PCr-based fMRSI Biomarker for Schizophrenia

基于 PCR 的 fMRSI 精神分裂症生物标志物

• 批准号: 8112970
• 负责人: JAY W PETTEGREW
• 金额: $ 21.79万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112970
• 关键词: Adolescence; Adolescent; Age; Anisotropy; Area; Biological Markers; Brain; Brain imaging; Brain region; Cerebrospinal Fluid; Childhood; Chronic Schizophrenia; Clinic; Cognitive deficits; Data; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Education; Electroencephalography; Exhibits; Female; Functional Magnetic Resonance Imaging; Gender; General Population; Genetic; Geniculate body structure; Hour; Human; Impaired cognition; Inferior; Institutes; Language; Left; Life; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Memory; Modification; Molecular; Monitor; Motor Cortex; Normal Range; Occipital lobe; Optics; Parietal Lobe; Phosphocreatine; Photic Stimulation; Prefrontal Cortex; Principal Component Analysis; Process; Psychotic Disorders; Publishing; Radial; Radiation; Recruitment Activity; Registries; Rest; Role; Scanning; Schizophrenia; Statistical Methods; Stimulus; Suggestion; Synapses; Synaptic Membranes; Temporal Lobe; Testing; Therapeutic; Visual Cortex; Visuospatial; area striata; base; cognitive control; cognitive function; cohort; executive function; first episode schizophrenia; functional outcomes; gray matter; illness length; in vivo; interest; magnetic resonance spectroscopic imaging; male; protocol development; response; sensory cortex; volunteer; water diffusion; white matter; young adult

DESCRIPTION (provided by applicant): Molecular evidence that schizophrenia is a disorder of synaptic elimination was provided by in vivo 31P MRS studies of never-medicated, first-episode schizophrenia subjects. Recent genetic studies also support the role of synaptic elimination in schizophrenia. A recent in vivo 31P-1H MRS study of normal childhood and adolescent subjects (N = 105, 6-18 years) showed that phosphocreatine (PCr) is the most sensitive molecular biomarker for regionally specific synaptic elimination. The aim of this proposal is to develop in Year 1 quantitative functional magnetic resonance spectroscopic imaging (fMRSI) at 3.0 Tesla (2x2x2 cm3 voxel size) with application to schizophrenia subjects in Year 2. Noninvasive in vivo, functional PCr-based 31P fMRSI (PCr-fMRSI) will use published fMRS activation paradigms with appropriate modification for PCr-fMRSI. PCr-fMRSI should be more closely linked to synaptic activity than fMRI. To examine neuromolecular underpinnings of schizophrenia we propose to setup and optimize visual stimulation and MR parameters in humans for a PCr-fMRSI visual stimulation paradigm (i.e., with and without primary visual cortical stimulation in the form of radial red/black checkerboard flickering at 8 Hz) which has been shown to stimulate the human primary visual cortex. Also, we propose to evaluate, clinically and neuropsychologically, a small cohort of chronic schizophrenia subjects (n = 16, ages 18 to 55 yrs; 8 cognitively intact, 4 males, 4 females; 8 cognitively impaired, 4 males, 4 females) whose cognitive function range from normal to severe, generalized cognitive impairment and control subjects matched for age, gender, length of illness, and parental education (Nn = 28, ages 18 to 55 yrs, 10 males, 6 females). We propose to perform PCr-fMRSI (2x2x2 cm3 voxel size) with primary visual cortical stimulation and MRI on these chronic schizophrenia and normal control cohorts to include the following regions of interest, left and right: dorsal prefrontal cortex; superior temporal cortex; inferior parietal cortex; and occipital cortex. Structural volumetric MRI will be performed enabling the volume of gray matter, white matter, and cerebrospinal fluid to be determined on the same voxels that the functional PCr- fMRSI measurements are obtained. Diffusion tensor imaging anisotropy measurements will be performed to study white matter deficits in schizophrenia and their relationship to regions that show fPCr-MRSI activation. This study will develop PCr-fMRSI to study synaptic membrane depolarization-repolarization which will be applied to chronic schizophrenia to test the hypothesis of exaggerated synaptic elimination in dorsal prefrontal cortex of schizophrenia subjects compared with healthy controls. PUBLIC HEALTH RELEVANCE: Cognitive deficits are relatively common in chronic schizophrenia with poor functional outcome. This application is to develop a molecular biomarker of schizophrenia based on PCr-based functional 31P MRS to detect differences in synaptic elimination in schizophrenia compared with healthy controls. This could be extremely useful in predicting functional outcome and monitoring response to therapeutic measures.

描述（由申请人提供）：对未服药的首发精神分裂症患者进行体内31P MRS研究，提供了精神分裂症是一种突触消除障碍的分子证据。最近的遗传学研究也支持突触消除在精神分裂症中的作用。最近对正常儿童和青少年（N = 105,6 -18岁）进行的体内31P-1H MRS研究表明，磷酸肌酸（PCr）是区域特异性突触消除最敏感的分子生物标志物。本提案的目的是在一年级发展3.0特斯拉（2x2x2 cm3体素大小）的定量功能磁共振光谱成像（fMRSI），并应用于二年级的精神分裂症受试者。无创活体、功能性基于pcr的31P fMRSI （PCr-fMRSI）将使用已发表的fMRS激活模式，并对PCr-fMRSI进行适当修改。PCr-fMRSI应该比fMRI与突触活动联系更紧密。为了研究精神分裂症的神经分子基础，我们建议设置并优化人类的视觉刺激和MR参数，用于PCr-fMRSI视觉刺激范式（即，以8赫兹闪烁的径向红/黑棋盘形式有或没有初级视觉皮层刺激），这已被证明可以刺激人类初级视觉皮层。此外，我们建议对慢性精神分裂症患者（n = 16，年龄18 - 55岁；8名认知完整，4名男性，4名女性；8名认知受损，4名男性，4名女性）进行临床和神经心理学上的评估，这些患者的认知功能范围从正常到严重，普遍认知障碍，8名男性，4名女性)和对照组（Nn = 28，年龄18 - 55岁，10名男性，6名女性）。我们建议对这些慢性精神分裂症和正常对照组进行PCr-fMRSI （2x2x2 cm3体素大小）和初级视觉皮层刺激和MRI，包括以下感兴趣的区域，左和右：前额叶背皮质；颞上皮层；下顶叶皮层；以及枕叶皮层。将进行结构体积MRI，使灰质、白质和脑脊液的体积能够在获得功能性PCr- fMRSI测量结果的相同体素上确定。扩散张量成像各向异性测量将用于研究精神分裂症患者的白质缺陷及其与显示fPCr-MRSI激活的区域的关系。本研究将利用PCr-fMRSI技术研究慢性精神分裂症患者的突触膜去极化-复极化现象，以验证精神分裂症患者前额叶背侧皮层突触消除现象是否比健康对照组严重。