MRI biomarkers of glial-specific metabolites and microstructure in aging

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PROJECT SUMMARY Individual manifestations of Alzheimer’s disease (AD) likely result from multiple pathological processes. Recent evidence indicates a critical role for inflammation, driven by glial cells (astrocytes, microglia) that comprise half of our brain tissue. When faced with an acute insult (illness, trauma), glia assume a defensive, active phenotype by proliferating and swelling. This protective glial response can be overwhelmed in normal aging and AD, resulting in chronic inflammation that disrupts the ability of glia to support neural structures and ultimately impacts cognition. Yet, there are few in vivo measures of inflammation in the human brain. Commonly used peripheral markers from blood and cerebrospinal fluid do not provide information about the brain regions that are impacted by inflammation. Positron emission tomography overcomes this limitation, but it involves injections of expensive ligands that may not be sensitive and specific to glia and their phenotypes (resting, activated). Magnetic resonance imaging and magnetic resonance spectroscopy (MRI/S) include equally promising and non-invasive approaches to measure neuroinflammation that have been validated in animal models but are only recently being used in humans, although rarely in studies of aging. One such under-studied approach is diffusion-weighted MRS (DW-MRS), which greatly improves on traditional MRS by selectively quantifying concentrations of metabolites commonly found within glial cells (intracellular metabolite concentration). DW-MRS also provides a measure of diffusion for each metabolite (metabolite diffusion coefficient), which may distinguish between the resting (low diffusion in non-swollen cells) and activated (high diffusion in swollen cells) glial phenotypes. Whereas glial-specific metabolites can be selectively targeted using DW-MRS, multi-compartment diffusion- weighted MRI (DWI) measures structural properties of brain tissue that are not specific to glia but may nonetheless be sensitive to glial proliferation and swelling. Demonstrating a relationship between these DW- MRS and DWI metrics will be valuable for other research groups interested in neuroinflammation as many existing and large-scale datasets have acquired multi-compartment DWI, but not DW-MRS. This project aims to test the sensitivity of these MRI/S approaches to neuroinflammation in aging and their relation to memory performance by acquiring both DW-MRS and DWI scans in cognitively normal younger and older adults who also complete a neuropsychological test battery. We will test whether older age is accompanied by higher DW- MRS glial-specific metabolite metrics (concentrations, diffusion coefficients) in the hippocampus (Specific Aim 1), consistent with evidence that this region in vulnerable to glial activation in aging. We will then test whether the DW-MRS glial-specific metabolite metrics are related to DWI measures of diffusion of molecular water within (intracellular diffusion) and between (dispersion of diffusion) cells (Specific Aim 2), as would be expected if the DWI metrics are also sensitive to proliferation and swelling of glia. Across both aims, higher DW-MRS glial- specific metabolite metrics and DWI diffusion metrics in the hippocampus are expected to relate to worse memory performance in older adults, but not in younger adults as they will have minimal neuroinflammation. Taken together, this project will provide a more detailed characterization of age-related neuroinflammation in humans in vivo and reveal novel biomarkers of an important inflammatory pathway linked to memory dysfunction in normal aging.