Reducing Hippocampal Hyperactivity and Improving Cognition in Schizophrenia

减少海马过度活跃并改善精神分裂症患者的认知

• 批准号: 10295165
• 负责人: JASON R TREGELLAS
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295165
• 关键词: Alzheimer' s disease model; Animal Model; Antiepileptic Agents; Antipsychotic Agents; Attention; Behavioral; Binding Proteins; Biological; Biological Markers; Characteristics; Clinical; Cognition; Cognitive; Cognitive deficits; Crossover Design; Data; Disease; Dose; Double-Blind Method; Epilepsy; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Goals; Hippocampus (Brain); Human; Hyperactivity; Impaired cognition; Investigation; Knowledge; Levetiracetam; Memory; Metabolism; Monitor; Neurobehavioral Manifestations; Neurobiology; Neurocognitive; Neurological status; Neurons; Neuropsychology; Occupations; Outcome; Outcome Measure; Pathology; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Placebo Control; Population; Prediction of Response to Therapy; Publishing; Quality of life; Randomized; Research; Rest; Rodent Model; Schizophrenia; Symptoms; Testing; Veterans; Work; base; clinical efficacy; cognitive enhancement; cognitive function; cognitive load; cognitive performance; cognitive testing; design; disability; effective therapy; experimental study; gray matter; imaging study; improved; interest; memory process; mild cognitive impairment; mouse model; novel; novel strategies; novel therapeutics; open label; prevent; processing speed; psychosocial; recruit; response; targeted biomarker; therapeutic development; treatment strategy

Schizophrenia is a leading cause of disability for Veterans. Due to the lack of an effective treatment, Veterans with schizophrenia suffer a myriad of cognitive impairments, including deficits in attention, memory, and processing speed. As a result, patients struggle on the job, in relationships, and in day-to-day activities, contributing to an overall poor quality of life. New treatments for cognitive dysfunction in schizophrenia clearly are needed. A potentially powerful approach for developing and evaluating novel therapeutics is to combine behavioral/neurocognitive outcome measures with functional imaging of a drug's effects on a neurobiological marker. A topic of current great interest in schizophrenia research is the finding that patients show increased activity of the hippocampus, particularly at “rest” or in other similar conditions of low cognitive load. This increased activity has been hypothesized to prevent further recruitment of the region as task demands increase, contributing to cognitive dysfunction. Furthermore, recently published work has demonstrated that cognitive performance in schizophrenia is negatively correlated with resting hippocampal activity. It follows that a drug treatment capable of reducing resting hippocampal activity may improve cognition in patients. Recent findings have demonstrated that low doses of the anti-epileptic drug levetiracetam (LEV) reduce hippocampal hyperactivity and improve performance on a memory task in patients with mild cognitive impairment. LEV also reduces hippocampal hyperactivity in mouse models of Alzheimer's disease, an effect also recently shown in a mouse model of schizophrenia. Unlike other anti-epileptics, LEV improves cognition in epilepsy patients. The drug is well tolerated at doses several fold higher than that used to demonstrate its effects on the hippocampus. As such, it is possible that low-dose LEV may be a useful strategy for reducing hippocampal hyperactivity and improving cognition in schizophrenia. A thorough investigation of the hypothesis that LEV will reduce hippocampal hyperactivity and improve cognition in Veterans with schizophrenia is proposed. In the first Aim, functional magnetic resonance imaging will be used to determine the lowest dose at which LEV engages the biological target of interest, hippocampal hyperactivity. This Aim will use a 2-week open-label crossover design to examine the effects of two low doses of LEV (125 mg b.i.d. and [62.5] mg b.i.d.) on resting hippocampal activity in schizophrenia. The second Aim will then use the dose optimized in Aim 1 in a 4-week placebo-controlled, double-blind, randomized, parallel design to assess the cognitive effects of LEV, utilizing the Repeatable Battery for the Assessment of Neurological Status (RBANS). The relationship between LEV effects on hippocampal activity and its effects on cognitive performance also will be examined. This project will use a novel approach to investigate the efficacy of a potential new pharmacologic target in schizophrenia. The project also will evaluate hippocampal hyperactivity as a biomarker in schizophrenia by examining its ability to predict treatment response. Understanding the cognitive and neurobiological effects of LEV will provide an early indication of whether LEV can be repurposed to enhance cognitive function in Veterans with schizophrenia.

精神分裂症是退伍军人残疾的主要原因。由于缺乏有效的 精神分裂症退伍军人患有无数的认知障碍，包括 注意力、记忆力和处理速度。因此，患者在工作中，在人际关系中， 日常活动，导致整体生活质量低下。 精神分裂症认知功能障碍的新疗法显然是需要的。一个潜在 开发和评估新疗法的有效方法是将联合收割机 行为/神经认知结果测量与药物对患者的影响的功能成像 神经生物学标志物目前精神分裂症研究中的一个非常感兴趣的话题是发现， 患者表现出海马体的活动增加，特别是在“休息”或其他类似的条件下， 低认知负荷据推测，这种增加的活动是为了防止进一步招募 随着任务需求的增加，区域会导致认知功能障碍。此外，最近出版的 研究表明，精神分裂症患者的认知能力与休息时间呈负相关， 海马活动因此，能够降低静息海马活动的药物治疗可能 提高患者认知能力。 最近的研究结果表明，低剂量的抗癫痫药物左乙拉西坦（LEV） 减轻轻度脑梗死患者海马过度活跃并改善记忆任务的表现 认知障碍LEV还减少了阿尔茨海默氏症小鼠模型中的海马活动过度 最近在精神分裂症的小鼠模型中也显示了这种效果。与其他抗癫痫药不同， LEV改善癫痫患者的认知能力。这种药物在剂量高出几倍的情况下耐受性良好， 用来证明它对海马体的影响。因此，低剂量LEV可能是可行的。 一个有用的策略，减少海马过度活跃和改善认知精神分裂症。 对LEV将减少海马过度活跃的假设进行了彻底的调查， 改善退伍军人精神分裂症患者认知功能。在第一个目标中，功能磁 共振成像将用于确定LEV与生物靶点接触的最低剂量 海马活动过度本Aim将采用2周开放标签交叉设计， 两种低剂量LEV（125 mg b.i.d.）和[62.5] mg b.i.d.）海马活动的影响 精神分裂症然后，第二个目标将在4周安慰剂对照中使用目标1中优化的剂量， 双盲、随机、平行设计，利用可重复性 神经系统状态评估组合（RBANS）。LEV效应之间的关系 还将检查海马活动及其对认知表现的影响。 该项目将使用一种新的方法来研究一种潜在的新药理学 精神分裂症的目标。该项目还将评估海马过度活跃作为生物标志物， 精神分裂症通过检查其预测治疗反应的能力。理解认知和 LEV的神经生物学效应将提供LEV是否可以重新用于 增强退伍军人精神分裂症患者的认知功能。