Accelerated Biological Aging in Schizophrenia

描述（由申请人提供）：精神分裂症（SZ）是最致残的精神疾病之一。它还与更高的医疗并发症和比普通人群短20至25年的寿命有关。有间接证据表明，SZ的生物老化可能会加速;然而，这将是第一项基于实验室的系统和神经生理学生物老化标志物的研究，比较SZ患者与正常受试者在成人寿命的关键时期（26-65岁）。这项研究将使用一组选定的系统性生物标志物来跟踪“生物老化”，并可能反映衰老的病理生理学，特别是在SZ中，在胰岛素失调方面（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）和细胞衰老（端粒长度），以及一个有效的基于脑电图的神经生理老化标志物在SZ患者中缺乏的（错配负性），与衰老和功能结果两者具有强相关性，并且在基因组关联研究中用作中间表型。受试者将包括140名SZ受试者和120名正常对照受试者（NC），年龄为26-65岁。我们将招募比NC更多的SZ受试者，因为SZ样本中结局的预期差异更大，并最大限度地提高SZ组疾病和治疗特异性变量分析的功效。每十年（26-35岁、36-45岁等）的受试者将在多队列纵向设计中每年随访长达4年，这是对横断面设计的显著改进，平衡招募每10年提供35例SZ受试者和30例NC受试者。虽然年龄在假设中主要被视为连续（如果可能是非线性）预测因素，但年龄队列将进入初步分析，以估计和检验可能存在的显著年龄队列和/或采样（例如，“健康的幸存者”）的影响。在控制实际年龄后，将比较NC组和SZ组的基线值和这些指标随时间的变化率。我们将研究个人相关因素，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SZ和NC组衰老生物标志物的个体差异;以及其他疾病和治疗相关因素（发病年龄，当前和累积抗精神病药物使用）是否预测SZ样本中这些标志物的变化。这项研究的第二个目的是检查日常功能是否可以通过衰老生物标志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，以确定何时，何地以及如何干预。这项研究是新颖的，其重点是在SZ的生物老化和这个过程中假定的解释变量。发现SZ是否发生加速生物老化并了解其潜在机制，应该会导致预测，跟踪和治疗该人群中常见的严重医学共病的新方法。

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.