Long-Term Nicotine Treatment of Mild Cognitive Impairment - Bridge Funding

轻度认知障碍的长期尼古丁治疗 - 过桥资助

• 批准号: 10435267
• 负责人: Paul S. Aisen
• 金额: $ 200.04万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435267
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Area; Attention; Biological Markers; Biological Monitoring; Biology; Brain imaging; Cerebrospinal Fluid; Cholinergic Receptors; Clinical; Cognitive; Dementia; Disease; Double-Blind Method; Early treatment; Episodic memory; Funding; Genetic; Impaired cognition; Interruption; Intervention; Investigation; Lead; Measures; Memory; Methods; Multi-Institutional Clinical Trial; Neurobehavioral Manifestations; Neurology; Nicotine; Nicotinic Agonists; Patients; Placebos; Risk; Safety; Structure; Testing; base; cholinergic; cholinergic neuron; cognitive enhancement; cognitive function; cognitive performance; improved; mild cognitive impairment; molecular pathology; nicotine treatment; novel; pilot trial; prevent; symptomatic improvement; tau Proteins; treatment strategy

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 based on molecular pathologies (such as Aβ) have thus far produced equivocal or negative results. Investigation is thus shifting to the potential treatment of precursor conditions, including MCI, pre-MCI, and subjects at risk with identification via genetics or other biomarkers. Losses of cholinergic neurons and particularly nicotinic cholinergic receptors have been shown to be principally related to cognitive decline in AD. However, 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 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 (Newhouse, P., K. Kellar, et al. (2012). Neurology 78(2): 91-101). We now propose 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. We also plan 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. Our primary hypothesis is that transdermal nicotine will enhance cognitive performance and symptoms of cognitive dysfunction compared to placebo and that this difference will be sustained over two years. This proposed study has broad clinical and scientific significance. If the hypotheses were validated, these findings would support a novel, broadly available, and inexpensive intervention for MCI and would encourage early treatment intervention to improve symptoms and/or retard progression of cognitive impairment. This would be the longest trial of nicotine or nicotinic agonists to date and if successful would lead to combined trials with other symptomatic agents and/or agents that might 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。AD的治疗策略基于 分子病理学（如Aβ）迄今为止产生了不确定的或阴性的结果。调查因此 转移到前驱疾病的潜在治疗，包括MCI，pre-MCI，和有风险的受试者 通过遗传学或其他生物标志物进行鉴定。 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，已批准的AD治疗方法并没有显著地 改善MCI，尽管有明确的证据表明在此阶段胆碱能功能改变，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的认知功能，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改善了 在注意力和情景记忆方面的认知表现有所改善，表现出改善的全球性 功能和自评记忆问题的评级，并具有良好的耐受性和令人印象深刻的安全性 并且没有滥用责任（纽豪斯，P.，K. Kellar，et al.（2012）. Neurology 78（2）：91-101）。我们现在提出一个 确定性的2年多中心临床试验，以测试每日透皮尼古丁是否会产生持续的 MCI患者的认知、临床和功能获益。我们还计划测试尼古丁是否会 通过监测生物标志物，包括结构， 以及脑功能成像和脊髓液中AD病理学的测量。我们的主要假设是 经皮尼古丁将提高认知能力和认知功能障碍的症状相比， 安慰剂，并且这种差异将持续两年以上。 这项研究具有广泛的临床和科学意义。如果假设成立， 这些发现将支持一种新的、广泛可用的、廉价的MCI干预措施， 鼓励早期治疗干预，以改善症状和/或延缓认知功能障碍的进展 损伤这将是迄今为止最长的尼古丁或尼古丁激动剂试验，如果成功， 与其他对症药物和/或可能直接与Aβ或tau相互作用的药物的联合试验- 相关机制。

项目成果

Advances in Drug Discovery and Development in Geriatric Psychiatry.

• DOI: 10.1007/s11920-018-0871-5
• 发表时间: 2018-03-05
• 期刊: CURRENT PSYCHIATRY REPORTS
• 影响因子: 6.7
• 作者: Conley, Alexander C.;Newhouse, Paul A.
• 通讯作者: Newhouse, Paul A.

In vivo network models identify sex differences in the spread of tau pathology across the brain.

体内网络模型可识别 tau 病理学在大脑中传播的性别差异。

• DOI: 10.1002/dad2.12016
• 发表时间: 2020
• 期刊: Alzheimer's & dementia (Amsterdam, Netherlands)
• 作者: Shokouhi,Sepideh;Taylor,WarrenD;Albert,Kimberly;Kang,Hakmook;Newhouse,PaulA;Alzheimer'sDiseaseNeuroimagingInitiative
• 通讯作者: Alzheimer'sDiseaseNeuroimagingInitiative

Mail and Telephone Outreach from Electronic Health Records for Research Participation on Cognitive Health and Aging.

• DOI: 10.14283/jpad.2021.18
• 发表时间: 2021
• 期刊: The journal of prevention of Alzheimer's disease
• 作者: Pun K;Zhu CW;Kinsella MT;Sewell M;Grossman H;Neugroschl J;Li C;Ardolino A;Velasco N;Sano M
• 通讯作者: Sano M

Estrogen, Stress, and Depression: Cognitive and Biological Interactions.

• DOI: 10.1146/annurev-clinpsy-050718-095557
• 发表时间: 2019-05-07
• 期刊: ANNUAL REVIEW OF CLINICAL PSYCHOLOGY
• 影响因子: 18.4
• 作者: Albert, Kimberly M.;Newhouse, Paul A.
• 通讯作者: Newhouse, Paul A.

Subjective cognition and mood in persistent chemotherapy-related cognitive impairment.

持续化疗相关认知障碍的主观认知和情绪。

• DOI: 10.1007/s11764-021-01055-1
• 发表时间: 2022-06
• 期刊: JOURNAL OF CANCER SURVIVORSHIP
• 影响因子: 3.7
• 作者: Vega, Jennifer N.;Albert, Kimberly M.;Mayer, Ingrid A.;Taylor, Warren D.;Newhouse, Paul A.
• 通讯作者: Newhouse, Paul A.