White Matter Metabolism in the Context of Aging, White Matter Hyperintensities and Alzheimer's Disease

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ABSTRACT White matter hyperintensities (WMH) are ubiquitous in the aging brain. Prevailing theories implicate arteriosclerosis and endothelial dysfunction followed by ischemic and hypoxic injury as a cause, but factors that resist or modify these mechanisms are unknown. Animal studies show that glycolysis is a principal metabolic feature of normal white matter and protective against mitochondrial failure. However, white matter glycolysis has been understudied in in vivo human studies and particularly in the context of WMH. Our laboratory has developed methods, now on a state-of-the-art PET scanner, to quantitatively measure brain glycolysis using multiple radiotracers, including 15O radiotracers to measure cerebral oxygen consumption (CMRO2), cerebral blood flow (CBF) and oxygen extraction fraction (OEF), and 18FDG to measure total glucose use (CMRglc), from which we can derive the rate of aerobic glycolysis (AG). Here we propose to apply these methods to provide gold-standard quantitative estimates of normal human white matter metabolism, and to specifically investigate white matter glycolysis in the context of WMH. In our first two aims, we will compare the topography of metabolic PET measurements to MRI measurements of white matter microstructure and WMH, both in healthy adults without WMH and in adults with WMH. In our third aim, we will analyze longitudinal MRI imaging data in a cohort of adults who have already undergone metabolic PET in our prior and ongoing studies on an older scanner, to test the hypothesis that relative differences in white matter glycolysis will predict subsequent WMH development and progression. Moreover, we will explore potential relationships between neurodegenerative pathology and WMH, which we hypothesize occurs due to effects of the aforementioned pathology on white matter metabolism, thereby reducing its resilience to WMH.