Treating hyperexcitability in AlzheimerâÂÂs disease with levetiracetam to improve brain function and cognition

用左乙拉西坦治疗阿尔茨海默氏病的过度兴奋，以改善大脑功能和认知

• 批准号: 10061519
• 负责人: Mouhsin Shafi
• 金额: $ 58.63万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10061519
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Americas; Animal Model; Antiepileptic Agents; Binding; Biological Markers; Brain; Cause of Death; Clinical Trials; Cognition; Cognition Disorders; Cognitive; Cross-Over Studies; Crossover Design; Dementia; Development; Disease; Disease Progression; Dose; Elderly; Electroencephalography; Elements; Epilepsy; Evaluation; Functional disorder; Hippocampus (Brain); Hour; Human; Impaired cognition; Implanted Electrodes; Incidence; Intervention; Intravenous; Lead; Levetiracetam; Magnetic Resonance Imaging; Measures; Medial; Modification; Monitor; Motor; Neurobehavioral Manifestations; Neuropsychological Tests; Neuropsychology; Participant; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Placebos; Play; Prospective cohort; Proteins; Randomized; Rest; Role; Scalp structure; Seizures; Spin Labels; Structure; Synaptic Vesicles; Techniques; Testing; Therapeutic; Transcranial magnetic stimulation; United States; Work; amnestic mild cognitive impairment; cognitive function; cognitive performance; cognitive task; cost; density; disability; human subject; improved; memory process; mouse model; novel; response

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.

摘要 阿尔茨海默病(AD)是导致痴呆的主要常见原因，也是导致老年人残疾的主要原因 这是美国最昂贵的疾病，每年的总成本超过2000亿美元。 不幸的是，治疗选择有限，需要新的治疗目标。最近在这两个领域的工作 人类患者和动物模型表明，皮质网络的过度兴奋性是一种基本的 疾病的病理生理学因素，导致癫痫样活动的发展，并在 疾病的发展。据推测，用抗癫痫药治疗皮质兴奋性亢进 左乙拉西坦(Lev)等药物可能会改善AD的认知功能，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一些指标。在……里面 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，以评估4周的 低剂量与大剂量利福平对大鼠皮层兴奋性、脑网络功能和认知功能的改善作用 轻度AD患者。患有AD的参与者将接受癫痫样异常的基线评估， 24小时视频脑电监测，随后进行256通道密集阵列脑电监测。在每个之前和之后 药物干预，我们将系统地评估大脑网络功能和皮质兴奋性，通过 采集静息脑电、结构磁共振、动脉自旋标记灌注磁共振、静息功能 连接性BOLD MRI、神经导航经颅磁刺激(TMS)与 同时进行脑电和肌电检查，并使用神经心理测试组合进行认知功能测试。要定义 皮质兴奋性(TMS测量、ASL灌注)和脑网络功能(EEG功率)异常 以及一致性、默认模式MRI连通性、TMS皮质可塑性)。类似的措施将是 收集在人口学上相似的健康受试者中。我们将确定基线之间的关系 大脑皮质兴奋性、脑网络功能和认知能力的异常；利福平的影响 对这些措施中的每一项进行治疗；并确定LEV剂量反应的预测因素。我们还将检查 LEV的认知效应是否与大脑皮层超兴奋性正常化有关 改善认知的生物标志物，用于其他研究。最后，我们将确定是否疗效和 LEV的最佳剂量与癫痫样异常的存在有关。因此，这项研究将提供关键 皮质过度兴奋性作为AD患者新的疾病靶点的治疗证据，并提供 令人信服的机械支持将LEV纳入阿尔茨海默病的治疗设施。