权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

用左乙拉西坦治疗阿尔茨海默病的过度兴奋，以改善大脑功能和认知

基本信息

批准号：
10534731
负责人：
Mouhsin Shafi
金额：
$ 59.87万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534731
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Animal Model Anticonvulsants Antiepileptic Agents Binding 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 Hour Human Impaired cognition Implanted Electrodes Incidence Intervention Intravenous Levetiracetam Magnetic Resonance Imaging Measures Medial Modification Monitor Motor Neurobehavioral Manifestations Neuronavigation Neuropsychological Tests Neuropsychology Participant Patients Perfusion Persons Placebo Control Placebos Play Prospective, cohort study Proteins Randomized Rest Role Scalp structure Seizures Synaptic Vesicles Techniques Testing Therapeutic Transcranial magnetic stimulation United States Work amnestic mild cognitive impairment arterial spin labeling biomarker identification cognitive function cognitive performance cognitive task cost density disability epileptiform human subject improved memory process mouse model novel pharmacologic response

项目摘要

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