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

基本信息

  • 批准号:
    10404631
  • 负责人:
  • 金额:
    $ 39.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 此应用程序响应PAR-16-365:“阿尔茨海默病谱系的试点临床试验 ...”,它呼吁“研究以确定和完善目标人群”和“解决 回应.识别特定个人.更多[vs.]不太可能从干预中受益”。 阿尔茨海默病(Alzheimer's Disease,AD)是一种严重的神经退行性脑疾病, 选项. NMDA受体拮抗剂美金刚(MEM)已被批准用于治疗中度至重度 AD;其机制尚不清楚,但可能包括谷氨酸介导的神经毒性的钝化。 虽然荟萃分析证实了MEM在延缓认知和行为进展方面的有效性, 尽管在AD中存在多种紊乱,但对MEM的临床反应是适度的、短暂的和高度异质的, AD患者即使在延长的MEM试验中也没有表现出任何获益。MEM在AD中的应用可能会大大增加 如果患者在治疗前被识别为“MEM敏感”与“MEM不敏感”, 试验,使用预测生物标志物。 在过去的十年中,PI在实验室中研究了MEM的急性神经生理学效应 动物、健康人受试者(HS)和精神分裂症(SZ)患者。这些研究表明,A 单次“激发剂量”的MEM(20 mg)显著增强了早期听觉的特定实验室指标, HS和SZ患者的信息处理(EAIP):前脉冲抑制(PPI)、失配负波(MMN)和 伽马波段听觉稳态反应(ASSR;包括伽马功率和同步)。这 应用程序将确定对急性MEM挑战的EAIP响应是否可用于 在24周的试验中,预测轻度至中度AD患者对MEM的积极治疗反应。 目的1检验假设(H1),即单剂量MEM(20 mg vs.安慰剂(PBO))将显著 增强轻度至中度AD患者的EAIP指标(n=88)。在整个队列中进行评估 MEM组PPI、MMN和ASSR均显著高于PBO组。然而, 这种“MEM效应”(MEM减去PBO)的影响将因测量和患者而异。Aim 2将利用这一点 反应异质性检验假设(H2),即对EAIP表现出较大“MEM效应”的患者将 与“MEM效应”较小的患者相比, 关于EAIP目标1检测后,将开始MEM治疗,并将所有患者的剂量调整至10 mg bid。临床 将在基线、第8、16和24周评估结果测量。分析将确定MEM是否 对EAIP指标(单独和复合评分)的影响可预测临床反应的程度 在这些患者中,将测试调节因素,包括特定的单核苷酸多态性 已知中度MEM敏感性。该应用程序利用了一套独特的实验室实证研究结果 开发一种新的生物标志物,预测AD患者对MEM治疗影响的敏感性。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

NEAL R SWERDLOW其他文献

NEAL R SWERDLOW的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('NEAL R SWERDLOW', 18)}}的其他基金

Pharmacologic augmentation of targeted cognitive training in schizophrenia
精神分裂症针对性认知训练的药物增强
  • 批准号:
    10231201
  • 财政年份:
    2020
  • 资助金额:
    $ 39.5万
  • 项目类别:
Pharmacologic augmentation of targeted cognitive training in schizophrenia
精神分裂症针对性认知训练的药物增强
  • 批准号:
    10039026
  • 财政年份:
    2020
  • 资助金额:
    $ 39.5万
  • 项目类别:
Pharmacologic augmentation of targeted cognitive training in schizophrenia
精神分裂症针对性认知训练的药物增强
  • 批准号:
    10460954
  • 财政年份:
    2020
  • 资助金额:
    $ 39.5万
  • 项目类别:
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:
    9764224
  • 财政年份:
    2018
  • 资助金额:
    $ 39.5万
  • 项目类别:
Psychiatric Research Residency Training Track
精神病学研究住院医师培训课程
  • 批准号:
    9087333
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Psychiatric Research Residency Training Track
精神病学研究住院医师培训课程
  • 批准号:
    10087710
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Psychiatric Research Residency Training Track
精神病学研究住院医师培训课程
  • 批准号:
    10447085
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Psychiatric Research Residency Training Track
精神病学研究住院医师培训课程
  • 批准号:
    10216625
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Psychiatric Research Residency Training Track
精神病学研究住院医师培训课程
  • 批准号:
    10533516
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Psychiatric Research Residency Training Track
精神病学研究住院医师培训课程
  • 批准号:
    8550325
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了