Environmental Factors in Cognition and Neurobiology of Early Onset Schizophrenia

描述（由申请人提供）：摘要：该项目的目标是描述与早发性精神分裂症（EOS）受试者认知障碍相关的潜在可治疗因素的特征。EOS是一种相对较少研究的严重精神疾病，与成人发作的精神分裂症（AOS）相比，具有更严重的认知障碍和更差的长期结局。由于发病较早，EOS患者会遭受更严重和持久的残疾。精神分裂症长期预后不良的一个重要因素是认知障碍。由于这些认知功能障碍是难治性的，目前规定的抗精神病药物，有迫切需要检查与SZ的认知功能障碍的因素。更重要的是，EOS中的疾病发作发生在神经发育的活跃期。因此，这是合乎逻辑的检查模式的暴露，包括产前暴露，可能有一个轴承与认知缺陷相关的神经发育。包括我们在内的人类研究表明，暴露于单纯疱疹病毒1型（HSV 1）可能是其中之一。HSV 1是一种双链DNA病毒，可引起常见的感冒疮，并需要在其生命周期中寄宿在神经系统中。在美国，近60%的孕妇和45%的青少年（12-19岁）暴露于这种病毒。大多数暴露于HSV 1的个体发展为慢性感染，只有少数发展为脑炎。早期的研究一致认为，在暴露于HSV 1的AOS受试者中，认知障碍和前额叶皮层灰质体积减少相关。我们观察了暴露于HSV 1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受试者相比，用抗疱疹药物（伐昔洛韦）加抗精神病药治疗的AOS受试者显示出工作记忆、言语记忆和视觉学习的改善。该提案旨在检查EOS受试者中认知障碍、形态测量和膜化学异常的相关性（目的1），并探索这些表型的暴露时间模式（目的2）。为了实现目标2，我们将利用马吉妇女医院一系列储存库中的怀孕、分娩和新生儿数据沿着库存血液样本。其中最大的数据库包含11万多名母亲的数据和血液样本。这些数据还得到了在不同的联邦资助项目下收集的3000多名母亲的前瞻性数据和生物样本的补充（PI：Simhan博士和Roberts博士）。Hyagliam Simhan博士是MWH储存库的主任，他的联邦资助项目的PI是该项目的共同研究员，以促进对储存库的访问。James Roberts博士是该项目的顾问，他将使这些患者可用于本研究。将前瞻性数据收集与访问储存库相结合是描述暴露于潜在可治疗因素的时间的最具成本效益和快速的方法。后者可能为未来研究潜在的预防策略铺平道路。

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.