Imaging the Hippocampal Formation in Alzheimer’s Disease.

Abstract

Entorhinal cortex dysfunction has been implicated early in Alzheimer’s disease, which is characterized by changes in tau protein and in the cleaved fragments of amyloid precursor protein (APP). This thesis presents work to address basic questions about entorhinal cortex pathophysiology using a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models of disease in the basal state. Recent work has demonstrated that the entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). We exploited the high-resolution capabilities of this fMRI variant, cerebral blood volume (CBV) imaging, to ask whether preclinical Alzheimer’s disease differentially affected these subregions. Next, we imaged three mouse models of disease to clarify the role that tau and APP play in driving entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in synaptically linked cortical areas. We found that the LEC was differentially affected by tau and APP in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction. Taken together, these findings help to explain regional vulnerability in Alzheimer’s disease.