La maladie d’Alzheimer comme syndrome de déconnexion et son impact sur le système du langage

The typical form of Alzheimer’s disease (AD) is characterized by progressive episodic memory impairments. Nonetheless, patients affected by this disease also present with language symptoms. Among common language deficits in AD, anomia, i.e. a difficulty to recall names, is recognized as the most predominant. Therefore, it represents an interesting cognitive marker for the detection of the disease as well as its differential diagnosis with other neurodegenerative diseases characterized by overlapping symptoms, such as the semantic variant of primary progressive aphasia (sv-PPA). Still, the anomic profile of AD patients remains incompletely characterized in terms of the naming of certain types of entities. Also, the cognitive and cerebral bases of anomia are still a matter of debate in AD.  In addition to structural damage or functional alteration in specific brain regions, many authors have recently suggested that a disconnection across brain networks could sustain cognitive difficulties experienced by AD patients, including language impairments. However, most studies demonstrating that AD is a disconnection syndrome have used functional connectivity techniques, and no study using the gray matter structural covariance networks technique has been conducted to support this hypothesis. In addition, very few studies have investigated the impact of AD on the language brain network, which could significantly extend our understanding of language symptoms such as anomia. The first section of this thesis aimed to better characterize the anomic profile of AD patients, to compare it with the profile of sv-PPA patients and finally, to clarify its cognitive and cerebral bases (article #1). The results first suggested a diffuse naming impairment affecting every type of items (non-unique entities, famous persons, famous places and famous logos) in AD patients in comparison to control subjects. Famous persons naming was nonetheless predominantly impaired in AD patients in comparison to other types of entities, suggesting a prosopoanomia. General semantic knowledge for these same entities was preserved in AD, although a slight but significant impairment was observed in terms of specific semantic knowledge. Behavioral results in AD patients clearly distinguished them from sv-PPA patients, in which naming, general and specific semantic knowledge were cleary impaired.  Famous persons naming in AD patients correlated with gray matter atrophy in the left temporo-parietal junction (a region functionally associated with lexical access), but not with the left anterior temporal lobe (a region functionally associated with semantics). Overall, these results underline the contribution of a lexical access deficit in anomia in AD patients, but nonetheless argue in favor of a mixed cognitive basis of anomia given that a slight semantic impairment for specific knowledge was also present. The second section of this thesis aimed at demonstrating that AD is a disconnection syndrome (article #2), and that this disconnection also affects the brain network responsible for language (article #3). Results showed significant changes in the structural connectivity of the key networks in AD. In fact, a reduced structural connectivity was observed in the subcomponents of the default-mode network, giving support to the theory of AD as a disconnection syndrome. Furthermore, our results confirmed that structural connectivity alterations were also present outside of the default-mode network, also affecting the language network. Reduced functional connectivity was mainly observed in the left posterior middle temporal gyrus as well as in the left anterior temporal lobe, in relation to other regions of the language network. These results have implications for our understanding of language symptoms in AD patients, since they are also compatible with a mixed basis (lexical access and semantic impairments) of anomia in AD.  Taken together, these results highlight the importance of anomia as a cognitive marker and structural/functional connectivity as a neuroimaging marker in the characterisation of AD as well as its differential diagnosis with other neurodegenerative diseases such as sv-PPA. Given the negative impact of language difficulties in the daily life of AD patients as well as their caregivers, we believe that a better characterisation of the cognitive and cerebral bases of their language deficits will contribute to the development of interventions.

Keyphrases: Alzheimer's disease, Language, Anomia, Brain connectivity, Semantic memory, Semantic variant of primary progressive aphasia