7T MRI as a potential tool for detection of pathology in Alzheimer's disease

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Project Summary/Abstract Amyloid-beta (Aβ) is a small piece of a larger protein called amyloid precursor protein. It accumulates in stages into microscopic amyloid plaques that are considered a hallmark of a brain affected by Alzheimer’s disease (AD). Positron emission tomography (PET) is an established technique to detect Aβ plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. magnetic resonance imaging (MRI) of Aβ plaques has been attempted using various techniques, notably with susceptibility contrast. The non-invasive detectability of Aβ plaques in MRI has so far been largely attributed to iron deposition accompanying Aβ plaques. It is believed that the susceptibility shortening effects of paramagnetic iron are the primary source of contrast between plaques and surrounding tissue. We hypothesized that aggregations of iron associated Aβ would increase electron density and induce notable changes in local susceptibility value. Due to higher susceptibility at ultra-high field (UHF) strengths, induced iron susceptibility is large enough to generate contrast relative to surrounding normal tissues that can be visualized by quantitative susceptibility techniques at 7 Tesla (7T) MRI. The goal of this proposal is to bring forward an alternative platform for analysis of pathologic biomarkers in AD patients, thanks to ultrahigh field (7T) MR neuroimaging. The development of specialized sequences for 7T susceptibility MRI will enable the comparison and microstructural data in AD patients at an unprecedented resolution; this, in turn, will provide a deeper understanding of the in vivo pathophysiology of AD and allow us to potentially identify a set of susceptibility-based markers of disease pathology. Specifically, we expect our integrated approach to help us validate UHF MRI as a unique tool to improve AD diagnosis and prognostic measurements. Our central hypothesis is that UHF MRI provides a unique and powerful measure of changes associated with AD in the brain, and may be integrated with existing neuroimaging tools to achieve unprecedented visualization of the consequences of disease pathology. This career development project also includes a training plan designed to refine and address gaps in the applicant’s technical and scientific knowledge and experience, develop his research career skills, expose him to the neuroimaging and neuroscience communities, and lay the groundwork for his career as an independent scientist. The training plan encompasses: coursework in neurological disorders, clinical neuroscience, research grant applications, and budget management; presentation of his work at technical MRI and neuroscience conferences; delivery of formal classroom lectures and small-group teaching sessions; mentorship of research volunteers; organizing a research symposium; and hands-on training during the conduct of the research project.