Cognitive Decline and Incident Dementia in Older Patients with Secondary Hyperparathyroidism

项目摘要 在400，000名患有终末期肾病（ESRD）的老年人（年龄≥55岁）中，87%的人在认知上 25%的人随后被诊断患有痴呆症。老年ESRD患者的痴呆事件 与1.5倍的残疾风险和2倍的住院和死亡风险相关。因此，在本发明中， 识别认知能力下降的可改变的危险因素对于老年肾病学领域是至关重要的。一个高度 认知能力下降和痴呆发生的可能危险因素是继发性甲状旁腺功能亢进（SHPT）， 几乎影响所有的ESRD患者。SHPT的特点是高血清甲状旁腺激素（PTH），是由于 ESRD中的矿物质异常。虽然PTH与非ESRD患者的认知障碍相关， 我们发现，在有认知障碍的ESRD患者中，中位PTH水平高出54 （p=0.03）和2倍高，在那些谁发展痴呆症。此外，我们的初步数据表明， PTH增加其他SHPT生物标志物，碱性磷酸酶（ALP，r=0.25，p<0.001）和FGF-23（r=0.27， p=0.01），这也与执行功能较差相关（r=0.64，p=0.01）。我们假设PTH可能 直接通过与大脑中的受体结合， 释放其他生物标志物。然而，我们发现缺乏高质量的研究PTH，新的生物标志物， 在我们的系统性综述中，ESRD患者的认知能力;没有评估认知轨迹。SHPT是 可通过多种药物治疗、手术甲状旁腺切除术（PTDx）或等到 肾移植（KT），以扭转SHPT的病因。然而，目前的SHPT治疗指南是 不一致，忽视认知后遗症，主要是由于缺乏高质量的研究， SHPT对认知功能的影响。了解SHPT对认知轨迹的影响将允许 量身定制的治疗，以减轻认知能力下降，相关的发病率，并改善共同的治疗决策- 在病人和治疗外科医生、老年病学家和肾病学家中进行。因此，我们的中央 假设SHPT导致老年ESRD患者认知功能下降和痴呆事件 并且可以通过治疗来改变。该提案将利用和扩大现有最古老的 NIA资助的KT患者（3，062例SHPT患者）认知和虚弱的纵向队列研究， 在一项辅助研究中前瞻性招募另外600名老年SHPT患者，在该研究中，我们将进行 新SHPT生物标志物的评估和新SHPT生物标志物的纵向综合评估 神经认知成套测验，以确定与SHPT直接相关的特定认知领域。我们的目标是：1）量化 老年SHPT患者中PTH与特定领域认知轨迹之间的关联2）为了检验 SHPT治疗是否影响认知结果，以及3）开发一种决策工具， 个性化SHPT治疗以减轻认知能力下降。认知轨迹和 SHPT生物标志物将改变老年ESRD患者的实践并改善治疗决策。

PROJECT SUMMARY Of the 400,000 older (age ≥55) adults living with end-stage renal disease (ESRD), 87% are cognitively impaired and 25% are subsequently diagnosed with dementia. Incident dementia in older ESRD patients is associated with a 1.5-fold higher risk of disability and 2-fold higher risk of hospitalization and mortality. Thus, identifying modifiable risk factors for cognitive decline is critical to the field of geriatric nephrology. A highly likely risk factor for cognitive decline and incident dementia is secondary hyperparathyroidism (SHPT), which affects nearly all ESRD patients. SHPT, characterized by high serum parathyroid hormone (PTH), is due to mineral abnormalities in ESRD. While PTH has been associated with cognitive impairment in non-ESRD populations we have found that median PTH levels are 54% higher in ESRD patients with cognitive impairment (p=0.03) and 2-fold higher in those who develop dementia. Furthermore, our preliminary data suggests that PTH increases other SHPT biomarkers, alkaline phosphatase (ALP, r=0.25, p<0.001) and FGF-23 (r=0.27, p=0.01), which also correlates with worse executive function (r=0.64, p=0.01). We hypothesize that PTH likely causes domain-specific cognitive decline both directly by binding to receptors in the brain and indirectly via release of other biomarkers. Yet, we found a paucity of high-quality studies of PTH, novel bio-markers, and cognition among ESRD patients in our systematic review; none evaluated cognitive trajectories. SHPT is modifiable with treatment including poly-pharmacotherapy, surgical parathyroidectomy (PTDx), or waiting until kidney transplant (KT) to reverse the etiology of SHPT. However, current SHPT treatment guidelines are inconsistent and ignore cognitive sequelae mainly due to the paucity of high-quality studies characterizing the impact of SHPT on cognitive function. Understanding the impact of SHPT on cognitive trajectories will allow for tailored treatment to mitigate cognitive decline, associated morbidity, and improve shared treatment decision- making among patients and treating surgeons, geriatricians, and nephrologists. Therefore, our central hypothesis is that SHPT contributes to cognitive decline and incident dementia in older ESRD patients and can be modified with treatment. This proposal will leverage and expand the scope of the oldest existing NIA-funded longitudinal cohort study of cognition and frailty among KT patients (3,062 SHPT patients) and prospectively enroll an additional 600 older SHPT patients in an ancillary study, in which, we will perform assessments of novel SHPT biomarkers and longitudinal, comprehensive assessments with a new neurocognitive battery to identify specific cognitive domains directly related to SHPT. We aim to: 1) To quantify the association between PTH and domain-specific cognitive trajectories among older SHPT patients 2) To test whether SHPT treatments impact cognitive outcomes, and 3) To develop a decision-making tool surrounding personalized SHPT treatment to mitigate cognitive decline. Novel incorporation of cognitive trajectories and SHPT biomarkers will transform practice and improve treatment decision-making in older ESRD patients.