One in five American adolescents are obese, and many of these patients exhibit some level of insulin resistance (IR). IR is associated with cerebrovascular disease, reduced memory, attention, and cognition, but how IR contributes to these in the course of adolescent brain development is unclear. The goal of this proposal is to investigate the extent and mechanisms by which IR drives reductions in neurocognitive function and cerebral blood flow (CBF) in adolescents at elevated risk of poor brain and cerebrovascular health. We are testing the overall hypothesis that neurocognitive decline is linked to severity of IR, as are reductions in brain perfusion, due to dysfunctional insulin signaling. We propose to study acute CBF control in healthy adolescents (12-18 years) across a range of IR (diabetes excluded) in collaboration with expert childhood neuropsychologists who lead a comprehensive testing protocol. Next, two complementary MRI methods (ASL and Phase Contrast), along with a physiologic stressor to challenge CBF, will be used to test whether the impact of IR on brain macrovascular CBF and microvascular perfusion is regionally specific, with more negative effects in temporal and parietal lobes. These lobes are some of the initial brain areas to change, and are involved in attention, memory, learning, and cognition. Finally, this study tests whether the degree of cognitive decline is linked to the CBF stress response and to severity of IR, and to what extent brain hypoperfusion mediates the IR-driven lower cognitive function. This study will provide the first comprehensive look at IR in adolescent brains, by utilizing extensive neuropsychological testing and state-of-the-art MR imaging, and drawing on interdisciplinary collaborations between developmental neuropsychologists, vascular physiologists, and pediatric endocrinologists. These studies are designed to uncover fundamental relationships between IR, neurocognitive function, and CBF in these blossoming adolescent brains. Exciting preliminary data support the aims?particularly uncovered by a physiologic insulin surge?signifying these findings will serve as a foundation for prospective, mechanistic studies to reduce the burden of IR and improve brain and cognitive health in this clinically important population.
Devastating diseases like obesity, prediabetes, and diabetes all share a degree of insulin resistance (IR). IR increases the risk of cardiovascular (e.g. heart disease), cerebrovascular (e.g. stroke), and cognitive diseases (e.g. dementia). As severity of IR increases (worsens), memory and cognition decline, as does blood vessel function. Consequently, IR can play a key role in long-term brain health since IR negatively affects brain function and blood supply. Experiencing IR may be particularly harmful to a rapidly developing adolescent brain. The goal of this application is to study adolescents (12-18 years) who are generally healthy?except for IR?and define when and where IR evokes the most destructive effects in brain function or blood vessel function. These findings will inform the scientific and clinical communities on how to limit brain dysfunction, in an effort to maximize brain health as these children mature.
