The long term objective of our research is to establish quantitative susceptibility mapping (QSM) as a noninvasive MRI marker for predicting neurodegeneration in Alzheimer’s disease (AD). Our scientific premise is that QSM can measure iron overload involved in AD progression. Our approach is to establish QSM as an MRI marker for predicting neurodegeneration ex vivo using AD brain tissue pathology and in vivo by correlating QSM with neurodegeneration measured on structural and metabolic MRI. The current AD research framework is termed AT(N): the pathological presence of amyloid-beta (Aβ) plaques (A) and phosphorylated tau neurofibrillary tangles (T) in the cortex and hippocampus cause neurodegeneration (N). However, tau tangles exist without Aβ plaques, and Aβ plaques are found in healthy elderly controls. Therapies targeting Aβ removed plaques but failed to improve cognition, suggesting that other contributors to neurodegeneration and cognitive decline in AD should be examined. Therefore, there is a need to expand the AT(N) framework to include new biomarker X or ATX(N). Iron is a candidate biomarker for AD. Iron is elevated in brains with clinical AD and predicts cognitive decline. Iron deposition appears before structural/metabolic changes on MRI and on metabolic PET. This promising prediction power of iron as a biomarker warrants further investigation for AD patient management. Accordingly, we propose to establish QSM as a biomarker to predict disease progression in AD. In this R21 project, we seek to obtain preliminary data through the following specific aims: Aim 1: Establish the QSM cellular sources in AD brain tissue using immunohistochemical assays of iron, microglia, Aβ, and tau, and using elemental iron measurements. Aim 2: Establish QSM as a biomarker that predicts neurodegeneration measured on structural and metabolic MRI of subjects with Aβ pathology. This proposed project is strongly supported by our experience and preliminary data, and its successful outcome will timely establish QSM a quantitative biomarker for AD pathogenesis, progression, and treatment monitoring.

The project will establish quantitative susceptibility mapping (QSM) as a noninvasive and widely accessible MRI marker for predicting neurodegeneration in Alzheimer’s disease (AD). A successful outcome of this research will lead to an easily applicable MRI method that will improve diagnosing, monitoring, and treating AD.