Schijndel, Peter J. Visser, Bob W. van Dijk, Jérôme Revillard, Remko A. de Jong, E. Mulder, Keith S. Cover, Soheil Damangir, David Manset, Kelvin K. Leung, Physics and medical technology, Amsterdam Neuroscience - Brain Imaging, and Radiology and nuclear medicine

Subjects
Male, Pathology, medicine.medical_specialty, Neuroscience (miscellaneous), Neuroimaging, Disease, Hippocampus, 030218 nuclear medicine & medical imaging, ddc:616.89, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Alzheimer Disease, medicine, Humans, Radiology, Nuclear Medicine and imaging, AdaBoost, Aged, Reproducibility, medicine.diagnostic_test, business.industry, Reproducibility of Results, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, Sample size determination, Female, Alzheimer's disease, Nuclear medicine, business, Psychology, Algorithms, 030217 neurology & neurosurgery
Abstract

The purpose of this study is to assess the reproducibility of hippocampal atrophy rate measurements of commonly used fully-automated algorithms in Alzheimer disease (AD). The reproducibility of hippocampal atrophy rate for FSL/FIRST, AdaBoost, FreeSurfer, MAPS independently and MAPS combined with the boundary shift integral (MAPS-HBSI) were calculated. Back-to-back (BTB) 3D T1-weighted MPRAGE MRI from the Alzheimer's Disease Neuroimaging Initiative (ADNI1) study at baseline and year one were used. Analysis on 3 groups of subjects was performed - 562 subjects at 1.5 T, a 75 subject group that also had manual segmentation and 111 subjects at 3 T. A simple and novel statistical test based on the binomial distribution was used that handled outlying data points robustly. Median hippocampal atrophy rates were -1.1%/year for healthy controls, -3.0%/year for mildly cognitively impaired and -5.1%/year for AD subjects. The best reproducibility was observed for MAPS-HBSI (1.3%), while the other methods tested had reproducibilities at least 50% higher at 1.5 T and 3 T which was statistically significant. For a clinical trial, MAPS-HBSI should require less than half the subjects of the other methods tested. All methods had good accuracy versus manual segmentation. The MAPS-HBSI method has substantially better reproducibility than the other methods considered.

Published
2016
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41. Can measuring hippocampal atrophy with a fully automatic method be substantially less noisy than manual segmentation over both 1 and 3 years?

Author

Soheil Damangir, Alberto Redolfi, Ronald A. van Schijndel, Keith S. Cover, Alzheimer's Disease Neuroimaging Initiative, Paolo Bosco, and Radiology and nuclear medicine

Subjects
Male, Time Factors, Databases, Factual, Computer science, Neuroscience (miscellaneous), Hippocampus, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Segmentation, Treatment effect, Longitudinal Studies, Aged, Aged, 80 and over, Measurement method, business.industry, 05 social sciences, Pattern recognition, Magnetic Resonance Imaging, Hippocampal atrophy, Data set, Psychiatry and Mental health, Cross-Sectional Studies, Positron-Emission Tomography, Fully automatic, Female, Manual segmentation, Noise (video), Artificial intelligence, Atrophy, business, 030217 neurology & neurosurgery
Abstract

To quantify the "segmentation noise" of several widely used fully automatic methods for measuring longitudinal hippocampal atrophy in Alzheimer's disease and compare the results to the segmentation noise of manual segmentation over both 1 and 3 years. The segmentation noise of 5 longitudinal hippocampal atrophy measurement methods was quantified, including checking its Gaussianity, using 264 subjects from the ADNI1 back-to-back (BTB) data set over both 1 year and 3 year intervals. The segmentation methods were FreeSurfer 5.3.0 both cross sectional and longitudinal, FreeSurfer 6.0.0 longitudinal, MAPS-HBSI and FSL/FIRST 5.0.8. The BTB manual segmentation of 75 ADNI subjects from a previous study provided the manual distributions for comparison. All methods, including the manual segmentation, violated the Gaussianity assumption. Two methods, FreeSurfer 6.0.0 and MAPS-HBSI, had a segmentation noise substantially less than a surrogate for manual segmentation. FreeSurfer 5.3.0 longitudinal was confirmed as a surrogate for manual segmentation. The violation of the Gaussian assumption by the segmentation methods assessed, including manual, suggests results of previous studies that assumed Gaussian statistics without confirmation may need review. Fully automatic FreeSurfer 6.0.0 and MAPS-HBSI both have lower segmentation noise than manual requiring less than two thirds of the subjects to detect the same treatment effect.

Published
2018
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43. ARIANNA: un Ambiente di Ricerca Interdisciplinare per l'Analisi di Neuroimmagini Nell'Autismo

Author

Silvia Arezzini, Paolo Bosco, Sara Calderoni, Alberto Ciampa, Simone Coscetti, Stefano Cuomo, Luca De Santis, Dario Fabiani, Maria Evelina Fantacci, Gerardo Giardiello, Alessia Giuliano, Enrico Mazzoni, Pietro Mercatali, Giovanni Miscali, Filippo Muratori, Massimiliano Pardini, Margherita Prosperi, Alessandra Retico, Francesco Romano, Elena Tamburini, and Michela Tosetti.

Subjects
dati sanitari, privacy, piattaforme telematiche
Abstract

Il progetto ARIANNA ha sviluppato un ambiente di ricerca collaborativo e interdisciplinare per lo studio dei Disturbi dello Spettro Autistico (DSA), facilmente accessibile alla comunità dei ricercatori che lavorano nell'ambito dei DSA tramite una piattaforma web (https://arianna.pi.infn.it). Il progetto oltre a fornire ai ricercatori l'accesso a risorse computazionali equipaggiate con i più moderni strumenti in termini di efficienza di calcolo, è stato sviluppato in modo da garantire che la gestione e conservazione dei dati fosse svolta secondo le indicazioni e le prescrizioni previste dalla normativa, così come applicata tramite i pareri dell'Autorità garante per la protezione dei dati personali.

Published
2018

44. Expression of Phosphodiesterase 4B cAMP-Specific Gene in Subjects With Cryptorchidism and Down's Syndrome

Author

Aldo E. Calogero, Mirella Vinci, Maria Grazia Salluzzo, Roberto Castiglione, Sandro La Vignera, Paolo Bosco, Carmela M. Bonaccorso, Cristina Campagna, Rosita A. Condorelli, Corrado Romano, Michele Salemi, and Carmelo Romano

Subjects
0301 basic medicine, Microbiology (medical), Infertility, medicine.medical_specialty, Biochemistry (medical), Clinical Biochemistry, Public Health, Environmental and Occupational Health, Phosphodiesterase, Hematology, Biology, medicine.disease, 03 medical and health sciences, Medical Laboratory Technology, 030104 developmental biology, medicine.anatomical_structure, Real-time polymerase chain reaction, PDE4B, Endocrinology, Internal medicine, medicine, Extracellular, Immunology and Allergy, Gene, Germ cell, Hormone
Abstract

Cryptorchidism represents a risk factor for infertility and germ cell testicular neoplasia. An increased rate of cryptorchidism has been reported in subjects with Down's syndrome. Cyclic nucleotide phosphodiesterases (PDEs) are important messengers that regulate and mediate a number of cellular responses to extracellular signals, such as neurotransmitters and hormones. PDE4B, cAMP-specific (PDE4B) gene which maps to chromosome 1p31.3 appears to be involved in schizophrenia, chronic psychiatric illness, learning, memory, and mood disturbances. Expression of PDE4 enzymes have been studied in testes of cryptorchid rats. Expression of PDE4B protein examination showed marked degenerative changes in the epithelial lining of the seminiferous tubules. These findings led us to evaluate PDE4 mRNA expression in leukocytes of peripheral blood of five men with DS and cryptorchidism and eleven subjects with DS without cryptorchidism compared with healthy men (controls) by quantitative Real Time PCR (qRT-PCR). This study showed that the PDE4B gene was downexpressed in men with DS and cryptorchidism compared to normal controls and DS without cryptorchidism. A lower expression of the PDE4B gene may be involved in the neurological abnormalities in subjects with Down's syndrome. Moreover, PDE4B gene may be involved in the testicular abnormalities of men with DS and cryptorchidism.

Published
2014
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45. Platelet-Rich Plasma (PRP) in the Treatment of Long COVID Olfactory Disorders: A Comprehensive Review

Author

Antonino Maniaci, Salvatore Lavalle, Edoardo Masiello, Jerome R. Lechien, Luigi Vaira, Paolo Boscolo-Rizzo, Mutali Musa, Caterina Gagliano, and Marco Zeppieri

Subjects
olfactory dysfunction, platelet-rich plasma, anosmia, smell loss, Long COVID, Biology (General), QH301-705.5
Abstract

Background: Long COVID has brought numerous challenges to healthcare, with olfactory dysfunction (OD) being a particularly distressing outcome for many patients. The persistent loss of smell significantly diminishes the affected individual’s quality of life. Recent attention has been drawn to the potential of platelet-rich plasma (PRP) therapy as a treatment for OD. This comprehensive review aims to evaluate the effectiveness of PRP therapy in ameliorating OD, especially when associated with long-term COVID-19. Methods: We executed a comprehensive search of the literature, encompassing clinical trials and observational studies that utilized PRP in treating OD limited to COVID-19. We retrieved and comprehensively discussed data such as design, participant demographics, and reported outcomes, focusing on the efficacy and safety of PRP therapy for OD in COVID-19 patients. Results: Our comprehensive analysis interestingly found promising perspectives for PRP in OD following COVID-19 infection. The collective data indicate that PRP therapy contributed to a significant improvement in olfactory function after COVID-19 infection. Conclusions: The evidence amassed suggests that PRP is a promising and safe therapeutic option for OD, including cases attributable to Long COVID-19. The observed uniform enhancement of olfactory function in patients receiving PRP highlights the necessity for well-designed, controlled trials. Such studies would help to refine treatment protocols and more definitively ascertain the efficacy of PRP in a broader, more varied patient cohort.

Published
2024
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46. LDOC1Gene Expression in Men With Klinefelter Syndrome

Author

Sandro La Vignera, Rosita A. Condorelli, Paolo Bosco, Carmelo Romano, Aldo E. Calogero, Cristina Campagna, Valentina Bullara, Michele Salemi, and Giusi Longo

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Clinical Biochemistry, Biology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Internal medicine, medicine, Immunology and Allergy, Transcription factor, X chromosome, Azoospermia, Biochemistry (medical), Public Health, Environmental and Occupational Health, Hematology, medicine.disease, Reverse transcription polymerase chain reaction, Medical Laboratory Technology, 030104 developmental biology, Real-time polymerase chain reaction, Endocrinology, Apoptosis, 030220 oncology & carcinogenesis, Klinefelter syndrome
Abstract

Klinefelter syndrome (KS) results from an extra chromosome X, which is due to the failure of normal chromosomal segregation during meiosis. Patients with KS have gynecomastia, small testes, and azoospermia. Apoptosis is a mechanism responsible for the normal regulation of spermatogenesis. LDOC1 gene is a known regulator of nuclear factor mediated pathway to apoptosis through inhibition of nuclear factor kappa B (NF-kappaB). Furthermore, the transcription factor myeloid zinc finger gene 1 (MZF-1) has been shown to interact with LDOC1 and to enhance LDOC1 activity favoring apoptosis. We investigated the expression of LDOC1 gene mRNA, by quantitative reverse transcription polymerase chain reaction (qRT-PCR), in peripheral blood leukocytes of 13 patients with KS compared to 13 healthy men chosen as controls. LDOC1 expression was higher in 9 of the 13 KS patient compared to normal controls. These finding led us to hypothesize that LDOC1 gene upregulation may play a role in the spermatogenesis derangement observed in patients with KS.

Published
2016
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47. Killer-specific secretory (Ksp37) gene expression in subjects with Down’s syndrome

Author

Paolo Bosco, Corrado Romano, Maria C. Morale, Michele Salemi, Salvatore Caniglia, Carmelo Romano, Concetta Barone, Alda Ragalmuto, Maria Grazia Salluzzo, and Rosanna Galati Rando

Subjects
Adult, Male, Down syndrome, Dermatology, Biology, Virus, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene expression, Leukocytes, medicine, Humans, Cytotoxic T cell, RNA, Messenger, 030212 general & internal medicine, Gene, Blood Proteins, General Medicine, Fibroblasts, Middle Aged, medicine.disease, Psychiatry and Mental health, Real-time polymerase chain reaction, Case-Control Studies, Immunology, Female, Neurology (clinical), Down Syndrome, 030217 neurology & neurosurgery, CD8
Abstract

Down syndrome is characterized by dysmorphic features, mental retardation and problems of immune deficiency. Chronic infection by Epstein-Barr virus is frequently present in subjects with Down syndrome. Ksp37 gene is commonly expressed by NK, CD8(+) T, γδ T and CD4(+) T cells; these data suggest that Ksp37 have cytotoxic properties. An increase of Ksp37 protein serum levels it has been showed during the acute phase of Epstein-Barr virus. In this study, we evaluated the expression of Ksp37 mRNA, in fibroblasts and leukocytes of DS subjects and in normal subjects with realtime reverse transcription-PCR. This analysis shows that in fibroblasts and leukocytes of Down syndrome subjects the KSP37 gene expression was increased compared with control subjects. The results of this study suggest that the expression of Ksp37 gene might be associated with increased susceptibility of individuals with Down syndrome to EBV infections and autoimmune problems.

Published
2016
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48. ICD lead extraction: Not a benign procedure. External chest compression: Not a benign manoeuvre

Author

Patrick M. Heck, Yasir Abu-Omar, Antonella Ferrara, Federico Sertic, and Paolo Bosco

Subjects
medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, treatment, business.industry, medicine.medical_treatment, Icd lead, Cardiology, Case Report, Liver Laceration, medicine.disease, emergency sternotomy and emergency laparotomy, CPR and emergency cardiac care, law.invention, Surgery, ICD lead extraction, law, Superior vena cava, lcsh:RC666-701, Laparotomy, Cardiac tamponade, superior vena cava repair, Cardiopulmonary bypass, medicine, Cardiopulmonary resuscitation, business
Abstract

This is the case of a 45-year-old man who was electively admitted to our hospital for revision and extraction of his faulty implantable cardioverter–defibrillator lead and box. The procedure was complicated by cardiac tamponade requiring pericardiocentisis (unsuccessful) and cardiopulmonary resuscitation. The patient was then rushed to theatre for emergency sternotomy and institution of cardiopulmonary bypass. A tear in the superior vena cava was identified and repaired. Unfortunately, the patient suffered of a liver laceration, due to chest compression, which required emergency laparotomy. The aim of this report is to highlight the combination and management of two rare life-threatening complications that occurred in a single case.

Published
2017

49. 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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50. [IC‐P‐132]: WHEN MEASURING HIPPOCAMPAL ATROPHY, DO THE SEGMENTATION NOISE DISTRIBUTIONS OF METHODS, AS DETERMINED BY THE BACK TO BACK REPRODUCIBILITY, HAVE GAUSSIAN DISTRIBUTIONS?

Author

Keith S. Cover, Ronald A. Schijndel, Adriaan Versteeg, Alberto Redolfi, Paolo Bosco, Soheil Damangir, Bob W. Dijk, Hugo Vrenken, Giovanni B. Frisoni, and Frederik Barkhof

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2017
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