PCr-based fMRSI Biomarker for Schizophrenia

描述(申请人提供)：从未服用药物的首发精神分裂症受试者的活体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)进行的活体31P-1HMRS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标志物。这项建议的目的是在第一年开发3.0特斯拉(2x2x2 cm3体素大小)的定量功能磁共振波谱成像(FMRSI)，并在第二年应用于精神分裂症患者。基于体内无创的31P功能磁共振波谱成像(PCR-fMRSI)将使用已发表的FMR激活范例，并对其进行适当的修改。与fMRI相比，聚合酶链式反应-fMRSI与突触活性的关系应该更密切。为了研究精神分裂症的神经分子基础，我们建议在人类中建立和优化视觉刺激和磁共振参数，以用于PCR-fMRSI视觉刺激范式(即，有和没有初级视觉皮质刺激，以8赫兹的放射状红/黑色棋盘闪烁的形式)，这已被证明刺激人类初级视觉皮质。此外，我们建议从临床和神经心理学角度评估一小部分慢性精神分裂症受试者(n=16，年龄18-55岁；8名认知功能正常，4名男性，4名女性；8名认知功能受损，4名男性，4名女性)，他们的认知功能从正常到严重，广泛性认知障碍和与年龄、性别、病程和父母教育相匹配的对照组受试者(NN=28名，年龄18-55岁，男性10名，女性6名)。我们建议对这些慢性精神分裂症患者和正常对照组进行初级视觉皮质刺激和磁共振成像的PCR-fMRSI(2x2x2 cm~3体素大小)，包括以下感兴趣区，左侧和右侧：背侧前额叶皮质、上颞叶皮质、下顶叶皮质和枕叶皮质。将进行结构体积磁共振成像，使灰质、白质和脑脊液的体积能够在获得功能性PCR-fMRSI测量的相同体素上确定。将进行扩散张量成像各向异性测量，以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。本研究将建立应用于慢性精神分裂症患者的突触膜去极化-复极化的聚合酶链式反应-核磁共振成像技术，以验证与健康对照组相比精神分裂症患者额叶背侧皮质过度突触消除的假说。

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.