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（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。与成人发病的精神分裂症（AOS）相比，EOS 是一种研究相对较少的严重精神疾病，具有更严重的认知障碍和更差的长期结果。由于发病较早，EOS 患者会遭受更严重和更持久的残疾。精神分裂症长期预后不良的一个重要因素是认知障碍。由于目前使用的抗精神病药物难以治疗这些认知缺陷，因此迫切需要检查与精神分裂症认知障碍相关的因素。更重要的是，EOS 的疾病发作发生在神经发育的活跃阶段。因此，检查可能影响与认知缺陷相关的神经发育的暴露模式（包括产前暴露）是合乎逻辑的。包括我们在内的人类研究表明，接触单纯疱疹病毒 1 亚型 (HSV1) 可能就是其中之一。 HSV1 是一种双链 DNA 病毒，会引起普通唇疱疹，并且在其生命周期中需要寄居在神经系统中。在美国，近 60% 的孕妇和 45% 的青少年（12-19 岁）都接触过这种病毒。大多数接触 HSV1 的人会发展为慢性感染，只有少数人会发展为脑炎。早期研究一致表明，接触 HSV1 的 AOS 受试者与认知障碍和前额皮质灰质体积减少有关。我们观察到暴露于 HSV1 的 AOS 受试者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物治疗的受试者相比，在抗精神病药物中添加抗疱疹药物（伐昔洛韦）治疗的 AOS 受试者的工作记忆、语言记忆和视觉学习方面表现出改善。该提案旨在检查 EOS 受试者的认知障碍、形态测量和膜化学异常之间的关联（目标 1），并探索暴露时间与这些表型的模式（目标 2）。为了实现目标 2，我们将利用对怀孕、分娩和新生儿数据的访问，以及 Magee 妇女医院 (MWH) 一组存储库中储存的血液样本。最大的数据库包含超过 110,000 名母亲的数据和血液样本。这些数据得到了在不同联邦资助项目下收集的 3000 多名母亲的前瞻性 ldata 和生物样本的补充（PI：Simhan 博士和 Roberts 博士）。博士。 Hyagriv Simhan 是 MWH 存储库的主任，其联邦资助项目的 PI 是该项目的联合研究员，以促进对存储库的访问。詹姆斯·罗伯茨博士是该项目的顾问，他将让他们参与这项研究。将前瞻性数据收集与存储库访问相结合是描述潜在可治疗因素暴露时间的最具成本效益和最快速的方法。后者可能为未来潜在预防策略的研究铺平道路。 公共卫生相关性：公共卫生意义 早发性精神分裂症 (EOS) 是一种比成人发病性精神分裂症 (AOS) 更严重的衰弱性疾病，且预后较差。这增加了严重精神疾病的重大公共卫生负担。由于根据定义，发病发生在生命早期，因此疾病导致的发病持续时间比 AOS 长得多。目前可用的治疗方法对认知障碍的影响微乎其微。描述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。这项工作是由有趣的数据推动的，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。