Aging-related hypometabolism in the anterior cingulate cortex mediates the relationship between age vs. executive function but not vs. memory in cognitively intact elders

Abstract

Elucidating the pathophysiology of cognitive decline during aging in those without overt neurodegeneration is a prerequisite to improved diagnosis, prevention, and treatment of cognitive aging. We showed previously the anterior cingulate cortex (ACC) and adjacent medial prefrontal cortex (mPFC) are centers for aging-related metabolic dysfunction that correlate with age-associated cognitive decline in healthy volunteers. Here, we examine using the extensive and well-characterized ADNI dataset the hypothesis that ACC metabolism in healthy seniors functions as a mediator in the relationship between age and executive function. In agreement with our previous findings, highly significant correlations arose between age and metabolism; metabolism and fluency; and age and fluency. These observations motivated a mediation model in which ACC metabolism mediates the relationship between age and fluency score. Significance of the indirect effect was examined by Sobel testing and bootstrapping. In these cognitively intact seniors with \"typical aging,\" there was neither a correlation between age and memory scores nor between ACC metabolism and memory scores. The metabolism in a control region, the primary motor cortex, showed no correlation with age or ACC metabolism. These findings motivate further research into aging-related ACC dysfunction to prevent, diagnose, and treat the decline in executive function associated with aging in the absence of known neurodegenerative diseases.\n\nSIGNIFICANCE STATEMENTThe pathophysiology of aging-related cognitive decline remains unclear but the anterior cingulate cortex (ACC), a major component of the anterior human attention system, shows decreasing metabolism that correlates with declining executive function despite otherwise intact cognition. Here, the relationships between ACC metabolism, age, executive function, and memory were examined using the large, public, ADNI database. Earlier findings were confirmed. In addition, ACC metabolism was found a mediator between age and executive function. In contrast, no correlation arose between memory and age or between memory and ACC metabolism. No correlations surfaced when using the metabolism of the right primary motor cortex as a control region. Development of preventive medicine and novel treatments will require elucidation of aging-related ACC pathophysiology requiring further research.