Development and evaluation of neuroimaging biomarkers of structural and functional network degeneration in Alzheimer’s disease - PROJECT SUMMARY The Amyloid-Tau-Neurodegeneration (A/T/N) biomarker framework for Alzheimer’s disease (AD) indicates binary (presence/absence) designations for each type of pathology. However, the anatomical information provided by imaging modalities, particularly in assessment of neurodegeneration “N”, is not currently incorporated into this framework. Further, preliminary data strongly suggests a dissociation between structural and functional brain alterations in AD, a phenomenon likely reflective of underlying pathophysiology and not yet explored in the literature. There is a clear opportunity for extending the ATN biomarker framework by incorporation of spatially- defined neuroimaging biomarkers. A robust, validated approach for neuroimaging biomarker development uses meta-analysis to define a node-and-edge model followed by validation in primary resting-state fMRI data. This was recently successfully applied to multiple sclerosis, with upcoming clinical trials planned. The current proposal utilizes a similar approach, with three aims: 1) to develop a meta-analytic node-and-edge model of structural changes in AD; 2) to develop a meta-analytic node-and-edge model of functional changes in AD; 3) to determine the ability of the models developed in Aims 1&2 to detect clinical (healthy à mild cognitive impairment àAD) and pathological (healthy à A+ à A+T+ à A+T+N+) progression of AD. Aim 3 will utilize primary resting-state fMRI data from the Alzheimer’s Disease Neuroimaging Initiative. Directly, completion of the proposed aims will provide characterization of the dissociation of structural and functional changes in AD (Aims 1&2) and a spatially- based functional connectivity imaging biomarker for disease progression along the AD continuum (Aim 3). Longitudinally, knowledge gained from the proposed project will advance the understanding of AD pathophysiology, allowing for development of targeted therapeutics, and ultimately decreasing morbidity and mortality from neurodegenerative diseases.
