Investigation of silent mesial temporal lobe hyperexcitability in Alzheimer's disease

项目摘要/摘要 在过去的15年里，没有新的治疗方法被批准用于阿尔茨海默病(AD)。它是 据估计，到2050年，AD将影响1400万美国人，并给国家造成超过1万亿美元的损失 每年一次。需要一个新的视角来看待AD，以发现驱动认知的新的疾病机制 AD的下降，并为更成功的药物开发确定新的治疗靶点。这项初步研究将 调查最近在两名AD患者中发现的一种新的脑电异常 使用卵圆孔电极的颅内记录(FOES)。敌人是一种安全和微创的手段 为了从内侧颞叶(MTL)获得高保真的电活动记录，MTL是第一个大脑 受AD病理影响的区域。这些AD患者的FOE记录显示丰富的MTL癫痫样 睡眠时出现放电和频繁的癫痫发作。这种癫痫样活动的绝大多数是 无声，无明显临床症状，头皮EEG无明显体征。是否 沉默的MTL癫痫样活动在AD的早期阶段很常见，以及这种活动是否有助于 AD患者的记忆障碍尚不清楚，因为AD患者几乎从未接受过颅内记录 需要检测到这一活动。这项提议的目标是进一步调查沉默的MTL的作用 阿尔茨海默病早期的癫痫样活动。最重要的假设是存在AD的子集 在患者中，沉默的MTL癫痫样活动是认知功能下降的有效和可修改的贡献者。如果 诚然，这种活动的减少可能包括针对症状缓解或疾病的新的治疗目标 AD中的修改。这项研究将在马萨诸塞州波士顿综合医院进行， 贝勒医疗中心/圣卢克医院(德克萨斯州休斯顿)。8名遗忘症轻度认知受试者 由于AD造成的损害或轻度痴呆症将被招募接受敌人的插入，随后3天 敌人和头皮脑电的连续记录。将对录音进行分析，以确定任何静默MTL 癫痫样异常的存在，并将这些发现与临床和头皮脑电特征相关联。这个 这项研究的具体目的是：1)确定和描述临床上无症状的MTL活动的谱 在AD的早期阶段发生；2)展示招募和记录AD参与者的可行性 并确定这些记录的持续时间和产量之间的关系；以及3)评估 临床和头皮EEG特征常见于无MTL癫痫样活动的AD患者。从长远来看， 这项研究有可能揭示一种新的、潜在的可治疗的神经生理学机制 在AD的早期阶段，哪种记忆功能会被破坏。这里获得的数据将被用来指导 使用AD患者的颅内记录进行更大规模研究的设计，而且将有助于 无创检测AD患者静止性MTL癫痫样活动的研究进展 用于颅内电极。

PROJECT SUMMARY / ABSTRACT There have been no new treatments approved for Alzheimer’s disease (AD) over the past 15 years. It is estimated that by the year 2050, AD will affect 14 million Americans and cost the nation over $1 trillion annually. A fresh perspective on AD is needed, to uncover new disease mechanisms that drive cognitive decline in AD, and to identify new treatment targets for more successful drug development. This pilot study will investigate a novel brain electrical abnormality that was recently discovered in two AD patients who underwent intracranial recordings with foramen ovale electrodes (FOEs). FOEs are a safe and minimally invasive means to obtain high fidelity recordings of electrical activity from the mesial temporal lobes (mTL), one of the first brain regions affected by AD pathology. FOE recordings from these AD patients revealed abundant mTL epileptiform discharges and frequent seizures occurring during sleep. The vast majority of this epileptiform activity was silent, occurring without any overt clinical symptoms and without any visible signs on scalp EEG. Whether silent mTL epileptiform activity is common in early stages of AD, and whether this activity contributes to memory impairment in AD is unknown, because AD patients almost never undergo the intracranial recordings needed to detect this activity. The goal of this proposal is to further investigate the role of silent mTL epileptiform activity in early stages of AD. The over-arching hypothesis is that there exists a subset of AD patients in whom silent mTL epileptiform activity is a potent and modifiable contributor to cognitive decline. If true, reduction of this activity could comprise a new treatment target for symptomatic relief or disease modification in AD. This study will be performed at the Massachusetts General Hospital (Boston, MA) and Baylor Medical Center / St. Luke’s Hospital (Houston, TX). Eight participants with amnestic mild cognitive impairment or mild dementia due to AD will be recruited to undergo insertion of FOEs, followed by 3 days of continuous recordings with FOEs and scalp EEG. Recordings will be analyzed to characterize any silent mTL epileptiform abnormalities present and to correlate these findings with clinical and scalp EEG features. The specific aims of this study are: 1) Identify and characterize the spectrum of clinically silent mTL activity that occurs in early stages of AD; 2) Demonstrate the feasibility of recruiting and recording AD participants with FOEs, and determine the relationship between the duration and yield of these recordings; and 3) Assess clinical and scalp EEG features common to AD patients with silent mTL epileptiform activity. In the long term, this research has the potential to reveal a novel and potentially treatable neurophysiologic mechanism by which memory function becomes disrupted in early stages of AD. The data obtained here will be used to guide the design of larger studies using intracranial recordings in AD patients, and moreover, will be instrumental for the development of non-invasive approaches to detect silent mTL epileptiform activity in AD, without the need for intracranial electrodes.