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

摘要/摘要： 在重症监护病房(ICU)住院的患者可能会经历新的或更糟糕的身体状况， 精神和/或认知障碍(称为重症监护后综合症(PICS))。最容易受到伤害的人 长期的身体和认知障碍是老年人(&gt；60岁)，因为先前存在与年龄相关的 身体虚弱或认知虚弱。这两者都会增加幸存者患阿尔茨海默氏症的可能性 疾病和相关痴呆症。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，在以下期间识别高危老年人 入院可能是困难的，因为1)患者的临床表现是同质性的。 年龄相关的身体虚弱和危重疾病与那些只患有危重疾病的人和2)许多人相比 病人到达时身体严重虚弱，进行身体功能或其他意志评估 很难。因此，新的生物标志物对早期诊断、预后和疾病的指导是至关重要的。 确定了监控。到目前为止，色氨酸衍生物，特别是犬尿氨酸和烟酰胺家族 (例如，NAD+)，已被证明在慢性炎症和生理关系中起中介作用 损伤或信号加速老化。然而，目前还不清楚是否存在类似的关联 老年ICU患者中神经毒性色氨酸代谢产物升高与预后的相关性 在ICU期间，神经保护性色氨酸代谢产物可预测不良健康结局。因此，要填补这一点 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， 住在ICU前、ICU内和ICU后的肌肉骨骼健康和认知功能。在此团契期间获得的技能 将通过犬尿氨酸途径提供对脆弱和肌肉-大脑串扰的更好理解，即 发生在ICU期间，以及它可能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.