Biomarkers validation in Alzheimer’s Disease and related pathologies

The aim of this research project was to investigate biomarkers of Alzheimer’s disease (AD) and related pathologies. The future of these biomarkers relies in their proper validation in all settings (analytical and clinical). In the first two papers, I cooperated with a task force of expert in AD and oncology field, who adapted a framework for biomarkers development used in oncology to AD. We assessed existing evidence based on this framework for amyloid-PET; CSF Abeta42, tau/phospho-tau; FDG-PET; hippocampal atrophy, 123I-Ioflupane, 123I-MIBG, and neuropsychology. Then, I focused my PhD projects on one of the most reliable biomarkers of AD: brain metabolism by means of FDG PET and its clinical and validity among the phases of the roadmap framework. As FDG-PET rely its utility in AD not only as a diagnostic but also as a progression biomarker, we tried to use this powerful tool to clarify functional pattern able to predict future conversion to AD. One of the limitations of the latter studies was to have excluded from the sample patients with other disease than AD. This was done essentially for research purpose, but hampered the possibility to explore different metabolic patterns underpinning a mild cognitive impairment not due to AD. So, we explore the utility of FDGPET in the context of a relatively frequent syndrome who could mimic early symptoms of AD, DPD. Our results were: by means of strategic five-phase roadmap, sufficient evidence of analytical validity (phase 1) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. In order to assess the accuracy of FDG PET in discriminating MCI patients who converted to AD from those who did not, we found that MCI patients not converting to AD within a minimum follow-up time of 5 years and MCI patients converting within 5 years, baseline FDG PET and volume based analysis identified those who converted with an accuracy of 89%. With the aim to identify the cortical regions where hypometabolism can predict the speed of conversion to dementia in MCIAD we found a diagnostic-pattern. This is a further, independent source of heterogeneity in MCI-AD and affects a primary-endpoint on interventional clinical trials (time of conversion to dementia). Finally, with the aim to explore the role of FDG PET in the diagnosis of DPD, we compared brain FDG-PET among DPD patients, patients with early AD and normal subjects. We found that DPD patients had a specific relative hypometabolism both on caudate nuclei and right anterior cingulate (BA 25). This study confirms the role of FDG PET in the diagnosis of DPD and pave the way of a better understanding of its underpinning biological alterations. In conclusion, during my PhD I explored the necessity to define the validity of biomarkers of AD and related pathologies in patients with MCI: from operative and analytic point of view, to clinical settings. Then I focused on the real clinical implication of one of the most useful and reliable biomarkers, FDG PET. Our findings support its role of a robust progression biomarker even in a naturalistic population, and underline its importance in the early diagnosis of AD.