Influence of Psychosis on Brain-Behavior Endophenotypes for Bipolar Disorder

描述(由申请人提供)：这项研究的目的将(1)开发双相I型障碍(BPI)的候选神经认知和神经成像内表型，(2)检查BPI患者的精神病史和这些脑行为标记物的相关性，以及(3)确定标记物是否对精神病的易感性敏感。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，以表征BPI的生物学机制，并促进发现易患这种疾病的基因。我们认为，对双相情感障碍和精神病史不一致的同胞对的神经心理功能和大脑结构和功能进行全面评估，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名精神愉悦的BPI患者(65名有精神病史)、130名未受影响的同性同胞和65名无关的对照对象进行解剖和功能神经成像以及神经心理学检查。在受影响的个体(无论有无精神病病史)及其未受影响的亲属中被发现异常的标记物将被认为是BPI的候选内表型(目标1)。神经心理学和神经成像测量区分有和没有精神病病史的BPI患者(AIM 2)和他们的兄弟姐妹(AIM 3)将被认为是精神病的潜在内表型。双相I型障碍是一个重大的经济负担，并与相当大的发病率和死亡率有关。虽然众所周知，BPI基本上是可遗传的，但这种疾病的分子遗传学基础仍然难以捉摸，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共病。面对BPI易感基因可能在没有临床表型表达的情况下传播的证据，人们对开发该病的内表型感兴趣，这是在基因型和表型之间进行调节的过程的指示器。鉴于BPI中精神病的高发生率，以及精神病病史可能改变大脑结构和功能，我们认为阐明这种疾病的神经认知和神经成像内表型必须考虑幻觉和妄想对这些标记物的潜在影响。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，并可能改善精神障碍患者的识别和治疗，而不依赖于他们的正式诊断。公共卫生相关性：双相I型障碍是一种主要的公共卫生负担，其生物学特性在很大程度上仍不清楚。通过开发对双相情感障碍遗传易感性敏感的大脑行为标记，拟议的研究将大大有助于发现易患疾病的基因，并有助于识别双相情感障碍的生物决定因素。反过来，这应该会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.