Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia

项目摘要 2020年NIMH研究战略计划呼吁针对精神疾病的神经生物学进行调查 在整个生命周期中的疾病。最近在早期精神病领域的创新已经建立了关键的 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）神经生物学和治疗。缺乏捕捉动态变化的特异性生物标志物 沿着SZ轨迹阻碍了靶向治疗开发的进展。越来越多的证据表明， 深圳的寿命是两个不同维度的产物：衰老和病程。但具体 这些方面的发展轨迹仍不清楚。捕获独特和/或重叠的特异性生物标志物 其机制的某些方面尚不清楚。认知和更广泛的临床与衰老和SZ疾病的相关性 其过程及其对治疗的影响尚待确定。我们建议研究微分 SZ神经生物学方面的衰老和疾病过程，以开发特定的生物标志物， 可以提供可操作的干预目标。该建议是基于一种新的SZ机制模型 跨越成人寿命的轨迹，在前边缘回路中定位不同的生物指纹 对于SZ的衰老和疾病过程：（1）在电路的功能和结构的改变，发生在早期， 寿命，并且在幅度上大于正常老化（加速老化）预期的变化 （2）SZ早期区域特异性前边缘“过度活跃”，随后 在晚期SZ中转化为“活动减退”（病程维度）。该模型具有很强的 证据基础;它是可测试的;如果得到证实，它将为未来的发展提供重要指导。 靶向治疗剂，例如，减少SZ早期的前边缘功能亢进， 功能在先进的SZ和沿着老化轨迹。在SZ和匹配的健康对照的样品中（n=168， 84/组）年龄在18-75岁之间，我们将确定一组广泛的生物标志物[通过多模式脑成像：新的 三重重聚焦1H-MRS、高分辨率灌注（血管空间占用）和基于任务的fMRI]，沿着 具有全面的认知和临床特征。将在基线时采集所有测量值， 在2年纵向随访时重复。使用尖端的计算方法，我们将研究（i） 衰老和SZ病程对前边缘系统生物标志物的影响，以及这些生物标志物之间的相互作用 影响;（ii）不同生物标志物的寿命轨迹;（iii）年龄和SZ中边缘系统生物标志物的模式 基于病程的亚组（例如，年轻人与老年人，早期课程与高级SZ），以及数据- 驱动子组（例如，有与无加速老化曲线的那些）;以及（iv） 生物标志物以及认知和临床结果。这项研究将通过提供新颖的 生物标志物，捕捉独特的神经生物学贡献的老化和疾病的过程中，在深圳，并将激励 在整个生命周期中对SZ机制的未来研究，以及精确治疗的发展。

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.