Mechanistic model-based biomarkers

Purpose: Chronic cerebral hypoperfusion has been identified as a possible initiator of neurodegenerative processes leading to Dementia. Lifestyle and environmental factors (LEFs), such as smoking, have an effect on the vascular system physiology. Pathophysiological changes in this system are therefore going to have an effect on the functioning of the brain. Methods and Materials: We propose to relate LEFs that act via the cardiovascular system and that have been shown to associate with AD. These LEFs are garnered from the preliminary data of a cross-sectional case-control study (Lido study). This multi-modal dataset is used to drive a patient-specific circulation model that provides predictions of CBF. The additional mechanistic components include a poroelasticity model used to acquire 4D maps of perfusion, clearance and ICP, in addition to a high-throughput imaging pipeline capable of providing anisotropic tissue permeability to capture the patterns of interstitial flow in addition to the parenchymal tissue and cerebroventricular representations required by the poroelasticity model. Results: Preliminary simulation results indicate that predisposition to cognitive loss may be linked to modifiable risk factors, such as those witnessed relating to ICP, perfusion and clearance. Based on the preliminary data obtained from the Lido study, the CBF parameters that were found to be associated with MCI status were: reduced total CBF, reduced total perfusion (in women), increased APP (in very old subjects), and increased PI. Conclusion: The multiscale model of brain fluid transport developed in VPH-DARE@IT will be used to account for the long-term response to hypothetical LEF patterns and timings.