Cognitive Decline and Incident Dementia in Older Patients with Secondary Hyperparathyroidism

继发性甲状旁腺功能亢进症老年患者的认知能力下降和痴呆

• 批准号: 10587339
• 负责人: Aarti Mathur
• 金额: $ 83.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587339
• 关键词: Accounting; Adult; Affect; Aftercare; Age; Alkaline Phosphatase; Ancillary Study; Binding; Biological Markers; Brain; Cardiovascular system; Clinical; Cognition; Cognitive; Computerized Medical Record; Data; Data Collection; Data Set; Decision Making; Decision Trees; Dementia; Diagnosis; Elderly; Eligibility Determination; End stage renal failure; Enrollment; Etiology; Fracture; Funding; Hospitalization; Impaired cognition; Infrastructure; Kidney Transplantation; Literature; Longitudinal cohort study; Measures; Mediating; Methods; Minerals; Modeling; Modification; Morbidity - disease rate; Nephrology; Neurocognitive; Neuropsychology; Odds Ratio; Older Population; Operative Surgical Procedures; Outcome; PTH gene; Parathyroidectomy; Patients; Persons; Pharmacotherapy; Physicians; Population; Process; Provider; Public Health; Risk; Risk Factors; Sampling; Secondary Hyperparathyroidism; Secondary to; Serum; Surgeon; Testing; Transplant Recipients; abstracting; clinical decision-making; clinical practice; cognitive function; cohort; dementia risk; design; disability risk; executive function; frailty; hazard; high risk; improved; individualized medicine; modifiable risk; mortality; novel; novel marker; older patient; patient oriented; pilot test; prognostication; prospective; receptor; risk stratification; systematic review; tool; treatment guidelines; usability; web-based tool

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.

项目总结 在400,000名患有终末期肾病的老年人(年龄为55岁)中，87%的人在认知方面 25%的人随后被诊断为痴呆症。老年ESRD患者的痴呆症发生率为 残疾风险增加1.5倍，住院和死亡风险增加2倍。因此， 识别认知功能下降的可改变的危险因素对老年肾病领域至关重要。一位高度 认知功能下降和痴呆的可能危险因素是继发性甲状旁腺功能亢进症(SHPT)，它 几乎所有终末期肾病患者都会受到影响。以血清甲状旁腺激素(PTH)升高为特征的SHPT是由于 终末期肾病的矿物质异常。而甲状旁腺激素与非ESRD患者的认知损害有关 我们发现有认知障碍的终末期肾病患者的甲状旁腺激素水平中位数高出54% (P=0.03)，痴呆症患者高出2倍。此外，我们的初步数据表明， 甲状旁腺素增加了其他SHPT生物标志物，碱性磷酸酶(r=0.25，p&lt；0.001)和成纤维细胞生长因子-23(r=0.27， P=0.01)，且与执行功能差相关(r=0.64，P=0.01)。我们假设PTH很可能 通过直接与大脑中的受体结合和间接通过 其他生物标志物的释放。然而，我们发现甲状旁腺激素、新型生物标记物和 我们系统回顾了终末期肾病患者的认知情况；没有人评估认知轨迹。SHPT是 可通过包括多种药物治疗、外科甲状旁腺切除术(PTDx)或等到 肾移植(KT)以逆转SHPT的病因。然而，目前的SHPT治疗指南是 不一致和忽视认知后遗症的主要原因是缺乏高质量的研究来表征 SHPT对认知功能的影响了解SHPT对认知轨迹的影响将允许 量身定制的治疗可缓解认知能力下降、相关发病率，并改善共同的治疗决策- 在病人和治疗外科医生、老年病医生和肾病学家之间做出决定。因此，我们的中央 假设SHPT导致老年ESRD患者认知功能减退和痴呆 并且可以通过处理进行修改。这项提案将利用并扩大现有最古老的 NIA资助的KT患者(3062名SHPT患者)和 前瞻性地将另外600名老年SHPT患者纳入一项辅助研究，在该研究中，我们将进行 新的SHPT生物标志物的评估和纵向、全面的评估 神经认知电池，识别与SHPT直接相关的特定认知域。我们的目标是：1)量化 老年SHPT患者甲状旁腺激素与特定领域认知轨迹的相关性2)检验 SHPT治疗是否影响认知结果，以及3)开发决策工具环境 个性化SHPT治疗，以缓解认知能力下降。将认知轨迹和 SHPT生物标志物将改变实践，改善老年ESRD患者的治疗决策。