Influence of Psychosis on Brain-Behavior Endophenotypes for Bipolar Disorder

精神病对双相情感障碍脑行为内表型的影响

• 批准号: 8241065
• 负责人: DAVID C GLAHN
• 金额: $ 42.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241065
• 关键词: Accounting; Adoption; Affect; Amygdaloid structure; Anatomy; Anterior; Antipsychotic Agents; Biological; Biological Markers; Biology; Bipolar Disorder; Brain; Characteristics; Clinical; Comorbidity; Data; Defect; Delusions; Development; Diagnosis; Diagnostic; Disease; Disease remission; Economic Burden; Emotional; Emotions; Etiology; Evaluation; Family; First Degree Relative; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genotype; Goals; Hallucinations; Health; Heterogeneity; Individual; Lateral; Lead; Link; Magnetic Resonance Imaging; Manic; Measures; Mediating; Memory; Molecular Genetics; Morbidity - disease rate; Nervous system structure; Neurocognition; Neurocognitive; Neurocognitive Deficit; Participant; Patients; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Process; Psychotic Disorders; Public Health; Quantitative Trait Loci; Recording of previous events; Recruitment Activity; Relative (related person); Research; Resolution; Risk; Short-Term Memory; Siblings; Structure; Substance abuse problem; Susceptibility Gene; Symptoms; Testing; Twin Multiple Birth; Ventral Striatum; Work; affection; affective psychoses; base; brain behavior; candidate identification; clinical phenotype; density; endophenotype; gene discovery; genetic pedigree; gray matter; improved; interest; millimeter; mortality; neuroimaging; neurophysiology; neuropsychological; proband; psychosocial; relating to nervous system; sex; treatment response

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.

描述（由申请人提供）：这项研究的目的将（1）发展为双相情感I障碍（BPI）的候选神经认知和神经影像学内表型，（2）检查精神病史和BPI患者的这些大脑行为标记的关联，以及（3）确定标记对精神病的责任敏感。因此，该项目有两个重叠的目标：广泛的BPI候选内表型的开发以及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，并促进发现易感疾病的基因。我们认为，对双相情感障碍不一致的兄弟姐妹对神经心理功能，大脑结构以及功能的全面评估和精神病史进行了分层是实现这些目标的战略性第一步。为此，我们将对130名BPI（65例精神病史），130名未受影响的同性兄弟姐妹和65名无关比较的受试者对130例BPI（65例精神病史）进行解剖和功能性神经影像学并进行神经心理学检查。在受影响的个体中发现的标记物异常（无论精神病史）及其未受影响的亲戚将被视为BPI的候选内表型（AIM 1）。区分有和没有精神病病史的BPI患者（AIM 2）及其兄弟姐妹（AIM 3）的神经心理学和神经影像学措施将被视为精神病的潜在内表型。双极I障碍代表着重大的经济负担，并且与大量发病率和死亡率有关。尽管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，这可能是由于疾病的复杂性，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。面对证据表明，易感BPI的基因可能在没有临床表型的情况下传播，因此引起了人们对疾病开发内跨表型的兴趣，这是基因型和表型之间介导的过程的指标。鉴于BPI的精神病率很高，精神病的史可能会改变大脑的结构和功能，因此我们认为，阐明神经认知和神经成像的内表型对该疾病的疾病必须说明幻觉和妄想对这些标记的潜在影响。这项研究将建立生物标志物，可以改善对BPI患者的识别和治疗，并可能与精神疾病患者相对于其正式诊断无关。公共卫生相关性：双相情感障碍是一种主要的公共卫生负担，其生物学仍然在很大程度上未知。通过对双相情感障碍遗传责任敏感的脑行为标志物的发展，拟议的研究应显着帮助发现易感疾病并促进双相情感障碍生物学决定因素的基因。反过来，这应导致躁郁症的表征和治疗改善。

项目成果

Polygenic risk and white matter integrity in individuals at high risk of mood disorder.

• DOI: 10.1016/j.biopsych.2013.01.027
• 发表时间: 2013-08-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Whalley, Heather C.;Sprooten, Emma;Hackett, Suzanna;Hall, Lynsey;Blackwood, Douglas H.;Glahn, David C.;Bastin, Mark;Hall, Jeremy;Lawrie, Stephen M.;Sussmann, Jessika E.;McIntosh, Andrew M.
• 通讯作者: McIntosh, Andrew M.

Using structural MRI to identify bipolar disorders - 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group.

• DOI: 10.1038/s41380-018-0228-9
• 发表时间: 2020-09
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Nunes A;Schnack HG;Ching CRK;Agartz I;Akudjedu TN;Alda M;Alnæs D;Alonso-Lana S;Bauer J;Baune BT;Bøen E;Bonnin CDM;Busatto GF;Canales-Rodríguez EJ;Cannon DM;Caseras X;Chaim-Avancini TM;Dannlowski U;Díaz-Zuluaga AM;Dietsche B;Doan NT;Duchesnay E;Elvsåshagen T;Emden D;Eyler LT;Fatjó-Vilas M;Favre P;Foley SF;Fullerton JM;Glahn DC;Goikolea JM;Grotegerd D;Hahn T;Henry C;Hibar DP;Houenou J;Howells FM;Jahanshad N;Kaufmann T;Kenney J;Kircher TTJ;Krug A;Lagerberg TV;Lenroot RK;López-Jaramillo C;Machado-Vieira R;Malt UF;McDonald C;Mitchell PB;Mwangi B;Nabulsi L;Opel N;Overs BJ;Pineda-Zapata JA;Pomarol-Clotet E;Redlich R;Roberts G;Rosa PG;Salvador R;Satterthwaite TD;Soares JC;Stein DJ;Temmingh HS;Trappenberg T;Uhlmann A;van Haren NEM;Vieta E;Westlye LT;Wolf DH;Yüksel D;Zanetti MV;Andreassen OA;Thompson PM;Hajek T;ENIGMA Bipolar Disorders Working Group
• 通讯作者: ENIGMA Bipolar Disorders Working Group

The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder.

• DOI: 10.1176/appi.ajp.2017.17010095
• 发表时间: 2017-12-01
• 期刊: The American journal of psychiatry
• 作者: Doucet GE;Bassett DS;Yao N;Glahn DC;Frangou S
• 通讯作者: Frangou S

Fronto-temporal dysregulation in remitted bipolar patients: an fMRI delayed-non-match-to-sample (DNMS) study.

• DOI: 10.1111/j.1399-5618.2009.00703.x
• 发表时间: 2009-06
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: Robinson JL;Bearden CE;Monkul ES;Tordesillas-Gutiérrez D;Velligan DI;Frangou S;Glahn DC
• 通讯作者: Glahn DC

Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history.

• DOI: 10.1016/j.biopsych.2012.07.031
• 发表时间: 2013-03-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Anticevic, Alan;Brumbaugh, Margaret S.;Winkler, Anderson M.;Lombardo, Lauren E.;Barrett, Jennifer;Corlett, Phillip R.;Kober, Hedy;Gruber, June;Repovs, Grega;Cole, Michael W.;Krystal, John H.;Pearlson, Godfrey D.;Glahn, David C.
• 通讯作者: Glahn, David C.