Brain Plasticity Measures in MCI

 描述（由申请人提供）：本提案的目标是促进我们对轻度认知障碍（MCI）的神经生物学底物的理解，MCI可能导致进行性年龄相关性痴呆，如阿尔茨海默病（AD），并开发一种可靠的检测方法用于其早期检测和纵向评估。 继续发展为AD的MCI患者显示出大脑皮层中淀粉样蛋白β（Aβ）积累增加的证据。我们假设Aβ毒性直接损害可塑性机制，这将通过非侵入性神经生理学方法证明，并解释认知功能障碍。 我们将评估MCI个体的皮质可塑性机制，并将其与现有的完整健康对照组进行比较。正电子发射断层扫描（PET）成像将用于将MCI个体分类为Aβ+和Aβ-。皮质可塑性的机制将通过评估由特定的重复经颅磁刺激（TMS）方案（称为θ波群刺激（TBS））诱导的皮质反应性的调制来探索。在TBS之前和之后由单脉冲TMS诱导的运动反应的比较提供了人类大脑可塑性的非侵入性测量。认知测试和任务的学习和记忆将被用来证明行为的相关性，这种措施的可塑性。我们的试点研究证明了我们的方法的可行性，并为我们的假设提供了支持性证据。 我们预计，这项研究的数据将解决一个重要的需求，快速，无创，可靠，可重复和安全的方法，直接评估MCI的神经可塑性机制的疗效。如果成功，基于TMS的皮质反应性和可塑性测量将提供MCI病理生理学变化的客观评估，并可作为评估MCI认知功能障碍的可翻译生物标志物，为有效治疗的开发提供信息，并在未来的临床试验中评估治疗反应。

 DESCRIPTION (provided by applicant): The goal of this proposal is to advance our understanding of the neurobiological substrates of mild cognitive impairment (MCI) that may lead to progressive age-related dementias such as Alzheimer's disease (AD), and develop a reliable assay for their early detection and longitudinal assessment. MCI patients who go on to develop AD show evidence of increasing accumulation of amyloid beta (Aβ) in the brain cortex. We hypothesize that Aβ toxicity directly impairs mechanisms of plasticity that will be demonstrable by a non-invasive neurophysiologic method and account for cognitive dysfunction. We will evaluate mechanisms of cortical plasticity in individuals with MCI and compare them to an existing cohort of intact healthy controls. Positron emission tomography (PET) imaging will be used to classify MCI individuals as Aβ+ and Aβ-. Mechanisms of cortical plasticity will be explored by assessing the modulation of cortical reactivity induced by a specific repetitive transcranial magnetic stimulation (TMS) protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS provides a noninvasive measure of brain plasticity in humans. Cognitive testing and tasks of learning and memory will be used to demonstrate the behavioral correlates of this measure of plasticity. Our pilot studies demonstrate the feasibility of our approach and provide supportive evidence for our hypothesis. We anticipate that data from this study will address an important need for a rapid, noninvasive, reliable, repeatable, and safe method to directly assess the efficacy of neuroplastic mechanisms in MCI. If successful, TMS-based measures of cortical reactivity and plasticity will provide an objective assessment of pathophysiological changes in MCI and may serve as a translatable biomarker to assess cognitive dysfunction in MCI, inform the development of effective therapies and evaluate treatment response in future clinical trials.