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

阿尔茨海默病患者沉默内侧颞叶过度兴奋性的研究

• 批准号: 9977778
• 负责人: Alice D Lam
• 金额: $ 18.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977778
• 关键词: Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Boston; Brain; Brain region; Child; Clinical; Clinical Trials; Cognition; Cognitive; Coupling; Craniotomy; Data; Dementia; Development; Disease; Disease Progression; Electrodes; Electroencephalography; Epilepsy; Exhibits; Failure; Future; General Hospitals; Goals; Hospitals; Human; Impaired cognition; Investigation; Lead; Light; Massachusetts; Medical center; Memory; Memory impairment; Methods; Modification; Neurons; Participant; Pilot Projects; Play; Population; Population Research; Procedures; Process; Public Health; Recording of previous events; Reporting; Research; Role; Sampling; Scalp structure; Seizures; Severities; Sleep; Sleep Fragmentations; Symptoms; Temporal Lobe; Time; Trephine hole; amnestic mild cognitive impairment; base; brain electrical activity; brain tissue; cost; critical period; design; drug development; experience; foramen ovale; high risk; improved; memory consolidation; minimally invasive; neurophysiology; novel; novel therapeutic intervention; patient subsets; recruit; study population; therapeutic development; tool

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.

项目摘要 /摘要 在过去的15年中，没有针对阿尔茨海默氏病（AD）的新疗法。这是 据估计，到2050年，广告将影响1400万美国人，并使全国损失超过1万亿美元 单程。需要对广告的新看法，以发现推动认知能力的新疾病机制 AD的下降，并确定新的治疗目标以进行更成功的药物开发。这项试验研究将 研究了最近在两名接受AD的患者中发现的新型大脑电气绝对 带有孔卵形电极（FOES）的颅内记录。敌人是一种安全且微创的手段 要从中临时爱情（MTL）获得高忠诚度记录，这是第一个大脑之一 受广告病理影响的地区。这些AD患者的敌人记录显示MTL癫痫样大量 睡眠期间出院和经常癫痫发作。这种癫痫样活动的绝大多数是 保持沉默，没有任何明显的临床症状，并且在头皮脑电图上没有任何明显的迹象。无论 沉默的MTL癫痫样活动在AD的早期阶段很常见，并且这种活动是否有助于 AD的记忆障碍尚不清楚，因为AD患者几乎从未经历过颅内记录 需要检测这项活动。该提议的目的是进一步研究无声MTL的作用 AD早期阶段的癫痫样活动。总结的假设是存在AD的子集 沉默的MTL癫痫样活动的患者是认知能力下降的潜在和可改变的患者。如果 的确，减少这项活动可能包括症状缓解或疾病的新治疗范围 AD修改。这项研究将在马萨诸塞州综合医院（马萨诸塞州波士顿）和 贝勒医疗中心 /圣卢克医院（德克萨斯州休斯顿）。八名具有柔滑温和认知的参与者 由于AD引起的损害或轻度痴呆将被招募以插入敌人，然后3天 连续记录敌人和头皮脑电图。将分析录音以表征任何无声的MTL 存在癫痫样异常，并将这些发现与临床和头皮EEG特征相关联。这 这项研究的具体目的是：1）识别和表征临床沉默的MTL活性的光谱 发生在AD的早期阶段； 2）证明与 敌人，并确定这些记录的持续时间和产量之间的关系； 3）评估 临床和头皮脑电图具有静音MTL癫痫样活性的AD患者的特征。从长远来看 这项研究有潜力通过 在AD的早期阶段，哪个内存功能被破坏。这里获得的数据将用于指导 使用AD患者中颅内记录的较大研究的设计，此外，对 不需 用于颅内电极。