Myelin Pathology in Schizophrenia

描述（由申请人提供）：精神分裂症越来越被视为一种神经元连接障碍，可能在几个层面受损。尸检研究清楚地表明，突触前机制和大脑皮层的树突棘都有异常。白色物质异常的证据主要来自磁共振成像研究，这些研究相当一致地证明了大脑白色物质的各向异性分数（FA）降低，以及FA缺陷与精神分裂症功能缺陷之间的相关性。这些异常的解剖学和生物化学基础尚不清楚，只能通过尸检研究来确定，迄今为止，尸检研究很少关注白色物质。然而，尸检研究表明，灰质中髓鞘相关基因的表达减少，不同程度的证据表明，这些减少与调节髓鞘形成的基因的多态性有关，可能与精神分裂症有关。我们实验室对前额白色物质中髓鞘进行常规组织化学染色的初步结果表明，老年精神分裂症患者和非精神病患者之间没有差异，但在精神分裂症发作时和生命的最后几年，髓鞘完整性与认知功能之间存在显著相关性。我们还发现，在右前扣带回中，几个髓鞘相关基因的mRNA表达降低的证据，该结构经常表明精神分裂症中FA降低。在同一区域，我们发现髓鞘碱性蛋白水平轻度降低。我们现在提出了第一个大的，多方面的尸检研究，重点是精神分裂症的白色物质。我们将比较腹侧和背侧左前额叶白色物质，并在一系列最佳收集的年轻（平均年龄~ 50岁）病例中补充常规髓鞘染色，进行更灵敏和更有针对性的检查，这些病例具有全面的临床、神经病理学和毒理学特征，包括对精神分裂症发作和结束时的认知障碍的回顾性评估。我们将雇用：（1）常规髓鞘染色和免疫组织化学染色对白色物质特定蛋白组分的系统半定量评估，（2）这些组分及其各自mRNA的生物化学定量，（3）轴突长度密度的体视学测定以及轴突直径和髓鞘厚度的分布;和（4）小胶质细胞活化的组织学评估，小胶质细胞活化是白色物质损伤的敏感指标。

DESCRIPTION (provided by applicant): Schizophrenia is increasingly coming to be seen as a disorder of neuronal connectivity, which may be impaired at several levels. Abnormalities in both presynaptic machinery and dendritic spines of the cerebral cortex are clearly implicated by autopsy studies. The evidence for abnormalities of the white matter comes largely from magnetic resonance imaging studies, which fairly consistently demonstrate decreased fractional anisotropy (FA) in cerebral white matter, as well as correlations between FA deficits and functional deficits in schizophrenia. The anatomical and biochemical substrates of these abnormalities are unknown and can only be determined by autopsy studies, which so far have focused little attention on white matter. Autopsy studies have, however, demonstrated diminished expression of myelin-related genes in grey matter, with varying degrees of evidence that these decreases are related to polymorphisms, possibly linked to schizophrenia, of genes that regulate myelination. Initial results from our laboratory with routine histochemical stains for myelin in prefrontal white matter demonstrate no difference between elderly schizophrenia and nonpsychiatric subjects but show a significant correlation between myelin integrity and cognitive function at the onset of schizophrenia and in the final years of life. We have also found evidence of decreased expression of mRNA for several myelin-related genes in the right anterior cingulum, a structure frequently demonstrating decreased FA in schizophrenia. In the same region, we find a mildly decreased level of myelin basic protein. We now propose the first large, multifaceted autopsy study to focus on white matter in schizophrenia. We will compare ventral and dorsal left prefrontal white matter and will supplement routine myelin staining with more sensitive and targeted examinations in a series of optimally collected, young (mean age -50) cases with thorough clinical, neuropathological, and toxicological characterization, including retrospective assessments of cognitive impairment at the onset and end of schizophrenia. We will employ: (1) systematic semiquantitative assessment of routine myelin stains and immunohistochemical stains for specific protein components of white matter, (2) biochemical quantitation of these components and their respective mRNA, (3) stereological determination of axon length density and the distributions of axon diameter and myelin sheath thickness; and (4) histological evaluation of microglial activation, a sensitive indicator of white matter damage.