Long-Term Nicotine Treatment of Mild Cognitive Impairment

描述（由申请人提供）：阿尔茨海默病（AD）的前兆条件，如轻度认知障碍（MCI），现在是患者识别和潜在治疗的目标，因为研究清楚地表明进展为痴呆症的风险非常高。尽管人们试图开发针对AD及其前体MCI的新疗法，但事实证明，中断病程和防止病情恶化的方法难以捉摸。迄今为止，基于分子病理（如A α）的AD治疗策略产生了模棱两可或阴性的结果。因此，研究正转向对前体疾病的潜在治疗，包括轻度认知损伤、轻度认知损伤前期，以及通过遗传或其他生物标志物识别的有风险的受试者。胆碱能神经元的损失，特别是烟碱胆碱能受体的损失，已被证明主要与阿尔茨海默病的认知能力下降有关。然而，尽管有明确的证据表明胆碱能功能在这一阶段发生改变，但已批准的AD治疗并没有显著改善MCI。因此，非特异性增强胆碱能功能似乎并不是一种有效的策略，既不能增强MCI的长期认知功能，也不能延缓AD的进展。人们一直在寻找新的治疗方法，既能改善认知症状，又能潜在地改善疾病。尼古丁可能就是其中一种分子，它很容易获得，价格低廉，而且易于使用。我们进行了一项为期6个月的双盲试点试验，结果显示尼古丁治疗显著改善了注意力和情景记忆领域的认知表现，改善了功能和自评记忆问题的整体评分，并且耐受性良好，具有令人印象深刻的安全性，没有滥用风险（Newhouse， P.， K. Kellar等人，2012）。神经病学杂志(2):91-101。我们现在建议进行一项为期2年的多中心临床试验，以测试每日经皮尼古丁是否会对轻度认知障碍患者产生持续的认知、临床和功能益处。我们还计划通过监测生物标志物，包括结构和功能脑成像以及脊髓液中AD病理的测量，来测试尼古丁是否会改变与AD发生相关的潜在生物学。我们的主要假设是，与安慰剂相比，经皮尼古丁会增强认知能力和认知功能障碍的症状，这种差异将持续两年以上。本研究具有广泛的临床和科学意义。如果这些假设得到验证，这些发现将支持一种新的、广泛可用的、廉价的MCI干预措施，并将鼓励早期治疗干预，以改善症状和/或延缓认知障碍的进展。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，将导致与其他可能直接与α或tau相关机制相互作用的对症药物和/或药物的联合试验。

DESCRIPTION (provided by applicant): 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 A�) have thus far produced equivocal or negative results. Investigation is thus shifting to the potential treatment of precursr 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 A� or taurelated mechanisms.