The Role of Dysmyelination in Cognitive Impairment of Psychotic Spectrum Disorders

 描述(申请人提供)：精神病谱系障碍(PSD)是一种发病率很高的致残严重精神综合征。在PSD缺陷中，认知功能障碍是预后不良和慢性残疾的最佳预测者的核心特征。然而，目前的治疗方法并不能充分解决认知症状。这一局限性在很大程度上反映了对涉及的神经机制的了解仍处于起步阶段和不完全状态。工作记忆能力是预测健康人和精神病患者认知能力的一个重要指标，这是一种认知领域，在许多形式的精神病理学中都受到损害。我们基于扩散峰度成像(DKI)技术的初步数据表明，a)在健康的大脑中，视觉工作记忆能力的个体间差异在很大程度上与连接已知参与工作记忆过程的大脑区域的白质通路的轴突密度(用轴突含水率(Faxon)测量)有关；b)精神分裂症(SZ)的白质缺陷是由轴外径向扩散率(RDExtra)的损害驱动的，RDExtra是髓鞘形成的假定标志；c)SZ是一种原发性PSD障碍，其视觉工作记忆能力与白质微结构特性的关联发生改变。与连接前额叶和颞叶脑区的关键路径的关系不再存在，也不再与轴突密度有关，而是与RDExtra有关，RDExtra是髓鞘功能障碍的假定标志。因此，在这些初步数据的支持下，本项目的主要目的是检验：1)PSD的视觉工作记忆能力和整体认知障碍在很大程度上是由脑白质微结构的缺陷解释的，因此2)髓鞘功能障碍的扩散峰度成像(DKI)标记是PSD的候选神经生物学内表型。将使用包括DKI、磁共振波谱和遗传分析在内的确证方法来验证髓鞘障碍假说。本研究的结果可能揭示更具体的脑白质微结构改变，并有助于理解PSD认知功能障碍的机制。建议的生物标志物可能被证明有助于表征治疗效果和识别高危个体。

 DESCRIPTION (provided by applicant): Psychotic spectrum disorders (PSD) are disabling severe mental syndromes with high prevalence. Among the PSD deficits, cognitive dysfunction represents a core characteristic shown to the best predictor of poor outcome and chronic disability. However, current therapies do not adequately address cognitive symptoms. This limitation reflects to a large degree the still incipient and incomplete understanding of the involved neural mechanisms. A significant predictor of cognitive ability in both healthy individuals and individuals on the psychotic spectrum is working memory capacity, a cognitive domain impaired in many forms of psychopathology. Our preliminary data, based on Diffusion Kurtosis Imaging (DKI) technique, suggest that a) in the healthy brain, interindividual variations in visual working memory capacity relates to a large degree to axonal density (measured by Axonal Water Fraction (faxon )) of the white matter pathways connecting brain regions known to be involved in working memory processes, b) white matter deficits in schizophrenia (SZ), a primary PSD syndrome, are driven by impairments in Extra-axonal Radial Diffusivity (RDextra), a putative marker of myelination, and c) visual working memory capacity associations to white matter microstructural properties are altered in SZ, a primary PSD disorder, with relationships with critical pathways connecting prefrontal and temporal brain regions no longer present or relating not to axonal density, but to RDextra, the putative marker of dysmyelination. Thus, supported by these preliminary data, the primary aims of this project are to test that: 1) visual working memory capacity and overall cognitive deficits in PSD are explained to a large degree by deficits in white matter microstructure and therefore 2) Diffusion Kurtosis Imaging (DKI) markers of dysmyelination are candidate neurobiological endophenotypes of PSD. The dysmyelination hypothesis will be validated using a corroborative approach that includes DKI, Magnetic Resonance Spectroscopy, and genetic assays. The results of this study may reveal more specific microstructural alterations of white matter and contribute to the understanding of the mechanisms underlying cognitive dysfunction in PSD. The proposed biomarkers may prove instrumental in characterizing treatment efficacy and identifying at risk individuals.