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

描述(由申请人提供)：摘要：本项目的目标是描述一种与早发性精神分裂症(EOS)受试者的认知障碍相关的潜在可治疗因素。EOS是一种研究相对较少的严重精神疾病，与成人起病精神分裂症(AOS)相比，具有更严重的认知障碍和更差的长期结果。由于发病早，EOS患者遭受更严重和持久的残疾。精神分裂症长期预后差的一个重要因素是认知障碍。由于这些认知缺陷对当前处方的抗精神病药物无效，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的疾病发生在神经发育的活跃阶段。因此，研究包括产前暴露在内的暴露模式是合乎逻辑的，这些暴露可能与认知缺陷相关的神经发育有关。包括我们在内的人体研究表明，接触1型单纯疱疹病毒(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，需要在神经系统中停留才能进入其生命周期。在美国，近60%的孕妇和45%的青少年(12-19岁)接触到这种病毒。接触HSV1的大多数人会发展为慢性感染，只有少数人会发展为脑炎。早期的研究一致认为，接触HSV1的AOS受试者前额叶皮质中的认知障碍和灰质体积减少。我们观察了接触HSV1的AOS受试者认知障碍和灰质丢失的纵向变化。有趣的是，与接受安慰剂和抗精神病药物治疗的患者相比，接受抗疱疹药物(Valacylovir)和抗精神病药物治疗的AOS患者在工作记忆、言语记忆和视觉学习方面表现出改善。这项建议旨在研究EOS受试者的认知障碍、形态测量和膜化学异常之间的联系(目标1)，并探索暴露于这些表型的时机模式(目标2)。为了实现目标2，我们将利用我们获得的怀孕、分娩和新生儿数据以及玛吉妇女医院(MWH)一套储存库中的血液样本。其中最大的数据库包含超过11万名母亲的数据和血液样本。在联邦政府资助的不同项目(PI：西姆汉博士和罗伯茨博士)下收集的3000多名母亲的预期数据和生物样本补充了这一数据。Hyagriv Simhan博士是MWH储存库的主任，PI在他的联邦资助项目中是该项目的联合调查员，以促进对储存库的访问。詹姆斯·罗伯茨博士是这个项目的顾问，他将把他们提供给这项研究。将预期数据收集与对储存库的访问相结合，是确定暴露于潜在可治疗因素的时间的最具成本效益和最快速的方法。后者可能为未来关于潜在预防策略的研究铺平道路。 公共卫生意义：早发性精神分裂症(EOS)是一种比成人型精神分裂症(AOS)更严重的衰弱疾病，预后相当差。这增加了严重精神疾病的重大公共卫生负担。根据定义，由于发病发生在生命的早期，这种疾病导致的发病率比AOS持续的时间要长得多。目前可用的治疗方法对认知障碍的影响最小。确定与认知障碍相关的潜在可治疗因素可能有助于更好的结果，从而降低发病率。这项拟议的努力是由耐人寻味的数据推动的，这些数据支持认知和大脑形态的纵向变化，以及抗疱疹药物逆转纵向认知变化。

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.