Anatomical correlates of executive function decline in normal aging.

DESCRIPTION (provided by applicant): Although many cognitive functions improve with advanced age (i.e., linguistic knowledge), declines in performance on so-called frontal lobe functions is well-documented (Kausler, 1991; Salthouse, 1985; Hasher & Zacks, 1988; West, 1996). In concert with these findings of behavioral degradations, functional neuroimaging studies commonly report changes in the magnitude and distribution of neuronal activity across networks implicated in executive functions in young and middle aged adults. The source of these age-related changes in executive function remains elusive. Two potential mechanisms for changes in neuronal activity and behavior are structural and physiological changes in the cerebrum that differentially affect the gray and white matter within the prefrontal cortex (PFC) (Haug & Eggers, 1991; Resnick et al., 2003; Tisserand et al., 2002). However, other than consistently reporting age-related declines in PFC gray and white matter volume and a decrease in white matter integrity, a review of the literature on the cognitive correlates of these anatomical changes does not delineate a clear relationship. Recent work highlights the role of white matter integrity for cognitive aging but does not differentiate between short and long range white matter fibers. The overall objective of the proposed investigation is to further define the specific mechanisms that elucidate the relationship between structure and function in normal aging. To do this we aim to (i) characterize the relationship between executive function, assessed behaviorally and with functional magnetic resonance imaging, (ii) characterize the relationship between neuronal activation and integrity of both gray and white matter volume, and finally to (iii) characterize the differential roles of small white matter fiber tracts, compared to large fiber tracts, as they relate to cognitive function in normal aging. To do this we will collect functional Magnetic Resonance Imaging (fMRI) data during performance of a verbal working memory task in a group of younger (n=15, aged 20-30), late-middle aged (n=25, aged 50-60) and super-healthy older (n=45, aged 70-80) community-dwelling adults. Four levels of difficulty will be used in the functional task so that each group of subjects will be able to attain high accuracy in one paradigm (lowest memory load) and chance performance in another paradigm (highest load). In addition to the functional data, structural MRI and diffusion tensor imaging (DTI) data will be collected and that will allow for analysis of gray matter density in PFC and calculation of white matter integrity (fractional anisotropy, FA) in the frontal lobes. Our specific aims are to characterize the relationship between executive function, measured behaviorally (accuracy, latency), and neuronal activation (signal change, volume of activation) and to characterize the relationship between neuronal response during performance of an executive function task (signal change, volume) and integrity of gray and white matter (volume) in PFC. The mechanisms that underlie the structure-function relationship in aging are poorly understood. A better understanding of these mechanisms is central to identifying basic mechanisms of cognitive aging in order to develop more targeted outcome measures in intervention studies and for investigation into the structural changes that accompany cerebrovascular risk factors. In this proposal, we present pilot data showing how the use of multiple neuroimaging modalities in a well-understood executive function paradigm narrows this structure-function question. Additionally, we propose to differentiate short from long white matter fibers to better address the relationship between white matter integrity and cognitive aging.

DESCRIPTION (provided by applicant): Although many cognitive functions improve with advanced age (i.e., linguistic knowledge), declines in performance on so-called frontal lobe functions is well-documented (Kausler, 1991; Salthouse, 1985; Hasher & Zacks, 1988; West, 1996). In concert with these findings of behavioral degradations, functional neuroimaging studies commonly report changes in the magnitude and distribution of neuronal activity across networks implicated in executive functions in young and middle aged adults. The source of these age-related changes in executive function remains elusive. Two potential mechanisms for changes in neuronal activity and behavior are structural and physiological changes in the cerebrum that differentially affect the gray and white matter within the prefrontal cortex (PFC) (Haug & Eggers, 1991; Resnick et al., 2003; Tisserand et al., 2002). However, other than consistently reporting age-related declines in PFC gray and white matter volume and a decrease in white matter integrity, a review of the literature on the cognitive correlates of these anatomical changes does not delineate a clear relationship. Recent work highlights the role of white matter integrity for cognitive aging but does not differentiate between short and long range white matter fibers. The overall objective of the proposed investigation is to further define the specific mechanisms that elucidate the relationship between structure and function in normal aging. To do this we aim to (i) characterize the relationship between executive function, assessed behaviorally and with functional magnetic resonance imaging, (ii) characterize the relationship between neuronal activation and integrity of both gray and white matter volume, and finally to (iii) characterize the differential roles of small white matter fiber tracts, compared to large fiber tracts, as they relate to cognitive function in normal aging. To do this we will collect functional Magnetic Resonance Imaging (fMRI) data during performance of a verbal working memory task in a group of younger (n=15, aged 20-30), late-middle aged (n=25, aged 50-60) and super-healthy older (n=45, aged 70-80) community-dwelling adults. Four levels of difficulty will be used in the functional task so that each group of subjects will be able to attain high accuracy in one paradigm (lowest memory load) and chance performance in another paradigm (highest load). In addition to the functional data, structural MRI and diffusion tensor imaging (DTI) data will be collected and that will allow for analysis of gray matter density in PFC and calculation of white matter integrity (fractional anisotropy, FA) in the frontal lobes. Our specific aims are to characterize the relationship between executive function, measured behaviorally (accuracy, latency), and neuronal activation (signal change, volume of activation) and to characterize the relationship between neuronal response during performance of an executive function task (signal change, volume) and integrity of gray and white matter (volume) in PFC. The mechanisms that underlie the structure-function relationship in aging are poorly understood. A better understanding of these mechanisms is central to identifying basic mechanisms of cognitive aging in order to develop more targeted outcome measures in intervention studies and for investigation into the structural changes that accompany cerebrovascular risk factors. In this proposal, we present pilot data showing how the use of multiple neuroimaging modalities in a well-understood executive function paradigm narrows this structure-function question. Additionally, we propose to differentiate short from long white matter fibers to better address the relationship between white matter integrity and cognitive aging.