America is aging; baby boomers are now seniors. Staying mentally astute is essential not only for economic survival but also for quality of life. Yet, the pathophysiology of cognitive aging remains ill-defined, a gap preventing development of novel diagnostic, therapeutic, or preventive strategies. This laboratory has identified the anterior cingulate cortex (ACC), the major component of the anterior attention system, as the principal region showing metabolic decline from young to late adulthood. This decline correlates with declining executive functions such as fluency. The ACC mediates statistically the relationship between increasing age and decreasing verbal fluency. Amyloid-free, cognitively intact elders show robust executive but lesser mnemonic deficits. This project will test the hypothesis that ACC dysfunction in the elderly free of preclinical Alzheimer’s disease (AD) is associated with redox dysfunction related to aging and severe stress, the latter as seen in PTSD. Oxidative stress will be measured with 7 T MRI/MRS using the NAD+/NADH ratio, a method developed here recently. Two factors will include: AGE (younger vs. older) and STRESS (healthy vs. chronic active PTSD). Neuropsychological testing and plasma phospho-tau181 [or 217] will confirm absence of preclinical AD as well as revisit the unusual observation: absence of aging-related memory impairment (Logical Memory I & II) —typically viewed as the sine qua non for aging. The anticipated outcomes are 1) the ACC undergoes redox stress related to aging and possibly emotional stress; 2) increasing ACC redox stress will correlate with declining ACC metabolism in the absence of preclinical AD; both will correlate more with declining executive and less with memory dysfunction; 3) ACC metabolism or redox status may serve as a biomarker for cognitive aging in the absence of neurodegeneration; and 4) scientific premise and infrastructure will poise the field to test the potential of antioxidant therapies in preventing or delaying cognitive aging. If successful, aging American would remain mentally sharp for more years. Since the ACC also participates in cognitive reserve, secondary prevention would delay symptoms even if neurodegeneration occurs.

Cognitive aging is the decline in performance with age seen in otherwise healthy people free of even of asymptomatic degenerative brain disease. The anterior cingulate cortex (ACC) appears to be the principal site of hypometabolism in cognitive aging; this decline correlates with declining executive function. A hypothesis posits ACC dysfunction is related to oxidative stress that is seen universally in models of aging. Furthermore, emotional stress can contribute to oxidation thereby aggravating ACC hypometabolism. This project tests whether aging and emotional stress, the latter as indexed by PTSD, is associated with redox stress in the ACC. If demonstrated and quantified, use of antioxidants such as nicotinamide riboside or N-acetyl cysteine will be motivated to treat and prevent this aging-related cognitive decline.