PROJECT SUMMARY This project is a renewal of an ongoing longitudinal study of brain structure, function, and cognition, the Dallas Area Longitudinal Lifespan Aging Study (D.A.L.L.A.S) with 3 waves of data spanning ~8 years. This proposal seeks renewal of this project for two additional waves (W4 and W5), as well as the addition of a new enrichment cohort. We hypothesize that a more granular approach to the study of cognitive neuroscience will advance understanding of the role of immune, inflammatory, metabolic, and energetic function mechanisms on individual differences in age-related change to brain structure, function and cognition, both across the lifespan and within-individuals across time. Thus, the study will be further enriched with the addition of select blood- based biomarkers of inflammation, cellular aging, and neuronal and glial integrity as well as neurometabolites using 1H magnetic resonance spectroscopy (MRS) at 7Tesla, and submillimeter measures of intracortical myelin content and cortical lamina imaging. A deeper understanding of the cellular activity that potentially influences brain structure and function, and ultimately cognition can be obtained by the multi-modal pairing of these neuroimaging techniques. MR spectra can act as proxies for variables otherwise difficult to measure, but paramount to the aging process, such as energy expenditure, neuroinflammation, and neural inhibition and excitation. The general goal of the renewal of this longitudinal project is to untangle the independent, interactive, and synergistic relationships among micro-meso-macro scale aging. The specific aims focus on testing biomarker-structure-function-cognition associations across the adult lifespan and within-individual across the waves utilizing sophisticated multivariate latent modeling techniques which allow for simultaneous estimation of all variables. Using within-person change information obtained from the previous project period to guide MRS regions of interest is a novel means of beginning to understand/identify what cellular/molecular process might underlie more established brain changes (e.g., regions that weaken in their ability to up- modulate activation to difficulty over time at the individual level). For example, those who maintain BOLD modulation to difficulty over the previous 8 years may display a healthier metabolic signature, such as lower inhibitory or lower excitation indices, lower markers of inflammation or greater neuroantioxidant concentrations. Only the pairing of longitudinal design with multi-modal imaging can address these questions. Studies assessing individual differences in change and data sets with greater than 3 time points are rare and sorely needed to increase reliability, decrease noise and to take full advantage of advanced nonlinear statistical methods. The proposed renewal project will yield 14-year change data across 5 waves and stands to add important, innovative, and novel information to the cellular, molecular, and metabolic factors that underlie relatively healthy or pathological aging trajectories, such as Alzheimer’s disease.

PROJECT NARRATIVE Better understanding of the mechanisms that underlie normal aging or a more pathological aging trajectory is an important public health goal. This proposal seeks to continue to follow a cohort of individuals aged across the adult lifespan for 14 years to investigate the cellular and molecular driven influences of within-person change in neurometabolic, cognitive, and brain aging. This project also investigates beta amyloid deposition and genetic risks for developing Alzheimer’s Disease.