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连接障碍，可能在几个层面上受损。在突触前机制和大脑皮层的树突棘的异常是由尸检研究清楚地牵连。白质异常的证据主要来自磁共振成像研究，该研究相当一致地表明脑白质的分数各向异性（FA）下降，以及FA缺陷与精神分裂症的功能缺陷之间的相关性。这些异常的解剖学和生化基础是未知的，只能通过尸检研究来确定，迄今为止，对白质的关注很少。然而，尸检研究表明，灰质中髓鞘相关基因的表达减少，有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。我们实验室对前额叶白质髓磷脂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与非精神分裂症患者之间没有差异，但髓磷脂完整性与精神分裂症发病时和生命最后几年的认知功能之间存在显著相关性。我们还发现了右侧前扣带中几个髓磷脂相关基因mRNA表达减少的证据，该结构经常显示精神分裂症患者FA减少。在同一区域，我们发现髓鞘碱性蛋白水平轻度下降。我们现在提出了第一个大型的，多方面的解剖研究，专注于精神分裂症的白质。我们将比较左前额叶前部和后部的白质，并将在一系列最佳收集的年轻（平均年龄-50岁）病例中进行更敏感和更有针对性的检查，以补充常规髓磷脂染色，这些病例具有全面的临床、神经病理和毒理学特征，包括对精神分裂症发病和末期认知障碍的回顾性评估。我们将采用：(1)对常规髓磷脂染色和免疫组织化学染色进行系统的半定量评估，以确定白质的特定蛋白质成分；(2)对这些成分及其各自的mRNA进行生化定量；(3)对轴突长度密度、轴突直径和髓鞘厚度的分布进行立体测定；(4)白质损伤敏感指标小胶质细胞活化的组织学评价。

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.