Primary Hyperparathyroidism: Neurocognitive Features

原发性甲状旁腺功能亢进症：神经认知特征

• 批准号: 8967918
• 负责人: MARCELLA Donovan WALKER
• 金额: $ 24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-09 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967918
• 关键词: Accounting; Address; Affect; Aorta; Area; Blood; Blood Vessels; Brain; Brain region; Calcium; Cerebral hemisphere; Cerebrum; Cognition; Cognitive; Data; Diagnosis; Disease; Disease Management; Disease of parathyroid glands; Educational workshop; Elderly; Endocrine System Diseases; Endocrinology; Epidemiologic Studies; Epidemiology; Etiology; Fibrosis; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Guidelines; Homeostasis; Hormones; Hypercalcemia; Hyperparathyroidism; Image; Impaired cognition; Incidental Discoveries; International; Investigation; Kidney Diseases; Knowledge; Lead; Magnetic Resonance; Maps; Measures; Medial; Memory; Nephrolithiasis; Neurobehavioral Manifestations; Neurocognitive; Neuropsychological Tests; Operative Surgical Procedures; Osteitis; Osteitis Fibrosa Cystica; Parathyroid gland; Parathyroidectomy; Patients; Perfusion; Process; Quality of life; Reporting; Research; Research Project Grants; Risk Factors; Sample Size; Secondary Hyperparathyroidism; Serum; Site; Symptoms; Thick; TimeLine; United States; Vascular Dementia; Vasomotor; Vitamin D Deficiency; Work; cognitive change; cognitive function; design; evidence based guidelines; hemodynamics; improved; innovation; interdisciplinary approach; neuroimaging; neuromuscular; neuropsychological; novel; novel strategies; psychologic; public health relevance; relating to nervous system; symposium; tool

 DESCRIPTION (provided by applicant): Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by over-active parathyroid gland(s) and elevated blood calcium levels. Although 80% of PHPT patients are said to be "asymptomatic" (i.e. lacking the classical manifestations of nephrolithiasis and osteitis fibrosa cystica), this term is a misnomer because most patients report neuropsychological symptoms, including reduced memory and concentration. Although both hypercalcemia and elevated parathyroid hormone (PTH) could have cognitive effects, the mechanism of cognitive dysfunction in PHPT has never been delineated. Most studies do indicate neuropsychological sequelae of PHPT but reversibility after parathyroidectomy (PTX) has been inconsistent across investigations. These inconsistencies may be related to small sample sizes in some studies and variability in the aspects of cognition examined. Because of such limitations, patients with cognitive symptoms are still deemed "asymptomatic" and cognitive dysfunction is not currently an indication for PTX. This remains the biggest unresolved issue in the management of asymptomatic PHPT. Recently, we made progress in this challenging area by showing with validated tools that specific cognitive dysfunction is present in PHPT and improves after surgical cure. A potential vascular mechanism is suggested by our work demonstrating increased aortic and carotid vascular stiffness in PHPT in association with extent of PTH elevation. Our new preliminary data supports the presence of similar PTH-dependent changes in the intracerebral vasculature that may underlie cognitive impairment in PHPT. There is support for this concept from work showing that cerebral hemodynamic dysfunction is associated with cognitive impairment in vascular dementia and carotid disease. Moreover, a recent epidemiological study found elevated PTH to be a risk factor for cognitive decline in older adults. The proposed studies are intended to determine if the above PTH-dependent vascular mechanism is responsible for cognitive dysfunction in PHPT, whether the process is attributable to PTH and reversible with cure of PHPT, and which brain regions are affected. First, we will use transcranial Doppler to confirm that intra- cerebral vasomotor reactivity (VMR) is reduced in PHPT, and associated with elevated PTH (but not calcium) and cognitive changes. Second, we will determine if impaired VMR is reversible with PTX. Finally, we will identify the sites in the brain affected by PHPT using functional magnetic resonance imaging. The data from these studies will address a research goal of the 4th International Conference on Asymptomatic PHPT (2013), which highlighted the need for data regarding the cognitive effects of PHPT. Ultimately this information may lead to alteration of surgical guidelines for PHPT patients. Further, if our hypothesis regarding PTH-dependent changes in cerebral vascular function and cognition is confirmed, these data would have implications for a much broader and larger group of patients with PTH excess, including those with secondary hyperparathyroidism from vitamin D deficiency, kidney disease and other disorders.

 描述（由申请人提供）：原发性甲状旁腺功能亢进（PHPT）是一种常见的内分泌疾病，其特征是甲状旁腺过度活跃和血钙水平升高。虽然80%的PHPT患者被认为是“无症状”（即缺乏肾结石和囊性纤维性骨炎的经典表现），但这个术语是一个用词不当，因为大多数患者报告神经心理学症状，包括记忆力和注意力下降。虽然高钙血症和甲状旁腺激素（PTH）升高都可能对认知功能产生影响，但PHPT中认知功能障碍的机制尚未阐明。大多数研究确实表明PHPT的神经心理学后遗症，但甲状旁腺切除术（PTX）后的可逆性在各研究中并不一致。这些不一致性可能与某些研究中的样本量小以及所研究的认知方面的可变性有关。由于这些限制，具有认知症状的患者仍然被认为是“无症状的”，并且认知功能障碍目前不是PTX的适应症。这仍然是无症状PHPT管理中最大的未解决问题。最近，我们在这一具有挑战性的领域取得了进展，通过验证工具显示，特定的认知功能障碍存在于PHPT中，并在手术治愈后得到改善。我们的研究表明PHPT患者的主动脉和颈动脉血管僵硬度增加与PTH升高程度相关，这可能是一种潜在的血管机制。我们新的初步数据支持脑内血管存在类似的PTH依赖性变化，这可能是PHPT认知障碍的基础。这一概念得到了工作的支持，表明脑血流动力学功能障碍与血管性痴呆和颈动脉疾病的认知障碍有关。此外，最近的一项流行病学研究发现，PTH升高是老年人认知能力下降的危险因素。拟定的研究旨在确定上述PTH依赖性血管机制是否是PHPT中认知功能障碍的原因，该过程是否可归因于PTH，以及PHPT治愈后是否可逆，以及哪些脑区受到影响。首先，我们将使用经颅多普勒证实PHPT患者的脑内血管反应性（VMR）降低，并与PTH（而不是钙）升高和认知变化相关。其次，我们将确定受损的VMR是否可以用PTX逆转。最后，我们将确定大脑中受PHPT影响的部位， 功能性磁共振成像来自这些研究的数据将解决第四届无症状PHPT国际会议（2013年）的研究目标，该会议强调了对PHPT认知影响数据的需求。最终，这些信息可能会导致PHPT患者手术指南的改变。此外，如果我们关于PTH依赖性脑血管功能和认知变化的假设得到证实，这些数据将对更广泛和更大的PTH过量患者群体产生影响，包括维生素D缺乏、肾脏疾病和其他疾病引起的继发性甲状旁腺功能亢进患者。