Characterizing and Predicting Drug Effects on Cognition

表征和预测药物对认知的影响

基本信息

批准号：
8658490
负责人：
SUSAN E MARINO
金额：
$ 54.11万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658490
关键词：
Address Adult Adverse effects Affect Alzheimer&apos s Disease Anti-Cholinergics Antiepileptic Agents Antipsychotic Agents Area Attention Behavior Brain Brain imaging Brain region Cerebellum Characteristics Clinical Clinical Pharmacology Cognition Cognitive Cognitive deficits Communication Complex Comprehension Computational Linguistics Cross-Over Studies Data Dementia Development Disease Dose Double-Blind Method Drug Exposure Drug Kinetics Drug usage Electroencephalography Engineering Epilepsy Foundations Frequencies Future Generations Goals Grant Impaired cognition Impairment Individual Investigation Laboratories Language Life Linguistics Maintenance Malignant Neoplasms Measures Medical Memory Mental Depression Mental disorders Methodology Methods Migraine Modeling Neurosciences Obesity Outcome Pain Parietal Lobe Patients Performance Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacotherapy Phase Physiological Placebos Plasma Process Production Prophylactic treatment Psycholinguistics Randomized Regimen Reporting Research Retrieval Short-Term Memory Speech System Testing Therapeutic Agents Time Titrations Translating Work design drug development executive function experience frontal lobe improved indexing innovation insight long term memory memory process multidisciplinary neurophysiology neuropsychological novel novel therapeutics prototype response tool topiramate

项目摘要

DESCRIPTION (provided by applicant): Drug therapy for a wide range of common disorders, including epilepsy, depression, and cancer often produces adverse cognitive side effects that are disruptive to daily life. They can be particularly debilitating when an essential function, suc as verbal communication, is adversely affected. However, little is known about the mechanisms underlying a drug's impact on cognition and consequently why some individuals are more prone to experience drug-induced cognitive deficits than others. The long-term goal of this project is to enhance clinical strategies and inform drug development in order to maximize the benefits of individual medication therapy while minimizing adverse cognitive/language-related side effects. TPM, a second generation and broad spectrum antiepileptic drug, is an ideal, initial choice for our studies because, in addition to being associated with adverse effects on attention and memory, it has a unique cognitive signature affecting language use in a subset of patients. Moreover, the mechanism by which TPM affects cognition, including linguistic behavior, has not been well established. The objective of this application is to elucidate the relationship among TPM exposure as measured by plasma drug levels, its neurophysiological effects, and consequent effect on the cognitive processes observable in everyday language. In order to accomplish this objective, the tools of clinical pharmacology, computational linguistics, neuroscience, and engineering will be applied to the design and execution of randomized, double blind, crossover studies using several levels of TPM exposure in healthy adults. A novel system for automated language and speech analysis (SALSA) makes possible an objective and quantitative characterization of linguistic behavior as reflected in spontaneous speech. SALSA, EEG, and pharmacokinetic-pharmacodynamic analyses will be used to achieve the specific aims of this grant: 1. Characterize TPM-induced effects on linguistic behavior 2. Determine the neurophysiological effects of TPM on recognized ERP indices of verbal working memory load and 3. Predict individual vulnerability to TPM-induced impairments in linguistic, memory, and executive functions. Achieving these aims will offer insight into the mechanisms underlying drug-induced cognitive deficits. It will also lay the foundation for a new line of research that wil further delineate these mechanisms and provide methods to predict individual patient response. Having an understanding of the physiological mechanism(s) that underlie language use and their relationship to spontaneous speech will enable us to apply this methodology in conjunction with state-of-the- art brain imaging and pharmacokinetic-pharmacogenomic analyses to obtain a comprehensive picture of how cognitive-impairing and, later, cognitive-enhancing medications interact with individual characteristics. Future directions will extend this approach to patients across different disorders (e.g., epilepsy, Alzheimer's) and multiple drug classes (e.g., anticholinergics, antipsychotics).

描述（由申请人提供）：针对癫痫、抑郁症和癌症等多种常见疾病的药物治疗常常会产生不良的认知副作用，从而扰乱日常生活。当语言交流等基本功能受到不利影响时，它们可能会特别衰弱。然而，人们对药物影响认知的机制以及为什么有些人比其他人更容易出现药物引起的认知缺陷知之甚少。该项目的长期目标是加强临床策略并为药物开发提供信息，以便最大限度地发挥个体药物治疗的益处，同时最大限度地减少与认知/语言相关的不良副作用。 TPM 是第二代广谱抗癫痫药物，是我们研究的理想首选，因为除了对注意力和记忆力产生不利影响外，它还具有影响部分患者语言使用的独特认知特征。此外，TPM 影响认知（包括语言行为）的机制尚未明确。本申请的目的是阐明通过血浆药物水平测量的 TPM 暴露、其神经生理学影响以及对日常语言中可观察到的认知过程的后续影响之间的关系。为了实现这一目标，临床药理学、计算语言学、神经科学和工程学的工具将被应用于设计和执行随机、双盲、交叉研究，在健康成人中使用不同水平的 TPM 暴露。一种新颖的自动语言和语音分析（SALSA）系统使得对自发语音中反映的语言行为进行客观和定量的表征成为可能。 SALSA、EEG 和药代动力学-药效学分析将用于实现本资助的具体目标： 1. 表征 TPM 对语言行为的影响 2. 确定 TPM 对公认的言语工作记忆负荷 ERP 指数的神经生理学影响 3 . 预测个体对 TPM 引起的语言、记忆和执行功能损伤的脆弱性。实现这些目标将有助于深入了解药物引起的认知缺陷的机制。它还将为新的研究奠定基础，进一步描述这些机制并提供预测个体患者反应的方法。了解语言使用背后的生理机制及其与自发言语的关系将使我们能够将这种方法与最先进的脑成像和药代动力学-药物基因组学分析结合起来应用，以获得对语言使用的全面了解。认知损害药物和后来的认知增强药物如何与个体特征相互作用。未来的方向是将这种方法扩展到不同疾病（例如癫痫、阿尔茨海默病）和多种药物类别（例如抗胆碱能药、抗精神病药）的患者。