A Biphasic model for cortical structural changes in preclinical AD: a multimodal MRI, CSF and PET study /

The Alzheimer’s disease (AD) neuropathological hallmarks are the presence of extracellular amyloid s (As) deposition and intracellular neurofibrillary tangles (hyperphosphorilated tau protein) as well as inflammation phenomena. These processes are associated with cerebral atrophy and neuronal loss and functional alterations which lead to cognitive dysfunction and, eventually, a clinical syndrome of dementia. These pathophysiological processes begin decades before the diagnosis of the clinical dementia even before the appearance of the first clinical symptoms, and constitute the preclinical AD (Sperling et al, 2011). Nowadays we can study the pathophysiological mechanisms that occur in preclinical AD through biomarkers (Dubois et al., 2016). It is crucial to understand the relationships between biomarkers in preclinical AD to further understand the disease pathophysiology and be able to develop treatments that could slow down or stop its course. However, these relationships are not clear, for example, the relationship between brain amyloidosis and brain structure is controversial (Fortea et al., 2014). The objective of this thesis was to study the cortical structural alterations that occur in preclinical AD. Specifically, 1) to study the relationship between As and cortical thickness and its potential interactions with p-tau, 2) to analyze the 2-year cortical longitudinal changes in preclinical AD, 3) to investigate cortical microstructure and understand its relationship with brain macrostructure in the disease continuum and, 4) to assess the local impact of amyloid deposition in brain structure in preclinical AD. In this thesis, we have used data from a public American database (Alzheimer’s Disease Neuroimaging Initiative, http://adni.loni.usc.edu/) and from a Spanish multicentric cohort (proyecto SIGNAL, https://www.signalstudy.es/). The results of this thesis have conducted to the proposal of a biphasic model of structural cortical changes in preclinical AD. Amyloid deposition in the absence of pathological tau levels would be associated with increased cortical thickness, less 2-year longitudinal cortical thinning and cortical diffusivity decreases. Then, in the presence of pathological tau levels, and as a result of the synergic toxic effect or interaction between pathologic processes, there would be an atrophy acceleration and cortical diffusivity increases that would spread following a pattern that has been described as the AD-signature (Dickerson et al., 2009). The results presented in this thesis have direct research and clinical implications. First, they impact on the models of biomarker evolution in AD (Jack et al., 2013), as the cortical thickening phase is not contemplated in previous models. Our model would help to understand previous contradictory results in the literature that assessed the effect of amyloid on brain structure. Current models do not take into account the interaction/synergy effect between biomarkers that define the aforementioned biphasic process. Second, our results have relevance in the design of clinical trials, both in the selection of patients and in the use of the MRI as a surrogate marker of efficacy, and might help explain some unexpected results in previous anti-amyloid immunotherapy trials. Finally, cortical diffusivity could be an early marker in the AD course. Further multimodal studies that incorporate tau- and inflammation-PET with longitudinal follow-ups are crucial to further investigate the pathophysiological process that underlies preclinical AD.