Substrats neuronaux de la mémoire épisodique et de la mémoire de travail dans le vieillissement normal et pathologique

Alzheimer's disease (AD) is by far the type most common dementia in the elderly. It is now possible to propose a number of interventions or preventive strategies to individuals with a diagnosis of AD or at risk of developing the disease. It is therefore important to diagnose this disease as soon as possible. Individuals with mild cognitive impairment (MCI) represent a population of interest as they are at high risk of developing dementia and many of these persons might thus be in a prodromal phase of AD.  The work of this thesis aims to explore the functional activations associated with episodic memory and working memory in MCI as well as studying the effects of disease severity and of task characteristics on these brain activations. Initially, we will review the current knowledge about the level of cognitive impairment, functional activation pattern and the more recent models developed to explain changes of functional activation in normal aging and disease (Chapter 1). Subsequently, the studies of this thesis will be presented. First, we studied the reliability of activation signal in people with MCI and healthy elderly individuals (HE) using tasks of encoding and retrieval of words (Chapter 2). We then compared the pattern of brain activation between HE and MCI persons while they were administered tasks of encoding and retrieval of words and pseudo-words. The effect of severity was assessed by correlating activations of MCI persons with their scores on a scale assessing their overall cognition (Chapter 3). The effect of severity was then examined in more details in a larger number of people using the median score of the MCI group on the scale of global cognitive assessment to determine a group of less impaired MCIs and a group of more impaired MCIs. These two groups were compared to a group of HE while conducting a task of encoding semantically related or unrelated pairs of words (Chapter 4), a recognition task of word pairs measuring either mainly familiarity processes or recollection processes (Chapter 5) and two tasks involving different components of working memory or executive functioning, the manipulation of information and division of attention (Chapter 6).  The results presented in this thesis have highlighted a distinction between the functional activation pattern of MCI persons and HE which seems to be characterized by an interaction between level of disease severity and the cognitive processes involved in the task. The effect of severity was observed in several tasks involving different cognitive processes during which less impaired MCIs showed primarily hyperactivations underlying compensatory mechanisms and more impaired MCIs showed mainly hypoactivations suggesting a degradation of these mechanisms. Moreover, the results of our studies have also shown that the effect of severity is modulated by the time of alteration of the cognitive processes involved in the task: the process altered early in MCI are caracterized by hyperactivations in less impaired MCIs while processes that are altered later on elicited hyperactivations in more impaired MCIs. The implications of these findings and the limitations of the studies are discussed (Chapter 7).

Keyphrases: Compensation, Neuroimagerie, Cognition, Mild cognitive impairment, Alzheimer’s disease, Brain imaging, Episodic memory, Executive functions