Neurobiology and Cognition in Early Onset Schizophrenia: Role of Environmental Fa

早发性精神分裂症的神经生物学和认知：环境 Fa 的作用

• 批准号: 8242207
• 负责人: Konasale M Prasad
• 金额: $ 22.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242207
• 关键词: Address; Adolescent; Adult; Affect; Antibodies; Antipsychotic Agents; Biological; Biological Assay; Blood specimen; Brain; Chemicals; Chronic; Cognition; Cognitive; Cognitive deficits; Common Cold; Data; Data Collection; Databases; Development; Disease; Double Stranded DNA Virus; Encephalitis; Ethanolamines; Evaluation; Exposure to; Funding; Future; Geographic Locations; Goals; Herpes Labialis; Herpesvirus 1; Hospitals; Human; Image; Impaired cognition; Impairment; Individual; Infection; Infectious Agent; Lead; Life; Life Cycle Stages; Light; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maternal Exposure; Measures; Membrane; Memory; Minority; Morbidity - disease rate; Mothers; National Institute of Mental Health; Neonatal; Nervous system structure; Neurobiology; Neurocognitive; Neuropil; Onset of illness; Outcome; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Phospholipids; Phosphorus; Pilot Projects; Placebos; Prefrontal Cortex; Pregnancy; Prevention strategy; Protons; Public Health; Recording of previous events; Refractory; Regulation; Relative (related person); Research Personnel; Role; Sampling; Schizophrenia; Serotyping; Serum; Short-Term Memory; Simplexvirus; Strategic Planning; Stress; Testing; Thick; Time; Variant; Virus; Weight; Woman; abstracting; age related; base; brain morphology; cingulate cortex; cognitive change; cohort; cost; cost effective; design; disability; early onset; effective therapy; executive function; gray matter; improved; neurodevelopment; neuropsychological; neurotropic; novel; novel therapeutics; phosphoethanolamine; postnatal; pregnant; prenatal; prenatal exposure; prevent; prospective; repository; severe mental illness; valacyclovir; visual learning

DESCRIPTION (provided by applicant): Abstract: The goal of this project is to characterize a potentially treatable factor associated with cognitive impairments in subjects with early onset schizophrenia (EOS). EOS is a relatively less well studied form of severe mental illness with more severe cognitive impairments and poorer long term outcomes compared to the adult onset schizophrenia (AOS). Because of early onset, individuals with EOS suffer from more severe and protracted disability. An important contributing factor to poor long term outcome in schizophrenia is cognitive impairments. Since these cognitive deficits are refractory to currently prescribed antipsychotics, there is an urgent need to examine factors associated with cognitive impairments in SZ. More importantly, the disease onset in EOS occurs during an active phase of neurodevelopment. Therefore, it is logical to examine the patterns of exposure including prenatal exposure that may have a bearing on neurodevelopment associated with cognitive deficits. Human studies including ours suggest that exposure to Herpes Simplex Virus, subtype 1 (HSV1) may be one of them. HSV1 is a double stranded DNA virus that causes common cold sores and requires lodging in the nervous system for its life cycle. In the US, nearly 60% of pregnant mothers and 45% of adolescents (12-19 years) are exposed to this virus. Majority of individuals exposed to HSV1 develop chronic infection and only a minority develop encephalitis. Earlier studies have consistently associated cognitive impairments and reduced grey matter volume in the prefrontal cortex among AOS subjects exposed to HSV1. We observed longitudinal changes in cognitive impairments and grey matter loss in AOS subjects exposed to HSV1. Interestingly, AOS subjects treated with an anti-herpes medication (Valacyclovir) added to an anti- psychotic showed improvement in working memory, verbal memory and visual learning compared to those who received placebo and an antipsychotic. This proposal seeks to examine the association of cognitive impairments, morphometric and membrane chemical abnormalities in subjects with EOS (aim 1) and to explore the patterns of timing of exposure with these phenotypes (aim 2). To accomplish aim 2, we will capitalize on our access to the pregnancy, delivery and neonatal data along with banked blood samples in a set of repositories at the Magee Women's Hospital (MWH). The largest of the databases contains data and blood samples on more than 110,000 mothers. This data is supplemented by prospective ldata and biological samples on more than 3000 mothers collected under different federally funded projects (PI: Dr. Simhan and Dr. Roberts). Drs. Hyagriv Simhan is the director of the MWH repository and PI on his federally funded projects is a co-investigator on this project to facilitate access to the repository. Dr. James Roberts is a consultant on this project who will make them available for this study. Combining the prospective data collection with access to the repository is the most cost effective and rapid approach to characterize timing of exposure to a potentially treatable factor. The latter may pave the way for future studies on potentially preventive strategies. PUBLIC HEALTH RELEVANCE: Public Health Significance Early Onset Schizophrenia (EOS) is a more severely debilitating disorder than the adult onset schizophrenia (AOS) with considerably poorer outcome. This adds to major public health burden of severe mental illness. Since the onset, by definition, occurs early in life, the morbidity due to the illness lasts much longer than the AOS. Currently available treatments minimally affect cognitive impairments. Characterizing potentially treatable factors associated with cognitive impairments may contribute to better outcomes, thus reducing the morbidity. The proposed effort is driven by intriguing data that supports longitudinal changes in cognition and brain morphology and the reversal of longitudinal cognitive changes by anti-herpes medication.

描述（申请人提供）：摘要：该项目的目的是表征与早期发作精神分裂症（EOS）受试者认知障碍相关的潜在可治疗因素。与成人精神分裂症（AOS）相比，EOS是一种相对较少的严重精神疾病形式，具有更严重的认知障碍和较差的长期结局（AOS）。由于早期发作，EOS患者患有更严重和持久的残疾。精神分裂症长期结局不良的重要因素是认知障碍。由于这些认知缺陷对于当前处方的抗精神病药是难治性，因此迫切需要检查与SZ认知障碍相关的因素。更重要的是，EOS中的疾病发作发生在神经发育的主动阶段。因此，检查暴露模式是合乎逻辑的，包括可能与认知缺陷相关的神经发育的产前暴露。包括我们的人的人类研究表明，暴露于单纯疱疹病毒，亚型1（HSV1）可能是其中之一。 HSV1是一种双链DNA病毒，会引起常见的唇疱疹，需要在神经系统中寄宿其生命周期。在美国，近60％的怀孕母亲和45％的青少年（12-19岁）暴露于该病毒。暴露于HSV1的大多数人会出现慢性感染，只有少数人会发展出脑炎。早期的研究一直将认知障碍和暴露于HSV1的AOS受试者的前额叶皮层中的灰质体积减少。我们观察到暴露于HSV1的AOS受试者的认知障碍和灰质损失的纵向变化。有趣的是，与接受安慰剂和抗精神病药的患者相比，用抗疱疹药物治疗的AOS受试者（Valacyclovir）在抗精神病患者中添加的AOS受试者在工作记忆，言语记忆和视觉学习方面有所改善。该提案旨在检查具有EOS受试者的认知障碍，形态和膜化学异常的关联（AIM 1），并探索与这些表型的暴露时间模式（AIM 2）。为了完成AIM 2，我们将利用在Magee妇女医院（MWH）的一组存储库中的孕妇，分娩和新生儿数据的机会。最大的数据库包含超过110,000名母亲的数据和血液样本。该数据由在不同的联邦资助项目（PI：Simhan博士和Roberts博士）下收集的3000多位母亲的前瞻性LDATA和生物样本补充。博士。 Hyagriv Simhan是MWH存储库的主管，PI在其联邦资助的项目中是该项目的共同投资者，旨在促进访问存储库。詹姆斯·罗伯茨（James Roberts）博士是该项目的顾问，将使他们可以进行本研究。将预期的数据收集与访问存储库相结合是最具成本效益和快速的方法来表征暴露于潜在可治疗因素的时间。后者可能为未来的潜在预防策略铺平道路。 公共卫生相关性：公共卫生意义早期发作精神分裂症（EOS）比成年精神分裂症（AOS）更严重地使人衰弱。这增加了严重精神疾病的重大公共卫生负担。从定义上讲，由于发病是生命早期发生的，因此由于疾病而产生的发病率比AOS长得多。目前可用的治疗最小影响认知障碍。表征与认知障碍相关的潜在可治疗因素可能会导致更好的结果，从而降低发病率。提出的努力是由吸引人的数据驱动的，该数据支持认知和脑形态的纵向变化，以及抗hearpes药物纵向认知变化的逆转。