亚临床型甲状腺功能减退症的认知损伤机制和替代治疗的价值
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摘要
亚临床型甲状腺功能减退症(Subclincal hypothyroidism,SCH)指病人血清中含有正常范围内的甲状腺素水平,但是促甲状腺素(plasma thyroid stimulatinghormone,TSH)水平上升。世界各地对SCH在普通人群中发病率的报道各有不同,Canaris等在美国克罗拉多州的一项大样本流行病学调查显示SCH的发病率为5%～10.4%,并有逐年升高的趋势,尤其是在女性、老年人、伴有其他自身免疫性疾病的人及碘缺乏地区的人群中更高。SCH的发病随年龄增加而增加,有报道在老年人群中发病率为5%～10%,在大于60岁的女性中可达20%,大于74岁的男性中为16%。
SCH可引起认知功能损害,包括胎儿神经发育受损,中青年学习、记忆及选择性注意方面损害,老年SCH患者观察也发现学习、语言流畅性、注意、运动能力降低。SCH还可导致血脂紊乱,总胆固醇、低密度脂蛋白、脂蛋白a上升,高密度脂蛋白下降;并可引起心血管系统损害,成为老年大动脉粥样硬化和心肌梗塞的危险因素之一。
为了系统地分析SCH对认知功能的影响,以及甲状腺激素替代治疗的价值,选取儿童、中年、老年三组SCH患者与年龄、性别、文化程度相匹配的对照组,采用神经心理量表和功能磁共振技术,分别观察了静止和激发状况下的认知功能状况,同时检测激素水平。并用左旋甲状腺素治疗6个月,通过认知功能检测判断治疗的价值。结果发现:
1、儿童原发性SCH患者30例,与正常儿童进行比较,SCH患儿的游离三碘甲状腺原氨酸(Free triiodothyronine,FT_3)、游离甲状腺素(Free tetraiodothyronine,FT_4)虽在正常范围内,但显著低于正常对照组;应用中国韦氏儿童智力量表(China-WechslerIntelligence Scale for Children,C-WISC)检测显示总分和亚项分值显著低于正常对照组。
2、成年原发性SCH病人11例,甲状腺功能正常被试12例,甲状腺功能亢进病人16例、甲状腺功能减退病人9例进行对照,通过修订韦氏记忆量表(WechslerMemory Scale-Revised by chinese,WMS-RC)评估被试的记忆能力。结果显示各组之间在总成绩上没有差别,在分项上也没有差别。SCH病人三碘甲状腺原氨酸(triiodothyronine,T3)、FT3、FT4水平比正常人低。同时使用N-back任务来评估SCH病人的工作记忆能力,SCH病人的成绩比正常组和甲状腺功能亢进组低,后两者无差异。
3、老年原发性SCH患者50例,与甲状腺功能正常志愿者25例进行对照,发现其FT_3、FT_4虽在正常范围内,但显著低于正常对照组,简易精神状态量表(Mini-Mental State Examination,MMSE)检测显示两组间总分无区别,剑桥老年认知检查表-中国修订版(Cambridge Cognitive Examination revised by Chinese,CAMCOG-C)检测SCH患者组总分和注意、记忆、知觉亚测试分值显著低于正常对照组。
4、激发试验:与N-back任务相关的负载实验结果显示,随记忆负载上升,SCH病人组、正常组、甲状腺功能亢进组正确率下降。功能磁共振成像显示正常组和甲亢组双侧感兴趣区(双侧额中/下回、双侧背外侧前额叶、双侧前运动区、辅助运动区/前扣带皮层、双侧顶叶),均发现和记忆负载相关血氧水平依赖对比度(bloodoxygen level dependent,BOLD)信号变化。在治疗前SCH病人组中,和记忆负载相关的BOLD信号变化只在双侧前运动区和双侧顶叶出现,在其他感兴趣区没有发现类似的趋势(即.双侧背外侧前额叶,双侧额中/下回,辅助运动区/前扣带皮层)。
5、治疗效果:儿童SCH患者服药后应用C-WISC进行替代治疗前后比较,除木块图以外的11个亚项均呈现显著改善。与安慰剂治疗组相比,儿童SCH患者接受替代治疗后分类、领悟、编码、知识、填图、言语量表总分、全量表总分的改善显著优于安慰剂组。替代治疗后,操作量表、领悟亚项的分值仍偏低于正常对照组。成年SCH病人在左旋甲状腺激素替代治疗后,2-back正确率与正常组比较无统计学差别,与N-back相关的BLOD负载信号显示与正常人一样的趋势。老年SCH病人左旋甲状腺素替代治疗后,TSH＞10 mIU/L患者的CAMCOG总分、记忆、思维及语言、TSH小于10mIU/L的患者接受替代治疗后记忆、思维及CAMCOG总分的改善显著优于接受安慰剂治疗者。服药后替代治疗组的MMSE及CAMCOG量表分值与正常对照组接近。所有受试者TSH水平均在6个月内恢复至正常范围。
综上所述,儿童、成年及老年SCH患者均存在认知损害,甲状腺激素替代治疗后认知功能可获得改善。儿童SCH病人应早期足量替代治疗,根据成年人功能磁共振的结果,提示即使替代治疗到甲状腺激素轻度升高时,其认知功能与正常人相似。老年SCH病人是否替代治疗还要取决于病人的心脏供血等个体情况,治疗中还必须严密观察。
Background Subclinical hypothyroidism (SCH) refers to patients with normal serum levels of thyroxine, but the plasma thyroid stimulating hormone(TSH) increased, around the world in the general population incidence of subclinical hypothyroidism reports vary. Canaris made a large epidemiological survey in Colorado of USA which randomly selected large sample of 25000 people,and observed their TSH levels and measured their symptoms. Canaris found in the sample 2,336 people was diagnosed with subclinical hypothyroidism about 3%～10.4% ,and the trend has increased.,especially in women, the elderly , those with other autoimmune diseases and the crowd in higher IDD areas. Subclinical hypothyroidism, the incidence increased with increasing age. It has been reported incidence rate is about 5% -10% in the elderly population. In women over 60 years old it is up to 20% (200% increase), and more than 16% of men 74 years of age.
Subclinical hypothyroidism results in the cognitive impairment, including the impairment of learning and memory, selective attention during childhood and young adulthood. In addition, the older patients with Subclinical hypothyroidism show the reduced the capacity of learning, language fluency, attention and exercise. Subclinical hypothyroidism can also result in dyslipidemia, such as higher level of total cholesterol (TC),low-density lipoprotein (LDL) and lipoprotein-a, lower level of high-density lipoprotein (HDL) and damage to the cardiovascular system, which becomes one of the risk factors to the old artery atherosclerosis and myocardial infarction.
Methods To systematic analysis the effect of Subclinical hypothyroidism on the cognitive function and the value of thyroid hormone replacement therapy, we selected children, the middle-aged and elder patients, with the same age, sex, education level as the patients screened for good general health. The subjects were evaluated for thyroid function, neuropsychological and functional magnetic resonance imaging test before and after 6 months 'treatment,
Results
1.30 children patients who were frist diagnosed as SCH (1.1 boys and 19 girls,14 from city, 16 from rural, age between 8 to 16) had lower plasma thyroid hormone than the normal subjects before treatment,although thyroxines were in normal ranges. SCH children showed a significant and extensive C-WISC lower score on all tests in baseline than the same age and education controls.
2.11 adult patients who were frist diagnosed as SCH (10 women and one man, all right-handed, aged between 18～47) had lower plasma T3, FT3, FT4 level than the 12 normal subjects (11 women and one man, all right-handed, aged between 20 and 40) before treatment, although thyroxines were in normal ranges. SCH patients showed no difference in total score by WMS-CR assessment of the memory ., SCH patients were lower accuracy rate than the normal subjects by the n-back task..
3.50 elderly patients who were frist diagnosed as SCH had lower plasma FT3, FT4 level than the 25 volunteers with normal thyroid function for control, although thyroxines were in normal ranges. SCH patients was significantly lower total scores and attention, memory, and perception sub-scores than the control group by CAMCOG test.
4.N-back tasks: before each condition, two seconds reminder show each load conditions in n-back (Repeat the current immediately: 0-back; Repeat the before one number: 1-back; Repeat the before two number: 2-back). Internal Group comparison indicate that in the normal group, the hyperthyroidism group and the adult SCH patients before treatment the accuracy rate decline as memory load increased. In normal bilateral interest areas (M/IFG, DLPFC, PreMA, SMA/ACC, and PA) we discover BOLD signal changes related to memory load, which showed the effects of load indicators can be used to analyze patient data. In the group of the SCH patients before treatment the BOLD signal which related to memory load appears only in the bilateral PreMA and bilateral parietal lobe, which is not found in other areas of interest (DLPFC, M/IFG, SMA/ACC; GLM) .
5.Therapeutic efficacy: After 6 months' treatment, SCH children patients showed no difference in plasma FT3, FT4 level compared with the control.(1)The children SCH patients' scores of classification, comprehend, coding, knowledge, mapping, speech total scores and the entire total score improvement was significantly better than placebo group,, replacement therapy group' scores of operating scale and understanding are still lower than the normal group.(2).the adult SCH patients exhibited the same accuracy rate as the euthyroid subjects in N-back task. SCH patiens have shown a normal trend in the five regions of interest.(3) elderly SCH patients with TSH>10 mIU/ L has significantly increased in total scores, memory, thinking and language scores by CAMCOG test. The patiens with TSH<10 mIU/ L has improved significantly superior to placebo treatment in total scores, memory and thinking scores by CAMCOG test scores in the L-thyroxine group is close to the normal control group. Conclusions: The children with SCH have broader scope of damage in cognitive impairment, which have significantly improved especially the language ability after replacement therapy. After proper treatment, SCH patients's corresponding neural basis of working memory capacity can be restored. The elderly patients with SCH have mild cognitive impairment.
These findings suggested that cognitive impairment is often seen symptoms in thyroid hormone diseases, the frontal cortext is the main neural network involved in the cognitive disoders in SCH patients. The early thyroid hormone replacement therapy improves the cognitive function and the life quality in patients with thyroid hormone diseases.
SCH可引起认知功能损害,包括胎儿神经发育受损,中青年学习、记忆及选择性注意方面损害,老年SCH患者观察也发现学习、语言流畅性、注意、运动能力降低。SCH还可导致血脂紊乱,总胆固醇、低密度脂蛋白、脂蛋白a上升,高密度脂蛋白下降;并可引起心血管系统损害,成为老年大动脉粥样硬化和心肌梗塞的危险因素之一。
为了系统地分析SCH对认知功能的影响,以及甲状腺激素替代治疗的价值,选取儿童、中年、老年三组SCH患者与年龄、性别、文化程度相匹配的对照组,采用神经心理量表和功能磁共振技术,分别观察了静止和激发状况下的认知功能状况,同时检测激素水平。并用左旋甲状腺素治疗6个月,通过认知功能检测判断治疗的价值。结果发现:
1、儿童原发性SCH患者30例,与正常儿童进行比较,SCH患儿的游离三碘甲状腺原氨酸(Free triiodothyronine,FT_3)、游离甲状腺素(Free tetraiodothyronine,FT_4)虽在正常范围内,但显著低于正常对照组;应用中国韦氏儿童智力量表(China-WechslerIntelligence Scale for Children,C-WISC)检测显示总分和亚项分值显著低于正常对照组。
2、成年原发性SCH病人11例,甲状腺功能正常被试12例,甲状腺功能亢进病人16例、甲状腺功能减退病人9例进行对照,通过修订韦氏记忆量表(WechslerMemory Scale-Revised by chinese,WMS-RC)评估被试的记忆能力。结果显示各组之间在总成绩上没有差别,在分项上也没有差别。SCH病人三碘甲状腺原氨酸(triiodothyronine,T3)、FT3、FT4水平比正常人低。同时使用N-back任务来评估SCH病人的工作记忆能力,SCH病人的成绩比正常组和甲状腺功能亢进组低,后两者无差异。
3、老年原发性SCH患者50例,与甲状腺功能正常志愿者25例进行对照,发现其FT_3、FT_4虽在正常范围内,但显著低于正常对照组,简易精神状态量表(Mini-Mental State Examination,MMSE)检测显示两组间总分无区别,剑桥老年认知检查表-中国修订版(Cambridge Cognitive Examination revised by Chinese,CAMCOG-C)检测SCH患者组总分和注意、记忆、知觉亚测试分值显著低于正常对照组。
4、激发试验:与N-back任务相关的负载实验结果显示,随记忆负载上升,SCH病人组、正常组、甲状腺功能亢进组正确率下降。功能磁共振成像显示正常组和甲亢组双侧感兴趣区(双侧额中/下回、双侧背外侧前额叶、双侧前运动区、辅助运动区/前扣带皮层、双侧顶叶),均发现和记忆负载相关血氧水平依赖对比度(bloodoxygen level dependent,BOLD)信号变化。在治疗前SCH病人组中,和记忆负载相关的BOLD信号变化只在双侧前运动区和双侧顶叶出现,在其他感兴趣区没有发现类似的趋势(即.双侧背外侧前额叶,双侧额中/下回,辅助运动区/前扣带皮层)。
5、治疗效果:儿童SCH患者服药后应用C-WISC进行替代治疗前后比较,除木块图以外的11个亚项均呈现显著改善。与安慰剂治疗组相比,儿童SCH患者接受替代治疗后分类、领悟、编码、知识、填图、言语量表总分、全量表总分的改善显著优于安慰剂组。替代治疗后,操作量表、领悟亚项的分值仍偏低于正常对照组。成年SCH病人在左旋甲状腺激素替代治疗后,2-back正确率与正常组比较无统计学差别,与N-back相关的BLOD负载信号显示与正常人一样的趋势。老年SCH病人左旋甲状腺素替代治疗后,TSH＞10 mIU/L患者的CAMCOG总分、记忆、思维及语言、TSH小于10mIU/L的患者接受替代治疗后记忆、思维及CAMCOG总分的改善显著优于接受安慰剂治疗者。服药后替代治疗组的MMSE及CAMCOG量表分值与正常对照组接近。所有受试者TSH水平均在6个月内恢复至正常范围。
综上所述,儿童、成年及老年SCH患者均存在认知损害,甲状腺激素替代治疗后认知功能可获得改善。儿童SCH病人应早期足量替代治疗,根据成年人功能磁共振的结果,提示即使替代治疗到甲状腺激素轻度升高时,其认知功能与正常人相似。老年SCH病人是否替代治疗还要取决于病人的心脏供血等个体情况,治疗中还必须严密观察。
Background Subclinical hypothyroidism (SCH) refers to patients with normal serum levels of thyroxine, but the plasma thyroid stimulating hormone(TSH) increased, around the world in the general population incidence of subclinical hypothyroidism reports vary. Canaris made a large epidemiological survey in Colorado of USA which randomly selected large sample of 25000 people,and observed their TSH levels and measured their symptoms. Canaris found in the sample 2,336 people was diagnosed with subclinical hypothyroidism about 3%～10.4% ,and the trend has increased.,especially in women, the elderly , those with other autoimmune diseases and the crowd in higher IDD areas. Subclinical hypothyroidism, the incidence increased with increasing age. It has been reported incidence rate is about 5% -10% in the elderly population. In women over 60 years old it is up to 20% (200% increase), and more than 16% of men 74 years of age.
Subclinical hypothyroidism results in the cognitive impairment, including the impairment of learning and memory, selective attention during childhood and young adulthood. In addition, the older patients with Subclinical hypothyroidism show the reduced the capacity of learning, language fluency, attention and exercise. Subclinical hypothyroidism can also result in dyslipidemia, such as higher level of total cholesterol (TC),low-density lipoprotein (LDL) and lipoprotein-a, lower level of high-density lipoprotein (HDL) and damage to the cardiovascular system, which becomes one of the risk factors to the old artery atherosclerosis and myocardial infarction.
Methods To systematic analysis the effect of Subclinical hypothyroidism on the cognitive function and the value of thyroid hormone replacement therapy, we selected children, the middle-aged and elder patients, with the same age, sex, education level as the patients screened for good general health. The subjects were evaluated for thyroid function, neuropsychological and functional magnetic resonance imaging test before and after 6 months 'treatment,
Results
1.30 children patients who were frist diagnosed as SCH (1.1 boys and 19 girls,14 from city, 16 from rural, age between 8 to 16) had lower plasma thyroid hormone than the normal subjects before treatment,although thyroxines were in normal ranges. SCH children showed a significant and extensive C-WISC lower score on all tests in baseline than the same age and education controls.
2.11 adult patients who were frist diagnosed as SCH (10 women and one man, all right-handed, aged between 18～47) had lower plasma T3, FT3, FT4 level than the 12 normal subjects (11 women and one man, all right-handed, aged between 20 and 40) before treatment, although thyroxines were in normal ranges. SCH patients showed no difference in total score by WMS-CR assessment of the memory ., SCH patients were lower accuracy rate than the normal subjects by the n-back task..
3.50 elderly patients who were frist diagnosed as SCH had lower plasma FT3, FT4 level than the 25 volunteers with normal thyroid function for control, although thyroxines were in normal ranges. SCH patients was significantly lower total scores and attention, memory, and perception sub-scores than the control group by CAMCOG test.
4.N-back tasks: before each condition, two seconds reminder show each load conditions in n-back (Repeat the current immediately: 0-back; Repeat the before one number: 1-back; Repeat the before two number: 2-back). Internal Group comparison indicate that in the normal group, the hyperthyroidism group and the adult SCH patients before treatment the accuracy rate decline as memory load increased. In normal bilateral interest areas (M/IFG, DLPFC, PreMA, SMA/ACC, and PA) we discover BOLD signal changes related to memory load, which showed the effects of load indicators can be used to analyze patient data. In the group of the SCH patients before treatment the BOLD signal which related to memory load appears only in the bilateral PreMA and bilateral parietal lobe, which is not found in other areas of interest (DLPFC, M/IFG, SMA/ACC; GLM) .
5.Therapeutic efficacy: After 6 months' treatment, SCH children patients showed no difference in plasma FT3, FT4 level compared with the control.(1)The children SCH patients' scores of classification, comprehend, coding, knowledge, mapping, speech total scores and the entire total score improvement was significantly better than placebo group,, replacement therapy group' scores of operating scale and understanding are still lower than the normal group.(2).the adult SCH patients exhibited the same accuracy rate as the euthyroid subjects in N-back task. SCH patiens have shown a normal trend in the five regions of interest.(3) elderly SCH patients with TSH>10 mIU/ L has significantly increased in total scores, memory, thinking and language scores by CAMCOG test. The patiens with TSH<10 mIU/ L has improved significantly superior to placebo treatment in total scores, memory and thinking scores by CAMCOG test scores in the L-thyroxine group is close to the normal control group. Conclusions: The children with SCH have broader scope of damage in cognitive impairment, which have significantly improved especially the language ability after replacement therapy. After proper treatment, SCH patients's corresponding neural basis of working memory capacity can be restored. The elderly patients with SCH have mild cognitive impairment.
These findings suggested that cognitive impairment is often seen symptoms in thyroid hormone diseases, the frontal cortext is the main neural network involved in the cognitive disoders in SCH patients. The early thyroid hormone replacement therapy improves the cognitive function and the life quality in patients with thyroid hormone diseases.
引文
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