Binswanger病患者肿瘤坏死因子-α含量观察
作者：陈春富 贾海燕 郭述苏 王和德 李怡
单位：济南军区总医院神经内科(济南 250031)
关键词：痴呆；血管性；肿瘤坏死因子-α
Binswanger病患者肿瘤坏死因子 摘要 目的和方法：观察Binswanger病患者血清肿瘤坏死因子-α的变化。Binswanger病组21例，多发性梗塞性痴呆组16例，健康对照组6例。应用放射免疫法测定血清及脑脊液中肿瘤坏死因子-α含量，用颈内静脉与肘静脉血清肿瘤坏死因子-α含量的比值反映脑循环中肿瘤坏死因子-α的水平。结果：Binswanger病组脑循环及脑脊液中肿瘤坏死因子-α显著高于其它两组，两个指标均与Binswanger病患者简易智力状态量表积分呈负相关。结论：肿瘤坏死因子-α可能参与了Binswanger病的发病机制。
Changes in tumor necrosis factor-α levels in
, 百拇医药
patients with Binswanger's disease
CHEN Chun-Fu,JIA Hai-Yan,GUO Shu-Su,WANG He-De,LI Yi
Department of Neurology,Jinan General Military Hospital,Jinan (250031)
Abstract AIM and METHODS: To measure serum tumor necrosis factor-α (TNF-α) levels in Binswanger's disease and explore the relationship between TNF-α and this disorder.The levels of TNF-α in serum and cerebrospinal fluid were examined by radioimmunoassay in 21 patients with Binswanger's disease,16 subjects with multi-infarction dementia,and 6 healthy controls.The ratio of the serum concentration of TNF-α in the blood from internal jugular vein to that from the antecubital vein was calculated as an indicator of TNF-α levels in cerebral circulation.RESULTS：TNF-α levels in cerebral circulation and in cerebrospinal fluid were significantly elevated in patients with Binswanger's disease as compared with those in other subjects,and both of these two parameters were negatively correlated with the Mini-mental state examination scores in subjects with Binswanger's disease.CONCLUSION：TNF-α may be involved in the pathogenesis of Binswanger's disease.
, 百拇医药
MeSH Dementia,vascular; Tumor necrosis factor-α
INTRODUCTION
Binswanger's disease (BD) is a form of vascular dementia characterized clinically by chronic progressive deterioration of memory,mood and cognition,and pathologically by diffuse demyelination and multiple lacunar infarctions in the cerebral white matter.This disease has been attributed to severe arteriosclerotic changes in the long perforating arteries of the brain.The pathogenetic mechanism underlying white matter lesions in BD,however,remains to be elucidated[1].Tumor necrosis factor-α (TNF-α) has been shown in vitro to disrupt oligodendrocytes and myelin sheath selectively.Up to now,there is no information concerning changes of TNF-α in BD.In this study,we determined the levels of TNF-α in the serum and cerebrospinal fluid (CSF) from patients with BD in order to delineate the possible role of TNF-α in the pathogenesis of BD.
, 百拇医药
MATERIALS AND METHODS
Subject: Sixteen patients with multi-infarction dementia (MID) were shown by CT scanning to have multiple lacunar infarction lesions in the gray matter of basal ganglia and centrum semiovale but no extensive white matter low attenuation (WMLA).Twenty-one patients with BD were diagnosed according to the criteria proposed by Bennett[2].The diagnosis of vascular dementia was based on DSM-Ⅲ-R standards.All these patients had no history of acute cerebrovascular accidents in the three months prior to the study,denoting that all of them were in a chronic state of the disease.The presence of major infarctions in the cortical regions(>3 cm in diameter),thalamus and/or hippocampus that may possibly lead to dementia was ruled out by radiological examination.Hypertension not effectively treated,congestive heart failure,severe diabetes mellitus and other diseases that may possibly give rise to WMLA were carefully excluded in the differential diagnosis of BD.Six healthy volunteers serving as controls had normal intelligence,no cerebrovascular risk factors and no evidence of vascular lesions on CT scanning examination.All of these individuals were subjected to conventional physical and neurological examinations as well as routine laboratory tests,Mini-mental state examination (MMSE) and Hachinski's ischemic score(HIS) evaluation.A list of background indices of these subjects in shown in Table 1.The differences in blood pressure,HIS and MMSE scores between patients with MID and BD were not significant.
, 百拇医药
Tab 1 Background indices of the subjects studied (
±s)
Clinical features
Healthy controls
Patients with MID
Patients with BD
Number (Sex: M/F)
6(4/2)
16(11/5)
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21(14/7)
Age(range)(year)
67.4±5.3(61～74)
67.6±6.4(59～79)
68.3±6.9(60～81)
Systolic blood pressure (kPa)
21.5±2.8
21.3±2.6
21.6±2.7
Diastolic blood pressure (kPa)
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11.8±1.4
11.5±1.5
11.6±1.6
WBC(×109/L)
7.11±3.82
7.15±3.98
7.10±3.79
Creatinine(μmol/L serum)
102.4±41.4
103.9±39.4
105.7±43.2
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Total cholesterol (mmol/L serum)
5.05±2.03
5.17±2.14
5.23±2.20
Fasting random glucose(mmol/L serum)
5.73±1.88
5.66±1.92
5.74±1.95
Hichinski's ischemic scale
0
, http://www.100md.com
8.6±2.4
8.7±2.3
MMSE scores
30.0±0
13.2±3.2
14.4±3.1
1 kPa=7.5 mmHg
Radioimmunoassay of TNF-α: Paired blood specimens were withdrawn simultaneouslyfrom the internal jugular vein (IJV) and the antecubital vein (ACV).IJV was punctured in the right carotid triangle along the pulsating carotid artery after IJV had been detected by B-mode ultrasonography.CSF sample was also collected for the measurement of TNF-α in addition to cell count.Clinical treatment was discontinued at least 12 hours prior to the blood collection for TNF-α determination with the use of double-antibody radioimmunoassay (RIA).The ratio of the serum concentration of TNF-α in the blood from the IJV to that from the ACV(IJV/ACV) was calculated125I.TNF-α assay was carried out according to the directions of the kits supplied by East Asia Immunology Institute,Beijing,China.The rabbit antiserum to recombinant human TNF-α used in the present study did not cross-react with interleukins(IL)-1α,IL-1β,IL-2 and TNF-β.The range of standard curve was 0.1～24.3 ng/mL,the minimum detection value of TNF-α was less than 0.06 ng/mL.Within-and between-assay coefficients of variation were 5% and 8%,respectively.Analytical recoveries ranged from 95% to 106%.
, 百拇医药
CT scanning:Brain CT scanning was performed with a 9800 scanner (GE Medical System ,Milwaukee Wis,USA),section thickness and intervals both being 10 mm.The extent of WMLA on CT scanning was graded arbitrarily into three ratings[3]:0=no visible lucency in cerebral white matter; 1=lucencies confined to anteriorly or posteriorly to the lateral ventricles; 2=periventricular lucencies anterior and posterior to the lateral ventricles; 3=periventricular lucencies all around the lateral ventricles.
, 百拇医药
Statistics:The comparisons of TNF-α concentrations among different groups were performed with the use of Student-t test,one-way analysis of variance (ANOVA) and Newman-Keuls test.The relationships among TNF-α levels and MMSE scores,as well as TNF-α ratio and age were assessed by linear correlation.These calculations were performed with SPSS statistical programs (Ver6.0) on a HP computer.
RESULTS
TNF-α concentrations in serum and CSF in different groups are summarized in Table 2.The differences in TNF-α/ACV among the three groups are not significant (P>0.05).The concentration of TNF-α/IJV has a tendency to be elevated in BD patients,but it is not significant when compared with MID subjects(P>0.05) and control subjects (P>0.05).Differences in TNF-α ratios(IJV/ACV) among the three groups are found to be significant (P<0.01).Higher TNF-α ratios are seen in patients with BD than in those with MID(P<0.05).Difference in TNF-α ratios among BD patients with different grades of WMLA are significant(P<0.01).TNF-α ratio in eight BD patients with rating-2 WMLA(1.141±0.070) was significantly increased as compared with that in seven BD patients with rating-1 WMLA (1.043±0.067)(P<0.05).TNF-α ratio in six BD patients with rating-3 WMLA(1.344±0.073) was significantly higher than those in BD patients with rating-1 WMLA(P<0.01) and with rating-2 WMLA (P<0.01) respectively.
, 百拇医药
Tab 2 Tumor necrosis factor-α levels in different groups (
±s)
Healthy controls
(n=6)
Patients with
MID(n=16)
Patients with
BD(n=21)
TNF-α/ACV(ng/mL)
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0.563±0.031△△
0.559±0.033△△
0.594±0.036△△
TNF-α/IJV(ng/mL)
0.563±0.050△△
0.564±0.049△△
0.687±0.055△△
TNF-α ratio
0.999±0.064
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1.013±0.065
1.161±0.069*＃
TNF-α/CSF(ng/mL)
0.204±0.071
0.214±0.076
0.426±0.088**＃＃
*P<0.05，**P<0.01，vs healthy controls; ＃P<0.05 ，＃＃P<0.01,BD group vs MID group; △△P<0.01,TNF-α/ACV and TNF-α/IJV vs corresponding TNF-α/CSF in the same group
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No significant correlation between TNF-α/ACV concentration and MMSE scores is found in patients with BD(r=-0.317,P>0.05 ).However,MMSE scores are correlated with TNF-α/IJV,TNF-α ratios and TNF-α level in CSF (TNF-α/CSF)(r=-0.484,P<0.05; r=-0.917,P<0.001; r=-0.484,P>0.05; respectively).Neither TNF-α/IJV,TNF-α/ACV,nor TNF-α ratio and TNF-α/CSF are correlated with MMSE scores in MID patients (r=-0.190,P>0.05; r=-0.267,P>0.05; r=0.328,P>0.05 ;r=0.024,P>0.05; respectively).There are no significant correlations between age and TNF-α/IJV,TNF-α/ACV,TNF-α ratio or TNF-α/CSF in MID subjects as well as BD subjects (P>0.05).There are no significant correlations between CSF cell counts and TNF-α ratio as well as TNF-α/CSF in BD subjects (P>0.05).In BD patients,both TNF-α ratio and TNF-α/IJV,but not TNF-α/ACV,are correlated to TNF-α/CSF significantly (r=0.815,P<0.01; r=0.642,P<0.01;r=0.298,P>0.05； respectively).
, 百拇医药
DISCUSSION
As blood is returned to the heart from the brain via the internal jugular vein,the ratio of TNF-α between IJV and the carotid artery should be able to reflect TNF-α changes in cerebral circulation.Considering the technical limitation in obtaining blood samples from the carotid artery,we used the TNF-α ratio (IJV/ACV) as an indicator of TNF-α level in cerebral circulation in the present study.This method was based on the assumption that TNF-α/ACV should be equivalent to that in the carotid artery if TNF-α is produced only in the cerebral blood circulation.Significantly higher TNF-α ratio was found in partients with BD than that in patients with MID and in controls.The difference in TNF-α ratio among BD partients with different WMLA ratings are also significant.These findings are in accordance with those denoting that MMSE scores are correlated with TNF-α ratio and TNF-α/CSF.All these results suggest that TNF-α play a certain role in the pathogenesis of BD.TNF-α has diverse effects on the central nervous system owing to its influence on astrocytes and oligodendrocytes.In particular,TNF-α can selectively injure myelin sheath,stimulate astrocyte secretion,and promote lysis of oligodendrocytes[6，7],the latter being the myelin-producing cells of the central nervous system.TNF-α has been shown to play a role in demyelination disease mediated by immune response[8].The mainly pathologic changes in BD patients are perivascular demyelination in the cerebral white matter.Therefore,higher TNF-α levels of TNF-α in the cerebral circulation and in CSF from patients with clinically stable BD suggest that TNF-α-mediated immune injuries may be one possible mechanism in demyelination in BD.Further,autoimmune-mediated demyelination process may be relevant to the disease progression in patients with BD.It was reported that TNF-α can injure endothelial cells of human blood vessels[4],resulting possibly in the formation of thrombus[5].Thus,the presence of an elevated TNF-α ratio may represent a tendency toward thrombosis in the cerebral vessels.This appears to be consistent with the common clinical feature of repeated minor strokes throughout the course of BD.In addition,TNF-α can cause severe injuries to endothelial and smooth muscle cells of blood vesscls,that may be relevant to the arteriosclerotic changes in the long penetrating arteries of the brain in BD patients.
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Circulating TNF-α protein is a 17-kDa monomer,it has an isolectric point of 5.3 and contains a disulfide bond.TNF-α can pass through blood-brain barrier both in physiological and pathological conditions[9].In the present study,there was no sign of infection in the subjects of BD group.The fact that TNF-α level was higher in serum than CSF,and that TNF-α/CSF and TNF-α ratio showed no significant correlation to CSF cell counts in BD patients,suggest that elevated TNF-α level in cerebral circulation may not be attributed to increased TNF-α production by intrathecal immunocompetent cells.Rather,the increased TNF-α may be liberated by local nervous tissue of the brain as a result of induction by nonbiogenic factors.Significantly increased TNF-α ratio together with the tendency of generally higher TNF-α/IJV than TNF-α/ACV in BD patients also lends support to the idea that TNF-α is mainly liberated by cells in the brain,whereas the relatively lower level of TNF-α/ACV could possibly reflect the rapid clearance of circulating TNF-α,leaving less time for accumulation in peripheral blood in BD patients.However,whether systemic secretion also contributes to the increased TNF-α in BD patients is not clear in the present study.The absence of frank perivascular cell exudation in the white matter ,the severe injures to endothelial and smooth muscle cells of the perforating arteries as a result of arteriosclerosis in BD patients render it unlikely that increased TNF-α is liberated by exudated cells,endothelial cells and smooth muscle cells.On contrast,astrocytes were found to proliferate in the white matter with simultaneous decrease in other neuroglias almost in every case of BD.It is known that astrocytes can secrete TNF-α upon stimulation[6].In theory,decreased oxygen tension may induce astrocytes to produce TNF-α[10].If increased TNF-α is actually secreted and released from brain astrocytes in BD,it seems reasonable to postulate that astrocytes might be related to the decrease in oligodendrocytes and demyelination in this disorder.
, 百拇医药
In conclusion,the increase in TNF-α in the cerebral blood circulation observed in BD patients might participate in the pathophysiology of this disease,but the exact site of TNF-α secretion needs to be identified by immunohistochemical technique in further study.In addition,our data also indicate that the pathogenesis of BD may be different from that of MID.
REFERENCES
1 Pantoni L,Garcia JH.The significance of cerebral white matter abnormalities 100 years after Binswanger's report: a review.Stroke,1995,26: 1293.
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2 Bennett DA,Wilson RS,Gilley DW,et al.Clinical diagnosis of Binswanger's disease.J Neurol Neurosurg Psychiatry,1990,53:961.
3 Koto H,Sugawara Y,Ito H,et al.White matter lucencies in multi-infarct dementia: a somatosensory evoked potential and CT study.Acta Neurol Scand,1990,81:181.
4 Redford EJ,Hall SM,Smith KJ.Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor.Brain,1995,118:869.
, http://www.100md.com
5 Siren AL,Heldman E,Doron DA,et al.Release of proinflammatory and prothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats.Stroke,1992,23:1643.
6 Chung IY,Benveniste EN.Tumor necrosis factor-α production by astrocytes: induction by lipopolysaccharide,IFN-γ,and IL-1β.J Immunol,1990,144: 2999.
7 Hartung HP,Archelos JJ,Zielasek J,et al.Circulating adhesion molecules and inflammatory mediators in demyelination: a review.Neurology,1995,45(suppl 6):22.
, http://www.100md.com
8 Ledeen RW,Chakraborty G.Cytokines,signal transduction,and inflammatory demyelination: review and hypothesis.Neurochem Res,1998,23: 277.
9 Gatiereez EG,Banks WA,Kastin AJ.Murine tumor necrosis factor alpha is transported from blood to brain in the mouse.J Neuroimmunol,1993,47:169.
10 Barath P,Fishbein MC,Cao J,et al.Detection and localization of tumor necrosis factor in human atheroma.Am J Cardiol,1990,65:297.
(Received 1998-08-10,Accepted 1999-04-02), http://www.100md.com
单位：济南军区总医院神经内科(济南 250031)
关键词：痴呆；血管性；肿瘤坏死因子-α
Binswanger病患者肿瘤坏死因子 摘要 目的和方法：观察Binswanger病患者血清肿瘤坏死因子-α的变化。Binswanger病组21例，多发性梗塞性痴呆组16例，健康对照组6例。应用放射免疫法测定血清及脑脊液中肿瘤坏死因子-α含量，用颈内静脉与肘静脉血清肿瘤坏死因子-α含量的比值反映脑循环中肿瘤坏死因子-α的水平。结果：Binswanger病组脑循环及脑脊液中肿瘤坏死因子-α显著高于其它两组，两个指标均与Binswanger病患者简易智力状态量表积分呈负相关。结论：肿瘤坏死因子-α可能参与了Binswanger病的发病机制。
Changes in tumor necrosis factor-α levels in
, 百拇医药
patients with Binswanger's disease
CHEN Chun-Fu,JIA Hai-Yan,GUO Shu-Su,WANG He-De,LI Yi
Department of Neurology,Jinan General Military Hospital,Jinan (250031)
Abstract AIM and METHODS: To measure serum tumor necrosis factor-α (TNF-α) levels in Binswanger's disease and explore the relationship between TNF-α and this disorder.The levels of TNF-α in serum and cerebrospinal fluid were examined by radioimmunoassay in 21 patients with Binswanger's disease,16 subjects with multi-infarction dementia,and 6 healthy controls.The ratio of the serum concentration of TNF-α in the blood from internal jugular vein to that from the antecubital vein was calculated as an indicator of TNF-α levels in cerebral circulation.RESULTS：TNF-α levels in cerebral circulation and in cerebrospinal fluid were significantly elevated in patients with Binswanger's disease as compared with those in other subjects,and both of these two parameters were negatively correlated with the Mini-mental state examination scores in subjects with Binswanger's disease.CONCLUSION：TNF-α may be involved in the pathogenesis of Binswanger's disease.
, 百拇医药
MeSH Dementia,vascular; Tumor necrosis factor-α
INTRODUCTION
Binswanger's disease (BD) is a form of vascular dementia characterized clinically by chronic progressive deterioration of memory,mood and cognition,and pathologically by diffuse demyelination and multiple lacunar infarctions in the cerebral white matter.This disease has been attributed to severe arteriosclerotic changes in the long perforating arteries of the brain.The pathogenetic mechanism underlying white matter lesions in BD,however,remains to be elucidated[1].Tumor necrosis factor-α (TNF-α) has been shown in vitro to disrupt oligodendrocytes and myelin sheath selectively.Up to now,there is no information concerning changes of TNF-α in BD.In this study,we determined the levels of TNF-α in the serum and cerebrospinal fluid (CSF) from patients with BD in order to delineate the possible role of TNF-α in the pathogenesis of BD.
, 百拇医药
MATERIALS AND METHODS
Subject: Sixteen patients with multi-infarction dementia (MID) were shown by CT scanning to have multiple lacunar infarction lesions in the gray matter of basal ganglia and centrum semiovale but no extensive white matter low attenuation (WMLA).Twenty-one patients with BD were diagnosed according to the criteria proposed by Bennett[2].The diagnosis of vascular dementia was based on DSM-Ⅲ-R standards.All these patients had no history of acute cerebrovascular accidents in the three months prior to the study,denoting that all of them were in a chronic state of the disease.The presence of major infarctions in the cortical regions(>3 cm in diameter),thalamus and/or hippocampus that may possibly lead to dementia was ruled out by radiological examination.Hypertension not effectively treated,congestive heart failure,severe diabetes mellitus and other diseases that may possibly give rise to WMLA were carefully excluded in the differential diagnosis of BD.Six healthy volunteers serving as controls had normal intelligence,no cerebrovascular risk factors and no evidence of vascular lesions on CT scanning examination.All of these individuals were subjected to conventional physical and neurological examinations as well as routine laboratory tests,Mini-mental state examination (MMSE) and Hachinski's ischemic score(HIS) evaluation.A list of background indices of these subjects in shown in Table 1.The differences in blood pressure,HIS and MMSE scores between patients with MID and BD were not significant.
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Tab 1 Background indices of the subjects studied (
±s)Clinical features
Healthy controls
Patients with MID
Patients with BD
Number (Sex: M/F)
6(4/2)
16(11/5)
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21(14/7)
Age(range)(year)
67.4±5.3(61～74)
67.6±6.4(59～79)
68.3±6.9(60～81)
Systolic blood pressure (kPa)
21.5±2.8
21.3±2.6
21.6±2.7
Diastolic blood pressure (kPa)
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11.8±1.4
11.5±1.5
11.6±1.6
WBC(×109/L)
7.11±3.82
7.15±3.98
7.10±3.79
Creatinine(μmol/L serum)
102.4±41.4
103.9±39.4
105.7±43.2
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Total cholesterol (mmol/L serum)
5.05±2.03
5.17±2.14
5.23±2.20
Fasting random glucose(mmol/L serum)
5.73±1.88
5.66±1.92
5.74±1.95
Hichinski's ischemic scale
0
, http://www.100md.com
8.6±2.4
8.7±2.3
MMSE scores
30.0±0
13.2±3.2
14.4±3.1
1 kPa=7.5 mmHg
Radioimmunoassay of TNF-α: Paired blood specimens were withdrawn simultaneouslyfrom the internal jugular vein (IJV) and the antecubital vein (ACV).IJV was punctured in the right carotid triangle along the pulsating carotid artery after IJV had been detected by B-mode ultrasonography.CSF sample was also collected for the measurement of TNF-α in addition to cell count.Clinical treatment was discontinued at least 12 hours prior to the blood collection for TNF-α determination with the use of double-antibody radioimmunoassay (RIA).The ratio of the serum concentration of TNF-α in the blood from the IJV to that from the ACV(IJV/ACV) was calculated125I.TNF-α assay was carried out according to the directions of the kits supplied by East Asia Immunology Institute,Beijing,China.The rabbit antiserum to recombinant human TNF-α used in the present study did not cross-react with interleukins(IL)-1α,IL-1β,IL-2 and TNF-β.The range of standard curve was 0.1～24.3 ng/mL,the minimum detection value of TNF-α was less than 0.06 ng/mL.Within-and between-assay coefficients of variation were 5% and 8%,respectively.Analytical recoveries ranged from 95% to 106%.
, 百拇医药
CT scanning:Brain CT scanning was performed with a 9800 scanner (GE Medical System ,Milwaukee Wis,USA),section thickness and intervals both being 10 mm.The extent of WMLA on CT scanning was graded arbitrarily into three ratings[3]:0=no visible lucency in cerebral white matter; 1=lucencies confined to anteriorly or posteriorly to the lateral ventricles; 2=periventricular lucencies anterior and posterior to the lateral ventricles; 3=periventricular lucencies all around the lateral ventricles.
, 百拇医药
Statistics:The comparisons of TNF-α concentrations among different groups were performed with the use of Student-t test,one-way analysis of variance (ANOVA) and Newman-Keuls test.The relationships among TNF-α levels and MMSE scores,as well as TNF-α ratio and age were assessed by linear correlation.These calculations were performed with SPSS statistical programs (Ver6.0) on a HP computer.
RESULTS
TNF-α concentrations in serum and CSF in different groups are summarized in Table 2.The differences in TNF-α/ACV among the three groups are not significant (P>0.05).The concentration of TNF-α/IJV has a tendency to be elevated in BD patients,but it is not significant when compared with MID subjects(P>0.05) and control subjects (P>0.05).Differences in TNF-α ratios(IJV/ACV) among the three groups are found to be significant (P<0.01).Higher TNF-α ratios are seen in patients with BD than in those with MID(P<0.05).Difference in TNF-α ratios among BD patients with different grades of WMLA are significant(P<0.01).TNF-α ratio in eight BD patients with rating-2 WMLA(1.141±0.070) was significantly increased as compared with that in seven BD patients with rating-1 WMLA (1.043±0.067)(P<0.05).TNF-α ratio in six BD patients with rating-3 WMLA(1.344±0.073) was significantly higher than those in BD patients with rating-1 WMLA(P<0.01) and with rating-2 WMLA (P<0.01) respectively.
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Tab 2 Tumor necrosis factor-α levels in different groups (
±s)Healthy controls
(n=6)
Patients with
MID(n=16)
Patients with
BD(n=21)
TNF-α/ACV(ng/mL)
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0.563±0.031△△
0.559±0.033△△
0.594±0.036△△
TNF-α/IJV(ng/mL)
0.563±0.050△△
0.564±0.049△△
0.687±0.055△△
TNF-α ratio
0.999±0.064
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1.013±0.065
1.161±0.069*＃
TNF-α/CSF(ng/mL)
0.204±0.071
0.214±0.076
0.426±0.088**＃＃
*P<0.05，**P<0.01，vs healthy controls; ＃P<0.05 ，＃＃P<0.01,BD group vs MID group; △△P<0.01,TNF-α/ACV and TNF-α/IJV vs corresponding TNF-α/CSF in the same group
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No significant correlation between TNF-α/ACV concentration and MMSE scores is found in patients with BD(r=-0.317,P>0.05 ).However,MMSE scores are correlated with TNF-α/IJV,TNF-α ratios and TNF-α level in CSF (TNF-α/CSF)(r=-0.484,P<0.05; r=-0.917,P<0.001; r=-0.484,P>0.05; respectively).Neither TNF-α/IJV,TNF-α/ACV,nor TNF-α ratio and TNF-α/CSF are correlated with MMSE scores in MID patients (r=-0.190,P>0.05; r=-0.267,P>0.05; r=0.328,P>0.05 ;r=0.024,P>0.05; respectively).There are no significant correlations between age and TNF-α/IJV,TNF-α/ACV,TNF-α ratio or TNF-α/CSF in MID subjects as well as BD subjects (P>0.05).There are no significant correlations between CSF cell counts and TNF-α ratio as well as TNF-α/CSF in BD subjects (P>0.05).In BD patients,both TNF-α ratio and TNF-α/IJV,but not TNF-α/ACV,are correlated to TNF-α/CSF significantly (r=0.815,P<0.01; r=0.642,P<0.01;r=0.298,P>0.05； respectively).
, 百拇医药
DISCUSSION
As blood is returned to the heart from the brain via the internal jugular vein,the ratio of TNF-α between IJV and the carotid artery should be able to reflect TNF-α changes in cerebral circulation.Considering the technical limitation in obtaining blood samples from the carotid artery,we used the TNF-α ratio (IJV/ACV) as an indicator of TNF-α level in cerebral circulation in the present study.This method was based on the assumption that TNF-α/ACV should be equivalent to that in the carotid artery if TNF-α is produced only in the cerebral blood circulation.Significantly higher TNF-α ratio was found in partients with BD than that in patients with MID and in controls.The difference in TNF-α ratio among BD partients with different WMLA ratings are also significant.These findings are in accordance with those denoting that MMSE scores are correlated with TNF-α ratio and TNF-α/CSF.All these results suggest that TNF-α play a certain role in the pathogenesis of BD.TNF-α has diverse effects on the central nervous system owing to its influence on astrocytes and oligodendrocytes.In particular,TNF-α can selectively injure myelin sheath,stimulate astrocyte secretion,and promote lysis of oligodendrocytes[6，7],the latter being the myelin-producing cells of the central nervous system.TNF-α has been shown to play a role in demyelination disease mediated by immune response[8].The mainly pathologic changes in BD patients are perivascular demyelination in the cerebral white matter.Therefore,higher TNF-α levels of TNF-α in the cerebral circulation and in CSF from patients with clinically stable BD suggest that TNF-α-mediated immune injuries may be one possible mechanism in demyelination in BD.Further,autoimmune-mediated demyelination process may be relevant to the disease progression in patients with BD.It was reported that TNF-α can injure endothelial cells of human blood vessels[4],resulting possibly in the formation of thrombus[5].Thus,the presence of an elevated TNF-α ratio may represent a tendency toward thrombosis in the cerebral vessels.This appears to be consistent with the common clinical feature of repeated minor strokes throughout the course of BD.In addition,TNF-α can cause severe injuries to endothelial and smooth muscle cells of blood vesscls,that may be relevant to the arteriosclerotic changes in the long penetrating arteries of the brain in BD patients.
, 百拇医药
Circulating TNF-α protein is a 17-kDa monomer,it has an isolectric point of 5.3 and contains a disulfide bond.TNF-α can pass through blood-brain barrier both in physiological and pathological conditions[9].In the present study,there was no sign of infection in the subjects of BD group.The fact that TNF-α level was higher in serum than CSF,and that TNF-α/CSF and TNF-α ratio showed no significant correlation to CSF cell counts in BD patients,suggest that elevated TNF-α level in cerebral circulation may not be attributed to increased TNF-α production by intrathecal immunocompetent cells.Rather,the increased TNF-α may be liberated by local nervous tissue of the brain as a result of induction by nonbiogenic factors.Significantly increased TNF-α ratio together with the tendency of generally higher TNF-α/IJV than TNF-α/ACV in BD patients also lends support to the idea that TNF-α is mainly liberated by cells in the brain,whereas the relatively lower level of TNF-α/ACV could possibly reflect the rapid clearance of circulating TNF-α,leaving less time for accumulation in peripheral blood in BD patients.However,whether systemic secretion also contributes to the increased TNF-α in BD patients is not clear in the present study.The absence of frank perivascular cell exudation in the white matter ,the severe injures to endothelial and smooth muscle cells of the perforating arteries as a result of arteriosclerosis in BD patients render it unlikely that increased TNF-α is liberated by exudated cells,endothelial cells and smooth muscle cells.On contrast,astrocytes were found to proliferate in the white matter with simultaneous decrease in other neuroglias almost in every case of BD.It is known that astrocytes can secrete TNF-α upon stimulation[6].In theory,decreased oxygen tension may induce astrocytes to produce TNF-α[10].If increased TNF-α is actually secreted and released from brain astrocytes in BD,it seems reasonable to postulate that astrocytes might be related to the decrease in oligodendrocytes and demyelination in this disorder.
, 百拇医药
In conclusion,the increase in TNF-α in the cerebral blood circulation observed in BD patients might participate in the pathophysiology of this disease,but the exact site of TNF-α secretion needs to be identified by immunohistochemical technique in further study.In addition,our data also indicate that the pathogenesis of BD may be different from that of MID.
REFERENCES
1 Pantoni L,Garcia JH.The significance of cerebral white matter abnormalities 100 years after Binswanger's report: a review.Stroke,1995,26: 1293.
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2 Bennett DA,Wilson RS,Gilley DW,et al.Clinical diagnosis of Binswanger's disease.J Neurol Neurosurg Psychiatry,1990,53:961.
3 Koto H,Sugawara Y,Ito H,et al.White matter lucencies in multi-infarct dementia: a somatosensory evoked potential and CT study.Acta Neurol Scand,1990,81:181.
4 Redford EJ,Hall SM,Smith KJ.Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor.Brain,1995,118:869.
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5 Siren AL,Heldman E,Doron DA,et al.Release of proinflammatory and prothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats.Stroke,1992,23:1643.
6 Chung IY,Benveniste EN.Tumor necrosis factor-α production by astrocytes: induction by lipopolysaccharide,IFN-γ,and IL-1β.J Immunol,1990,144: 2999.
7 Hartung HP,Archelos JJ,Zielasek J,et al.Circulating adhesion molecules and inflammatory mediators in demyelination: a review.Neurology,1995,45(suppl 6):22.
, http://www.100md.com
8 Ledeen RW,Chakraborty G.Cytokines,signal transduction,and inflammatory demyelination: review and hypothesis.Neurochem Res,1998,23: 277.
9 Gatiereez EG,Banks WA,Kastin AJ.Murine tumor necrosis factor alpha is transported from blood to brain in the mouse.J Neuroimmunol,1993,47:169.
10 Barath P,Fishbein MC,Cao J,et al.Detection and localization of tumor necrosis factor in human atheroma.Am J Cardiol,1990,65:297.
(Received 1998-08-10,Accepted 1999-04-02), http://www.100md.com