Biomarker Predictors of Memantine Sensitivity in patients with Alzheimer's Disease

摘要 此应用程序响应PAR-16-365：“阿尔茨海默氏病的临床试验 ...“，并呼吁”对目标人群进行界定和细化的研究“，并”解决 响应…特定个人的身份识别…更多[与]从干预中获益的可能性较小(S)。 阿尔茨海默病(AD)是一种严重的神经退行性脑疾病，治疗方法有限 选择。NMDA受体拮抗剂美金刚(MEM)被批准用于治疗中到重度 其机制尚不清楚，但可能包括钝化谷氨酸介导的神经毒性。 而Meta分析证实了MEM在延缓认知和行为发展方面的有效性 在阿尔茨海默病中，MEM的临床反应是适度的、短暂的和高度异质性的，有许多 AD患者即使在延长的MEM试验中也没有显示出任何进展。MEM在AD中的应用可能会很大 如果患者可以被识别为对MEM敏感的患者与治疗性治疗前的“MEM不敏感” 试验，使用一种预测性生物标志物。 在过去的十年里，PI在实验室研究了MEM的急性神经生理学效应。 动物、健康人(HS)和精神分裂症(SZ)患者。这些研究表明， 单次“激发剂量”的MEM(20毫克)显著增强了早期听觉的特异性实验室测量 HS和SZ患者的信息加工(EAIP)：脉冲前抑制(PPI)、失配负波(MMN)和 伽马频段听觉稳态反应(ASSR；包括伽马功率和同步)。这 应用程序将确定EAIP对急性MEM挑战的响应是否可用于 在24周的试验中，预测轻中度AD患者对MEM的积极治疗反应。 目的1检验假设(H1)，即单剂MEM(20毫克与安慰剂(PBO))将显著 轻中度AD患者(n=88)加强EAIP措施。对整个队列进行评估 在患者中，MEM术后的PPI、MMN和ASSR应显著高于PBO。然而，其规模 这种“MEM效应”(MEM减去PBO)的大小将因措施和患者而异。AIM 2将利用这一点 反应异质性来检验假设(H2)，即在EAIP上表现出更大的MEM效应的患者将 与“MEM效应”较小的患者相比，MEM的临床反应明显更大 在EAIP上。在Aim 1测试后，所有患者将开始MEM治疗，并滴定至10 mg Bid。临床 将在基线、8周、16周和24周评估结果衡量标准。分析将决定MEM是否 对EAIP测量的影响(单独和综合评分)预测临床反应的大小 对这些患者的MEM。将测试调节因子，包括特定的单核苷酸多态 已知对MEM的敏感度中等。该应用程序利用了一组独特的经验性实验室发现 与MEM合作开发一种新的生物标志物，预测MEM对阿尔茨海默病患者治疗效果的敏感性。

Abstract This application responds to PAR-16-365: “Pilot Clinical Trials for the Spectrum of Alzheimer's Disease ...”, and its calls for “Studies to define and refine the target population” and “address heterogeneity of response… identification of specific individuals… more [vs.] less likely to benefit from the intervention(s).” Alzheimer's Disease (AD) is a severe neurodegenerative brain disorder, with limited therapeutic options. The NMDA receptor antagonist, memantine (MEM) is approved for treatment of moderate-to-severe AD; its mechanisms are not well understood, but may include a blunting of glutamate-mediated neurotoxicity. While meta-analyses confirm MEM's effectiveness in delaying the progression of cognitive and behavioral disturbances in AD, the clinical response to MEM is modest, short-lived and highly heterogeneous, with many AD patients showing no gains even with an extended MEM trial. The utility of MEM in AD might be greatly enhanced if patients could be identified as “MEM-sensitive” vs. “MEM-insensitive” in advance of a therapeutic trial, using a predictive biomarker. For the past decade, the PI has studied the acute neurophysiological effects of MEM in laboratory animals, healthy human subjects (HS) and schizophrenia (SZ) patients. These studies demonstrated that a single “challenge dose” of MEM (20 mg) significantly enhanced specific laboratory measures of early auditory information processing (EAIP) in HS and SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and gamma band auditory steady-state response (ASSR; including gamma power and synchronization). This application will determine whether the EAIP response to an acute MEM-challenge can be used to predict a positive therapeutic response to MEM in patients with mild-to-moderate AD, over a 24 week trial. Aim 1 tests the hypothesis (H1) that a single dose of MEM (20 mg vs. placebo (PBO)) will significantly enhance EAIP measures in patients with mild-to-moderate severity AD (n=88). Assessed across the full cohort of patients, PPI, MMN and ASSR should be significantly greater after MEM vs. PBO. However, the magnitude of this “MEM effect” (MEM minus PBO) will vary across measures and patients. Aim 2 will leverage this response heterogeneity to test the hypothesis (H2) that patients exhibiting a larger “MEM effect” on EAIP will experience a significantly greater clinical response to MEM, compared to patients with a smaller “MEM effect” on EAIP. After Aim 1 testing, MEM treatment will be initiated and titrated to 10 mg bid in all patients. Clinical outcome measures will be assessed at baseline, 8, 16 and 24 weeks. Analyses will determine whether MEM effects on EAIP measures (individually, and in composite scores) predict the magnitude of the clinical response to MEM in these patients. Moderating factors will be tested, including specific single nucleotide polymorphisms known to moderate MEM sensitivity. This application leverages a unique set of empirical laboratory findings with MEM to develop a novel biomarker predicting sensitivity to MEM's therapeutic impact in patients with AD.