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

项目总结/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）。是 据估计，到2050年，AD将影响1400万美国人，使国家损失超过1万亿美元 每年。需要对AD有一个新的视角，以揭示新的疾病机制， 减少AD，并确定新的治疗靶点，以获得更成功的药物开发。这项试点研究将 研究一种新的脑电异常，最近发现在两个AD患者， 使用卵圆孔电极（FOE）进行颅内记录。FOE是一种安全且微创的方法 为了获得来自内侧颞叶（mTL）的电活动的高保真记录， 受AD病理影响的区域。这些AD患者的FOE记录显示， 在睡眠期间发生的放电和频繁的癫痫发作。绝大多数癫痫样活动是 无症状，发生时没有任何明显的临床症状，头皮EEG上也没有任何可见的体征。是否 沉默的mTL癫痫样活动在AD的早期阶段是常见的，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。 需要检测这种活动。本提案的目的是进一步研究沉默型mTL的作用 在AD的早期阶段癫痫样活动。过度假设是存在AD的子集 无症状mTL癫痫样活动是认知功能下降的有效和可改变的促成因素的患者。如果 的确，这种活性的降低可能包括症状缓解或疾病的新治疗靶点， AD中的修改本研究将在马萨诸塞州综合医院（Boston，MA）进行， 贝勒医疗中心/圣卢克医院（德克萨斯州休斯顿）。八名患有遗忘性轻度认知障碍的参与者 将招募由AD引起的损伤或轻度痴呆的患者进行FOE插入，然后进行3天的 用FOE和头皮EEG连续记录。将对记录进行分析，以表征任何无症状mTL 癫痫样异常的存在，并将这些结果与临床和头皮脑电图特征。的 本研究的具体目的是：1）鉴定和表征临床沉默的mTL活性谱， 发生在AD的早期阶段; 2）证明招募和记录AD参与者的可行性， FOE，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特征与无症状mTL癫痫样活动的AD患者相同。从长远来看， 这项研究有可能揭示一种新的和潜在的可治疗的神经生理机制， 这种记忆功能在AD的早期阶段被破坏。这里获得的数据将用于指导 在AD患者中设计使用颅内记录的大型研究，此外，将有助于 开发非侵入性方法来检测AD中的沉默mTL癫痫样活动，而不需要 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.