Influence of Psychosis on Brain-Behavior Endophenotypes for Bipolar Disorder

描述（由申请人提供）：本研究的目的将：(1)开发双相I型障碍（BPI）的候选神经认知和神经影像学内表型，(2)检查精神病史与BPI患者这些脑行为标记物的关联，(3)确定这些标记物是否对精神病的责任敏感。因此，该项目有两个重叠的目标：广泛开发BPI的候选内表型和鉴定精神病的候选内表型。这项研究的最终希望是开发标记物，以表征BPI的生物学机制，并促进发现易患该疾病的基因。我们认为，对双相情感障碍不一致的兄弟姐妹的神经心理功能和大脑结构和功能进行全面评估，并对精神病史进行分层，是实现这些目标的战略上强有力的第一步。为此，我们将对130名心境良好的BPI患者（65名有精神病史）、130名未患病的同性兄弟姐妹和65名无血缘关系的对照者进行解剖和功能神经影像学检查，并进行神经心理学检查。在受影响个体（无论精神病史如何）及其未受影响亲属中发现异常的标记将被视为BPI的候选内表型（目的1）。神经心理学和神经影像学指标可以区分有和没有精神病史的BPI患者（Aim 2）及其兄弟姐妹（Aim 3），这些指标将被视为精神病的潜在内表型。I型双相情感障碍是一个重大的经济负担，并与大量发病率和死亡率相关。虽然已经确定BPI基本上是可遗传的，但这种疾病的分子遗传基础仍然难以捉摸，可能是因为疾病的复杂性、疾病表达的异质性以及与其他可能扭曲临床表现的疾病的合并症。有证据表明，易患BPI的基因可能在没有临床表型表达的情况下传播，因此人们开始关注该疾病的内部表型，即基因型和表型之间中介过程的指标。鉴于BPI患者中精神病的高发率以及精神病病史可能改变大脑结构和功能，我们认为阐明该疾病的神经认知和神经影像学内表型必须考虑到幻觉和妄想对这些标志物的潜在影响。这项研究将建立生物标记物，可以改善BPI患者的识别和治疗，并有可能改善精神障碍患者的识别和治疗，独立于他们的正式诊断。公共卫生相关性：I型双相情感障碍是一个主要的公共卫生负担，其生物学仍在很大程度上未知。通过开发对双相情感障碍遗传倾向敏感的大脑行为标记物，本研究将显著有助于发现易患双相情感障碍的基因，并有助于确定双相情感障碍的生物学决定因素。反过来，这应该导致改善双相情感障碍的特征和治疗。

DESCRIPTION (provided by applicant): The aims in this study will (1) develop candidate neurocognitive and neuroimaging endophenotypes for bipolar I disorder (BPI), (2) examine the association of history of psychosis and these brain-behavior markers in BPI patients, and (3) determine if markers are sensitive to liability for psychosis. Thus, the project has two overlapping goals: the development of candidate endophenotypes for BPI broadly and the identification of candidate endophenotypes for psychosis. The ultimate promise of this research is to develop markers that will characterize the biological mechanisms of BPI and facilitate the discovery of genes that predispose the illness. We believe that a comprehensive assessment of neuropsychological functioning and brain structure and function in sibling pairs discordant for bipolar disorder and stratified for psychosis history is a strategically strong first step towards reaching these goals. To this end, we will perform anatomic and functional neuroimaging and conduct neuropsychological examinations on 130 euthymic patients with BPI (65 with history of psychosis), 130 of their unaffected same-sex siblings and 65 unrelated comparison subjects. Markers found to be aberrant in both affected individuals (regardless of history of psychosis) and in their unaffected relatives will be considered candidate endophenotypes for BPI (Aim 1). Neuropsychological and neuroimaging measures that distinguish between BPI patients with and without history of psychosis (Aim 2) and their siblings (Aim 3) will be considered potential endophenotypes for psychosis. Bipolar I disorder represents a significant economic burden and is associated with substantial morbidity and mortality rates. Although it is well established that BPI is substantially heritable, the molecular genetic basis for this illness remains elusive, potentially because of illness complexity, heterogeneity of disease expression, and comorbidity with other disorders that may distort clinical presentation. In the face of evidence that genes predisposing to BPI may be transmitted without expression of the clinical phenotype, interest has arisen in developing endophenotypes for the illness, indicators of processes mediating between genotype and phenotype. Given the high rates of psychosis in BPI and that history of psychosis may alter brain structure and function, we believe that elucidating neurocognitive and neuroimaging endophenotypes for the disorder must account for the potential impact of hallucinations and delusions on these markers. This research will established biomarkers that could improve the identification and treatment of BPI patients and, potentially, patients with psychotic disorders, independent of their formal diagnosis. PUBLIC HEALTH RELEVANCE: Bipolar I disorder is a major public health burden whose biology is still largely unknown. Through the development of brain-behavior markers sensitive to genetic liability for bipolar disorder, the proposed research should significantly aid the discovery of genes that predispose the illness and facilitate the identification of the biological determinants of bipolar disorder. This, in turn, should lead to improved characterization and treatment of bipolar disorder.