2017 — 2021 |
Raichle, Marcus E (co-PI) [⬀] Vlassenko, Andrei G. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aerobic Glycolysis in the Development Ofalzheimer's Disease
PROJECT SUMMARY/ABSTRACT In this project, we will evaluate the trajectory of changes in regional oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis or AG) and in brain circulation through the course of preclinical AD to symptomatic AD in late middle-aged and older adults. It is currently established that AG is a marker of a group of metabolic functions which includes biosynthesis, neuroprotection, and apoptosis, which, in the context of the normal brain is involved in synaptic remodeling, learning and memory, and generation of energy for membrane pumps. AG is about 10-15% in the normal adult human brain, and it demonstrates more substantial changes compared to other measures of brain metabolism in response to physiological activation or pathophysiological challenges associated with brain diseases. Our cross-sectional observations in cognitively normal adults suggest that areas of the human brain targeted by AD pathology have uniquely high levels of AG, and higher levels of AG are associated with less PIB deposition, higher levels of CSF A?42 and better scores on cognitive tests. In our current project, we will determine the role of AG as a potential early biomarker of evolving AD pathology and predictor of cognitive decline. Our specific aims include estimation for the first time of AG in individuals with mild-to-moderate symptomatic AD combined with that in cognitively normal individuals to evaluate a hypothesis that low baseline AG will be associated with the subsequent development of AD pathology and cognitive decline. We will also determine the relationship between the rate of change in AG and rate of change in clinical assessments and biomarkers of AD. In most cases, this information will be combined with the previously collected data in the same individuals to provide a multipoint trajectory over time. These longitudinal assessments will allow us to evaluate changes in AG and other PET measures of metabolism and circulation during the transition from no AD pathology to preclinical AD, and through the preclinical stages to symptomatic AD. We will evaluate the hypothesis that AG changes prior to other parameters, and that the rate of change in AG will predict progression in AD pathology and cognitive decline. Our work may not only expand significantly our understanding of the role of glucose in brain function beyond providing energy via oxidative phosphorylation, but also provide important new insights into the pathophysiology of AD and neuroprotective potential of AG. This project is innovative because it proposes to combine different biomarkers of AD to address novel questions, in vivo, in humans to produce findings relevant to both clinical disorders and fundamental human neurophysiology. The methods chosen, with which our group has substantial expertise, will allow us to study intrinsic regional brain activity and energy utilization, in vivo, in humans, which appear to be associated with the regional development of AD pathology. This project will evaluate a potential of AG as a highly specific biomarker of synaptic function, and provide novel insight into the development and control of the efficacy of preventive treatments aimed to reduce AD pathology by modulating synaptic function.
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0.958 |
2017 — 2021 |
Goyal, Manu S (co-PI) [⬀] Vlassenko, Andrei G. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aerobic Glycolysis: a Marker of Brainresilience to Aging and Alzheimer's Disease
PROJECT SUMMARY/ABSTRACT The growing prevalence of Alzheimer?s disease (AD) within an aging population has heightened the need to determine the etiologic and modifying factors that influence healthy brain aging and its shift to neuropathological processes such as AD. Aging of the human brain is a multifaceted, complex process that might be vulnerable to various changes/illnesses and is also the biggest risk factor for AD. An integrative approach to the study of brain aging is essential to better understand both healthy changes and neurodegenerative processes such as AD. A critical question is why do some individuals with AD develop cognitive symptoms earlier than others, even in the face of similar degrees of AD pathology? Also, why are certain brain regions more vulnerable to AD pathology than others? We believe that investigating brain metabolism, as a reflection of the demanding and dynamic physiology occurring in the brain throughout the lifespan, might provide key insights into these questions and of the pathophysiology of aging and AD in general. Our project is aimed at using brain metabolism to reveal sources of inter-individual differences that influence brain aging and the development and progression of AD. Simultaneous measurement of brain glucose uptake and oxygen utilization using positron emission tomography (PET) allows calculation of brain aerobic glycolysis (glucose metabolism in excess of oxidative phosphorylation or AG), which is a marker of synaptic plasticity and neuroprotection. Brain AG decreases with age and identifies regions subsequently targeted by AD pathology. In this project, we propose to combine our unique, multi-tracer PET imaging to evaluate how brain metabolism ? in particular AG ? relates to brain structure and cognition during healthy aging and in the preclinical and symptomatic stages of AD. Based on our PET measurements we will also calculate a ?metabolic brain age? and investigate its relationship with biological age and structural, functional and cognitive assessments. We will test our hypothesis that brain metabolism might predict aging-related changes in brain structure and function. We will evaluate whether inter-individual differences in brain metabolism correlate with inter-individual differences in cortical volume, connectivity and cognitive function. Our hypothesis is that low brain AG is associated with a more rapid appearance of imaging and cognitive features of AD. Conversely, high AG will be associated with increased resilience to the effects of brain aging and progression of AD. This project will thus establish the role of brain metabolism in determining what causes selective vulnerability of certain brain regions and individuals to aging and AD, and in doing so may provide an avenue to identify modifiable factors that influence the trajectory of brain aging and AD.
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0.958 |