Impact de la charge amyloïde, des lésions de la substance blanche et des changements de la matière grise sur la cognition dans le vieillissement normal

Compelling evidence shows that pathological changes are highly prevalent in the aging brain, even in otherwise healthy individuals who remain fully functional. Among the most common age-related brain lesions are the abnormal deposition of beta-amyloid (A) peptide, a well-known hallmark of Alzheimer’s disease (AD), and white matter hyperintensities (WMH), which are regarded as a radiological marker of cerebral small vessel disease. Converging evidence from neuropathological, neuropsychological and neuroimaging data suggests that normal older adults harboring high levels of brain pathology exhibit exacerbated cognitive decline. Thus, neuropathological changes in healthy elderly people deserve particular attention as they are potential targets for early intervention and might contribute to the early identification of AD. This thesis sought to examine the associations between Aβ burden, WMH, cortical thickness and cognitive performances across multiple domains in a cohort of 104 cognitively normal older adults, while accounting for age, sex and years of formal education. All participants underwent an extensive neuropsychological assessment along with structural magnetic resonance imaging (MRI) and positron emission tomography (PET) with Pittsburgh Compound B (PIB). WMH severity was assessed using the age-related white matter changes (ARWMC) scale. Combined findings from the two empirical articles making up this thesis demonstrate independent, additive effects of A burden and right hippocampal volume on episodic memory whereby increased A deposition and reduced volume predict decreased performance. A burden and WMH contributed additively to poorer working memory and exerted deleterious synergistic effects on mental flexibility and attention. WMH was the most important predictor of linguistic abilities with higher lesion severity being associated with worse performances on language tasks. Conversely, neither A deposition nor WMH were correlated with semantic memory, processing speed and visuospatial abilities. In article 1, we demonstrated that age-dependent decline in episodic memory, working memory, mental flexibility and language was fully mediated by the extent of brain pathology. In article 2, cognition was not found to be positively associated with cortical thickness in the vertex-wise analyses, except for the domain of semantic memory. Furthermore, A burden, WMH and structural MRI measures were independent of one another, supporting the notion of distinct pathophysiological pathways. A notable finding of article 2 was that thinner cortical thickness in the left anterior temporal lobe (ATL) predicted poorer semantic memory, which is coherent with the role of the ATL in heteromodal semantic processing. The results presented in this thesis shed light on the role of prevalent brain pathologies, namely A burden and WMH, in driving age-related cognitive changes, and suggest that these changes can occur through pathways that are distinct from brain atrophy. Clinically speaking, this work lends support for the inclusion of a wider array of measures to routine screening for cognitive impairment in older adults, with an emphasis on semantic memory.

Keyphrases: Pittsburgh Compound B, Alzheimer’s disease, Beta-amyloid burden, Cognitive aging, Cortical thickness, Neuroimaging, White matter hyperintensities