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

阿尔茨海默病(AD)的先兆条件，如轻度认知障碍(MCI)，现在是 患者识别和潜在治疗，因为研究清楚地表明，进展为痴呆症的风险 非常高。尽管试图开发治疗AD及其前体MCI的新方法，但干扰方法 病程和预防进展已被证明是难以捉摸的。阿尔茨海默病的治疗策略 到目前为止，分子病理学(如Aβ)产生了模棱两可或阴性的结果。调查是这样进行的 转向对先兆疾病的潜在治疗，包括MCI、MCI前期和有 通过遗传学或其他生物标志物进行鉴定。 胆碱能神经元，特别是烟碱型胆碱能受体的丧失已被证明是 主要与阿尔茨海默病认知功能下降有关。然而，已批准的治疗AD的方法并没有显著 改善的MCI，尽管在这个阶段有明显的胆碱能功能改变的证据，因此是非特异性的 增强胆碱能功能似乎不是一种富有成效的策略，无论是对于增强长期 MCI的认知功能，也不会延缓进展为AD。 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 疾病修正。尼古丁可能是这些分子中的一种，而且很容易获得，价格低廉，很容易获得 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 在注意力和情景记忆领域的认知表现有所改善，显示出总体上的改善 功能评级和自我评级的记忆问题，并以令人印象深刻的安全配置文件被很好地容忍 并且没有滥用责任(Newhouse，P.，K.Kella，等人)。(2012年)。神经病学78(2)：91-101)。我们现在提出一项 权威的两年多中心临床试验，以测试每天的尼古丁透皮吸收是否会产生持续的 MCI患者的认知、临床和功能益处。我们还计划测试尼古丁是否会 通过监测生物标记物，包括结构，改变与阿尔茨海默病发生相关的潜在生物学 和脑功能成像及脑脊液中AD的病理指标。我们的主要假设是 与尼古丁相比，尼古丁透皮后可提高认知能力和认知功能障碍的症状 安慰剂，这一差异将持续两年以上。 本研究具有广泛的临床和科学意义。如果假设得到证实， 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/或延缓认知进展 减损。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 与其他症状药物和/或可能直接与β或tau-1相互作用的药物进行联合试验 相关机制。

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.