Resumen de Complex neuroimaging changes in metabolite, cortical structures and regional vulnerabilities in the alzheimer disease continuum
Alzheimer disease (AD) is the most important cause of dementia. Its histopathological hallmarks are intracellular hyperphosphorylated tau and extracellular amyloid plaques, which start to accumulate decades before the onset of clinical symptoms and eventually lead to neurodegeneration and brain atrophy. Magnetic resonance imaging (MRI) provides a window to characterize in vivo the cortical changes in the preclinical and clinical phases of the disease. This thesis studied the cortical macrostructural, microstructural and metabolite changes along the AD continuum. It highlights the complex and non-linear alterations in the preclinical phase and analyzes the characteristic regional vulnerability underlying the spread of tau in early stages of the disease. Specifically, the first work of the thesis mathematically modeled the trajectory of cortical thickness and cortical mean diffusivity in autosomal dominant Alzheimer disease. This work demonstrated a biphasic trajectory of cortical alterations, in which the initial increases of amyloid were associated with increased cortical thickness and decreased cortical diffusivity, but were followed by cortical thinning and increased cortical diffusivity once tau becomes abnormal (15 years prior to symptom onset). The second work of this thesis characterized the alterations of metabolites along the AD continuum in a cohort of Down Syndrome using magnetic resonance spectroscopy (MRS). This work showed the potential of MRS to detect AD-related inflammation and neurodegeneration. The third work of this thesis investigated the potential of cortical diffusivity as a marker of neurodegeneration and its relationship with the accumulation of tau in preclinical AD. This work showed cortical diffusivity decreases were associated with the accumulation of tau in inferior temporal regions and predicted clinical deterioration. The fourth work of this thesis studied the genetic regional vulnerability associated to the stereotypical pattern of tau accumulation. This work developed a novel graph-theory-based framework to characterize the spread of tau integrating a high-resolution data of gene expression. This thesis has several important potential implications. First, it consolidates the biphasic trajectory of cortical alterations that reconciles previous conflicting results in the literature, greatly expand the potential of MRI to track changes in preclinical AD and provides a rationale to understand the (otherwise) paradoxical findings of increased atrophy in the active arm of anti-amyloid trials. Second, this thesis showed MRS could be a good noninvasive disease-stage biomarker in Down syndrome to track neurodegeneration and neuroinflammation. Third, it shows cortical mean diffusivity could be a more sensitive marker of neurodegeneration than cortical thickness that could be implemented in clinical trials. Finally, it provides a new framework to analyze the regional vulnerability underlying the spread of tau which could lead to the identification of new drug targets. In conclusion, this thesis highlights the complexity of the cortical changes preclinical AD and their regional vulnerability, but also demonstrates the potential of MRI to track these changes when using a multimodal approach, nonlinear models and new analytical frameworks.
