摘要
研究背景
血管性痴呆(Vascular dementia,VD)是由于血管因素引起的记忆、视空间能力、性格改变及认知功能下降，是老年期痴呆的主要类型之一。脑缺血性病变尤其是多发性脑梗塞是VD的主要病理基础，VD可由于多发性脑梗塞、大面积脑梗塞、皮层下动脉硬化性脑病、特殊部位梗塞等基础病变所致，其中主要为脑动脉闭塞引起脑梗死，梗死脑组织容积超过80-150ml临床即可出现痴呆症状，以额叶、颞叶及边缘系统等部位血管源性病变更易导致痴呆。研究显示颈动脉狭窄造成的脑血流慢性失代偿或脑结构损害亦可引起认知功能障碍，对严重颈动脉狭窄患者行颈动脉内膜剥脱术后，其认知功能有所恢复。VD的发病机制一直在不断的探索中，老年期明显改变的内分泌水平对VD发病的影响引起越来越多的关注，有学者研究正常甲状腺功能的老年病人其认知功能变化与甲状腺激素水平的关系，发现血清低T_4水平者认知功能下降的可能性为相对高T_4水平者的双倍；老年甲状腺功能减退患者往往伴有认知功能障碍，用外源性甲状腺激素替代治疗后，其甲状腺功能及认知功能均得到改善，可以认为认知功能障碍的发生与甲状腺激素代谢紊乱存在一定联系。但目前国内外这方面的研究报道不多，研究结果也不一致。故本课题通过永久性结扎双侧颈总动脉建立大鼠血管性痴呆模型，研究VD模型大鼠脑垂体TSH、血清甲状腺激素变化特点及其与认知功能的关系，为系统性研究血管性痴呆大鼠认知功能改变与甲状腺激素系统变化的关系提供实验支持；同时在临床上对血管性痴呆(VD)、阿尔茨海默病(AD)、脑梗塞患者及对照组进行神经心理学量表的评估，并与血清、脑脊液甲状腺激素的相关性进行分析，以期为临床痴呆的防治提供新的思路。
研究方法
第一部分血管性认知障碍与甲状腺激素代谢关系的实验研究
一．实验分组：25只雄性成年SD大鼠随机分三组：假手术组10只(仅做颈前切口，钝性分离双侧颈总动脉，不行结扎)；单纯手术组7只(永久性结扎双侧颈总动脉5周)；术后给药组8只(双侧颈总动脉结扎后次日给予L-甲状腺素片20mg／日／只灌胃共5周)。
二．Morris水迷宫测试：各组均于实验终点进行定位航行试验、空间探索试验，同时记录大鼠的搜索策略。
三．放射免疫法测定垂体TSH
1．脑匀浆的制备：于实验终点大鼠断头取脑，除去表面脑膜及血管，用PB液冲洗，用滤纸吸干水分后，在冰盘上进行解剖，于蝶鞍上取垂体，冰浴下垂体置于玻璃匀浆器内，均加入1ml 1mol／L盐酸充分匀浆；
2．室温下放置100分钟后，均加入0.8ml 1mol／NAOH溶液，4℃、4000r／min离心10分钟，取上清液立即行放免检测。
3．放射免疫法测定脑垂体TSH：按照试剂盒说明操作，以~(125)I多探头γ计数器分别测各管放射性计数，并进行数据处理。
四．放射免疫法测定血清T_3、T_4、TSH
1．标本的采集：各组大鼠于实验终点行摘眼球取血法，离心取上清液行放免测定。
2．放射免疫法测定血清T_3、T_4、TSH：按照试剂盒说明操作，以~(125)I多探头γ计数器分别测各管放射性计数，并进行数据处理。
五．统计方法：实验数据以均值±标准差表示，采用SPSS10.0统计软件中的随机方差分析(one-way ANOVA)进行统计学分析，进一步分析采用LSD法，检验水准α=0.05，比较各组之间相关测试指标差异。
第二部分血管性认知障碍与甲状腺激素代谢关系的临床研究
一．病例分组：
1．血清：对照组30例，脑梗塞组32例，血管性痴呆组16例，阿尔茨海默病组21例。
2．脑脊液：对照组15例，脑梗塞组15例，血管性痴呆组8例，阿尔茨海默病组10例。
二．神经心理学量表测定：所有病例均行Folstein简易精神状态检查(MMSE)、画钟测验(CDT)、日常生活自理能力量表(ADL)、Hachinski缺血量表(HIS)、临床痴呆分级量表(CDR)、Cornell抑郁量表(CSDD)测定。
三．放射免疫法测定血清、脑脊液T_3、FT_3、FT_4、T_4、TSH
1．标本的采集：所有病例和对照组于上午7时空腹常规采肘静脉血液4ml左右于抗凝试管中，混匀，4℃冰箱静置1小时。4℃，3000rpm，离心15分钟，取上清液；在病人和／或家属签定知情同意书后行腰椎穿刺术采取脑脊液2ml左右；标本均置于-70℃冰箱保存待用。
2．放射免疫法测定血清T_3、FT_3、FT_4、T_4、TSH：按照试剂盒说明操作，以~(125)I多探头γ计数器分别测各管放射性计数，并进行数据处理。
四．统计方法：实验数据以均值±标准差表示，采用SPSS10.0统计软件中的随机方差分析(ore-way ANOVA)进行统计学分析，进一步分析采用LSD法，检验水准α=0.05，比较各组之间相关测试指标差异。
研究结果
第一部分血管性认知障碍与甲状腺激素代谢关系的实验研究
一．水迷宫结果：
1．定位航行试验：假手术组、术后给药组、单纯手术组三者间差异有显著性意义(F=6.665，P=0.005)。单纯手术组较假手术组、术后给药组逃避潜伏期差异有显著性意义(P值分别为0.002和0.012)，术后给药组与假手术组之间差异差异没有显著性意义(P=0.496)。
2．空间探索试验：假手术组、术后给药组、单纯手术组三者间差异有显著性意义(F=8.723，P=0.002)。单纯手术组较假手术组间差异有显著性意义(P=0.001)，术后给药组较单纯手术组有所延长，但仍比假手术组显著性缩短，差异有显著性意义(P=0.013)。
二．甲状腺激素测定结果：
1．血清T_3测定结果：假手术组、单纯手术组、术后给药组三者间差异有显著性意义(F=9.992，P=0.001)。单纯手术组较假手术组、术后给药组间差异有显著性意义(P值分别为0.000和0.003)，术后给药组较假手术组低，但两者相比差异没有显著性意义(P=0.36)。
2．血清T_4、TSH测定结果：T4：单纯手术组、假手术组及术后给药组三组间差异没有显著性意义(F=1.742，P=0.198)；TSH：单纯手术组、假手术组及术后给药组三组问差异没有显著性意义(F=2.709，P=0.089)。
3．脑垂体TSH测定结果：单纯手术组、假手术组及术后给药组三组间差异没有显著性意义(F=2.545，P=0.101)。
第二部分血管性认知障碍与甲状腺激素代谢关系的临床研究
一．各组MMSE、ADL、CDT评分对比：
1．MMSE评分：VD组、AD组、脑梗塞组和对照组四者问差异有显著性意义(F=129.741，P=0.000)。VD组、AD组分别较脑梗塞组、对照组显著降低，差异有显著性意义(P值均为0.000)，脑梗塞组与对照组间差异没有显著性意义(P=0.304)、VD组与AD组间差异没有显著性意义(P=0.448)；
2．ADL评分：VD组、AD组、脑梗塞组和对照组四者问差异有显著性意义(F=56.112，P=0.000)。VD组、AD组分别较脑梗塞组、对照组显著降低，差异有显著性意义(P值均为0.000)，脑梗塞组与对照组间差异没有显著性意义(P=0.175)、VD组与AD组问差异没有显著性意义(P=0.063)；
3．画钟测验评分：VD组、AD组、脑梗塞组和对照组四者间差异有显著性意义(F=40.772，P=0.000)。VD组、AD组分别较脑梗塞组、对照组显著降低，差异有显著性意义(P值均为0.000)，脑梗塞组较对照组差异有显著性意义(P=0.005)，而VD组与AD组间差异没有显著性意义(p=0.584)。
二．各组血清T_3、T_4、TSH、FT_3、FT_4水平对比分析：
1．各组血清T_4、FT_4、TSH水平对比：VD组、AD组、脑梗塞组和对照组四者间血清T_4差异没有显著性意义(F=0.688，P=0.562)；各组间血清FT_4水平差异没有显著性意义(F=2.258，P=0.087)；各组间血清TSH水平差异没有显著性意义(F=0.182，P=0.908)
2．各组血清T_3、FT_3水平对比：
T_3：VD组、AD组、脑梗塞组和对照组四者间差异有显著性意义(F=8.967，P=0.000)。VD组、AD组分别较对照组显著下降，差异有显著性意义(P=0.000)；脑梗塞组和VD组间差异有显著性意义(P=0.006)；脑梗塞组和AD组间差异有显著性意义(P=0.010)、和对照组间差异没有显著性意义(P=0.080)，VD组与AD组间无统计学差异(P=0.715)。
FT_3：VD组、AD组、脑梗塞组和对照组四者间差异有显著性意义(F=30.690，P=0.000)。VD组、AD组及脑梗塞组分别较对照组显著降低，差异有显著性意义(P=0.000)；脑梗塞组和VD组间差异有显著性意义(P=0.031)、和AD组间差异有显著性意义(P=0.045)；VD组与AD组问差异没有显著性意义(P=0.763)。
三．各组脑脊液甲状腺激素水平对比：
1．各组脑脊液T_3、TSH水平对比：
脑脊液T_3：VD组、AD组、脑梗塞组和对照组四者间差异有显著性意义(F=19.184，P=0.000)。VD组、AD组较对照组显著下降，差异有显著性意义(P值分别为0.000和0.001)；脑梗塞组较VD组、AD组显著增高，差异有显著性意义(P值分别为0.001和0.002)，但仍较对照组低，两者间差异有显著性意义(P=0.003)，VD组与AD组间差异没有显著性意义(0.672)。
脑脊液TSH：各组间差异没有显著性意义(F=0.931，P=0.434)。
2．各组脑脊液T_4、FT_3、FT_4水平对比：
脑脊液T_4：各组间差异有显著性意义(F=2.850，P=0.048)。VD组比对照组显著降低，差异有显著性意义(P=0.022)、而与AD组、脑梗塞组差异没有显著性意义(P值分别为0.836和0.101)。
脑脊液FT_3：各组间差异有显著性意义(F=54.943，P=0.000)。VD组、AD组及脑梗塞组均较对照组显著降低，差异有显著性意义(P=0.000)；脑梗塞组较VD组、AD组均显著增高，差异有显著性意义(P值分别为0.005和0.004)而VD组与AD组间差异没有显著性意义(P=0.918)。
脑脊液FT_4：各组间差异有显著性意义(F=46.964，P=0.000)。VD组、AD组及脑梗塞组均较对照组显著降低，差异有显著性意义(P=0.000)；脑梗塞组较VD组、AD组均显著增高，差异有显著性意义(P值分别为0.007和0.001)而VD组与AD组间差异没有显著性意义(P=0.0.565)。
四．不同程度痴呆血清甲状腺激素水平对比：
VD组中度痴呆的血清T_3、FT_3与轻度痴呆间比较均显著降低(t=2.20，P=0.046：t=2.65，P=0.019)，FT_4亦显著下降(t=3.35，P=0.005)，中度痴呆的TSH水平较轻度显著升高(t=3.01，P=0.009)，两级别问T_4水平无统计学差异(t=2.02，P=0.063)。
研究结论
一．双侧颈总动脉结扎导致大鼠对空间的学习记忆能力全面受损，2-VO模型为研究血管性痴呆的较理想模型。
二．2-VO大鼠“脑甲减”的存在可能是导致其认知功能变化的原因之一，而外周甲状腺激素浓度异常改变可能与其脑内甲状腺激素变化有关。
三．甲状腺激素治疗在改善血管性痴呆大鼠体内甲状腺激素代谢的同时也使其认知功能损害得了一定程度的恢复。
四．血管性痴呆患者体内甲状腺激素存在广泛的代谢紊乱，其中以血清内T_3、FT_3、脑脊液T_3、FT_3、FT_4水平下降为特征。在判断临床VD患者脑脊液与血清甲状腺激素变化差异时，T_4和或FT_4可能有不可或缺的作用。
五．甲状腺激素变化程度与痴呆程度密切相关，TSH水平对于痴呆程度的判断也可能有不可忽视的影响，即TSH水平越高，其痴呆程度可能也越高。
六．动态观察患者脑缺血改变后体内(特别是脑脊液)的甲状腺激素水平，将为痴呆(特别是血管性痴呆)的防治提供更大的价值。
Background
As one of the main type of senile dementia, Vascular dementia(VD) includingchanges of memory, character, spatial ability and cognition. Cerebral ischemiaespecially multi-cerebral infarction has been proved to be the main cause of vasculardementia only if the volume of ischemia more than 80-150ml, and patients withcerebral ischemia in frontal lobe、temporal lobe、limbic system has higher risk. Studyshows that cognition will be impaired in patients with carotid artery stenosis, and thesymptoms will be improved after Carotid Endoarterectomy.VD's pathogenesis needsto be further studied .Recently, the levels of hormones in the aged were focused. Onestudied the relationship between cognition and thyroid hormone in old patients withnormal thyroid gland function, result showed patients with lower T_4 concentration inserum had a twofold risk of cognition decline, cognitive impairment always can beseen in old patients with hypothyroidism, and it was improved after exogenousthyroid hormone treatment, therefore there might be a correlation between cognitiveimpairment and change of thyroid hormone metabolism. There has little study withdiscordant results in this aspect. In our study, a rat model of chronic cerebral ischemiawas established by permanently bilateral common carotid artery ligation.Cognition and concentrations of TSH in pituitary、thyroid hormones in serum were detected atthe end of experiment in order to further disclose the relationship between TH systemand cognitive dysfunction from chronic cerebral ischemia .On the other hand, scalesof neuropsychology were evaluated and concentrations of thyroid hormones inserum、CSF were measured in patients with VD,AD, cerebral infarction (CI)to givenew theory to the therapy of VD.
Method
Part one:experiment study of relationship between thyroid hormones andvascular dementia
一.25 Sprague-Dawley(SD)male rats were random divided into three group:i.e.sham operation group(SO); the pure operation group(PO, permanently Bilateralcommon carotid artery ligation was performed for 5 weeks); TH treatment group(TT,the rat was feed with TH from the next day of the operation for 5 weeks).
二.Morris Water Maze Test:place orientation, spatial probe was performed at theend of experiment.
三.TSH in pituitary gland detected by using radioimmunoassay(RIA).
1.Homogenate preparation: Rats were killed by decapitation. The brain wereremoved, rapidly dissected, washed in cold phosphate buffer, blotted. The pituitarygland were separated and homogenated in 1ml 1mol/L hydrochloric acid.
2.After placed for 100 minutes, adding 0.8ml 1mol/L NaOH ,followingcentrifugation(4000r/min) at 4℃, collecting the supernatants.
3.TSH concentration were detected by using RIA.
四.T_3、T_4、TSH concentrations in serum detected by RIA.
1.Collection of specimen: Blood of rats were collectioned by eyeballextirpation, following centrifugation, the supernatants were collected.
2.T_3、T_4、TSH were detected by RIA according to the description of kit.
五.One-way ANOVA was used to estimate the item differences among thegroups using SPSS10.0 for windows.Further analysis with LSD method.Size of test a=0.05.
Part two:Clinical study of relationship between thyroid hormones and vasculardementia.
一.Groups:
1.Serum: Control group 30, CI group32, VD group 16, AD group 21;
2.CSF. Control group 15, CI group 15, VD group 8, AD group 10;
二. Scales of neuropsychology: Patients were evaluated by MMSE、CDT、ADL、HIS、CDR、CSDD.
三. T_3、FT_3、T_4、FT_4、TSH concentrations in serum、CSF detected by RIA.
1.Collection of specimen: Blood were drawed at 7am, placed at 4℃for 1 hour,following centrifugation (4000r/rain) for 15rain at 4℃. The supematants werecollected; CSF were collected by spinal puncture. All specimen were stored inrefrigerator at -70℃.
2.T_3、FT_3、T_4、FT_4、TSH were detected by RIA according to the description ofkit.
四.One-way ANOVA was used to estimate the item differences among thegroups using SPSS10.0 for windows. Further analysis with LSD method. Size of testa=0.05.
Results
Part one:Experiment study of relationship between thyroid hormones andvascular dementia.
一.Praxiology study:
1.Place orientation test: The latent period was12.44±9.95s in SO, 33.27±16.12sin PO, 16.37±9.94s in TT.The latent periods of PO were longer than that of the other groups(P＜0.05), and there was no significant difference between SO and TT.
2.Spatial probe test: The probe time was 54.87±7.60s in SO, 38.74±10.72s inPO, 44.43±5.86s in TT. The score of SO was better than that of PO、TT (p＜0.05). Thescore of PO was the poorest among groups.
二.Thyroid hormone
1.Serum T_3 concentration：T_3 concentration of PO was lower than that of SO、TT(P＜0.01).There was no difference between TT and SO(P＜0.01).
2.Concentration of serum T_4、TSH：There was no difference between SO、POand TT.
3.TSH concentration in pituitary gland:There was no difference between SO、PO and TT.
Part two:Clinical study of relationship between thyroid hormones and vasculardementia
一.Scores of MMSE, ADL, CDT:
1.MMSE: Scores of VD、AD were significant poorer than CI and controlgroup(P＜0.01).There was no difference between CI and control group, so do VD andAD.
2.ADL: Scores of VD、AD were significant poorer than CI and controlgroups(P＜0.01).There was no difference between CI and control group, so do VD andAD.
3.CDT: Scores of VD、AD were significant poorer than CI and controlgroups(P＜0.01).Score of CI was poorer than control group. There was no differencebetween VD and AD.
二.Concentrations of T_3、T_4、TSH、FT_3、FT_4 inserum:
1.T_4、FT_4、TSH: There were no difference of T_4、FT_4、TSH concentrations inserum among groups;
2.T_3、FT_3:T_3 concentration of VD、AD were significant lower than that ofcontrol group(P＜0.01).T_3 concentration of CI was higher than that of VD(P＜0.01)、AD (P＜0.05).FT_3 concentration of control group was higher than those of VD、AD、CI groups (P＜0.01). FT_3 concentration of CI group was also higher than VD、ADgroups (P＜0.05).
三.Thyroid hormones in CSF:
1.T_3、TSH in CSF:T_3 concentration in CSF of VD、AD、CI were significantlower than that of control group(P＜0.01).T_3 concentration of CI was higher thanthose of VD、AD(P＜0.01).TSH: there was no difference among groups.
2.T_4、FT_3、FT_4 in CSF:
T_4:T_4 concentrations in CSF of VD、AD were lower than that of controlgroup(P＜0.05).There were no difference among the other groups.
FT_3、FT_4: FT_3、FT_4 concentrations of VD、AD、CI were all lower than thoseof control group(P＜0.01).FT_3、FT_4 concentrations of CI were higher than those ofVD、AD groups(P＜0.01).There were no difference between VD and AD group.
四.Serum thyroid hormones of dementia in difference degree.
T_3、FT_3、FT_4 concentrations in moderate vascular dementia patients weresignificant lower than those of mild ones(P＜0.01). TSH concentration of moderatevascular dementia patients were higher than that of mild ones(P＜0.01).
Conclusion
一.Rat's cognitive function were totally damaged by permanently bilateralcommon carotid artery ligation. The 2VO rat can be concerned as a typical vasculardementia model.
二."cerebral hypothyroidism"in 2VO rats was maybe one of the factors whichcan influence cognition. The changes of T_3、FT_3 concentrations in serum maybecorrelated with the thyroid hormone levels in brain.
三.The cognitive function of rats with VD was improved by the TH treatmentfollowing the elevated level of thyroid hormone.
四.Metabolism of thyroid hormones in VD patients were obviously changedwith the lower levels of T_3、FT_3 in serum, T_3、FT_3、FT_4 in CSE
五.Diversity Change of thyroid hormones were correlated with dementia indifferent degree.The higher levels of TSH in serum, the more serious in dementiapatient.
六.Dynamic observation of thyroid hormone concentrations in patients(especiallyCSF) with cerebral ischemia is benefit for dementia (especially vascular dementia)prevention and cure.
引文
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