Long-Term Nicotine Treatment of Mild Cognitive Impairment

描述(申请人提供)：阿尔茨海默病(AD)的前驱症状，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。尽管试图开发治疗AD及其前驱疾病MCI的新方法，但事实证明，中断病程和防止进展的方法难以捉摸。到目前为止，基于分子病理学(如A�)的AD治疗策略产生了模棱两可或阴性的结果。因此，研究转向对前驱疾病的潜在治疗，包括MCI、前MCI和通过遗传学或其他生物标记物进行识别的风险受试者。胆碱能神经元，特别是烟碱型胆碱能受体的缺失已被证明与AD的认知功能下降有关。然而，尽管有明确的证据表明，在这个阶段胆碱能功能发生了变化，但已批准的治疗AD的方法并未显著改善MCI，因此，非特异性增强胆碱能功能似乎不是一种有效的策略，既不能增强MCI的长期认知功能，也不能延缓向AD的进展。人们正在继续寻找新的治疗方法，这种方法将改善认知症状，同时有可能改善疾病。尼古丁可能就是这些分子中的一种，而且容易获得，价格低廉，易于使用。我们进行了一项为期6个月的双盲试点试验，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，显示出改善了全球功能评级和自我评估的记忆问题，并且耐受性良好，具有令人印象深刻的安全概况，没有滥用责任(Newhouse，P.，K.Kella，等人)。(2012年)。神经病学78(2)：91-101)。我们现在建议进行一项为期两年的多中心临床试验，以测试每日经皮尼古丁是否会对MCI患者的认知、临床和功能产生持续的益处。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发展相关的潜在生物学。我们的主要假设是，与安慰剂相比，透皮尼古丁将改善认知能力和认知功能障碍的症状，而且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。如果假说得到证实，这些发现将支持一种新颖、广泛、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。这将是迄今为止时间最长的尼古丁或尼古丁激动剂试验，如果成功，将导致与其他有症状的药物和/或可能直接与A�或tau相关机制相互作用的药物进行联合试验。

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.