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.

摘要