4 results on '"Giorgio, Giaccone"'
Search Results
2. Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort
- Author
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Giacomina Rossi, Erika Salvi, Elkadia Mehmeti, Martina Ricci, Cristina Villa, Sara Prioni, Fabio Moda, Giuseppe Di Fede, Pietro Tiraboschi, Veronica Redaelli, Cinzia Coppola, Giacomo Koch, Elisa Canu, Massimo Filippi, Federica Agosta, Giorgio Giaccone, and Paola Caroppo
- Subjects
frontotemporal dementia ,semantic variant ,right temporal variant ,next generation sequencing ,genetic variant ,pathogenic ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype–phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.
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- 2022
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3. PMCA-Based Detection of Prions in the Olfactory Mucosa of Patients With Sporadic Creutzfeldt–Jakob Disease
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Federico Angelo Cazzaniga, Edoardo Bistaffa, Chiara Maria Giulia De Luca, Sara Maria Portaleone, Marcella Catania, Veronica Redaelli, Irene Tramacere, Giuseppe Bufano, Martina Rossi, Paola Caroppo, Anna Rita Giovagnoli, Pietro Tiraboschi, Giuseppe Di Fede, Roberto Eleopra, Grazia Devigili, Antonio Emanuele Elia, Roberto Cilia, Michele Fiorini, Matilde Bongianni, Giulia Salzano, Luigi Celauro, Federico Giuseppe Quarta, Angela Mammana, Giuseppe Legname, Fabrizio Tagliavini, Piero Parchi, Gianluigi Zanusso, Giorgio Giaccone, and Fabio Moda
- Subjects
Creutzfeldt–Jakob disease ,olfactory mucosa ,protein misfolding cyclic amplification ,neurodegeneration ,prion ,peripheral biomarker ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrPC) into an abnormally folded form, named prion (or PrPSc). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrPSc type 1 or 2) gives rise to different PrPSc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrPSc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrPSc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrPSc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrPSc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrPC with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrPSc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrPSc was generated, regardless of the tissues analyzed. Notably, all amplified PrPSc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials.
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- 2022
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4. Dreaming of a New World Where Alzheimer’s Is a Treatable Disorder
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Marcella Catania, Giorgio Giaccone, Mario Salmona, Fabrizio Tagliavini, and Giuseppe Di Fede
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Alzheimer ,amyloid-beta ,multi-target ,tau ,amyloid cascade hypothesis ,amyloid precursor protein ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Alzheimer’s disease (AD) is the most common form of dementia. It’s a chronic and untreatable neurodegenerative disease with irreversible progression and has important social and economic implications in terms of direct medical and social care costs. Despite prolonged and expensive efforts employed by the scientific community over the last few decades, no effective treatments are still available for patients, and the development of disease-modifying drugs is now a really urgent need. The recent failure of clinical trials based on the immunotherapeutic approach against amyloid-β(Aβ) protein questioned the validity of the “amyloid cascade hypothesis” as the molecular machinery causing the disease. Indeed, most attempts to design effective treatments for AD have been based until now on molecular targets suggested to be implicated in AD pathogenesis by the amyloid cascade hypothesis. However, mounting evidence from scientific literature supports the view of AD as a multifactorial disease that results from the concomitant action of multiple molecular players. This view, together with the lack of success of the disease-modifying single-target approaches, strongly suggests that AD drug design needs to be shifted towards multi-targeted compounds or drug combinations acting synergistically on the main core features of disease pathogenesis. The discovery of drug candidates targeting multiple factors involved in AD would greatly improve drug development. So, it is reasonable that upcoming strategies for the design of preventive and/or therapeutic agents for AD point to a multi-pronged approach including more than one druggable target to definitely defeat the disease.
- Published
- 2019
- Full Text
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