Intact cognitive function is the best predictor of quality of life and functional ability in older age. Thus, preventing cognitive decline is central to any effort to guarantee successful aging for our growing population of elderly. The purpose of the work discussed in this outlook paper is to bridge knowledge from basic and clinical neuroscience with the aim of improving how we understand, predict, and treat age- and disease-related cognitive impairment. Over the past six years, our research team has focused on intermediate neuroimaging phenotypes of brain vulnerability in midlife and isolating the underlying physiological mechanisms. The ultimate goal of this work was to pave the road for the development of early interventions to enhance cognitive function and preserve brain integrity throughout the lifespan. 1. Introduction The most rapidly rising threat to brain health in US adults is the clustering of obesity, high blood pressure, elevated fasting glucose, and abnormal lipid metabolism in a single individual, a condition known as metabolic syndrome. A staggering 34–45% of US adults currently fulfill criteria for metabolic syndrome [1]. These numbers are alarming as metabolic syndrome is associated not only with increased risk for cardiovascular disease and diabetes [2], but also with current cognitive dysfunction and risk for future cognitive decline, over and above the detrimental effects of its components [3–10]. While we have some information about each of the disrupted peripheral physiological mechanisms in turn, very little is known about the central mechanisms that connect metabolic syndrome to brain health and cognition. The goal of our work over the past six years has been to explore the underlying neural mechanisms of midlife brain vulnerability related to peripheral vascular and metabolic disturbances, before clinically significant and permanent cognitive dysfunction has developed. Understanding the preclinical stages of disease has the enormous advantage of presenting opportunities for early intervention, a task with much higher prospect of success than attempting to restore lost function later in life. Early identification of brain vulnerability is crucial; yet it presents a significant challenge due to the low sensitivity of clinical paper-and-pencil measures of cognitive impairment and lack of norms for tests with higher ceiling performance values. Our team has endeavored to solve this problem through combining sophisticated behavioral analyses with modern neuroimaging techniques. 2. Early Markers of Brain Vulnerability As noted
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