Age-associated cognitive decline (AACD) in otherwise healthy, elder veterans has surfaced as a major impediment to their quality of life and economic viability. In the last decade, the number of veterans aged 85 years and older has tripled. AACD often heralds dementia, the principal cause of institutionalization, both undesirable and costly. To date, only non-specific interventions exist for AACD. The long term goal of this research program is to understand the biology of cognitive aging so as to prevent or treat it. The fundamental hypothesis for this project posits the anterior cingulate cortex (ACC) plays an early and pivotal role in cognitive aging through dysfunction of its metabolism and/or of its functional connectivity to related neural networks. Corollary hypotheses include the following: 1) Elders will show evidence of resting ACC hypometabolism even at the level of the individual, providing a potential biomarker for AACD. 2) ACC metabolism will decline with aging and APOE4 genotype and will further anticipate conversion to MCI. 3) ACC metabolism will correlate best with tests of executive rather than mnemonic functions. To accomplish these goals, the project has the following specific aims: 1) Characterize in a cross-sectional design resting ACC hypometabolism and functional connectivity in matched groups of carefully characterized healthy young and related elder subjects (i.e., child/parent pairs). 2) Model in a longitudinal design using existing normative ADNI data resting ACC metabolism as a function of age, APOE genotype, education, etc. and determine whether ACC hypometabolism predicts those who convert to MCI. 3) Characterize the cognitive sequelae of aging-related ACC hypometabolism. The approach for this work consists of an innovative blending of resting FDG PET, resting BOLD fMRI at 3T, neuropsychological testing, and neuroinformatics. This work is expected to establish ACC dysfunction, occurring during otherwise healthy aging, is associated with impaired executive function and is the primary neurological substrate for AACD. Upon achieving these goals, this research can focus the field vertically upon ACC dysfunction for more reductionist and mechanistic approaches that can truly lead to basic, fundamental advances. The ultimate potential medical impact is the prevention and/or treatment of AACD.

Public Health Relevance

Age-associated cognitive decline describes the loss of higher mental functions in otherwise healthy elders. Remaining intact cognitively is critical for successful aging. It impacts upon occupation, retirement age, self-sufficiency, motor vehicle accidents, etc. Veterans 85 years and older have tripled in the last decade, making the problem imminent. Yet, the biology of cognitive aging is minimally understood. Only non-specific approaches, such as diet, exercise, and controlling aging- related disease (e.g., hypertension), exist today. Recent data identify for the first time a brain target for intervention: the anterior cingulate cortex, a region with a critical role in selective attention. This proposal will examine the effects of aging and modulators (e.g., education, APOE54) upon anterior cingulate activity and connectivity. The ultimate goal is to define the pathophysiology in the anterior cingulate cortex to prevent or treat age-associated cognitive decline and conversion to dementia.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science B (MHBB)
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Minneapolis VA Medical Center
United States
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