A FMRI PILOT STUDY OF ESTROGEN AND CHOLINERGIC SYSTEM IN POST-MENOPAUSE

绝经后雌激素和胆碱能系统的 FMRI 试点研究

• 批准号: 8166967
• 负责人: PAUL A. NEWHOUSE
• 金额: $ 4.54万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166967
• 关键词: Aging; Alzheimer' s Disease; Anti-Cholinergics; Brain; Brain imaging; Cerebrum; Cholinergic Agents; Cholinergic Antagonists; Cholinergic Receptors; Clinical; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Data; Disease; Estradiol; Estrogen Replacements; Estrogens; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Goals; Gonadal Steroid Hormones; Grant; Human; Image; Impaired cognition; Institution; Investigation; Knowledge; Laboratories; Lesion; Measures; Mediating; Menopause; Modeling; Muscarinics; Neurodegenerative Disorders; Pattern; Performance; Pharmaceutical Preparations; Pilot Projects; Postmenopause; Process; Research; Research Personnel; Resources; Risk; Role; Sensory Receptors; Short-Term Memory; Simulate; Source; Structure; System; Techniques; Testing; United States National Institutes of Health; Woman; age effect; age related; blood oxygen level dependent; cholinergic; cognitive function; neurochemistry; neuron loss; normal aging; older women; postsynaptic; presynaptic; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goals of this pilot project are to demonstrate that (1) we can validate and replicate our preliminary data (obtained at the Brain Imaging Laboratory at Dartmouth-Hitchcock) showing specific cognitive and brain activation effects of anti-muscarinic and anti-nicotinic drugs in older women, utilizing our new brain fMRI imaging system here at UVM/FAHC; 2) examine preliminarily whether estradiol (E2) can blunt the effects of cholinergic antagonist drugs on brain activation measured by fMRI. There is contradictory evidence that the gonadal steroid E2 may slow or prevent cognitive decline, enhance cognitive functioning, and may lower the risk of developing Alzheimer's disease. The overarching question we propose to investigate is whether these effects might be mediated in part through interactions with CNS cholinergic systems. We have preliminary evidence that administration of E2 can significantly blunt the cognitive impairing-effects of cholinergic antagonists in postmenopausal women (PMW). In addition, we have recently begun to investigate the effects of anti-cholinergic drugs on brain activation during working memory performance utilizing fMRI. An important aspect of furthering our understanding of the actions of E2 on CNS function is to examine the cerebral circuitry that appears to be influenced by the cholinergic antagonist drugs and the presence or absence of E2. If E2 influences the integrity, stability, or activity of cholinergic systems that are important for cognitive function, then such effects may be detectable by functional imaging strategies. Direct imaging of cerebral function after neurochemical challenge will make a vital connection between knowledge of cognitive performance changes associated with aging and the neuroanatomical structures that underlie these age-related changes. As the effects of E2 on CNS are unlikely to be uniform and perhaps related to particular cognitive domains, knowledge of neuroanatomical circuits and their analysis becomes vital to understanding the clinical implications and potential usefulness of estrogen for women after menopause. The basic model that we will use is to test the effects of gonadal steroids on a neurochemical "lesion" model utilizing cholinergic antagonist drugs. This approach simulates the effects of age- or disease-related neuroreceptor and/or neuronal loss by temporarily blocking pre- and postsynaptic muscarinic and nicotinic cholinergic receptors. This model reliably produces mild and quantifiable but rapidly reversible cognitive impairment and has proved valuable in understanding the role of the cholinergic system and its loss on human cognitive functioning. We have utilized this model successfully to establish the effects of the loss of muscarinic and nicotinic cholinergic receptors in aging and neurodegenerative disorders. We have now extended this model to examine the effects of estrogen replacement on cholinergic function and cognitive performance in normal aging. While there have been investigations of the effects of estrogen on cognitive processes using fMRI, we believe this will be the first investigation directly testing whether E2 can, through effects on central cholinergic systems, alter brain activity patterns associated with cognitive processes as measured by Blood Oxygen Level Dependent (BOLD) fMRI techniques.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这个试点项目的目标是证明（1）我们可以验证和复制我们的初步数据（在达特茅斯-希区柯克的脑成像实验室获得）显示了抗毒蕈碱和抗烟碱药物对老年妇女的特定认知和脑激活作用，利用我们在UVM/FAHC的新脑功能磁共振成像系统; 2）初步研究雌二醇（E2）是否能减弱胆碱能拮抗剂对fMRI脑激活的影响。 有矛盾的证据表明，性腺类固醇E2可以减缓或防止认知能力下降，增强认知功能，并可能降低患阿尔茨海默病的风险。我们建议调查的首要问题是，这些影响是否可能介导的部分通过与中枢神经系统胆碱能系统的相互作用。我们有初步的证据表明，管理的E2可以显着钝化认知功能障碍的影响，胆碱能拮抗剂在绝经后妇女（PMW）。此外，我们最近开始研究抗胆碱能药物对工作记忆过程中大脑激活的影响。 进一步了解E2对中枢神经系统功能作用的一个重要方面是检查似乎受到胆碱能拮抗剂药物以及E2存在或不存在影响的大脑回路。 如果E2影响对认知功能重要的胆碱能系统的完整性、稳定性或活性，那么这种影响可以通过功能成像策略来检测。 神经化学物质刺激后的脑功能直接成像将在与衰老相关的认知性能变化的知识与这些年龄相关变化的神经解剖结构之间建立重要联系。 由于E2对CNS的影响不太可能是一致的，并且可能与特定的认知领域有关，因此神经解剖学回路及其分析的知识对于了解绝经后女性雌激素的临床意义和潜在用途至关重要。 我们将使用的基本模型是利用胆碱能拮抗剂药物测试性腺类固醇对神经化学“损伤”模型的影响。这种方法通过暂时阻断突触前和突触后毒蕈碱和烟碱胆碱能受体来模拟年龄或疾病相关的神经受体和/或神经元损失的影响。该模型可靠地产生轻度和可量化但快速可逆的认知障碍，并已被证明在理解胆碱能系统的作用及其对人类认知功能的丧失方面很有价值。我们已经成功地利用该模型建立了衰老和神经退行性疾病中毒蕈碱和烟碱胆碱能受体丢失的影响。我们现在已经扩展了这个模型，以研究雌激素替代对正常衰老中胆碱能功能和认知能力的影响。虽然已经有研究雌激素对认知过程的影响，使用功能磁共振成像，我们相信这将是第一个调查直接测试是否E2可以，通过对中枢胆碱能系统的影响，改变大脑活动模式与认知过程中测量的血氧水平依赖（BOLD）功能磁共振成像技术。