Les substrats cérébraux du déclin de la mémoire sémantique dans le vieillissement pathologique : contributions de la magnétoencéphalographie

La mémoire sémantique (MS) contient l’ensemble de nos connaissances sur l’organisation et la signification du monde qui nous entoure. Elle supporte ainsi plusieurs opérations cognitives complexes, telles que la communication et le raisonnement, et joue un rôle déterminant à l’égard de notre bon fonctionnement au quotidien. Sur le plan neuroanatomique, la MS repose sur un réseau étendu de régions et de connexions, ce qui la rend particulièrement robuste au déclin neuronal. Elle représente d’ailleurs le seul système mnésique qui demeure stable au cours du vieillissement normal. En revanche, la présence d’un déclin sémantique précoce chez les personnes âgées est plutôt observée dans le contexte de maladies neurodégénératives telles que la maladie d’Alzheimer (MA) et la variante sémantique de l’aphasie primaire progressive (APPvs). Or, les corrélats neurofonctionnels associés au déclin sémantique dans ces maladies demeurent à ce jour encore mal compris. En utilisant la magnétoencéphalographie (MEG) comme méthode d’investigation, la présente thèse vise ainsi à explorer la dynamique cérébrale associée au traitement sémantique dans ces deux syndromes neurodégénératifs, afin de documenter, d’une part, les changements neurofonctionnels associés au déclin sémantique, et d’autre part, les mécanismes cérébraux de compensation fonctionnelle qui sont déployés afin de permettre un traitement résiduel lorsque l’intégrité du réseau sémantique est compromise. Cette thèse vise également à déterminer s’il existe des mécanismes de plasticité cérébrale communs dans ces deux maladies en lien avec la détérioration sémantique, et à amorcer une réflexion sur les potentielles implications cliniques de ces changements neurofonctionnels. Dans le contexte de l’atteinte subtile observée dans le stade prodromal de la MA, ces mécanismes cérébraux pourraient être indicateurs de l’installation d’un processus pathologique avant même l’émergence d’altérations structurelles significatives, leur conférant un intérêt face à l’établissement d’un diagnostic précoce. Dans le cas de l’APPvs, où l’atteinte en MS est franche, centrale et circonscrite, ces mécanismes pourraient être informatifs relativement à la capacité du réseau sémantique à se réorganiser afin de soutenir un traitement résiduel. Ils pourraient alors être utiles pour guider le choix des interventions (rééducatives ou palliatives) à privilégier auprès des patients. La première étude (chapitre 2), avait ainsi comme objectif de documenter les substrats cérébraux qui sous-tendent les troubles sémantiques dans le stade infraclinique de la MA (TCLa), au moyen d’une épreuve de jugement sémantique sur des visages célèbres. Cette étude a ainsi permis d’appuyer l’idée que l’altération cérébrale observée chez ces individus n’est pas limitée à la région hippocampique et qu’elle s’étend plutôt au sein de plusieurs régions du réseau sémantique élargi, incluant les lobes temporaux antérieurs (LTA). Ces résultats suggèrent également que le patron de dysfonctionnement neuronal observé chez ces patients précède l’émergence de changement structuraux au sein du réseau sémantique, et que les mécanismes de compensation fonctionnelle déployés pour soutenir le traitement sémantique plus fin associé aux visages célèbres chez ces patients reposent notamment sur la sollicitation accrue du LTA droit. La deuxième étude (chapitre 3) avait comme objectif de mieux comprendre les bases cérébrales du traitement sémantique résiduel dans le contexte d’une atteinte significative, mais sélective de la MS, à travers l’étude de cas d’une patiente atteinte d’APPvs. Au moyen d’une épreuve de catégorisation sémantique d’entités biologiques et d’objets manufacturés, cette étude a permis de mettre en évidence chez la patiente un patron d’hyperactivation au sein de régions-clé du réseau sémantique, s’étendant au gyrus temporal inférieur gauche et au LTA droit, en dépit d’une performance comportementale comparable à celle de personnes âgées saines. Dans l’ensemble, ces résultats soulignent l’implication des régions temporales péri-atrophiques dans le maintien de capacités résiduelles de traitement sémantique. Finalement, la dernière partie de la thèse (chapitre 4) est consacrée à une réflexion sur les implications cliniques et théoriques associées aux résultats de ces deux études, et permet également d’aborder les limites et perspectives futures en lien avec ces travaux.Semantic memory (SM) contains all of our knowledge of the organization and meaning of the world around us. It supports many complex cognitive operations such as communication and reasoning and plays a decisive role in our daily functioning. At the neuroanatomical level, SM relies on a widely distributed network, which makes it particularly resistant to neuronal decline. It is, in fact, the only memory system that is known to remain stable during normal aging. As a result, the presence of an early semantic decline in older adults is generally observed in a neurodegenerative context, such as in Alzheimer's disease (AD) and in the semantic variant of primary progressive aphasia (svPPA). However, the neurofunctional correlates associated with semantic decline in pathological aging remain to this day poorly understood. Therefore, the main objective of this thesis is to explore the cerebral changes associated with semantic processing in these two neurodegenerative diseases, using magnetoencephalography (MEG) as a method of investigation, in order to document the neurofunctional changes associated with semantic decline, as well as the functional compensatory brain mechanisms that are deployed to allow residual processing when the integrity of the semantic network is compromised. This thesis also aims to determine if common mechanisms of neural plasticity are at play to counteract the effects of semantic deterioration in these two diseases, and to initiate a reflection on the potential clinical implications of these neurofunctional changes. In the context of the subtle SM alterations observed in the prodromal stage of AD, these mechanisms could be reflective of the neuropathological decline even before the emergence of significant structural alterations, highlighting their relevance regarding an early diagnosis. In the case of manifest but relatively circumscribed alteration of SM, such as in svPPA, these mechanisms are informative of the capacity of the compromised semantic network to adjust in order to support residual processing, which can also be useful in deciding which interventions (rehabilitation, palliative) are likely to be most helpful for patients. The first study (chapter 2) is aimed to investigate the neural correlates underlying semantic disorders in the subclinical stage of AD (aMCI), using a semantic judgment task about famous faces. Our results support the assumption that the pattern of neural alterations observed in aMCI patients is not limited to the hippocampal region, as it extends within several regions of the extended semantic network, including the anterior temporal lobes (ATL). These results also suggest that the pattern of neural dysfunction observed in aMCI patients precedes the emergence of structural alterations within the semantic network, and that the compensatory mechanisms deployed to support the finer semantic processing associated with famous faces in these patients rely notably on an increased recruitment of the right ATL region. The second study (chapter 3) is aimed to better understand the neural correlates of residual semantic processing in the context of a significant but selective impairment of SM, through the single case study of a svPPA patient, using a semantic categorization task about biological entities and manufactured objects. Despite equivalent behavioral performance, this study revealed a pattern of significant hyperactivation within key regions of the semantic network in the svPPA patient in comparison with controls, extending to the left inferior temporal gyrus and right ATL region. Overall, these findings emphasize that peri-atrophic regions within the ATL may support remaining semantic abilities. Finally, the last chapter of this thesis (chapter 4) is dedicated to reflect on the clinical and theoretical implications associated with the results of these two studies. The limitations of this thesis and future perspectives are also addressed in this section

Neural changes associated with semantic processing in healthy aging despite intact behavioral performance

Semantic memory recruits an extensive neural network including the left inferior prefrontal cortex (IPC) and the left temporoparietal region, which are involved in semantic control processes, as well as the anterior temporal lobe region (ATL) which is considered to be involved in processing semantic information at a central level. However, little is known about the underlying neuronal integrity of the semantic network in normal aging. Young and older healthy adults carried out a semantic judgment task while their cortical activity was recorded using magnetoencephalography (MEG). Despite equivalent behavioral performance, young adults activated the left IPC to a greater extent than older adults, while the latter group recruited the temporoparietal region bilaterally and the left ATL to a greater extent than younger adults. Results indicate that significant neuronal changes occur in normal aging, mainly in regions underlying semantic control processes, despite an apparent stability in performance at the behavioral level

A MEG study of the neural substrates of semantic processing in semantic variant primary progressive aphasia

Despite a well-documented pattern of semantic memory (SM) impairment, the patterns of brain activation during semantic processing in svPPA still remain poorly understood. The current study aimed to investigate the neural substrates of residual semantic processing in the context of this significant but selective SM impairment, through the case study of one svPPA patient. One svPPA patient (EC) and six elderly controls carried out a general-level semantic categorization task (biological and manufactured objects) while their brain activity was recorded using magnetoencephalography (MEG). Despite similar behavioral performance, EC showed hyperactivation of the left inferior temporal gyrus (ITG) and right anterior temporal lobe (ATL) relative to controls. This suggests that periatrophic regions within the ATL region may support preserved semantic abilities in svPPA. These results thus contribute to our understanding of the brain regions which are recruited to compensate for bilateral atrophy of the ATL and ensure residual semantic processing in svPPA

Functional changes in the cortical semantic network in amnestic mild cognitive impairment

Semantic memory impairment has been documented in older individuals with amnestic Mild cognitive impairment (aMCI), who are at risk of developing Alzheimer’s disease (AD), yet little is known about the neural basis of this breakdown. The main objective of this study was to investigate the brain mechanisms associated with semantic performance in patients with aMCI. Method: A group of aMCI patients and a group of healthy older controls carried out a semantic categorization task while their brain activity was recorded using magnetoencephalography (MEG). During the task, participants were shown famous faces and had to determine whether each famous person matched a given occupation. The main hypotheses were that: (i) semantic processing should be compromised for aMCI patients, and (ii) these deficits should be associated with cortical dysfunctions within specific areas of the semantic network. Results: Behavioural results showed that aMCI participants were significantly slower and less accurate than control participants at the semantic task, corroborating previous reports. Additionally, relative to controls, a significant pattern of hyperactivation was found in the aMCI group within specific regions of the semantic network, including the right anterior temporal lobe and inferior prefrontal cortex. Conclusions: Abnormal functional activation within key areas of the semantic network suggests that it is compromised early in the disease process. Moreover, this pattern of increased activation in aMCI was positively associated with grey matter integrity in specific areas, but was not associated with any specific pattern of atrophy, suggesting that functional hyperactivation may precede atrophy of the semantic network in aMCI