The Effects of Kynurenine Aminotransferase Inhibition in People with Schizophrenia

项目摘要 有一致的证据表明，犬尿氨酸途径紊乱可能与 精神分裂症的病理生理学特别是，临床、遗传和尸检研究表明， 关键调节途径酶的破坏导致犬尿烯酸（KYNA）的CNS产生增加; ±-7烟碱和N-甲基-D-天冬氨酸（NMDA）谷氨酸受体的已知拮抗剂。关于KYNA 这些受体的拮抗作用被假设为是认知发展中的关键机制。 在精神分裂症中观察到的损伤。在我们以前的工作中，我们证明了增加KYNA （色氨酸（TRYP）激发后）在健康儿童的言语和视觉记忆测试中学习受损 对照此外，我们发现增加KYNA减少整个大脑和额叶皮质灰质， 精神分裂症患者的脑血流量（CBF）;重要的是，较低的静息CBF与较差的 精神分裂症的认知功能此外，我们确定了一个精神分裂症患者的亚组， 血清KYNA水平升高，其特征为BPRS总水平、阳性症状和思维水平较高， 障碍因子得分;并且在持续注意力方面表现出显着恶化的人 任务后TRYP，而不是安慰剂给药。最后，我们最近报道，较高的循环KYNA 与人类较低的大脑谷氨酸相关，并提出了初步证据，表明较高的大脑KYNA是 与较低的白色物质分数各向异性相关。这些结果的融合进一步提供了 支持KYNA增加与认知障碍的病理生理学相关的假设， 精神分裂症建议的研究旨在探讨新来港儿童是否能阻断 通过KAT II增加KYNA对脑功能、结构、化学和行为的选择性测量 抑制作用本研究将是一项双盲、安慰剂对照、随机交叉激发研究， 精神分裂症患者接受高剂量NAC（140 mg/kg，最多15 g，或安慰剂，然后接受TRYP，6 g。我们将收集基线和治疗后的临床，认知， 电生理学、实验室和神经成像测量。我们将研究新来港儿童与 安慰剂阻断犬尿氨酸向KYNA的外周转化;减弱TRYP对ASL CBF的影响 测量;并增加白色物质完整性的弥散加权成像（DWI）指数; ERP 半球间转移;和MRS谷氨酸测量。我们亦会研究新来港定居人士会否影响 上述神经成像测量与注意力、言语和视觉的认知测量的变化有关 记忆和工作记忆。最后，我们将检查基线血清KYNA水平和/或PBMC 犬尿氨酸3-单加氧酶（KMO）活性与NAC对预期结局的影响相关 措施NAC逆转KYNA水平增加的不利影响的证明将重要地 支持开发KAT II抑制剂以增强精神分裂症患者的认知能力。

PROJECT SUMMARY There is converging evidence to suggest that kynurenine pathway disturbances may be related to the pathophysiology of schizophrenia. In particular, clinical, genetic, and post-mortem studies suggest that the disruption of key regulatory pathway enzymes results in increased CNS production of kynurenic acid (KYNA); a known antagonist of ±-7 nicotinic and N-Methyl-D-aspartate (NMDA) glutamate receptors. The KYNA antagonism of these receptors is hypothesized to be a critical mechanism in the development of the cognitive impairments observed in schizophrenia. In our previous work, we demonstrated that increased KYNA (following tryptophan (TRYP) challenge) impaired learning on verbal and visual memory tests in healthy controls. In addition, we found that increased KYNA decreased whole brain and frontal cortical gray matter cerebral blood flow (CBF) in people with schizophrenia; importantly, lower resting CBF is related to poorer cognitive function in schizophrenia. Furthermore, we identified a subgroup of people with schizophrenia with elevated serum KYNA levels, who were characterized by higher BPRS total, positive symptom, and thought disorder factor scores; and who exhibited a significant worsening of their performance on a sustained attention task following TRYP, but not placebo, administration. Finally, we recently reported that higher circulating KYNA correlates with lower brain glutamate in humans and present preliminary evidence that higher brain KYNA is associated with lower white matter fractional anisotropy. The convergence of these results provides further support for the hypothesis that increased KYNA is related to the pathophysiology of cognitive impairments in schizophrenia. The proposed study is designed to examine whether NAC blocks the adverse effects of increased KYNA on selected measures of brain function, structure, chemistry, and behavior through KAT II inhibition. The study will be a double-blind, placebo-controlled, randomized cross-over challenge study, in which people with schizophrenia are pretreated with either high-dose NAC, 140 mg/kg up to a maximum of 15 g, or placebo, then receive TRYP, 6 gms. We will collect baseline and post-treatment clinical, cognitive, electrophysiological, laboratory, and neuroimaging measures. We will examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA; attenuates the effects of TRYP on ASL CBF measures; and increases diffusion weighted imaging (DWI) indices of white matter integrity; ERP interhemispheric transfer; and MRS glutamate measures. We will also examine whether the NAC effects on the above neuroimaging measures are related to changes in cognitive measures of attention, verbal and visual memory, and working memory. Finally, we will examine if baseline serum KYNA levels and/or PBMC kynurenine 3-monooxygenase (KMO) activity are related to the effects of NAC on the proposed outcome measures. The demonstration that NAC reverses the adverse impact of increased KYNA levels will importantly support the development of KAT II inhibitors for the enhancement of cognition in schizophrenia.