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

阿尔茨海默病患者美金刚敏感性的生物标志物预测因子

• 批准号: 10404631
• 负责人: NEAL R SWERDLOW
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404631
• 关键词: Acute; Address; Adult; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Anatomy; Auditory; Behavioral; Biological Markers; Brain; Brain Diseases; Clinical; Clinical Sensitivity; Clinical Trials; Cognition; Cognitive; Crossover Design; Dose; Double-Blind Method; Effectiveness; Exhibits; FDA approved; Genotype; Glutamates; Heterogeneity; Impaired cognition; Individual; Intervention; Laboratories; Laboratory Animals; Laboratory Finding; Measures; Mediating; Mediation; Memantine; Meta-Analysis; Modeling; NMDA receptor antagonist; Nerve Degeneration; Neuropsychology; Outcome Measure; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Placebos; Randomized; Reporting; Role; Schizophrenia; Severities; Signal Transduction; Single Nucleotide Polymorphism; Structure; Target Populations; Testing; Therapeutic; Therapeutic Effect; Therapeutic Trials; base; brain circuitry; clinical effect; clinical outcome measures; clinical predictors; cohort; experience; human subject; indexing; information processing; neurophysiology; neurotoxicity; novel marker; open label; personalized medicine; pill; predictive marker; prepulse inhibition; response; source localization; treatment response; voltage; week trial

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.

抽象的 该申请对16-365 PAR响应：“阿尔茨海默氏病谱的试验临床试验 ...”，及其要求“定义和完善目标人群的研究”和“解决异质性”的呼吁 回应…确定特定个人……更多的[与]从干预中受益的可能性较小。” 阿尔茨海默氏病（AD）是一种严重的神经退行性脑疾病，治疗有限 选项。 NMDA受体拮抗剂纪念（MEM）被批准用于中度至重度的治疗 广告;它的机制尚不清楚，但可能包括谷氨酸介导的神经毒性的钝化。 荟萃分析证实了MEM在延迟认知和行为发展方面的有效性 AD的干扰，对MEM的临床反应是适度的，短暂的且高度异质的，许多 AD患者即使进行了延长的MEM试验也没有收益。 MEM在广告中的效用可能很棒 在治疗之前，是否可以将患者识别为“膜敏感”与“内在不敏感” 试验，使用预测性生物标志物。 在过去的十年中，PI研究了MEM在实验室中的急性神经生理效应 动物，健康的人类受试者（HS）和精神分裂症（SZ）患者。这些研究表明 MEM（20 mg）的单个“挑战剂量”显着增强了早期听觉的特定实验室测量 HS和SZ患者中的信息处理（EAIP）：预硫抑制（PPI），不匹配谈判（MMN）和 伽玛带听觉稳态响应（ASSR；包括伽马功率和同步）。这 应用程序将确定是否可以使用EAIP对急性Mem-challenge的响应 在24周的试验中，预测轻度至中度AD患者的MEM的阳性治疗反应。 AIM 1检验了一个假设（H1），即单一剂量的MEM（20 mg vs.安慰剂（PBO））将显着 在轻度至中度严重性AD的患者中提高EAIP测量（n = 88）。在整个队列中进行评估 在MEM与PBO之后，在患者中，PPI，MMN和ASSR应明显更大。但是，大小 在措施和患者中，这种“ MEM效应”（MEM负PBO）将有所不同。 AIM 2将利用这一点 响应异质性测试假设（H2），即对EAIP表现出更大“ MEM效应”的患者将会 与具有较小“ MEM效应”的患者相比，对MEM的临床反应明显更大 在鹰上。 AIM 1测试后，所有患者将开始并滴定为10 mg竞标。临床 结果指标将在基线8、16和24周时评估。分析将确定是否存在 对EAIP测量的影响（单独和复合分数）预测了临床反应的大小 在这些患者中。将测试调节因子，包括特定的单核苷酸多态性 已知中等的mem灵敏度。该应用程序利用了一套独特的经验实验室发现 MEM开发出一种新型的生物标志物，可以预测对AD患者的MEM热影响的敏感性。