Alzheimer's disease (AD) is a major public health problem due to its socio-economic weight. An early diagnosis of AD is urgently needed as it would constitute a determinant breakthrough from a social, financial and research standpoints. Therefore, the investigators need predictive markers of AD, and neuroimaging is a particularly promising tool, especially when using complementary neuroimaging techniques and a longitudinal design, allowing to assess the relationships between the different biomarkers of the disease, their dynamic and their chronology.

Brief Title

Multi-modal Neuroimaging in Alzheimer's Disease

Official Title

Study of the Predictive Markers and the Pathophysiological Mechanisms of Alzheimer's Disease: Transverse and Longitudinal Approach in Anatomical and Functional Multimodal Imaging

Brief Summary

Alzheimer's disease (AD) is a major public health problem due to its socio-economic weight.<br /> An early diagnosis of AD is urgently needed as it would constitute a determinant breakthrough<br /> from a social, financial and research standpoints. Therefore, the investigators need<br /> predictive markers of AD, and neuroimaging is a particularly promising tool, especially when<br /> using complementary neuroimaging techniques and a longitudinal design, allowing to assess the<br /> relationships between the different biomarkers of the disease, their dynamic and their<br /> chronology.

Detailed Description

The three main objectives of this project are:

- To Identify, compare and combine the predictive markers of AD,

- To better understand the pathophysiologic mechanisms of AD,

- To study the ability of different neuroimaging techniques to monitor AD's evolution.

For these purposes, detailed neuropsychological evaluations, biological measures and brain
structural & functional imaging measures are associated for a fully-comprehensive description
of the different manifestations of AD through disease progression and toward identifying
early markers.

Subjects are evaluated using neuropsychological tests of episodic memory (encoding vs.
retrieval), executive functions (inhibition, flexibility, and updating processes),
self-judgment, theory of mind, mental imagery and verbal fluency. A FDG-PET measure of
resting state glucose consumption, an AV45-PET measure of amyloid deposition as well as
anatomical, resting-state and activation fMRI scans are performed for each volonteer. In
addition, blood and cerebro-spinal fluid samples will be performed to determine different
biomarkers (Aβ1-40, Aβ1-42 and tPA as circulating blood proteins and Aβ40, Aβ42, tau and its
phosphorylated form in CSF). The investigators also study the polymorphism of Apolipoprotein
E as a genetic risk factor of AD.

One hundred and twenty healthy controls (40 young, 40 middle age and 40 elderly), 40 Mild
Cognitive Impairment patients (MCI; i.e. isolated memory impairment and increased risk of
developing AD) and 30 AD patients will be selected. Participants with increased risk of
developing AD and without objective evidence will be also studied: 50 asymptomatic subjects
from families carrying a genetic mutation with an autosomal dominant transmission (NORMA) and
40 Subjective Cognitive Impairment patients (SCI).

Clinical follow-up of patients will be completed during 36 months (18 months for AD
patients), as a neuropsychological evaluation every 6 months. Comparable neuropsychological
and imaging exams will be proposed once again after 18 months for all participants as well as
after 36 months for elderly controls, NORMA and SCI & MCI patients.

To study and compare the effectiveness of different in vivo markers (to predict cognitive
decline in populations at risk of developing AD), each data set (i.e. modality) will be first
analyzed independently from one another (intra-modality analyses), including inter-group
comparisons, correlations and connectivity analyses, as well as longitudinal assessment of
cognitive, biological and brain changes. Baseline data will also be analyzed in function of
patient's clinical evolution to assess their predictive value. Comparisons and correlations
between the different patterns of alterations will then be performed through inter-modality
analyses. More specifically, the investigators will address the questions of the
relationships between cognitive and cerebral alterations and structural / functional brain
changes over our different patient samples, neuroimaging data sets, and through disease
evolution.

This project is expected to identify specific and early markers of the MA and also to compare
the diagnostic efficiency of different measures. It should contribute to better understand
brain and cognitive alterations in AD. Finally, the investigators will be able to appreciate
the dynamic properties of these alterations in the evolution of the disease through the
longitudinal study.