L'atrophie de l'hippocampe dans la maladie d'Alzheimer et la variante sémantique de l'aphasie primaire progressive

The increase in the prevalence of dementia is a major international concern. Unlike normal aging, dementia refers to the progressive weakening of all intellectual functions: memory, attention, judgment, reasoning ability, and the resulting behavioral changes. Globally, it is estimated that 35.6 million people are affected by dementia, and 7.7 million of new cases are reported each year (WHO, 2012). In this context, early detection, prediction and dissociation of these different syndromes are of primary interest, particularly for treatment purposes. Over the past decade, the scientific literature has shown, with the help of neuroimaging tools, an association between the episodic memory impairments observed in patients with Alzheimer's disease (AD) and the hippocampal atrophy found in the majority of these patients (Petersen et al., 2000). However, several studies regarding the semantic variant of primary progressive aphasia (svPPA), previously known as semantic dementia (Gorno- Tempini et al., 2011), find a similar hippocampal atrophy pattern to that found in AD patients (Brambati et al., 2009; Chan et al., 2001; Davies et al., 2004; Desgranges et al., 2007; Galton et al., 2001; Nestor et al., 2006). However, from a cognitive perspective, these patients rather demonstrate a deterioration of semantic memory and do not generally show episodic memory impairments, at least during the beginning of the disease (Gorno-Tempini et al., 2011). It is therefore essential to compare and clarify our knowledge regarding the involvement of the hippocampus in these two pathologies in order to guide their respective clinical diagnoses and available intervention methods. A recent study has shown, in healthy participants, that different parts of the hippocampus are involved in the episodic versus semantic memory networks (La Joie et al., 2014). The anterior part of the hippocampus would be involved in semantic memory, whereas the posterior part of this structure would be associated to episodic memory. Our general hypothesis is that different parts of the hippocampus are affected in both diseases, because of their distinct connections to the two systems supporting episodic and semantic memory, and thus that the anterior part of the hippocampus would be impaired in svPPA whereas the posterior part would be impaired in AD. The first article of the thesis aimed to identify and compare the pattern of cerebral atrophy associated with svPPA and AD through a meta-analysis based on previous anatomical studies, and to further characterize the volume of the hippocampus under an antero-posterior axis in both diseases. The results of the study confirmed the hypothesis that, in addition to the classical signature of cerebral atrophy observed in both diseases, the hippocampus is affected bilaterally in AD and svPPA. In svPPA, however, the atrophy is limited to the anterior part of the structure whereas a more general atrophy was observed in AD. In addition, when both groups were directly compared, a more pronounced posterior atrophy was observed in the AD versus svPPA group. The second article of the thesis aimed to investigate the impact of AD and svPPA on the functional connectivity patterns of the anterior versus posterior hippocampus. The results showed two different patterns of functional connectivity, between the anterior and posterior hippocampus and the rest of the brain, in controls. A reduction in functional connectivity in the anterior hippocampus was observed in svPPA, whereas a comparable functional connectivity pattern to that of controls was observed in the posterior hippocampus. Overall, our results confirm that atrophy of the hippocampus is present, but affects different parts of the structure, in both diseases. Our results also support the hypothesis that neurodegenerative syndromes such as AD and svPPA do not only implicate focal atrophies, but rather derive from a disconnection between various anatomical regions, and that clinical symptoms are caused by this rupture in the neural networks supporting cognitive functions such as semantic and episodic memory.

Keyphrases: Alzheimer’s disease, Dementia, Hippocampus, Neuroimaging, Semantic dementia, Primary progressive aphasias