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 治疗，精神分裂症的退伍军人遭受了无数的认知障碍，包括缺陷 注意，记忆和处理速度。结果，患者在工作，人际关系和中挣扎 日常活动，导致整体生活质量差。 显然需要针对精神分裂症认知功能障碍的新疗法。潜在的 开发和评估新疗法的有力方法是结合 行为/神经认知结果测量通过药物对A的影响的功能成像 神经生物学标记。当前对精神分裂症研究的极大兴趣的话题是，发现 患者显示海马的活动增加，特别是在“休息”或其他类似条件下 低认知负荷。假设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，区域导致认知功能障碍。此外，最近出版了 工作表明，精神分裂症的认知表现与休息呈负相关 海马活动。因此，能够减少静息海马活动的药物治疗可能 改善患者的认知。 最近的发现表明，低剂量的抗癫痫药物左旋乙酰氨基烷（LEV） 减少海马多动并提高中期患者的记忆任务的性能 认知障碍。 LEV还降低了阿尔茨海默氏症小鼠模型中海马过度活跃性 疾病，最近在精神分裂症的小鼠模型中也表明了这一作用。与其他抗癫痫药不同， LEV改善了癫痫患者的认知。该药物的耐受性良好，剂量比 这曾经证明了其对海马的影响。因此，低剂量LE​​V可能是 一种有用的策略，是减少海马多动和改善精神分裂症认知的有用策略。 对LEV将减少海马多动和的​​假设的彻底研究 提出了精神分裂症退伍军人的认知。在第一个目标中，功能磁性 共振成像将用于确定LEV接合生物靶的最低剂量 感兴趣的是海马多动。此目标将使用2周的开放标签跨界设计来检查 两种低剂量的LEV（125 mg B.I.D.和[62.5] Mg B.I.D.）对静息海马活动的影响 精神分裂症。然后，第二个目标将在AIM 1中使用4周的安慰剂对照中优化的剂量， 使用可重复 评估神经系统状况（RBAN）的电池。 LEV对 还将检查海马活动及其对认知性能的影响。 该项目将使用一种新颖的方法来研究潜在的新药理学的效率 精神分裂症的目标。该项目还将评估海马过度活动作为生物标志物 精神分裂症通过检查其预测治疗反应的能力。了解认知和 LEV的神经生物学效应将提供早期的指示，表明LEV是否可以重新使用为 提高精神分裂症退伍军人的认知功能。