Long-Term Nicotine Treatment of Mild Cognitive Impairment

轻度认知障碍的长期尼古丁治疗

• 批准号: 10535051
• 负责人: Paul S. Aisen
• 金额: $ 608.89万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535051
• 关键词: Acetylcholine; Activities of Daily Living; Agonist; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anterior; Area; Attention; Attenuated; Biological; Biological Markers; Biological Monitoring; Biology; Blood; Brain; Brain Pathology; Brain imaging; COVID-19; Cerebrospinal Fluid; Cholinergic Receptors; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Cohort Studies; Data; Dementia; Development; Disease; Disease Progression; Double-Blind Method; Double-blind trial; Early treatment; Enrollment; Episodic memory; Family; Functional disorder; Grant; Hippocampus (Brain); Image; Impaired cognition; Interruption; Intervention; Knowledge; Lead; Measures; Memory; Methodology; Methods; Monitor; Multi-Institutional Clinical Trial; Neurobehavioral Manifestations; Neuronal Injury; Nicotine; Nicotinic Receptors; Pathology; Patients; Placebos; Plasma; Positron-Emission Tomography; Research; Rest; Risk; Safety; Sampling; Short-Term Memory; Site; Structure; Synapses; System; Testing; abuse liability; amyloid imaging; attenuation; basal forebrain; base; cholinergic; cholinergic neuron; cognitive enhancement; cognitive function; cognitive performance; cohort; effective therapy; experience; imaging biomarker; improved; indexing; informant; mild cognitive impairment; molecular pathology; nicotine patch; nicotine treatment; novel; open label; pandemic disease; personalized approach; pilot trial; prevent; prodromal Alzheimer' s disease; recruit; response; side effect; symptomatic improvement; tau Proteins; therapeutic development; therapy design; treatment comparison; treatment effect; treatment strategy; virtual

Precursor conditions to Alzheimer’s disease (AD) such as Mild Cognitive Impairment (MCI) are now a target of patient identification and potential treatment, as studies clearly showing that the risk of progression to dementia is very high. Despite attempts to develop new treatments for AD and its precursor, MCI, methods of interrupting the course of illness and preventing progression have proven elusive. Treatment strategies for AD or MCI based on molecular pathologies (such as Aβ) have thus far produced equivocal or negative results. Losses of cholinergic neurons and particularly nicotinic cholinergic receptors have been shown to be principally related to cognitive decline in AD. However, currently approved treatments for AD have not significantly improved MCI, despite clear evidence of alteration of cholinergic function at this stage, Thus nonspecific enhancement of cholinergic function does not appear to be a fruitful strategy for either enhancing long-term cognitive functioning in MCI, nor retarding the progression to AD. There is a continuing search for new treatments that will improve cognitive symptoms while potentially be disease modifying. Nicotine may be one of those molecules and is easily available, inexpensive, and easy to use. We have previously performed a double-blind 6-month pilot trial showing that nicotine treatment significantly improved cognitive performance in the areas of attention and episodic memory, showed improving global ratings of functioning and self-rated memory problems, and was well tolerated with an impressive safety profile and no abuse liability. In the previous grant period, we initiated a larger longer trial, a definitive 2-year multi-center clinical trial to test whether daily transdermal nicotine will produce sustained cognitive, clinical, and functional benefits in patients with MCI and to test whether nicotine will change the underlying biology related to developing AD by monitoring biological markers including structural and functional brain imaging and measures of AD pathology in spinal fluid. In this subsequent grant period, we will enlarge the cohort to account for COVD-19 pandemic attrition, complete the enrollment of the study, and take advantage of new biomarker approaches (e.g. amyloid PET) to expand our analysis of the potential impact of nicotine on brain pathology of MCI/AD. This proposed study has broad clinical and scientific significance. If the hypotheses are validated, these findings would support a novel, broadly available, and inexpensive intervention for MCI. Further, the unique biological information will be obtained regarding the effects of nicotinic stimulation on AD biomarkers, brain structure/function, and brain amyloid will make an invaluable contribution to AD research. This will be the longest trial of nicotinic stimulation on brain function to date and if successful would lead to combined trials with other symptomatic agents and/or agents that directly interact with Aβ or tau-related mechanisms.

阿尔茨海默病（AD）的前驱病症，如轻度认知障碍（MCI），现在是治疗的目标。 患者识别和潜在的治疗，因为研究清楚地表明进展为痴呆症的风险 非常高。尽管尝试开发用于AD及其前体MCI的新治疗，但中断AD及其前体MCI的方法仍然存在。 疾病的过程和预防进展已被证明是难以捉摸的。基于AD或MCI的治疗策略 迄今为止，对分子病理学（如Aβ）的研究产生了模棱两可或负面的结果。 胆碱能神经元，特别是烟碱胆碱能受体的损失已被证明是 主要与AD中的认知下降有关。然而，目前批准的AD治疗方法还没有 显著改善MCI，尽管在此阶段有明确证据表明胆碱能功能改变，因此 非特异性增强胆碱能功能似乎不是一种有效的策略， MCI患者的长期认知功能，也不延缓向AD的进展。 目前正在继续寻找新的治疗方法，这些方法将改善认知症状，同时可能 疾病修饰尼古丁可能是这些分子中的一种，并且容易获得，便宜，易于制造。 使用.我们之前进行了一项为期6个月的双盲试验，结果显示尼古丁治疗显著降低了 在注意力和情景记忆方面的认知表现有所改善，显示出整体评分的改善 功能和自我评定的记忆问题，耐受性良好，安全性令人印象深刻， 滥用责任在上一个资助期，我们启动了一项更大更长的试验，一项确定的2年多中心试验， 临床试验，以测试每日透皮尼古丁是否会产生持续的认知，临床和功能 研究尼古丁对MCI患者的益处，并测试尼古丁是否会改变与MCI发展相关的潜在生物学。 通过监测生物标志物，包括结构和功能脑成像和AD的测量， 脊髓液病理学在随后的资助期内，我们将扩大队列，以考虑COVD-19 大流行自然减员，完成研究招募，并利用新的生物标志物方法（例如 淀粉样蛋白PET），以扩大我们对尼古丁对MCI/AD脑病理学的潜在影响的分析。 这项研究具有广泛的临床和科学意义。如果这些假设得到验证， 研究结果将支持一种新的、广泛可用的、廉价的MCI干预措施。此外，独特的 将获得关于烟碱刺激对AD生物标志物、脑 结构/功能和脑淀粉样蛋白将为AD研究做出宝贵贡献。这将是最长的 到目前为止，尼古丁刺激对大脑功能的试验，如果成功，将导致与其他药物的联合试验。 对症药物和/或与Aβ或tau相关机制直接相互作用的药物。