Characterization Of Neuropsychological Impairment In Schizophrenia

精神分裂症神经心理损伤的特征

• 批准号: 8556919
• 负责人: Karen FAITH Berman
• 金额: $ 150.57万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8556919
• 关键词: Age of Onset; Asia; Back; Behavior; Behavior assessment; Behavioral; Behavioral Mechanisms; Characteristics; Clinical; Cognitive; Cognitive deficits; Collection; Consensus; Data; Data Aggregation; Data Analyses; Data Set; Development; Dimensions; Disease; Europe; Factor Analysis; Family; Future; Genes; Genetic; Genetic Code; Genetic Polymorphism; Genome; Genotype; Geographic Locations; Growth; Heritability; Heterogeneity; Impaired cognition; Impairment; Individual; Japan; Journals; Link; Literature; Manuscripts; Memory; Meta-Analysis; Methodology; Methods; Modafinil; Modeling; Motivation; Neuropsychological Tests; Neuropsychology; North America; Outcome; Paper; Patients; Pattern; Performance; Personality; Personality Disorders; Pharmaceutical Preparations; Phenotype; Preparation; Protocols documentation; Psychiatry; Psychopathology; Publications; Quality Control; Questionnaires; Recording of previous events; Reporting; Research; Risk; Sampling; Schizophrenia; Short-Term Memory; Siblings; Social Adjustment; Sodium Channel; Sorting - Cell Movement; Stream; Structure; Symptoms; Syndrome; Techniques; Testing; Update; Variant; Work; base; case control; data management; depressive symptoms; design; falls; genetic analysis; genome wide association study; genome-wide; improved; information processing; interest; memory process; neuroimaging; neuropsychological; normal aging; novel; phenomics; processing speed; sex; sound; symposium; tolcapone; trait; treatment trial; visual memory

Current and recent work generally has focused on understanding and improving cognitive and behavioral phenotypes and applying these in analyses of whole genome association data. In Dickinson et al (2011) we extended earlier analyses of cognitive structure in schizophrenia cases and controls (Dickinson et al., 2006; Genderson, Dickinson et al., 2007). To achieve greater cognitive phenotype reliability and avoid redundant statistical comparisons, we used exploratory and confirmatory factor analyses separately in the CBDB samples (schizophrenia n=496, unaffected siblings n= 504, and controls n=823) and identified six positively correlated cognitive factors (for verbal memory, visual memory, n-back working memory, processing speed, card sorting, and span working memory). Data also supported a higher-order factor reflecting general cognitive ability, so-called g. We found that this structure was reasonably consistent across schizophrenia cases and controls, as had been shown previously (Dickinson et al., 2006), and extended this finding to include unaffected siblings. These findings guided construction of cognitive composite scores, which are in wide use in CBDB data analyses. One application of these composite scores has been to explore genome-wide associations in the CBDB samples. One exciting finding has been presented at genetics and psychiatry conferences and will be submitted for publication in the near future. We have identified an exciting and novel genome-wide significant association between our global cognitive composite and a sodium channel gene polymorphism that explains substantial variance in the cognitive impairment in our sample of people with schizophrenia and in their unaffected siblings an association that would not have been detected without the cognitive data aggregation strategy and composite scores developed by the Neuropsychology Lab. To gauge better which cognitive variables are best suited for genetics analysis, separate work has taken different approaches to estimate the heritability of these variables. Recently, a novel technique (GCTA) has been developed that permits estimates of heritability based on genome-wide genotype data from samples of unrelated people. The technique correlates pair-wise distances between genotypes for all possible pairs from a sample, with pair-wise differences in performance on a trait of interest (in our case, cognitive variables). We will present our first results contrasting GCTA methods with more traditional family-based methods at an upcoming conference and are beginning work on an associated manuscript. Wallwork et al. (2011) describes our efforts to determine a more empirically sound dimensional structure for patient data from the Positive and Negative Syndrome Scale (PANSS). The 30-item scale was developed with three syndrome scores, but previous analyses suggest that the scale really captures 5 or more dimensions of schizophrenia-associated symptomatology. We used existing literature to build a consensus five-dimension model of PANSS data then tested variations of this model using confirmatory factor analysis in the CBDB schizophrenia data and in an independent data set from Japan, supporting construction of new PANSS composite scores for positive, negative, depressive, agitated, and concrete/disorganized symptoms. Analogous lines of work are examining the dimensional structure of typical and abnormal personality in the CBDB data. We have elaborated and are refining five-dimension models for the Tri-dimensional Personality Questionnaire (TPQ) and for the SCID-II Personality Questionnaire (SCID-II). The TPQ targets personality more in the non-clinical range. The SCID-II is used to assess maladaptive personality disorder symptomatology. All of this work has been presented at scientific conferences and a paper on the SCID-II analyses is nearing completion. We design cognitive batteries for and collect, score and manage data from pharmacological trials seeking evidence of treatment-related changes in cognitive performance in schizophrenia patients and healthy controls. Recently, we have helped to develop the assessment and analysis strategy for a protocol examining an experimental agent (LX6171) and have worked on data analyses of information from tolcapone and modafinil treatment trials. We have completed an update of earlier meta-analyses of cognitive impairment in schizophrenia (Dickinson et al., 2007), showing that the cognitive impairment seen in people with schizophrenia has been consistent in magnitude and pattern over the past 30 years, and across different geographic regions around the world (i.e., North America, Europe and Asia). An early version of this work was presented at a conference and is accepted for publication as a chapter in an edited collection (Dickinson et al., in press), and a journal manuscript describing the final analysis is in preparation. Illness heterogeneity is a major challenge to the development of improved treatments in schizophrenia. As described in Cole et al. (2012), we have utilized latent class growth analysis (LCGA) in an effort to derive illness subtypes based on pre-morbid academic and social adjustment. We found evidence supporting three developmental trajectory subtypes: good/stable, insidious onset, and poor/deteriorating. These classes differed significantly in terms of age of onset, processing speed, and functioning after onset. The finding illustrates a potentially powerful methodology to attack heterogeneity challenges in schizophrenia research. Higher degrees of intra-individual variability (IIV) across neuropsychological tests have been recently linked to risk for schizophrenia, other clinical disorders, and normal aging. Cole et al (2011) is the first report showing decreasing IIV across cognitive domains in people with schizophrenia, their siblings and controls, respectively. Ongoing work is examining whether IIV might be useful as an intermediate phenotype. We have a large sample of unaffected siblings in the CBDB dataset, who, on average, share half their genetic code with an ill sibling, but do not share confounds, such as medication history and low motivation. In Wisner et al. (2011) we further characterized this sample, showing how sex and psychopathology history associate with sibling cognitive performance.

当前和最近的工作通常集中在理解和改善认知和行为表型上，并将其应用于整个基因组关联数据的分析。 在Dickinson等人（2011年）中，我们扩展了对精神分裂症病例和对照的认知结构的早期分析（Dickinson等，2006； Genderson，Genderson，Dickinson等，2007）。 To achieve greater cognitive phenotype reliability and avoid redundant statistical comparisons, we used exploratory and confirmatory factor analyses separately in the CBDB samples (schizophrenia n=496, unaffected siblings n= 504, and controls n=823) and identified six positively correlated cognitive factors (for verbal memory, visual memory, n-back working memory, processing speed, card sorting, and span working 记忆）。 数据还支持反映一般认知能力的高阶因子，即所谓的g。 我们发现，正如先前所示的（Dickinson等，2006），这种结构在精神分裂症病例和对照中相当一致，并扩展了这一发现以包括未受影响的兄弟姐妹。 这些发现指导了认知综合评分的构建，这些分数在CBDB数据分析中广泛使用。 这些复合分数的一种应用是探索CBDB样品中全基因组关联的一种应用。 在遗传学和精神病学会议上提出了一个令人兴奋的发现，并将在不久的将来提交出版。 我们已经确定了我们的全球认知复合材料与钠通道基因多态性之间的令人兴奋的新型基因组的显着关联，这解释了我们精神分裂症患者样本的认知障碍和未受影响的兄弟姐妹样本中的认知障碍差异，而在没有被认知数据集合策略和Neuropsysems Iropsysemy开发的情况下，这种关联将无法检测到这种关联。 为了更好地衡量哪些认知变量最适合遗传学分析，单独的工作采取了不同的方法来估计这些变量的遗传力。 最近，已经开发了一种新型技术（GCTA），该技术允许根据来自无关人员样本的全基因组基因型数据进行遗传力的估计。 该技术将基因型与样本的所有可能对之间的基因型之间的距离相关联，在感兴趣的特征（在我们的情况下，认知变量）上具有成对的性能差异。 我们将在即将举行的会议上提出第一个结果与更传统的基于家庭的方法对比的GCTA方法，并开始在相关的手稿上进行工作。 Wallwork等。 （2011年）描述了我们为确定正面和负综合征量表（PANSS）的患者数据更经验声音的尺寸结构的努力。 30个项目量表是通过三个综合征得分开发的，但先前的分析表明，该量表确实捕获了5个或更多的精神分裂症相关症状学。 我们使用现有文献来构建PANSS数据的共识五维模型，然后在CBDB精神分裂症数据中使用验证性因子分析测试了该模型的变化，并在日本的独立数据中，支持了新的PANSS复合分数，以构建正面，负，抑郁，搅动，搅动和混凝土/混蛋/混蛋症状。 类似的工作线正在检查CBDB数据中典型和异常人格的维度结构。 我们已经详细介绍了三维人格问卷（TPQ）和SCID-II人格问卷（SCID-II）的五维模型。 TPQ在非临床范围内更多地针对人格。 SCID-II用于评估适应不良的人格障碍症状。 所有这些工作都在科学会议上介绍，有关SCID-II分析的论文即将完成。 我们为从药理学试验中设计，收集，评分和管理数据的认知电池，以寻求精神分裂症患者和健康对照的认知性能变化的证据。 最近，我们帮助制定了检查实验剂（LX6171）的协议的评估和分析策略，并从Tolcapone和Modafinil治疗试验中进行了信息分析。 我们已经完成了较早的精神分裂症认知障碍荟萃分析的最新信息（Dickinson等，2007），表明在过去30年中，在精神分裂症患者中看到的认知障碍在大小和模式中一直保持一致，在过去的30年中，以及整个世界各地的不同地理区域（即北部美国，欧洲，欧洲，ASIA）。 这项工作的早期版本是在会议上提出的，并被接受作为编辑集合中的一章（Dickinson等人，印刷中），并且描述了最终分析的期刊手稿正在准备。 疾病异质性是改善精神分裂症治疗的主要挑战。 如科尔等人所述。 （2012年），我们利用了潜在的班级增长分析（LCGA），以根据疗效前的学术和社会调整来得出疾病亚型。 我们发现了支持三种发展轨迹亚型的证据：良好/稳定，阴险的发作和差/恶化。这些类别在发作年龄，加工速度和发作后功能方面有显着差异。该发现说明了一种潜在的有力方法论，可以攻击精神分裂症研究中的异质性挑战。 在神经心理学测试中，较高的个体内变异性（IIV）最近与精神分裂症，其他临床疾病和正常衰老的风险有关。 Cole等人（2011年）是第一个报告，该报告分别是精神分裂症，兄弟姐妹和对照人的认知领域跨认知领域的减少。正在进行的工作正在研究IIV是否可以作为中间表型有用。 我们在CBDB数据集中有大量未受影响的兄弟姐妹样本，他们平均与疾病的兄弟姐妹共享一半的遗传代码，但没有共享混杂的遗传，例如药物病史和动机较低。 在Wisner等。 （2011年）我们进一步表征了该样本，展示了性别和心理病理学史与兄弟姐妹认知表现如何联系在一起。