This proposal will pursue in cognitively normal individuals from the Adult Children Study (ACS;POI AG026276) detailed, quantitative cross-sectional and longitudinal measurements of regional brain circulation, oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis (AG;glucose use outside of oxidative phosphorylation)), and compare for the first time these more comprehensive measurements of brain circulation and metabolism with state-of-the-art biomarkers and clinical assessments in the same individuals. This work is motivated by our observation that while AG represents about 15% of the total glucose metabolized by the normal adult human brain it is strikingly nonuniform in its distribution being highest the brain's default mode network (DMN). The DMN is noteworthy from a disease perspective in that it represents a primary site of beta-amyloid (A?) plaque accumulation in Alzheimer's disease (AD). This apparent association between AG and AD prompted us to explore further this relationship in transgenic mice where we found that AG (but not total glucose consumption) and AP vary together not only regionally but with changes in synaptic activity. Furthermore, reducing synaptic activity chronically not only reduces AG and A? levels but also retards plaque deposition. Here we propose measuring for the first time AG in individuals in whom A? plaque distribution will be assessed with [11C]PIB PET imaging along with other state-of-the-art biomarkers and clinical assessments. The overarching aim of this application is to substantially enhance our knowledge of the pathophysiology of preclinical AD and specifically to more fully characterize AG as a biomarker of synaptic activity, a potential aggravating factor in the development of AD pathology. We will determine the chronology (cross-sectionally and longitudinally) of changes in AG and its relationship to clinical assessments and other biomarkers of AD. This project will not only provide novel and important information about development of preclinical AD and its transition to clinical stages, but also may provide a useful marker of the efficacy of anti-Abeta treatments especially those designed to modify synaptic function.
The focus of the ACS and this project is the discovery of predictive and diagnostic biomarkers of AD. A more complete view of brain metabolism, specifically as it relates to synaptic function, and AD pathology would be extremely helpful in achieving a better understanding of AD pathophysiology and assisting in the design and control of appropriate preventive treatments which may seek to modify synaptic function.
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