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
- 来源:
- 关键词:AcuteAddressAdultAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAnatomyAuditoryBehavioralBiological MarkersBrainBrain DiseasesClinicalClinical SensitivityClinical TrialsCognitionCognitiveCrossover DesignDoseDouble-Blind MethodEffectivenessExhibitsFDA approvedGenotypeGlutamatesHeterogeneityImpaired cognitionIndividualInterventionLaboratoriesLaboratory AnimalsLaboratory FindingMeasuresMediatingMediationMemantineMeta-AnalysisModelingNMDA receptor antagonistNerve DegenerationNeuropsychologyOutcome MeasurePatientsPerformancePersonsPharmaceutical PreparationsPhasePlacebosRandomizedReportingRoleSchizophreniaSeveritiesSignal TransductionSingle Nucleotide PolymorphismStructureTarget PopulationsTestingTherapeuticTherapeutic EffectTherapeutic Trialsbasebrain circuitryclinical effectclinical outcome measuresclinical predictorscohortexperiencehuman subjectindexinginformation processingneurophysiologyneurotoxicitynovel markeropen labelpersonalized medicinepillpredictive markerprepulse inhibitionresponsesource localizationtreatment responsevoltageweek trial
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
项目成果
期刊论文数量(1)
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{{ 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:
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