The Role of Dysmyelination in Cognitive Impairment of Psychotic Spectrum Disorders

 描述（由申请人提供）：精神病谱系障碍（PSD）是致残性严重精神综合征，患病率高。在PSD缺陷中，认知功能障碍是一个核心特征，是预后不良和慢性残疾的最佳预测因子。然而，目前的疗法并不能充分解决认知症状。这种局限性在很大程度上反映了对所涉及的神经机制的理解仍然处于初期阶段和不完全。健康个体和精神病谱系个体的认知能力的一个重要预测因素是工作记忆能力，这是一个在许多形式的精神病理学中受损的认知领域。我们基于扩散峰度成像（DKI）技术的初步数据表明：a）在健康大脑中，视觉工作记忆容量的个体间差异在很大程度上与轴突密度有关（通过轴突水分数（faxon）测量），B）精神分裂症（SZ）中的白色缺陷，一种原发性PSD综合征，由轴突外径向扩散率（RDextra）（髓鞘形成的推定标记）的损伤驱动，和c）视觉工作记忆能力与白色物质微结构性质的关联在SZ（一种原发性PSD病症）中改变，与连接前额和颞脑区域的关键通路的关系不再存在或与轴突密度无关，但对于RDextra，假定的髓鞘形成障碍的标记物。因此，在这些初步数据的支持下，本项目的主要目的是测试：1）PSD中的视觉工作记忆能力和整体认知缺陷在很大程度上可以通过白色物质微观结构的缺陷来解释，因此2）髓鞘形成障碍的弥散峰度成像（DKI）标记物是PSD的候选神经生物学内表型。将使用包括DKI、磁共振光谱和遗传测定在内的确证方法验证髓鞘形成障碍假说。本研究的结果可能揭示更具体的白色物质的微结构改变，并有助于了解PSD的认知功能障碍的机制。所提出的生物标志物可能有助于表征治疗效果和识别风险个体。

 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.