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.

项目摘要 在患有末期肾脏疾病（ESRD）的400,000名年龄较大（≥55岁）的成年人中，有87％是认知 受损和25％的人随后被诊断出患有痴呆症。老年ESRD患者的痴呆症是 与残疾风险高1.5倍，住院和死亡率高2倍。那， 识别可改变的危险因素的认知能力下降对老年肾病学领域至关重要。高度 认知能力下降和事件痴呆的可能危险因素是继发性甲状旁腺功能亢进症（SHPT），这是 影响几乎所有ESRD患者。 Shpt的特征是高血清甲状旁腺骑马（PTH），是由于 ESRD的矿物质异常。虽然PTH与非ESRD的认知障碍有关 人群我们发现，ESRD认知障碍患者的PTH中位水平高出54％ （p = 0.03），患有痴呆症患者中的人2倍。此外，我们的初步数据表明 PTH增加了其他shpt生物标志物，酒精磷酸酶（ALP，r = 0.25，p <0.001）和FGF-23（r = 0.27，r = 0.27， p = 0.01），这也与执行功能较差有关（r = 0.64，p = 0.01）。我们假设PTH可能 通过与大脑的受体结合并间接通过 释放其他生物标志物。然而，我们发现对PTH，新型生物标记和的高质量研究很少 在我们的系统评价中，ESRD患者之间的认知；没有评估认知轨迹。 Shpt是 可修饰的治疗方法，包括多药治疗，手术甲状旁腺切除术（PTDX），或等到 肾脏移植（KT），以扭转Shpt的病因。但是，当前的SHPT治疗指南是 不一致和忽略认知后遗症主要是由于缺乏表征的高质量研究 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 - 在患者和治疗外科医生，老年医生和肾脏科医生中制造。因此，我们的中心 假设是SHPT有助于老年ESRD患者的认知下降和入射痴呆 并且可以通过治疗进行修改。该建议将利用和扩大现有最古老的范围 NIA资助的KT患者认知和脆弱的纵向队列研究（3,062例SHPT患者）和 前瞻性地招募了另外600名较老的Shpt患者参加辅助研究，其中我们将执行 对新型SHPT生物标志物和纵向，全面评估的评估 神经认知电池以识别与SHPT直接相关的特定认知领域。我们的目标是：1）量化 PTH与域特异性认知轨迹之间的关联 SHPT治疗是否影响认知结果，以及3）开发围绕的决策工具 个性化的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。