Probing the Intracellular Environment in Normal Aging Using Magnetic Resonance

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DESCRIPTION (provided by applicant): This project proposes to identify intracellular molecular probes that are sensitive to changes that take place on the cellular level during aging in the human brain. The cellular changes include shrinkage in cell size, decrease in total dendritic length, and total number of dendritic segments. MR measurement of transverse relaxation (T2) is sensitive to reduction in cell body size, modification in the intracellular macromolecular and organelle composition, and iron content. Another, MR measure, the apparent diffusion coefficients (ADC), is sensitive to decrease in neuronal space and changes in viscosity. Metabolites present in the human brain are predominantly intracellular, and some are cell specific, such as N-acetylaspartate that is located in neurons and myo-inositol located in glia. By measuring the T2 and ADC values of several metabolites, the approach will specifically probe differing cellular and subcellular compartments. The T2 and ADC values of N- acetylaspartate, total creatine, total choline, glutamate and myo-inositol will be measured noninvasively in multiple brain regions that may or may not be affected by aging. One aim is to measure T2 values of those metabolites in three brain regions in young and elderly subjects to determine whether recently found lower T2 values in cognitively normal elderly subjects are more widespread than the occipital cortex. A complementary specific aim is to measure ADC values of the metabolites in the same brain regions. The measurements will be performed at the clinically relevant field strength of 3 T. The acquisition protocols for measuring T2 and ADC values of J-coupled metabolites, such as glutamate and myo-inositol, will be optimized as sub aims. The data processing and analysis will be fully automated using commercially available software. Successful completion of this project will determine whether low T2 and ADC values are widespread in the elder human brain. Additionally, we will learn if the T2 and ADC measurements for metabolites are sensitive and specific to cellular changes that take place in aging. Long term, this proposal has the potential to lead towards the discovery of quantitative, non-invasive, intracellular imaging biomarkers which can play an important role in clinical evaluation for early diagnosis, monitoring of disease progression, and testing of therapeutic approaches for neurodegenerative disorders, such as Alzheimer's disease.