Neuroprogression across the Psychosis Spectrum in the Early Course of Illness

项目摘要/摘要 这是NIMH R01的一项建议，题为：“精神病早期的神经进展 疾病的威胁。“在疾病的最初几年中发生的神经渐进性变化已经被描述为 神经认知测试、PET、CT、fMRI和死后脑研究；然而，这些研究主要依赖于 涉及频繁测量的横断面数据和纵向研究很少见，这限制了我们的 了解这些措施在这一关键时期的实际时间和轨迹。这个 开发和实施有针对性和有效的治疗方法至关重要地依赖于 了解疾病进展的时间和性质，以便有针对性地 干预。因此，迫切需要仔细地描述早期神经进展的特征。 如果我们要开发有效的干预措施，以保留功能的区域为目标，潜在地 防止进一步衰退和慢性功能丧失。这一知识鸿沟严重限制了我们 在可能最有效的时候开发有针对性的治疗方法，并根据患者的需要量身定做治疗方法。 本提案的目的是系统地、多模式地描述神经进展 在精神病患者的早期病程中，使用 加速纵向设计。首先，我们将测量神经认知和神经生物学的变化 前八年的疾病，以表征神经进展的时间和幅度的变异性 跨越关键措施。第二，我们将评估神经进步轨迹在临床上的预测性。 和功能结果。我们还将利用基线认知和大脑测量的异质性来 通过神经进展情况描述患者的特征，并测试基线情况是否提供更好的预测 临床和功能病程。这些数据的丰富性也将使我们能够探索 神经进展轨迹及其与临床和功能结果的关系。有人争辩说 结合临床、结构和功能成像以及认知测量的数据优于 单峰数据在预测病程和结局中的作用(6)。这个项目的发现将加速 确定与临床结果密切相关的可操作的治疗目标，并提供 早期干预策略关键时期个体化治疗实施指导 可能是最有效的。值得注意的是，这项提案旨在为早期的人类连接项目建立基础 精神病(U01MH109977，PI：Shenton)通过使用相同的高质量方法学并添加 对基线数据收集的纵向评估已经在进行中，使 HCP-EP数据的研究现状和使用情况。PI是早期调查员，K23 Awardee拥有 职业生涯专注于表征多维症状领域的性质和过程(例如 认知、奖赏处理)和精神病的靶向治疗方法。

PROJECT SUMMARY/ABSTRACT This is an NIMH R01 proposal entitled, “Neuroprogression across the Psychosis Spectrum in the Early Course of Illness.” Neuroprogressive changes that occur through the early years of illness have been described using neurocognitive testing, PET, CT, fMRI, and post-mortem brain studies; however, these studies rely mainly on cross-sectional data, and longitudinal studies involving frequent measurements are rare, limiting our understanding of the actual timing and trajectories of these measures within this critical time period. The development and implementation of targeted and effective treatments is critically dependent on clear understanding of the timing and nature of disease progression in order to target processes amenable to intervention. Thus, there is an urgent need to carefully characterize neuroprogression in the early course of psychosis if we are to develop effective interventions to target areas of preserved functioning, potentially preventing further decline and chronic loss of functioning. This knowledge gap severely limits our ability to develop targeted treatments when they may be most effective, and to tailor treatment to patients' needs. The aim of the present proposal is the systematic, multimodal characterization of neuroprogression throughout the early course of illness in a cross-diagnostic sample of patients with psychosis using an accelerated longitudinal design. First, we will measure neurocognitive and neurobiological change over the first eight years of illness in order to characterize variability of timing and magnitude of neuroprogression across key measures. Second, we will assess the predictive utility of neuroprogressive trajectories on clinical and functional outcomes. We will also leverage the heterogeneity in baseline cognitive and brain measures to characterize patients by neuroprogressive profile and test whether baseline profiles offer improved prediction of clinical and functional course. The richness of these data will also position us to explore heterogeneity of neuroprogressive trajectories and their associations with clinical and functional outcomes. It has been argued that combining data from clinical, structural and functional imaging, and cognitive measures is superior to monomodal data in the prediction of course and outcome (6). Findings from this project will hasten identification of actionable treatment targets that are closely associated with clinical outcomes, and provide guidance for individualized treatment implementation during a critical period where early intervention strategies may be most effective. Notably, this proposal aims to build on the Human Connectome Project for Early Psychosis (U01MH109977, PI: Shenton) by utilizing the same high-quality methodology and adding longitudinal assessments to baseline data collection already underway, maximizing both the power of the present study and the utility of the HCP-EP data. The PI is an early stage investigator and K23 Awardee with a career focus on characterization of the nature and course of multidimensional symptom domains (e.g. cognition, reward processing), and targeted treatment approaches in psychosis.