Association between tryptophan derivatives, frailty, and brain health in older adult ICU survivors

摘要/总结： 在重症监护室（ICU）住院治疗后幸存的患者可能会经历新的或恶化的身体状况， 精神和/或认知障碍（称为重症监护后综合征（PICS））。最容易受到 长期的身体和认知障碍是老年人（>60岁），因为预先存在的年龄相关的 身体虚弱或认知脆弱。这两者都增加了幸存者患老年痴呆症的可能性 疾病和相关的痴呆症。然而，尽管重症监护治疗的进步降低了死亡率， 在老年ICU幸存者中，大约67%患有PICS。然而，在老年人中识别风险 入院可能是困难的，因为1）患者的临床表现具有同质性， 与年龄相关的身体虚弱和严重疾病相比，只有严重疾病和2）许多 患者到达时严重虚弱，需要进行身体功能或其他意志评估 难因此，有必要寻找新的生物标志物来指导疾病的早期诊断、预后和治疗。 监测是确定的。就此而言，色氨酸衍生物，特别是犬尿氨酸和烟酰胺家族 (e.g., NAD+）介导慢性炎症和身体炎症之间的关系。 损伤或信号加速老化。然而，目前尚不清楚是否存在类似的关联。 在老年ICU患者中，神经毒性色氨酸代谢物升高相对于 神经保护性色氨酸代谢物来预测ICU中的不良健康结果。为了填补这一 知识缺口我设计了三项研究来探索色氨酸衍生物之间的联系， 肌肉骨骼健康和认知功能的前，内，和后ICU留。在本研究期间获得的技能 将通过犬尿氨酸途径更好地了解虚弱和肌肉-大脑串扰， 在ICU住院期间发生，以及它如何影响长期的身体和认知健康。

ABSTRACT/SUMMARY: Patients who survive an Intensive Care Unit (ICU) hospitalization will likely experience new or worsened physical, mental, and/or cognitive impairments (termed Post-Intensive Care Syndrome (PICS)). The most vulnerable to long-term physical and cognitive impairments are older adults (>60 y) because of pre-existing age-related physical frailty or cognitive frailty. Both of which increase a survivor’s likelihood of developing Alzheimer’s diseases and related dementias. However, although advances in critical care treatments have reduced mortality rates among older adult ICU survivors, roughly 67% suffer PICS. Yet, identification of at-risk older adults during admittance is likely difficult because of the 1) homogeneity in the clinical presentation of patients with pre-existing age-related physical frailty and critical illness compared to those suffering from only critical illness and 2) many patients arrive severely debilitated making administration of physical function or other volitional assessments difficult. Therefore, it is essential that new biomarkers to guide early diagnosis, prognosis, and disease monitoring are identified. To this point, tryptophan derivatives, particularly kynurenines and nicotinamide family (e.g., NAD+), have been shown to mediate the relationship between chronic inflammation and physical impairment or signal accelerated aging, respectively. However, it remains unknown if similar associations exist in older adult ICU patients and the prognostic utility of elevated neurotoxic tryptophan metabolites relative to neuroprotective tryptophan metabolites to predict adverse health outcomes while in the ICU. Thus, to fill this knowledge gap I have design three studies to explore the associations between tryptophan derivatives, musculoskeletal health, and cognitive function pre-, intra-, and post-ICU stay. Skills gained during this fellowship will provide be a better understanding of frailty and muscle-brain crosstalk, via the kynurenine pathway, that occurs during an ICU stay and how it may influence long-term physical and cognitive health.