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.

Public Health Relevance

Studies in both human subjects and animal models suggest that Alzheimer's Disease (AD) is characterized by an abnormal cortical hyperexcitability that can lead to development of epileptic activity, and plays a key role in cognitive symptoms and disease progression. In this study, we propose to systematically investigate the effects of levetiracetam in subjects with mild AD on neuropsychological, electroencephalographic, MRI and Transcranial Magnetic Stimulation measures of brain function and cognition. This study will thus provide key information about the utility and indications for inclusion of levetiracetam in the therapeutic armamentarium for AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ryan, Laurie M
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Beth Israel Deaconess Medical Center
United States
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