Individualized risk prediction in persons at clinical high-risk for psychosis using neuromelanin-sensitive MRI.

摘要 精神障碍是一种严重的、使人虚弱的疾病，治疗选择有限。身份识别 患精神障碍风险增加的个人是关键的第一步 预防。先前的研究已经证实，那些处于临床高危状态(CHR)的人 作为一个群体，发展成全面的精神障碍(变性者)，往往表现出过量的多巴胺 在黑质-纹状体通路，如正电子发射计算机断层扫描所测。但这一发现不太可能有助于确定 个别受试者由于其预测价值低和与PET相关的实际限制 (例如，辐射暴露)。之前的研究也证实了广泛的 可用的临床变量-NAPLS2计算器-可以预测中度转换的风险 预测性价值。在这里，我们建议使用神经黑色素敏感核磁共振(NM-MRI)，一种新的，易于... 获得可安全用于儿童个体的非侵入性MRI技术，并提供 精神病相关黑质-纹状体多巴胺过量的替代物，作为风险的预测生物标记物 在CHR个体中的转换。此外，我们的目标是将这一客观生物标记物与 NAPLS2计算器中的临床(主观)信息，以测试该生物标记物是否可以改善 个人风险预测的准确性超过了仅靠临床信息实现的准确性，这是一个关键 先前在慢性阻塞性肺疾病人群中进行的影像研究的生物标记物的潜在临床实用性的测试 很大程度上被忽视了。因此，我们的目标是结合易于获取的客观核磁共振成像的优点 利用生物标记物研究精神病和已建立的风险算法的病理生理学 基于临床数据，以更准确地识别有可能发展为全面精神病的个体 并预测转化的时间。具体地说，根据我们的初步数据，我们 第一个目的是确定黑质致密部(SNC)的基线NM-MRI是否可以 显示信号异常增加，特别是在慢性阻塞性肺疾病患者中有更严重的衰减 精神病症状。其次，我们的目标是确定基线NM-MRI SNC信号是否 特别是在CHR转换者中，与非转换者相比，在社会人口学上是升高的 与健康对照组相匹配。第三，我们的目标是评估NM-MRI SNC信号是否可以改善 风险预测的准确性高于从NAPLS2计算器得出的预测。如果成功， 因此，这项提议将建立一种新的MRI生物标记物的潜在临床实用价值，该生物标记物可以 在儿科和非儿科人群中广泛采用和安全使用，以提高风险预测 用于精神病的发展，并可能监测个性化的治疗和援助 治疗选择。

ABSTRACT Psychotic disorders are severe, debilitating illnesses with limited treatment options. Identification of individuals who are at elevated risk for developing psychotic disorders is a critical first step for prevention. Prior research has established that those individuals at clinical high risk (CHR) who go on to develop a full-blown psychotic disorder (converters), as a group, tend to exhibit excess dopamine in the nigro-striatal pathway, as measured by PET. But this finding is unlikely to help identify individual subjects given its low predictive value and the practical limitations associated with PET (e.g., radiation exposure). Previous research has also established that a combination of widely available clinical variables –the NAPLS2 calculator– can predict risk of conversion with moderate predictive value. Here, we propose to use neuromelanin-sensitive MRI (NM-MRI), a novel, easy-to- acquire, non-invasive MRI technique that can be safely used in pediatric individuals and that provides a proxy for psychosis-related nigro-striatal dopamine excess, as a predictive biomarker for risk of conversion in CHR individuals. Furthermore, we aim to combine this objective biomarker with the clinical (subjective) information in the NAPLS2 calculator to test whether this biomarker can improve the accuracy of individual risk prediction beyond that achieved by clinical information alone, a critical test of the potential clinical utility of a biomarker that previous imaging studies in CHR populations have largely ignored. Thus, we aim to combine the strengths of an easy-to-acquire, objective MRI biomarker tapping into the pathophysiology of psychosis and those of an established risk algorithm based on clinical data to more accurately identify individuals at risk for developing full-blown psychotic disorders and predict time to conversion. Specifically, and as supported by our preliminary data, we first aim to determine whether baseline NM-MRI of the substantia nigra, pars compacta (SNc) can reveal abnormally increased signal specifically in those CHR individuals with more severe attenuated psychotic symptoms. Second, we aim to determine whether baseline NM-MRI SNc signal is particularly elevated in CHR converters compared to non-converters and to sociodemographically matched healthy controls. Third, we aim to assess whether NM-MRI SNc signal can improve the accuracy of risk predictions over and above those derived from the NAPLS2 calculator. If successful, this proposal will thus establish the potential clinical utility of a novel MRI biomarker that can be adopted widely and used safely in pediatric and non-pediatric populations to enhance risk predictions for the development of psychosis and potentially to monitor treatment and aid in personalized treatment selection.