Tau networks in AD psychosis

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Project Summary/Abstract The overarching goal of this K01 application is to examine cerebral mechanisms that underlie psychotic symptoms (PS) in Alzheimer’s disease (AD) using positron emission tomography (PET), diffusion tensor imaging (DTI), and resting state functional magnetic resonance imaging (rs-fMRI) techniques. I will specifically address the role of tau pathology and structural and functional network disruptions in the manifestation of PS in AD. Cerebrospinal fluid (CSF) and post-mortem studies have suggested a role of tau pathology in the manifestation of PS in AD. However, the cerebral mechanisms that underlie this association remain poorly understood. A thorough and comprehensive plan for additional training and related career development activities is proposed based on: 1) Phenomenology of psychosis in the context of AD from both psychiatric and cognitive perspectives; 2) Tau neurobiology and tau positron emission tomography (PET) imaging; 3) Diffusion tensor imaging (DTI), tractography, and resting-state functional magnetic resonance imaging (rs-fMRI) network connectivity. These training goals are intended to provide crucial scientific skills needed to test the following hypotheses: 1) AD patients with PS will show greater tau accumulation in frontal, cingulate, lateral temporal and parieto-occipital cortices regions compared to AD without PS; 2) AD with PS will show more abnormal diffusivity, compared to AD without PS, in white matter tracts that connect frontal, cingulate, lateral temporal, parietal, and occipital lobes, and functional network connectivity abnormalities in cortical circuits involving the frontal lobe, specifically the default mode network (DMN) and the salience network (SN); in addition, I expect that tau aggregation in central nodes of the DMN will correlate with delusions, whereas tau aggregation in the SN will be associated with hallucinations; 3) Tau aggregation will be greater in the central nodes of these structural and functional networks in AD patients with PS compared to AD patients without PS; and 4) Tau aggregation in frontal, temporal and posterior cingulate regions, will correlate with social cognition and executive function impairments in AD patients with PS. I will use a second generation tau radiotracer ([18F]- PI2620) that has shown excellent imaging properties and high specificity, in combination with a comprehensive assessment of both psychiatric (delusions and hallucinations) and cognitive (social cognition and executive function impairment) manifestations of PS. The proposed combination of training and research plans will lay the ground to launch my independent career to test neurobiological hypotheses regarding behavioral manifestations of AD from a neuroimaging perspective.