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.

项目概要 在 400,000 名患有终末期肾病 (ESRD) 的老年人（年龄≥55 岁）中，87% 存在认知障碍 老年终末期肾病 (ESRD) 患者中，有 25% 的人随后被诊断为痴呆症。 导致残疾风险增加 1.5 倍，住院和死亡风险增加 2 倍。 识别认知能力下降的可改变危险因素对于老年肾病学领域至关重要。 认知能力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)， SHPT 影响几乎所有 ESRD 患者，其特征是血清甲状旁腺激素 (PTH) 升高，其原因是 ESRD 中矿物质异常，而非 ESRD 中 PTH 与认知障碍有关。 我们发现，患有认知障碍的 ESRD 患者中位 PTH 水平高出 54% (p=0.03)，而患有痴呆症的人则高出 2 倍。此外，我们的初步数据表明， PTH 会增加其他 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），这也与较差的执行功能相关（r=0.64，p=0.01）。 通过与大脑中的受体结合直接导致特定领域的认知能力下降，并通过 然而，我们发现缺乏关于 PTH、新型生物标志物和其他生物标志物的高质量研究。 我们的系统评价中 ESRD 患者的认知情况；没有评估 SHPT 的认知轨迹。 可通过治疗进行修改，包括多种药物治疗、手术甲状旁腺切除术 (PTDx)，或等到 肾移植（KT）可扭转 SHPT 的病因。然而，目前的 SHPT 治疗指南是。 不一致并忽视认知后遗症，主要是由于缺乏表征认知后遗症的高质量研究 了解 SHPT 对认知轨迹的影响将有助于理解 SHPT 对认知功能的影响。 量身定制的治疗，以减轻认知能力下降、相关发病率，并改善共同治疗决策 因此，我们的核心是患者和治疗外科医生、老年病学家和肾脏病学家。 假设 SHPT 会导致老年 ESRD 患者认知能力下降和痴呆 并且可以通过治疗进行修改，该提案将利用并扩大现有最古老的范围。 NIA 资助的 KT 患者认知和虚弱纵向队列研究（3,062 名 SHPT 患者）和 前瞻性地招募另外 600 名老年 SHPT 患者参加一项辅助研究，其中我们将进行 对新型 SHPT 生物标志物的评估以及使用新的纵向、综合评估 神经认知电池来识别与 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) 测试 SHPT 治疗是否影响认知结果，以及 3) 开发围绕 个性化 SHPT 治疗可减轻认知衰退。 SHPT 生物标志物将改变老年 ESRD 患者的实践并改善治疗决策。