Cellular Viscosity as a Marker for Alzheimer’s Disease Pathology: A Combined Multiparametric MR Spectroscopy and PET Study

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Project Summary The number of Americans with Alzheimer’s Disease (AD) is projected to reach almost 14 million by 2050, highlighting the urgent need for biomarkers to monitor and predict disease progression, especially at its early stages. The existing “AT(N)” framework includes imaging of three key AD hallmarks: amyloid beta (Aβ) plaques (A) and tau neurofibrillary tangles (T), using Positron Emission Tomography (PET); and neurodegeneration (N), using structural MRI volumetry and Fluorodeoxyglucose PET. These AT(N) markers provide the crucial ability to stage AD, but are not fully capable of robust prognostication of disease progression, especially in early disease. Imaging biomarkers for other important molecular processes and homeostatic networks impaired in AD, are therefore needed to complement the AT(N) framework. This project proposes the use of magnetic resonance-based biomarkers of intracellular viscosity, which is of fundamental importance for proper cellular function, and is closely linked to AD pathophysiology. We recently pioneered a rapid and robust technique termed Magnetic Resonance Spectroscopic Fingerprinting (MRSF), which can quantify changes to intracellular viscosity separately within neurons and astrocytes. MRSF does so by measuring the relaxation times (T1, T2) of two cell-type specific metabolites: N-acetyl-aspartate (NAA), which is confined to neurons, and myo-inositol (mI), which is confined to astrocytes. We have received approval from the NIA-funded NYU AD Research Center to include our MRSF sequence within their routine tau-PET/MRI protocol. This will allow a serial follow-up of a large cohort of cognitively normal individuals and patients with mild cognitive impairment. Both sets of subjects will undergo yearly neurocognitive assessments, plasma Aβ and plasma tau evaluations; and biennial Aβ-PET, tau-PET, and MRI+MRSF scans. The project has the following hypotheses: (H1) Reduced NAA relaxation times, and elevated mI relaxation times will predict the hallmarks of AD progression: cognitive decline, atrophy and tau accumulation. (H2) These relaxation times, alongside NAA and mI concentrations, will improve the ability of Aβ-PET, tau-PET and MRI atrophy to predict future cognitive decline. (H3) Replacing Aβ-PET and tau-PET in H2 by cost-effective and easy-to-collect plasma Aβ and plasma tau will provide the same or better statistical power for predicting cognitive decline. The expected outcome of this work is a set of novel markers for neuronal and astrocytic intracellular viscosity which will potentially become biomarkers for early prediction of neurodegeneration and cognitive decline in AD, addressing gaps in the current imaging armamentarium of the AT(N) network.