Treating hyperexcitability in Alzheimer's disease with levetiracetam to improve brain function and cognition

摘要 阿尔茨海默病（AD）是痴呆症的主要常见原因，是老年人残疾的主要原因。 这是美国最昂贵的疾病，每年的总费用超过2000亿美元。 不幸的是，治疗选择是有限的，新的治疗目标是必要的。最近在两个领域的工作 人类患者和动物模型已经表明，皮质网络过度兴奋性是一种基本的 疾病病理生理学的一个要素，导致癫痫样活动的发展，并在 疾病进展。据推测，抗癫痫治疗皮质过度兴奋 药物如左乙拉西坦（LEV）可改善AD的认知功能并减缓疾病进展。 对患者的初步研究表明，LEV改善了大脑网络功能的某些指标。在 在这项研究中，我们提出了一项随机、安慰剂对照的交叉研究，评估4周的 低剂量与高剂量LEV在改善大脑皮质过度兴奋性、脑网络功能和认知方面的差异 轻度AD患者。AD受试者将接受癫痫样异常的基线评价， 24小时视频脑电图监测，随后进行256通道密集阵列脑电图。前后各 药物干预，我们将系统地评估大脑网络功能和皮质兴奋性， 采集静息态EEG、结构MRI、动脉自旋标记灌注MRI、静息态功能 连接BOLD MRI，神经导航经颅磁刺激（TMS）结合 同步EEG和EMG，以及认知功能与神经心理测试组合。以限定 皮质兴奋性（TMS测量，ASL灌注）和脑网络功能（EEG功率）异常 和相干性、默认模式MRI连接性、TMS皮质可塑性）。类似措施将在 在人口统计学相似的健康受试者中收集。我们将确定基线之间的关系 皮质兴奋性、脑网络功能和认知能力异常; LEV的影响 这些措施的每一个治疗;并确定预测LEV剂量反应。我们亦会研究 LEV的认知效应是否与皮质过度兴奋的正常化有关，并确定 用于其他研究的改善认知的生物标志物。最后，我们将确定是否有效， LEV的最佳剂量与癫痫样异常的存在有关。这项研究将提供关键 作为AD患者新的疾病靶点治疗皮质过度兴奋的证据，并提供 将LEV纳入AD治疗设备的有力机制支持。

ABSTRACT Alzheimer's Disease (AD) is the leading common cause of dementia, the leading cause of disability in older persons, and the most expensive disease in the United States, with total costs over $200 billion per year. Unfortunately, therapeutic options are limited, and new treatment targets are necessary. Recent work in both human patients and animal models has suggested that cortical network hyperexcitability is a fundamental element of disease pathophysiology, leads to the development of epileptiform activity, and plays a key role in disease progression. It has been hypothesized that treatment of cortical hyperexcitability with anti-seizure medications such as levetiracetam (LEV) may improve cognitive function and slow disease progression in AD. Preliminary studies in patients have shown that LEV improves some measures of brain network function. In this study, we propose a randomized, placebo-controlled crossover study evaluating the effects of 4 weeks of low-dose versus high-dose LEV in improving cortical hyperexcitability, brain network function and cognition in patients with mild AD. Participants with AD will undergo baseline evaluation for epileptiform abnormalities with a 24-hour video-EEG monitoring followed by a 256-channel dense array EEG. Before and after each pharmacologic intervention, we will systematically evaluate brain network function and cortical excitability by collecting resting-state EEG, structural MRI, Arterial spin-label perfusion MRI, resting-state functional connectivity BOLD MRI, neuronavigated Transcranial Magnetic Stimulation (TMS) in combination with simultaneous EEG and EMG, and cognitive function with the Neuropsychological Test Battery. To define abnormalities in cortical excitability (TMS measures, ASL perfusion) and brain network function (EEG power and coherence, default-mode MRI connectivity, TMS cortical plasticity) in AD. Similar measures will be collected in demographically similar healthy subjects. We will determine the relationship between baseline abnormalities in cortical excitability, brain network function, and cognitive performance; the effects of LEV therapy on each of these measures; and identify predictors of the LEV dose-response. We will also examine whether the cognitive effects of LEV are related to normalization of cortical hyperexcitability, and identify biomarkers of improved cognition for use in other studies. Finally, we will determine whether the efficacy and optimum dose of LEV are related to the presence of epileptiform abnormalities. This study will thus provide key evidence for treatment of cortical hyperexcitability as a novel disease target in patients with AD, and provide compelling mechanistic support for inclusion of LEV in the treatment armamentarium for AD.