Structural and Functional Brain Aging in Bipolar Disorder

描述(申请人提供)：双相情感障碍是一种致残且代价高昂的精神疾病。未来几十年，老年精神病患者的数量将迅速增加，但很少有针对老年躁郁症患者的研究。特别是，人们对衰老导致的大脑结构和功能的变化知之甚少，这可能是认知恶化的原因。NIMH已经认识到了这一令人遗憾的差距，PA-07-077呼吁“进行新的研究……旨在描绘神经回路……与晚年情绪和焦虑症有关。”这项拟议的研究结合了临床和神经科学的专业知识和尖端技术，由一位新的研究人员领导，旨在(1)调查双相情感障碍患者前额叶皮质(PFC)的结构、功能和连接性与年龄相关的差异，以及这些差异是否因正常年龄相关的变化而大于预期，(2)检查灰质和白质结构完整性是否可能作为年龄与PFC功能和功能连接性之间关系的中介，以及(3)PFC功能和功能连接性是否可能作为年龄和认知表现之间关系的中介。重要的二次分析将审查与衡量双相情感疾病的慢性化和病程有关的类似问题，例如自第一次发作以来的持续时间、躁狂和抑郁发作的次数以及累积接触精神药物。PFC结构和功能缺陷是公认的双相病理特征，可能与神经营养和细胞信号通路的生物学变化有关。一些研究发现，在双相情感障碍患者中，结构缺陷随着年龄的增长而恶化的程度比正常衰老时的预期更严重，但还没有研究将PFC灰质大小、白质完整性和组织、静息灌流以及脑功能反应和连接性的测量结合在一起，对双相情感障碍和健康个体一生中的大脑变化进行单一调查。我们的研究还旨在检查与年龄相关的大脑测量指标之间以及与认知表现之间的关系。我们将使用横断面设计来研究85名青少年或青壮年起病的双相I型障碍患者和85名年龄在30岁到79岁之间的健康人。患者将得到稳定的药物治疗，不会经历情绪发作或明显的情绪或精神症状，也不会有其他Axis I障碍，包括目前或最近的药物滥用或依赖。参与者将接受诊断和临床病史、当前症状、认知能力以及磁共振成像测量的大脑结构和功能的评估。在工作记忆任务中，将测量PFC灰质厚度、与PFC连接的束中的白质组织、前额叶皮质和连接区域的静息灌流和功能反应。这项研究的结果将有助于描述双相情感障碍的脑病理过程，并使未来能够使用最佳措施进行纵向研究，并将重点放在最有可能发生变化的时间段上。 公共卫生相关性： 关于患有双相情感障碍的成年人的大脑在衰老过程中可能会发生什么变化，以及这些变化是否与健康老龄化中的变化不同，人们知之甚少。我们将研究年龄与前额叶皮质灰质厚度、白质组织和完整性以及认知活动中功能反应的磁共振成像指标在稳定性双相情感障碍患者和健康个体之间的关系。我们还将研究大脑测量如何相互联系，以及如何与认知能力相关，并检查其他慢性性测量如何与双相情感组的年龄差异有关。这项研究的结果将提高我们对衰老如何影响双相情感障碍大脑异常的了解，并可能提出旨在防止负面影响和利用任何积极变化的新治疗方法。

DESCRIPTION (provided by applicant): Bipolar disorder is a disabling and costly mental illness. The number of elderly mentally ill individuals will increase rapidly in the coming decades, yet there has been little research focused on geriatric bipolar patients. In particular, little is known about changes in brain structure and function due to aging that may underlie worsening cognition. NIMH has recognized this unfortunate gap, and PA-07-077 calls for "new research...aimed at delineating the neural circuitry...involved in late-life mood and anxiety disorders." Combining clinical and neuroscience expertise and cutting-edge technologies, the proposed study, led by a new investigator, aims to (1) investigate age-related differences in the structure, function, and connectivity of the prefrontal cortex (PFC) in bipolar disorder and whether these differences are greater than would be expected due to normal age-related changes, (2) examine whether gray and white matter structural integrity serve as possible mediators of the relationship between age and PFC function and functional connectivity, and (3) examine whether PFC function and functional connectivity serve as possible mediators of the relationship between age and cognitive performance. Important secondary analyses will examine similar questions regarding measures of chronicity of bipolar illness and illness course, such as duration since first episode, number of manic and depressive episodes, and cumulative exposure to psychotropic medications. PFC structural and functional deficits are recognized features of bipolar pathology and may be related to biological alterations in neurotrophic and cell signaling pathways. Some studies have found that structural deficits worsen with age among bipolar patients to a greater degree than expected in normal aging, but no study has yet combined measures of PFC gray matter size, white matter integrity and organization, resting perfusion, and functional brain response and connectivity in a single investigation of brain changes across the lifespan in bipolar disorder and healthy individuals. Our study is also designed to examine how age-associated brain measures relate to one another and to cognitive performance. We will use a cross-sectional design to study 85 patients with adolescent- or young-adult-onset Bipolar I disorder and 85 healthy individuals ranging in age from 30 to 79 years. Patients will be stably medicated, not experiencing a mood episode or significant mood or psychotic symptoms, and free of other Axis I disorders including current or recent substance abuse or dependence. Participants will be assessed for diagnosis and clinical history, current symptoms, cognitive performance, and brain structure and function as measured by magnetic resonance imaging. PFC gray matter thickness, white matter organization in tracts that connect with the PFC, resting perfusion and functional response of the prefrontal cortex and connected regions during working memory tasks will be measured. Results of this study will help characterize the course of brain pathology in bipolar disorder and enable future longitudinal investigations using the best measures and focusing on the most likely time period for change. PUBLIC HEALTH RELEVANCE: Little is known about how the brains of adults with bipolar disorder may change during aging and whether these changes are different from those seen in healthy aging. We will study the relationship of age to magnetic resonance imaging measures of prefrontal cortex gray matter thickness, white matter organization and integrity, and functional response during cognitive activities among groups of stable bipolar patients and healthy individuals. We will also examine how the brain measures relate to one another and to cognitive ability and examine how other chronicity measures may relate to age differences in the bipolar group. The results of this study will improve our knowledge about how aging influences brain abnormalities in bipolar disorder and may suggest new treatments designed to prevent negative effects and capitalize on any positive changes.