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.

精神分裂症是导致退伍军人残疾的主要原因。由于缺乏一个有效的 在接受治疗的过程中，患有精神分裂症的退伍军人遭受了无数的认知障碍，包括精神障碍 注意力、记忆力和处理速度。因此，患者在工作中、人际关系中以及在 日常活动，导致整体生活质量不佳。 精神分裂症的认知功能障碍显然需要新的治疗方法。一个潜在的 开发和评估新疗法的有效途径是联合 用药物作用的功能成像测量行为/神经认知结果 神经生物标志物。目前对精神分裂症研究非常感兴趣的一个话题是发现 患者表现出海马体活动增强，特别是在“休息”或其他类似的情况下。 认知负荷低。这种增加的活动被认为是为了防止进一步招募 随着任务需求的增加，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 海马区活动。因此，一种能够减少静息海马区活动的药物治疗可能会 改善患者的认知。 最近的研究结果表明，低剂量的抗癫痫药物左乙拉西坦(Lev) 减少轻度痴呆患者的海马区过度活动并改善记忆任务的表现 认知障碍。LEV还可减少阿尔茨海默病小鼠模型的海马区多动 疾病，这一效应最近也在精神分裂症的小鼠模型中表现出来。与其他抗癫痫药物不同， LEV可改善癫痫患者的认知功能。这种药物的耐受性很好，剂量比 用来证明它对海马体的影响。因此，低剂量的LEV有可能是 减少精神分裂症患者海马区过度活动和改善认知的有效策略。 对LEV将减少海马区过度活动和 目的：提高退伍军人精神分裂症患者的认知水平。在第一个目标中，功能磁性 磁共振成像将被用来确定LEV与生物靶点接触的最低剂量 有趣的是，海马区过度活跃。这一目标将使用为期两周的开放标签交叉设计来检查 两个小剂量的利福平(125 mg，tid。和[62.5]mg，b.i.d。)大鼠静息状态下海马区活动的研究 精神分裂症。第二个目标将在为期4周的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，评估LEV的认知效应，利用可重复的 神经状态评估电池(RBANS)。LEV效应与细胞周期的关系 海马体的活动及其对认知能力的影响也将被研究。 这个项目将使用一种新的方法来研究一种潜在的新药理的疗效。 精神分裂症的目标。该项目还将评估海马区过度活动作为一种生物标志物 通过检测其预测治疗反应的能力来诊断精神分裂症。了解认知和 LEV的神经生物学效应将为LEV是否可以被改变用途提供早期迹象 增强退伍军人精神分裂症患者的认知功能