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.

项目概要/摘要 过去 15 年来，还没有新的治疗阿尔茨海默病 (AD) 的方法被批准。 预计到 2050 年，AD 将影响 1400 万美国人，并使国家损失超过 1 万亿美元 每年都需要对AD有一个新的视角，以揭示驱动认知的新疾病机制。 AD 下降，并确定新的治疗目标以实现更成功的药物开发。 研究最近在两名接受过治疗的 AD 患者身上发现的一种新的脑电异常 使用卵圆孔电极 (FOE) 进行颅内记录是一种安全且微创的方法。 获得内侧颞叶 (mTL) 电活动的高保真记录，内侧颞叶是最早的大脑之一 这些 AD 患者受 AD 病理学影响的区域显示出丰富的 mTL 癫痫样。 放电和频繁的癫痫发作发生在睡眠期间。 安静，没有任何明显的临床症状，头皮脑电图也没有任何明显的迹象。 沉默 mTL 癫痫样活动在 AD 早期阶段很常见，这种活动是否有助于 AD 的记忆障碍尚不清楚，因为 AD 患者几乎从未接受过颅内记录 该提案的目的是进一步研究沉默 mTL 的作用。 AD 早期阶段的癫痫样活动 总体假设是存在 AD 的一个子集。 沉默 mTL 癫痫样活动是导致认知能力下降的有效且可改变的因素的患者。 确实，减少这种活动可能成为缓解症状或疾病的新治疗目标 AD 的修改本研究将在马萨诸塞州总医院（马萨诸塞州波士顿）进行 贝勒医疗中心/圣卢克医院（德克萨斯州休斯顿）八名患有遗忘症轻度认知功能的参与者。 因 AD 导致的损伤或轻度痴呆将被招募来接受 FOE 插入，然后进行 3 天的治疗 将分析 FOE 和头皮脑电图的连续记录，以表征任何无声 mTL。 存在癫痫样异常，并将这些发现与临床和头皮脑电图特征相关联。 本研究的具体目标是： 1) 识别并描述临床沉默 mTL 活性的范围， 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，并确定这些录音的持续时间和产量之间的关系；以及 3) 评估 长期来看，具有无症状 mTL 癫痫样活动的 AD 患者具有常见的临床和头皮脑电图特征。 这项研究有可能揭示一种新颖且可能可治疗的神经生理机制 AD 早期阶段哪些记忆功能会受到干扰 这里获得的数据将用于指导。 使用 AD 患者的颅内记录设计更大规模的研究，而且将有助于 开发非侵入性方法来检测 AD 中沉默的 mTL 癫痫样活动，而不需要 用于颅内电极。