Anatomical correlates of executive function decline in normal aging.

描述（由申请人提供）：尽管许多认知功能随着年龄的增长而改善（即语言知识），但所谓的额叶功能的表现下降是有充分证据的（Kausler, 1991; Salthouse, 1985; Hasher & Zacks, 1988; West, 1996）。与这些行为退化的发现相一致，功能性神经影像学研究通常报告了青壮年和中年人执行功能相关网络中神经元活动的大小和分布的变化。这些与年龄相关的执行功能变化的来源仍然难以捉摸。神经元活动和行为变化的两种潜在机制是大脑的结构和生理变化，它们不同地影响前额叶皮层（PFC）内的灰质和白质（Haug & Eggers, 1991; Resnick et al., 2003; Tisserand et al., 2002）。然而，除了不断报道与年龄相关的PFC灰质和白质体积下降以及白质完整性下降外，对这些解剖变化的认知相关文献的回顾并没有描绘出明确的关系。最近的研究强调了白质完整性在认知老化中的作用，但没有区分短段和长段白质纤维。该研究的总体目标是进一步明确阐明正常衰老中结构和功能之间关系的具体机制。为了做到这一点，我们的目标是(i)描述执行功能之间的关系，通过行为评估和功能性磁共振成像，（ii）描述神经元激活与灰质和白质体积完整性之间的关系，最后（iii）描述与正常衰老中认知功能相关的小白质纤维束与大纤维束相比的不同作用。为了做到这一点，我们将收集一组年轻的（n=15，年龄在20-30岁之间），中老年（n=25，年龄在50-60岁之间）和超健康的老年人（n=45，年龄在70-80岁之间）在执行口头工作记忆任务时的功能磁共振成像（fMRI）数据。在功能性任务中将使用四个难度级别，以便每组受试者能够在一个范式（最低记忆负荷）中获得高精度，并在另一个范式（最高负荷）中获得机会表现。除了功能数据外，还将收集结构MRI和弥散张量成像（DTI）数据，这将允许分析PFC中的灰质密度和计算额叶中的白质完整性（分数各向异性，FA）。我们的具体目标是表征执行功能，测量行为（准确性，延迟）和神经元激活（信号变化，激活体积）之间的关系，以及表征执行功能任务执行过程中神经元反应（信号变化，体积）与pfc灰质和白质完整性（体积）之间的关系。更好地了解这些机制对于确定认知衰老的基本机制至关重要，从而在干预研究中制定更有针对性的结果措施，并对伴随脑血管危险因素的结构变化进行调查。在本提案中，我们提出了试点数据，显示了如何在一个充分理解的执行功能范式中使用多种神经成像模式来缩小这个结构-功能问题。此外，我们建议区分短和长白质纤维，以更好地解决白质完整性和认知衰老之间的关系。

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.