Neurocognitive and Metabolic Effects of Mild Hypothyroidism

轻度甲状腺功能减退症的神经认知和代谢影响

• 批准号: 8431427
• 负责人: MARY H SAMUELS
• 金额: $ 18.87万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431427
• 关键词: 3-iodothyronamine; Adult; Affect; American; Area; Biological Assay; Body Composition; Brain; Chronic; Cognition; Cognitive; Confusion; Consensus; DEXA; Data; Decarboxylation; Decision Making; Diagnosis; Dose; Double-Blind Method; Energy Metabolism; Epidemiologic Studies; Experimental Designs; Experimental Models; Fatty acid glycerol esters; Food; Functional disorder; Funding; Genetic Transcription; Health; Heart; Hormone replacement therapy; Human; Hypothyroidism; Indirect Calorimetry; Individual; Investigation; Label; Laboratories; Lead; Liver; Measurement; Measures; Mediating; Metabolic; Metabolism; Modeling; Monitor; Moods; National Institute of Diabetes and Digestive and Kidney Diseases; Nervous System Physiology; Neuraxis; Neurocognitive; Normal Range; Organ; Outcome; Outcome Measure; Patients; Physical activity; Population; Public Health; Quality of life; Randomized; Recommendation; Research; Research Design; Research Personnel; Rest; Serum; Short-Term Memory; Skeletal Muscle; Symptoms; Syndrome; System; Techniques; Text; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Time; Titrations; Triiodothyronine; Visit; Water; Work; base; bone; clinically relevant; cognitive function; design; executive function; insight; model design; motor learning; novel; older women; oxidation; population based; psychologic; respiratory

DESCRIPTION (provided by applicant): Hypothyroidism is common, affecting 3% of the U.S. population, and up to 20% of older women. Therapy is straightforward, with optimization of target organ function expected when thyroid stimulating hormone (TSH) levels are normalized using L-thyroxine (L-T4). Despite this, millions of patients have mildly elevated TSH levels, and recent data also imply that patients may be undertreated if their TSH levels are high- normal. Decrements in quality of life, mood, cognitive function, and fuel metabolism are seen in hypothyroidism, but much less is known regarding these outcomes in mild hypothyroidism, or in L-T4 treated subjects with high-normal TSH levels. Preliminary data: The investigator's work utilizes a unique experimental model of experimentally-induced mild thyroid disease in hypothyroid subjects on chronic L-T4 therapy. This NIDDK R21-funded work has resulted in intriguing preliminary data that form the basis for the current R01 application. Experimental design: The current proposal is to extend this model to the mildest forms of hypothyroidism, associated with high-normal or mildly elevated TSH levels. L-T4 treated hypothyroid subjects will be randomized to doses of L-T4 that target three TSH ranges: 0.28 2.49 mU/L (the lower normal range, the theoretical optimal range), 2.5 5.0 mU/L (the upper normal range), or 5.1 12 mU/L (the mild hypothyroid range). Precisely titrated L-T4 doses will be given in a double-blinded, parallel study lasting 6 months, in order to achieve these TSH levels. Outcomes focus on the most clinically relevant and least studied systems: the brain (mood and cognition) and intermediary metabolism (energy expenditure and body composition), for which the investigator has already found effects in previous work. These outcome variables will be measured using validated techniques at baseline and at 6 months, with interim visits to allow precise titration of L-T4 doses. Relevance: This is the first investigation that focuses on neurocognitive and metabolic effects of mild hypothyroidism utilizing a rigorous study design and validated, relevant outcome measures. There is no consensus over whether to treat patients with TSH levels in the ranges proposed in this study, and these TSH ranges are the subject of intense debate within the thyroid field. Therefore, this study has major public health implications for the millions of Americans who receive thyroid hormone replacement therapy, as well as for the additional millions with high-normal serum TSH levels. PUBLIC HEALTH RELEVANCE: Millions of people in the U.S. have mild hypothyroidism or thyroid function in the low-normal range. Recent preliminary studies, including those from the investigator's laboratory, suggest that there are clinically relevant end-organ effects of thyroid function in this range, but there is a dearth of conclusive data, especially in the critical areas of brain function and fuel metabolism. This study will utilize a rigorous interventional design and validated outcome measures to study this for the first time, with results that have the potential to inform treatment decisions for millions of people.

描述(由申请人提供)：甲状腺功能减退症很常见，影响3%的美国人口，高达20%的老年女性。治疗很简单，当促甲状腺激素(TSH)水平用L-甲状腺素(L-T4)正常化时，目标器官功能有望得到优化。尽管如此，数以百万计的患者TSH水平略有升高，最近的数据也表明，如果患者的TSH水平高于正常水平，他们可能得不到足够的治疗。生活质量、情绪、认知功能和燃料代谢的下降在甲状腺功能减退症中可见，但在轻度甲状腺功能减退症或L-T4治疗的正常TSH水平较高的受试者中，关于这些结果的了解要少得多。初步数据：研究人员的工作利用了一种独特的实验模型，在接受慢性L-T4治疗的甲状腺功能减退患者中，实验诱导了轻度甲状腺疾病。这项由NIDDK R21资助的工作产生了耐人寻味的初步数据，这些数据构成了当前R01应用的基础。实验设计：目前的建议是将这一模型扩展到最轻微的甲状腺功能减退症，与高正常或轻度升高的TSH水平相关。L-T4治疗的甲减患者将被随机分为三个TSH范围的L-T4剂量：0.28，2.49 mU/L(下限正常范围，理论最优范围)，2.5，5.0 mU/L(上正常范围)，5.12 mU/L(轻度甲减范围)。精确滴定的L-T4剂量将在为期6个月的双盲平行研究中给予，以达到这些TSH水平。研究结果集中在临床上最相关、研究最少的系统：大脑(情绪和认知)和中间代谢(能量消耗和身体成分)，研究人员已经在之前的工作中发现了这两个系统的影响。这些结果变量将在基线和6个月时使用经过验证的技术进行测量，并进行中期访问，以精确滴定L-T4剂量。相关性：这是第一次利用严格的研究设计和经过验证的相关结果测量方法，重点研究轻度甲状腺功能减退症对神经认知和代谢的影响。对于是否治疗TSH水平在本研究建议的范围内的患者，目前还没有达成共识，这些TSH范围是甲状腺领域激烈辩论的主题。因此，这项研究对数百万接受甲状腺激素替代治疗的美国人以及另外数百万血清TSH水平高于正常水平的人具有重大的公共卫生意义。与公共健康相关：在美国，数百万人患有轻度甲状腺功能减退或甲状腺功能处于低正常范围。最近的初步研究，包括研究人员实验室的研究表明，在这一范围内存在与临床相关的甲状腺功能的终末器官效应，但缺乏确凿的数据，特别是在大脑功能和燃料代谢的关键领域。这项研究将首次利用严格的干预设计和有效的结果测量来研究这一问题，其结果有可能为数百万人的治疗决策提供信息。