PCr-based fMRSI Biomarker for Schizophrenia

描述（由申请方提供）：从未接受过药物治疗的首次发作精神分裂症受试者的体内31 P 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。最近在正常儿童和青少年受试者（N = 105，6-18岁）的体内31 P-1H MRS研究表明，磷酸肌酸（PCr）是区域特异性突触消除的最敏感的分子生物标志物。本提案的目的是在第1年开发3.0特斯拉（2x2 x2 cm 3体素大小）下的定量功能磁共振光谱成像（fMRSI），并在第2年应用于精神分裂症受试者。无创体内功能性PCR 31 P fMRSI（PCr-fMRSI）将使用已发表的fMRS激活范例，并对PCr-fMRSI进行适当修改。PCr-fMRSI应该比fMRI与突触活动更密切相关。为了检查精神分裂症的神经分子基础，我们提出在人类中设置和优化PCr-fMRSI视觉刺激范例的视觉刺激和MR参数（即，具有和不具有以8Hz闪烁的放射状红/黑棋盘形式的初级视觉皮层刺激），其已经显示刺激人类初级视觉皮层。此外，我们建议评估，临床和神经心理学，一个小队列的慢性精神分裂症的主题（n = 16，年龄18 - 55岁，8例认知功能完整，4例男性，4例女性; 8名认知受损者，4名男性，4名女性），其认知功能范围从正常到严重，广泛性认知受损和对照受试者在年龄、性别、疾病持续时间方面匹配，父母教育（Nn = 28，年龄18 ~ 55岁，男10例，女6例）。我们建议对这些慢性精神分裂症和正常对照组进行PCr-fMRSI（2x2 x2 cm 3体素大小），包括以下感兴趣区域（左侧和右侧）：背侧前额叶皮层;上级颞叶皮层;顶叶下皮层;和枕叶皮层。将进行结构体积MRI，以便在获得功能PCr- fMRSI测量的相同体素上确定灰质、白色物质和脑脊液的体积。将进行扩散张量成像各向异性测量，以研究精神分裂症中的白色物质缺陷及其与显示fPCr-MRSI激活的区域的关系。本研究将开发PCr-fMRSI研究突触膜去极化-复极化，并将其应用于慢性精神分裂症，以检验精神分裂症受试者与健康对照者相比背侧前额叶皮层突触消除过度的假设。 公共卫生相关性：认知缺陷在慢性精神分裂症中相对常见，功能结局较差。本申请旨在开发一种基于PCR的功能性31 P MRS的精神分裂症分子生物标志物，以检测精神分裂症患者与健康对照组相比突触消除的差异。这在预测功能结果和监测对治疗措施的反应方面可能非常有用。

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.