The present Ph.D. thesis has been mainly developed on the data of the project with the short name PharmaCog (2010-2015), granted by the European Framework Programme 7 with about 28 millions of Euro (i.e. Innovative Medicine Initiative, IMI, grant agreement n°115009; www.pharmacog.org). This project involved 15 academic institutions, 12 global pharmaceutical companies, and 5 small and medium sized enterprises (SMEs). The PharmaCog project aimed at improving the pathway of drug discovery in Alzheimer’s disease (AD), based on a major interest of pharma companies, namely the validation of electrophysiological, neuroimaging, and blood biomarkers possibly sensitive to the effect of disease-modifying drugs reducing Ab42 in the brain in AD patients at the prodromal stage of amnesic mild cognitive impairment (aMCI). The core concept of the PharmaCog project was that the pathway of drug discovery in AD may be enhanced by (1) the validation of biomarkers derived from blood, EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) in patients with aMCI due to AD diagnosed by in-vivo measurement of Ab42 and phospho-tau in the brain and (2) the evaluation of the translational value of those human biomarkers in wild type (WT) mice and animal models of AD including transgenic mice with the mutation of PS1 and/or APP (i.e. PDAPP and TASTPM strains). Those genetic factors induce an abnormal accumulation of Ab42 in the brain and related cognitive deficits. The expected results may be (1) the identification of a matrix of biomarkers sensitive to the prodromal AD (aMCI cognitive status) and its progression in patients and (2) the selection of similar biomarkers related to AD neuropathology and cognitive deficits in PDAPP and TASTPM strains. These biomarkers were expected to be very useful in clinical trials testing the efficacy and neurobiological impact of new disease-modifying drugs against prodromal AD. For the development of this Ph.D. thesis, the access to the experiments and the data of the PharmaCog project was allowed by Prof. Claudio Babiloni, leader of an Italian Unit (University of Foggia in 2010-2012 and Sapienza University of Rome in 2013-2015) of the PharmaCog Consortium and coordinator of study activities relative to biomarkers derived from electroencephalographic (EEG) signals recorded from human subjects and animals in that project. Specifically, Prof. Claudio Babiloni was in charge for the centralized qualification and analysis of EEG data recorded from aMCI patients (Work Package 5, WP5) and transgenic mouse models of AD such as PDAPP and TASTPM strains (WP6). The data of the present Ph.D. thesis mostly derived from the WP5 and WP6. This document illustrating the Ph.D. thesis is structured in three main Sections: ▪ An Introductive part illustrating concisely the AD neuropathology, the mouse models of AD used in this thesis, and basic concepts of EEG techniques useful to understand the present study results; ▪ An Experimental part describing the result of the four research studies led in the framework of this Ph.D. project. Two of these studies were published in international journals registered in ISI/PubMed with impact factor, while the other two are being currently under minor revisions in those journals; ▪ A Conclusion section.

Backtranslation of EEG biomarkers of Alzheimer's disease from patients to mouse model / Lopez, Susanna. - (2018 Sep 18).

Backtranslation of EEG biomarkers of Alzheimer's disease from patients to mouse model

LOPEZ, SUSANNA
18/09/2018

Abstract

The present Ph.D. thesis has been mainly developed on the data of the project with the short name PharmaCog (2010-2015), granted by the European Framework Programme 7 with about 28 millions of Euro (i.e. Innovative Medicine Initiative, IMI, grant agreement n°115009; www.pharmacog.org). This project involved 15 academic institutions, 12 global pharmaceutical companies, and 5 small and medium sized enterprises (SMEs). The PharmaCog project aimed at improving the pathway of drug discovery in Alzheimer’s disease (AD), based on a major interest of pharma companies, namely the validation of electrophysiological, neuroimaging, and blood biomarkers possibly sensitive to the effect of disease-modifying drugs reducing Ab42 in the brain in AD patients at the prodromal stage of amnesic mild cognitive impairment (aMCI). The core concept of the PharmaCog project was that the pathway of drug discovery in AD may be enhanced by (1) the validation of biomarkers derived from blood, EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) in patients with aMCI due to AD diagnosed by in-vivo measurement of Ab42 and phospho-tau in the brain and (2) the evaluation of the translational value of those human biomarkers in wild type (WT) mice and animal models of AD including transgenic mice with the mutation of PS1 and/or APP (i.e. PDAPP and TASTPM strains). Those genetic factors induce an abnormal accumulation of Ab42 in the brain and related cognitive deficits. The expected results may be (1) the identification of a matrix of biomarkers sensitive to the prodromal AD (aMCI cognitive status) and its progression in patients and (2) the selection of similar biomarkers related to AD neuropathology and cognitive deficits in PDAPP and TASTPM strains. These biomarkers were expected to be very useful in clinical trials testing the efficacy and neurobiological impact of new disease-modifying drugs against prodromal AD. For the development of this Ph.D. thesis, the access to the experiments and the data of the PharmaCog project was allowed by Prof. Claudio Babiloni, leader of an Italian Unit (University of Foggia in 2010-2012 and Sapienza University of Rome in 2013-2015) of the PharmaCog Consortium and coordinator of study activities relative to biomarkers derived from electroencephalographic (EEG) signals recorded from human subjects and animals in that project. Specifically, Prof. Claudio Babiloni was in charge for the centralized qualification and analysis of EEG data recorded from aMCI patients (Work Package 5, WP5) and transgenic mouse models of AD such as PDAPP and TASTPM strains (WP6). The data of the present Ph.D. thesis mostly derived from the WP5 and WP6. This document illustrating the Ph.D. thesis is structured in three main Sections: ▪ An Introductive part illustrating concisely the AD neuropathology, the mouse models of AD used in this thesis, and basic concepts of EEG techniques useful to understand the present study results; ▪ An Experimental part describing the result of the four research studies led in the framework of this Ph.D. project. Two of these studies were published in international journals registered in ISI/PubMed with impact factor, while the other two are being currently under minor revisions in those journals; ▪ A Conclusion section.
18-set-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1149967
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