Long-Term Nicotine Treatment of Mild Cognitive Impairment

 描述（由申请人提供）：阿尔茨海默病（AD）的前驱疾病，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。尽管试图开发新的治疗AD及其前体MCI的方法，中断疾病进程和预防进展的方法已被证明是难以捉摸的。迄今为止，基于分子病理学（如Ablation）的AD治疗策略产生了模棱两可或负面的结果。因此，研究正在转向对阿尔茨海默病的潜在治疗，包括MCI，前MCI和通过遗传学或其他生物标志物识别的风险受试者。 胆碱能神经元，特别是烟碱胆碱能受体的丧失已被证明主要与AD中的认知下降有关。然而，已批准的AD治疗并未显著改善MCI，尽管有明确证据表明在此阶段胆碱能功能发生改变。因此，非特异性增强胆碱能功能似乎不是增强MCI长期认知功能或延缓AD进展的有效策略。 人们一直在寻找新的治疗方法，以改善认知症状，同时可能改善疾病。尼古丁可能是这些分子之一，容易获得，便宜，易于使用。我们已经进行了一项为期6个月的双盲试验，表明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，改善了功能和自我评定记忆问题的整体评级，并且耐受性良好，具有令人印象深刻的安全性特征，没有滥用倾向（纽豪斯，P.，K. Kellar，et al.（2012）. Neurology 78（2）：91-101）。我们现在提出了一项为期2年的多中心临床试验，以测试每日透皮尼古丁是否会对MCI患者产生持续的认知，临床和功能益处。我们的主要假设是，与安慰剂相比，经皮尼古丁将增强认知能力和认知功能障碍的症状，并且这种差异将持续两年以上。我们还计划在一项较小的子研究中，通过监测生物标志物（包括结构和功能性脑成像以及脊髓液中AD病理学的测量），测试是否有证据表明尼古丁治疗会影响MCI/AD相关的基础生物学。 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，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，将导致与其他对症药物和/或可能直接与April或tau相关机制相互作用的药物的联合试验。

 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 Aß) 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. 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. We also plan to test in a smaller sub study whether there is evidence that nicotine treatment will affect the underlying biology related to MCI/AD by monitoring biological markers including structural and functional brain imaging and measures of AD pathology in spinal fluid. 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 Aß or tau- related mechanisms.