Neurocognitive effects of subclinical thyroid disease

描述(由申请人提供)：这一试点和可行性计划(R-21)申请代表了研究人员Mary Samuels博士在成人轻度(或“亚临床”)甲状腺疾病认知影响领域的一个新的研究方向。5%的普通人群患有亚临床甲状腺疾病，定义为孤立的TSH异常，20%的老年妇女患有轻度甲状腺功能减退(孤立的TSH升高)。因此，亚临床甲状腺疾病是否会改变认知的问题具有重要的公共卫生意义。如果亚临床甲状腺疾病与认知障碍有关，这将是一个重要的治疗适应症。这与老年人口尤其相关，他们早期痴呆症的发生率很高，由于轻度甲状腺疾病而增加认知缺陷可能会恶化这一情况。 为了研究这一问题，研究人员设计了一种新的实验诱导的亚临床甲状腺疾病模型，并提出了一系列实验来检验和完善该模型。目前正在服用L-甲状腺素(L-T4)进行慢性替代治疗的受试者将被随机分配到他们通常剂量的L-T4，或略低剂量(诱导轻度亚临床甲状腺功能减退)，或略高剂量(诱导轻度亚临床甲状腺功能亢进)。治疗分配为随机、安慰剂对照、双盲。每个治疗臂设计为持续3个月。在每只手臂的开始和结束时，都会进行一系列认知测试。已经选择了特定的认知结果指标来针对最有可能受到轻度甲状腺疾病影响的认知领域。在整个研究过程中，受试者还被监测安全性、生活质量、情绪和甲状腺功能改变的其他影响。这项应用的广泛的具体目标是：1)通过在接受L-T4替代疗法的受试者中测试L-T4的剂量增量，开发和完善实验诱导的亚临床甲状腺疾病的模型；2)利用该模型获得关于亚临床甲状腺功能减退症在年轻人和老年人中引起的认知影响的初步数据；以及3)利用该模型获得关于老年人亚临床甲亢引起的认知障碍的初步数据。在这些初步研究的基础上，研究人员的长期目标是调查成年人甲状腺状态改变对认知的具体影响。

DESCRIPTION (provided by applicant): This Pilot and Feasibility Program (R-21) application represents a new research direction for the investigator, Dr. Mary Samuels, in the field of cognitive effects of mild (or "subclinical") thyroid disease in the adult human. 5% of the general population has subclinical thyroid disease, as defined by isolated TSH abnormalities, and 20% of older women have mild hypothyroidism (isolated TSH elevations). Therefore, the question of whether subclinical thyroid disease alters cognition has important public health implications. If subclinical thyroid disease were associated with cognitive deficits, this would be an important treatment indication. This is especially relevant to the older population, which has high rates of incipient dementia that could be worsened by the addition of cognitive deficits due to mild thyroid disease. In order to investigate this question, the investigator has designed a new model of experimentally-induced subclinical thyroid disease, and proposes a series of experiments to test and refine this model. Subjects who are currently taking L-thyroxine (L-T4) for chronic replacement therapy will be randomized to their usual doses of L-T4, vs. slightly lower doses (to induce mild subclinical hypothyroidism), or slightly higher doses (to induce mild subclinical hyperthyroidism). Treatment assignment is randomized, placebo-controlled, and double-blinded. Each treatment arm is designed to last 3 months. At the beginning and end of each arm, a battery of cognitive tests is administered. The specific cognitive outcome measures have been chosen to target cognitive domains most likely to be affected by mild thyroid disease. Throughout the studies, subjects are also monitored for safety, quality of life, mood, and other effects of altered thyroid function. The broad specific aims of this application are: 1) To develop and refine a model of experimentally-induced subclinical thyroid disease by testing dose increments of L-T4 in subjects receiving L-T4 replacement therapy; 2) To utilize the model to obtain pilot data on cognitive effects induced by subclinical hypothyroidism in younger and older human subjects; and 3) To utilize the model to obtain pilot data on cognitive deficits induced by subclinical hyperthyroidism in older subjects. Based on these pilot studies, it is the long-term goal of the investigator to investigate specific cognitive effects of altered thyroid status in the adult human.