Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia

项目总结 2020年NIMH研究战略计划呼吁开展针对精神疾病神经生物学的研究 一生中都有疾病。最近在早期精神病领域的创新已经确立了关键的 及时干预的重要性。然而，在更广泛的寿命方法方面进展甚微 精神分裂症(SZ)的神经生物学和治疗。缺乏捕捉动态变化的特定生物标志物 沿着深圳的轨迹阻碍了靶向治疗发展的进展。越来越多的证据表明 SZ的寿命是两个不同维度的产物：衰老和病程。然而，准确的 这些维度的轨迹仍不清楚。捕捉唯一和/或重叠的特定生物标志物 他们机制的某些方面是不可用的。衰老和SZ病的认知和更广泛的临床相关性 当然，它们对治疗的影响还有待确定。我们建议调查差异 通过衰老和病程捕捉SZ神经生物学的方面，以开发特定的生物标记物 可能会为干预提供可行的目标。这一建议是基于SZ的一种新的机理模型 成人寿命的轨迹，在前缘环路内定位不同的生物指纹 对于SZ的衰老和病程：(1)早期发生的电路功能和结构的改变 寿命并比正常老化(加速老化)时预期的变化幅度更大 (2)SZ早期区域特异性的前缘“多动”，随后 转化为进展期SZ的“活动不足”(病程维度)。提出的模型具有很强的通用性 它是可以检验的，如果得到证实，将为未来的发展提供重要指导 靶向治疗，例如，减少早期SZ的前缘过度活动与增强同一回路的 在晚期SZ和老化轨迹中发挥作用。在SZ和匹配的健康对照组的样本中(n=168， 84/组)年龄18-75岁，我们将确定广泛的生物标记物[通过多模式脑成像：新奇 三重聚焦1H-MRS、高分辨率灌注(血管空间占有率)和基于任务的fMRI]，以及 具有全面的认知和临床特征。所有措施都将在基线和 重复2年的纵向随访。使用尖端的计算方法，我们将研究(I) 增龄和SZ病程对前缘系统生物标志物的影响及其相互作用 影响；(Ii)不同生物标志物的寿命轨迹；(Iii)边缘系统生物标志物在年龄和深圳的模式 基于病程的亚组(例如，年轻人与老年人、早期病程与晚期SZ)，以及在数据中- 驱动亚组(例如，那些具有加速老化特征的亚组与不具有加速老化特征的亚组)；以及(Iv) 生物标记物以及认知和临床结果。这项研究将通过提供新颖的 捕捉深圳衰老和病程的独特神经生物学贡献的生物标志物，并将激励 未来对SZ机制的研究跨越寿命，并开发精确的治疗方法。

PROJECT SUMMARY The 2020 NIMH Strategic Plan for Research calls for investigations targeting neurobiology of mental illness across the lifespan. Recent innovations in the field of early psychosis have established the critical importance of timely interventions. However, little progress has been made in broader lifespan approaches to schizophrenia (SZ) neurobiology and treatment. The lack of specific biomarkers capturing dynamic alterations along the SZ trajectory hinders progress in targeted treatment development. Growing evidence suggests that the SZ lifespan is the product of two distinct dimensions: aging and disease course. However, the exact trajectories of these dimensions remain unclear. Specific biomarkers capturing unique and/or overlapping aspects of their mechanisms are unavailable. Cognitive and broader clinical correlates of aging and SZ disease course, and their implications for treatment, are yet to be identified. We propose to investigate differential aspects of SZ neurobiology captured by aging and disease course, in order to develop specific biomarkers which may offer actionable targets for intervention. The proposal is predicated on a novel mechanistic Model of SZ Trajectories across the Adult Lifespan, positing distinct biological fingerprints within the anterior limbic circuit for aging and disease course in SZ: (1) alterations in the circuit’s function and structure that occur earlier in the lifespan and are larger in magnitude than the alterations expected with normal aging (accelerated aging dimension); and (2) regionally-specific anterior limbic “hyperactivity” in early SZ, with a subsequent transformation into “hypoactivity” in advanced SZ (disease course dimension). The proposed Model has a strong evidential basis; it is testable; and, if confirmed, it will provide important guidance for the development of future targeted therapeutics, e.g., reducing anterior limbic hyperactivity in early SZ vs. enhancing this same circuit’s function in advanced SZ and along the aging trajectory. In a sample of SZ and matched healthy controls (n=168, 84/group) aged 18-75 years we will ascertain a broad panel of biomarkers [via multimodal brain imaging: novel triple-refocusing 1H-MRS, high-resolution perfusion (Vascular Space Occupancy), and task-based fMRI], along with comprehensive cognitive and clinical characterization. All measures will be acquired at baseline and repeated at 2-year longitudinal follow-up. Using cutting-edge computational approaches, we will examine (i) effects of aging and SZ disease course on anterior limbic system biomarkers, and interactions between these effects; (ii) lifespan trajectories for different biomarkers; (iii) patterns of limbic system biomarkers in age- and SZ disease course-based subgroups (e.g., Younger vs. Older, Early-Course vs. Advanced SZ), as well as in data- driven subgroups (e.g., those with vs. without accelerated aging profiles); and (iv) associations between biomarkers and cognitive and clinical outcomes. This research will advance the field by providing novel biomarkers that capture unique neurobiological contributions of aging and disease course in SZ, and will motivate future studies on SZ mechanisms across the lifespan, and development of precision treatments.