PCr-based fMRSI Biomarker for Schizophrenia

基于 PCR 的 fMRSI 精神分裂症生物标志物

基本信息

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
项目类别：
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

项目摘要

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）：精神分裂症是突触消除障碍的分子证据，由体内31p MRS的MRS研究提供了从未接受过的，第一集精神分裂症患者的研究。最近的遗传研究还支持突触消除在精神分裂症中的作用。最新的体内31p-1h MRS研究对正常儿童和青少年受试者（n = 105，6-18岁）表明，磷酸蛋白（PCR）是区域特异性突触消除的最敏感的分子生物标志物。该提案的目的是在3.0 Tesla（2x2x2 cm3 voxel大小）中开发1年级的定量功能磁共振光谱成像（FMRSI），并在2年内适用于精神分裂症受试者。 PCR-FMRSI的修改。与fMRI相比，PCR-FMRSI应与突触活动更紧密地联系在一起。为了检查精神分裂症的神经分子基础，我们提议在人类中设置和优化人机中的视觉刺激和MR参数，以进行PCR-FMRSI视觉刺激范式（即，在8 hz时刺激了辐射红色/黑色棋盘的形式，以刺激了人类的辐射式闪烁的形式，以刺激了人类的主要视觉刺激。 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疾病和父母教育（NN = 28，年龄在18至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的主要视觉皮质刺激进行PCR-FMRSI（2x2x2 cm3体素尺寸），并在这些慢性精神分裂症上进行MRI，以包括以下感兴趣的区域，左右：背前额叶皮层；颞上皮；下顶皮层；和枕叶皮质。将进行结构体积MRI，以便在获得功能性PCR-FMRSI测量的相同体素上确定灰质，白质和脑脊液的体积。扩散张量成像各向异性测量将进行研究，以研究精神分裂症的白质缺陷及其与显示FPCR-MRSI激活的区域的关系。这项研究将开发PCR-FMRSI来研究突触膜去极化 - 偏振度，该脱极化将应用于慢性精神分裂症，以测试与健康对照相比，精神分裂症受试者背侧前额叶皮层中夸张的突触消除的假设。公共卫生相关性：认知缺陷在慢性精神分裂症中相对常见，功能效果不佳。该应用是基于基于PCR的功能31p MRS开发精神分裂症的分子生物标志物，以检测与健康对照组相比，精神分裂症中突触消除的差异。这对于预测功能结果和监测对治疗措施的反应可能非常有用。