Accelerated Biological Aging in Schizophrenia

描述(申请人提供)：精神分裂症(SZ)是致残最严重的精神疾病之一。它还与较高的医疗合并症和比普通人群短20至25年的寿命有关。有间接证据表明，SZ的生物衰老可能会加速；然而，这将是第一次对SZ患者与正常受试者在成年生命的关键时期(26-65岁)进行生物衰老的实验室系统和神经生理学标记物的比较研究。这项研究将使用一组跟踪“生物老化”的系统生物标记物，并可能反映衰老的病理生理学，特别是在SZ，在胰岛素失衡(胰岛素抵抗的稳态模型评估)、炎症(C反应蛋白)、氧化应激(F2-异前列腺素)和细胞老化(端粒长度)方面，以及基于脑电的神经生理性老化标记物(错配负性)，该标记物在SZ患者中缺乏，与衰老和功能结果都有很强的相关性，并作为基因组关联研究的中间表型。受试者包括140名SZ患者和120名年龄在26-65岁之间的正常对照受试者。我们将招募比NC受试者更多的SZ受试者，因为预计SZ样本的结果差异更大，并在SZ组中最大限度地分析疾病和治疗特定变量。每十年(26-35、36-45等)的受试者将在多队列纵向设计中每年跟踪最多四年，这是对横断面设计的重大改进，平衡招聘每十年提供35名SZ和30名NCS。虽然在假设中，年龄将主要被视为一个连续的(如果可能是非线性的)预测因素，但年龄队列将被纳入初步分析，以估计和测试是否可能存在显著的年龄队列和/或抽样(例如，“健康幸存者”)影响。在控制了时间顺序年龄后，将比较NC组和SZ组中这些测量随时间变化的基线值和变化率。我们将在SZ和NC组中检查个人相关因素(如感知压力、吸烟状况、药物使用、认知功能和体力活动模式)在多大程度上预测衰老生物标记物的个体差异；以及其他与疾病和治疗相关的因素(发病年龄、当前和累积的抗精神病药物使用)是否预测SZ样本中这些标记物的差异。这项研究的第二个目的将是检查日常功能是否可以通过衰老生物标记物的个体差异来预测。该项目与NIMH战略目标2有关：绘制精神疾病轨迹图，以确定何时、何地和如何干预。这项研究在关注深圳的生物老化和这一过程的假定解释变量方面是新颖的。发现深圳是否发生了加速的生物衰老，并了解其潜在的机制，应该会导致预测、跟踪和治疗在该人群中常见的严重医学合并症的新方法。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is one of the most disabling mental illnesses. It also is associated with higher medical comorbidity and a 20- to 25-year shorter life span than the general population. There is indirect evidence suggesting that biological aging may be accelerated in SZ; however, this will be the first study of laboratory-based systemic and neurophysiological markers of biological aging comparing persons with SZ to normal subjects during critical periods of the adult lifespan (26-65 years). The study will use a selected panel of systemic biomarkers that track "biological aging" and may reflect the pathophysiology of aging, especially in SZ, in terms of insulin dysregulation (Homeostatic Model Assessment of Insulin Resistance), inflammation (C-reactive protein), oxidative stress (F2-isoprostanes), and cell aging (telomere length), as well as a validated EEG-based marker of neurophysiological aging (mismatch negativity) that is deficient in SZ patients, has robust associations with both aging and functional outcome, and serves as an intermediate phenotype in genomic association studies. Subjects will include 140 with SZ and 120 normal comparison subjects (NCs) aged 26-65 years. We will recruit more SZ than NC subjects because of expected greater variation in outcomes in the SZ sample, and to maximize power in analyses of illness- and treatment-specific variables in the SZ group. Subjects in each decade (26-35, 36-45, etc.) will be followed annually for up to four years in a Multi-cohort Longitudinal Design, a significant improvement over cross-sectional designs, with balanced recruitment providing 35 subjects with SZ and 30 NCs per decade. While age will be treated primarily as a continuous (if potentially nonlinear) predictor in the hypotheses, age cohort will be entered in preliminary analyses to estimate and test for the possible presence of significant age cohort and/or sampling (e.g., "healthy survivor") effects. Baseline values and rates of change in these measures over time in the NC and SZ groups will be compared, after controlling for chronological age. We will examine the extent to which person-related factors such as perceived stress, smoking status, drug use, cognitive function, and physical activity patterns predict individual variation in biomarkers of aging in SZ and NC groups; and whether additional illness- and treatment-related factors (age of onset of illness, current and cumulative antipsychotic use) predict variation in those markers in the SZ sample. A secondary aim of the study will be to examine if everyday functioning is predicted by individual differences in biomarkers of aging. This project is related to the NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. This study is novel in its focus on biological aging in SZ and on putative explanatory variables of this process. Discovering whether accelerated biological aging occurs in SZ and understanding the underlying mechanisms should lead to new ways of predicting, tracking, and treating the serious medical co-morbidities commonly seen in this population.