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Vascular dementia and anticardiolipin antibodies

Authors:

Abstract

An association between anticardiolipin antibodies and dementia has been reported in several recent studies; however, its physiopathological mechanism remains controversial. The aim of this study was to evaluate the association of vascular dementia and anticardiolipin antibodies. Material/Methods: A random prospective investigation of 17 male and 13 female patients with vascular dementia was made with regard to anticardiolipin antibodies. Their ages ranged from 56 to 77 years (average: 67.2 years). The criteria of NINDS-AIREN were used to defi ne the vascular dementia. A control group of 25 female and 9 male patients was formed with ages ranging from 62 to 80 years (mean: 68 years). Evaluation of the anticardiolipin antibodies was performed by means of Enzyme-Linked Immunoabsorbent Assay (ELISA) for the quantitative measurement of IgG and IgM antibodies against cardiolipins in serum. Statistical analysis was done using the Fisher’s exact test, where p<0.05 was considered signifi cant. Results: Elevated levels of anticardiolipin antibodies were detected in 56.6% of the patients with vascular dementia and 26.4% of the control group (p<0.02). Conclusions: There was a signifi cant difference in the prevalence of high levels of anticardiolipin antibodies between the group of patients with vascular dementia and the control group. This proves that anticardiolipin antibodies present a risk factor for vascular dementia.
Vascular dementia and anticardiolipin antibodies
José Maria Pereira de Godoy1ABCDEF, Maria Regina Pereira de Godoy2ABCDEF,
José Paulo Cipulo2ACD, Valdir Antonio Tognola3ACD
1 Department of Cardiology and Vascular Surgery, São José do Rio Preto University School of Medicine, São Paulo,
Brazil
2 Department of Clinics, São José do Rio Preto University School of Medicine, São Paulo, Brazil
3 Department of Neurology, São José do Rio Preto University School of Medicine, São Paulo, Brazil
Source of support: Departmental sources
Summary
Background:
An association between anticardiolipin antibodies and dementia has been reported in several re-
cent studies; however, its physiopathological mechanism remains controversial. The aim of this
study was to evaluate the association of vascular dementia and anticardiolipin antibodies.
Material/Methods:
A random prospective investigation of 17 male and 13 female patients with vascular dementia was
made with regard to anticardiolipin antibodies. Their ages ranged from 56 to 77 years (average:
67.2 years). The criteria of NINDS-AIREN were used to defi ne the vascular dementia. A control
group of 25 female and 9 male patients was formed with ages ranging from 62 to 80 years (mean:
68 years). Evaluation of the anticardiolipin antibodies was performed by means of Enzyme-Linked
Immunoabsorbent Assay (ELISA) for the quantitative measurement of IgG and IgM antibodies
against cardiolipins in serum. Statistical analysis was done using the Fisher’s exact test, where p<0.05
was considered signifi cant.
Results:
Elevated levels of anticardiolipin antibodies were detected in 56.6% of the patients with vascular
dementia and 26.4% of the control group (p<0.02).
Conclusions:
There was a signifi cant difference in the prevalence of high levels of anticardiolipin antibodies be-
tween the group of patients with vascular dementia and the control group. This proves that anti-
cardiolipin antibodies present a risk factor for vascular dementia.
key words: dementia • vascular • anticardiolipin antibodies
Full-text PDF: http://www.medscimonit.com/fulltxt.php?IDMAN=4031
Word count: 797
Tables: 2
Figures:
References: 32
Author’s address: José Maria Pereira de Godoy, M.D, Ph.D., Rua Floriano Peixoto, 2950, São José do Rio Preto, SP, Brazil, CEP:
15010-020, e-mail: godoyjmp@riopreto.com.br
Authors’ Contribution:
A Study Design
B Data Collection
C Statistical Analysis
D Data Interpretation
E Manuscript Preparation
F Literature Search
G Funds Collection
Received: 2003.07.29
Accepted: 2004.03.16
Published: 2005.09.01
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© Med Sci Monit, 2005; 11(9): CR430-433
PMID: 16127362
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BACKGROUND
Antiphospholipid antibodies (aPL) are a heterogeneous
group of circulating autoantibodies against anionic phos-
pholipids [1–3]. The clinical symptoms of venous and ar-
terial thrombosis and recurrent miscarriages are caused by
antiphospholipid antibodies, including anticardiolipin an-
tibodies (aCL) and lupus anticoagulant (LA) [1–4]. They
present variable clinical symptoms affecting all vessels, both
great to small, veins and arteries alike, causing myocardial
infarction, superfi cial thrombophlebitis, and arterial throm-
bosis of the retina, amongst other diseases, which shows
the wide range of involvement of these antibodies [4–6].
The association of the cerebral and pre-cerebral arteries
has been frequently reported [7,8]. There are many neu-
rological manifestations, including dementia with multiple
cerebral infarcts (strokes) [9–12], progressive ischemic en-
cephalopathy [13], amaurosis fugax [14], chorea [15], tran-
sient global amnesia [16], cerebral pseudo tumor [17], ret-
inal arterial thrombosis [5] with Sneddon’s syndrome [18],
and multiple sclerosis ]19].
The association of dementia [2,3] and aCL has been report-
ed in recent investigations in patients with elevated aCL lev-
els; however, further studies are important to evaluate the
prevalence of this association and its repercussions. The ob-
jective of this study was to evaluate anticardiolipin antibod-
ies as a risk factor for vascular dementia.
MATERIAL AND METHODS
A random prospective study of 30 patients with vascular
dementia was performed to detect elevated aCL levels.
Seventeen patients were male and 13 were female, with
ages ranging from 56 to 77 years old and a mean age of 67.2
years. The patients, who were selected in the neuro-geri-
atric outpatients’ clinic, were diagnosed with vascular de-
mentia by means of their clinical history, physical and lab-
oratory examinations, neuropsychological assessment, and
neuro-imaging. The criteria of the ‘National Institute of
Neurological and Communicative Disorders and Stroke’ and
the ‘Alzheimer’s Disease and Related Disorders Association’
(NINCDS-ADRDA) [11] were used to diagnose the disease
[20]. A control group of 25 women and 9 men was formed
from a senior citizen support group with ages ranging from
62 to 80 years and a mean of 68 years, thus with similar gen-
ders and ages. Measurements of the aCL levels were made
by means of the Enzyme-Linked Immunoabsorbent Assay
(ELISA) for quantitative measurement of IgG and IgM an-
tibodies against cardiolipins in serum. IgG levels were con-
sidered normal at less than 7, borderline between 7 and 10,
and elevated at greater than 10 GPL units/ml, and IgM lev-
els were considered normal below 4, borderline between 4
and 7, and elevated greater than 7 MPL, as recommended by
the test manufacturers. Statistical analysis was done using the
Fisher’s exact test, where p<0.05 was considered signifi cant.
RESULTS
Of the 30 patients with vascular dementia, elevated levels
of aCL were detected in 17 (56.6%) (Table 1). In the con-
trol group, nine (26.4%) of the 34 individuals also had el-
evated levels of aCL (Table 2). The Fisher exact test gave a
p-value<0.02, which is considered signifi cant.
DISCUSSION
This investigation demonstrated a signifi cant association
between aCL levels and vascular dementia. However, there
are few published studies analyzing this relation. In one
study, the presence of dementia in patients with elevated
aCL levels was detected in which 13 out of 23 (56%) of the
patients presented with dementia in a group with an aver-
age age of 68 years old [21]. Another report evidenced an
association between Alzheimer’s disease and aCL levels [11].
In yet another, an association between vascular dementia
Patient IgG (GPL) IgM (MPL)
1 2.79 6.62
2 26.8 5.0
3 6.74 11.26
4 5.74 15.7
5 15.58 6.32
6 6.2 16.7
7 4.71 13.7
8 14.4 3.57
9 4.93 0.41
10 1.6 3.4
11 4.02 6.0
12 2.71 6.75
13 10.2 1.48
14 10.32 14.57
15 20.70 21.33
16 2.47 7.1
17 15.0 1.7
18 3.38 9.0
19 2.19 1.84
20 19.7 3.7
21 62.6 15.3
22 21.5 16.8
23 4.7 3.7
24 12.7 6.6
25 2.24 2.29
26 20.7 1.8
27 9.8 3.16
28 86.0 58.7
29 3.6 1.9
30 4.9 3.0
Table1. The concentrations of IgG and IgM in patients. IgG values
>10 GPL units/ml and IgM >7 MPL units/ml are considered high.
Med Sci Monit, 2005; 11(9): CR430-433 Pereira de Godoy JM et al – Vascular dementia and anticardiolipin antibodies
CR431
CR
and aCL was detected [22]. In a case report, a histopatho-
logical study was performed in which the patient presented
with multiple infarction factors and elevated levels of aCL. A
study in the region of the left frontal cortex was performed
in which non-infl ammatory vasculopathy was detected, asso-
ciated with endothelial hyperplasia and thrombosis of the
small arterioles [23].
Among the few publications found, an association between
dementia and aCL was demonstrated [21–23]. Thrombotic
events triggered by aCL might contribute to the multiple
cerebral thrombotic symptoms and greater aggression to
the brain [24]. Another hypothesis is that patients with aCL
have a more aggressive evolution of arteriosclerosis, as has
been reported in some publications [25–31]. In this case, it
seems to contribute to greater cerebral ischemia and cere-
bral deterioration. However, these physiopathological mech-
anisms require further investigation.
In this study, the prevalence of the aCL was high both in the
study group (56.6%) and the control group (26.4%) when
compared with a control group of donors from a blood
bank with ages of less than 60 years [32]. This suggests an
increase of the prevalence with age [32].
CONCLUSIONS
The prevalence of elevated aCL levels in this study was sig-
nifi cantly higher in patients with vascular dementia com-
pared with the control group. Thus, elevated aCL levels
constitute a risk factor for vascular dementia and its inves-
tigation is important for these patients.
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Patient IgG (GPL) IgM (MPL)
1 6.8 3.2
2 7.2 3.8
3 6.5 4.0
4 12.8 3.2
5 6.8 2.8
6 7.2 7.8
7 11.4 4.1
8 6.5 3.6
9 5.8 3.8
10 5.9 3.2
11 6.8 4.1
12 7.1 12.9
13 5.6 3.1
14 4.8 2.6
15 6.7 3.8
16 6.1 7.5
17 15.9 4.5
18 7.3 3.7
19 6.4 2.9
20 5.8 3.2
21 7.1 2.8
22 8.2 4.2
23 5.4 2.4
24 11.8 3.0
25 6.7 4.5
26 5.6 1.2
27 7.2 2.8
28 9.8 4.0
29 5.8 9.7
30 5.6 1.2
31 6.7 3.2
32 4.3 7.6
33 5.1 3.8
34 3.5 4.6
Table 2. The concentrations of IgG and IgM in the control individuals.
IgG values >10 GPL units/ml and IgM >7 MPl units/ml are
considered high.
Clinical Research Med Sci Monit, 2005; 11(9): CR430-433
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Med Sci Monit, 2005; 11(9): CR430-433 Pereira de Godoy JM et al – Vascular dementia and anticardiolipin antibodies
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... Among the included studies, four were from China (Tan et al., 2001;Zhao and Tan, 2004;Zeng et al., 2006;Qian et al., 2015), two were from Brazil (de Godoy et al., 2005(de Godoy et al., , 2012, and the remaining three studies were from Israel (Mosek et al., 2000), Canada (Juby and Davis, 1998), and United States (Lopez et al., 1992). Across the nine studies, there were 709 subjects (dementia patients: n = 372; controls: n = 337) in total. ...
... All of the studies were designed as case-control and evaluated the presence of aCL as the only aPLs in dementia patients compared to controls. In particular, six of the studies were on VD (Lopez et al., 1992;Tan et al., 2001;Zhao and Tan, 2004;de Godoy et al., 2005;Zeng et al., 2006;Qian et al., 2015) and two on DAT (Juby and Davis, 1998;de Godoy et al., 2012) and one study with both VD and DAT patients (Mosek et al., 2000). The age range of the dementia patients and controls was 65-80.5 and 50.1-78.3 ...
... The median score of NOS was 7. Among the nine studies, seven studies were of high quality (low risk of bias) scoring ≥ 7 (Lopez et al., 1992;Juby and Davis, 1998;Mosek et al., 2000;Tan et al., 2001;de Godoy et al., 2005de Godoy et al., , 2012Qian et al., 2015) and two studies were of low quality (high risk of bias) scoring < 7 (Zhao and Tan, 2004;Zeng et al., 2006). ...
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Antiphospholipid syndrome (APLS) is a complex systemic disease with a wide variety of clinical manifestations. In the obstetric population, recurrent early pregnancy loss, fetal loss, and thrombosis are hallmarks of the disease. Patients with APLS have developed one or more pathogenic auto-antibodies directed against plasma and cell surface proteins. These antibodies are characterized by their affinity for anionic phospholipids. Interactions between APLS antibodies and their protein targets influence a wide variety of biological systems and signaling pathways, including monocytes, platelets, the complement system, and endothelial cells. While much research is currently directed at understanding the mechanisms involved in this autoimmune disease, the key clinical presentation is the hypercoagulable state resulting in thrombosis occurring in essentially any arterial or venous location, as well as numerous obstetrical complications. Treatment of APLS is generally directed at preventing thrombosis and poor pregnancy outcomes by ameliorating the hypercoagulable state. Birth Defects Research (Part C), 2015. © 2015 Wiley Periodicals, Inc.
Article
AimWe describe the clinical profile of elderly with primary antiphospholipid syndrome (APS).Methods Charts of seven elderly patients diagnosed with APS between 1996 and 2012 were retrospectively assessed.ResultsThe mean age at diagnosis was 77 ± 6 years (67–84 years). Two patients had experienced frequent miscarriages. Five patients presented with deep venous thrombosis of the lower limb, one had venous thrombosis of the upper limb and brachiocephalic vein and another had a cerebral ischemic stroke. The antiphospholipid antibodies tests revealed the presence of significant amounts of anticardiolipin antibodies, 12 weeks apart, twice in four patients. The antibodies to β2-glycoprotein 1 were positive twice in two patients and lupus anticoagulant in one of these. All patients were treated with heparin and long-term anti-vitamin K and thrombosis was cleared in all cases. Two patients presented with bleeding complications: hematuria and hematoma of the buttock in one patient and rectal bleeding in another case. Two elderly developed a colon cancer and lymphoma 1 year later.Conclusion In this report, we report on primary APS in the elderly, to discuss its prevalence and the clinical significance of positive antiphospholipid antibodies in subjects over the age of 65 years.
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The present study was undertaken to compare the role of aspirin versus aspirin plus heparin combination in pregnant women with poor obstetric history and raised anticardiolipin antibodies IgG (IgG(acl)). The study was conducted on 550 pregnant women, 450 with a history of two or more spontaneous abortions forming the study group, while 100 women with one or more live births and no history of abortion were controls. Their blood was tested to assess the level of IgG(acl) by enzyme-linked immunosorbent assay (ELISA). The test was strongly positive in 72 (16%) patients of the study group, who were randomized to receive either low-dose aspirin (80 mg/day) or a combination of low-dose aspirin (80 mg/day) and 5000 IU of unfractionated heparin subcutaneously 12 hourly under hospital surveillance. The pregnancy outcomes were statistically compared. Of the 39 patients treated with low-dose aspirin, 24 (61.5%) gave birth to live issues compared with 28 (84.8%) of the 33 women given a combination of aspirin and heparin (p<0.05), an overall success rate of 72.2%. Mean birth weight of the babies given treatment with heparin and aspirin was 3.21+/-0.33 kg compared with 2.77+/-0.14 kg achieved with aspirin alone (p<0.001). Both treatments were well tolerated. The study provides evidence that in cases of recurrent abortions with raised IgG(acl), treatment with a combination of aspirin and heparin showed better outcome than treatment with aspirin alone.
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The patient, a 55 year-old man, developed an episode of transient global amnesia. He was a smoker and had hypercholesterolemia. He was found to have a positive rapid plasma reagin test and high levels of anticardiolipin antibodies. Other investigations were negative. The presence in this patient of antiphospholipid antibodies suggests a vascular mechanism for transient global amnesia.
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Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.
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Backgronnd-beta(2)-Glycoprotein I (beta 2GPI) is a major antigenic target of antiphospholipid antibodies, which possesses natural anticoagulant properties. The aim of the present study was to determine its presence and localization within human atherosclerotic plaques and to study its association with endothelial cells and monocyte macrophages in vitro. Methods and Results-Human atherosclerotic lesions were obtained after carotid endarterectomies and studied immunohistochemically with anti-beta 2GPI as well as antibodies to CD4/CD8, macrophages, and adhesion molecules. In vitro, human umbilical vein endothelial cells (HUVECs) and U937 (myelomonocytic cell line) cells were investigated for their ability to associate with radiolabeled beta 2GPI. We found beta 2GPI to be abundantly expressed within the subendothelial regions and intimal-medial borders of human atherosclerotic plaques and to colocalize with CD4-positive lymphocytes. This observation was confirmed by Western blot applied on homogenates of atherosclerotic lesions with anti-beta 2GPI antibodies. Both HUVECs and U937 cells bound labeled beta 2GPI, and the process was inhibited by oxidized LDL and not by native LDL. Conclusions-The abundant presence of human beta 2GPI within the lesions, its association with endothelial cells and macrophages, and its colocalization with CD4-positive lymphocytes suggests that it may serve as a target for an immune-mediated reaction that can influence lesion progression.
Article
There are few reports describing histopathologic changes associated with the antiphospholipid antibody syndrome. We describe a patient with multi-infarct dementia and antiphospholipid antibody syndrome, in whom a brain biopsy was performed. Biopsy material from the left frontal cortex, including meninges, cortex, and underlying subcortical white matter, was investigated. Microscopic examination and special staining were performed. Microscopic examination showed lumenal occlusion by thrombi, and marked endothelial hyperplasia of small meningeal and cortical arterioles. These findings suggest that the pathogenesis of this cerebral vasculopathy is noninflammatory and is associated with reactive endothelial hyperplasia and thrombosis of small arterioles.
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Two patients with positive antiphospholipid antibody and early multi-infarction dementia as a presenting feature of their illness are reported. One was included in the so called primary antiphospholipid antibody syndrome, while the second one met the criteria for systemic lupus erythematosus. We point out to the presence of aortic regurgitation in one of the patients and its possible relation with these antibodies. Although the precise mechanism of thrombosis is incompletely known, the recognition of this type of dementia is of paramount importance as it is a potentially treatable condition.
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In more than 50% of amaurosis fugax patients under 45 years of age no cause for the episodes of visual loss is identifiable. We have encountered 6 young adults (4 women and 2 men) with episodes of amaurosis fugax associated with elevated levels of antiphospholipid antibodies. Splinter hemorrhages of the nail beds were present in most patients. Treatment with antiplatelet medications and anticoagulants appeared to reduce the frequency of episodes and might prevent central retinal artery occlusions or stroke.
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The purpose of this review has been to draw the attention of clinicians towards the possibility that some of the patients they are treating for thrombosis may have an underlying immune disturbance. This could involve functional abnormalities of the complement system (as in acquired angioneurotic oedema or in paroxysmal nocturnal haemoglobinuria), or cell-mediated immunological damage to the vessel wall (as in Behcet's syndrome or Buerger's disease), or the presence of circulating antibodies (the lupus anticoagulant or antibodies to heparin). While obviously our knowledge on most aspects is still very incomplete, the awareness of the association of thrombosis with certain immune disorders should encourage further detailed studies of mechanisms and enhance our understanding of the role of blood constituents and the vessel wall in thrombogenesis.
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The lupus anticoagulant (LAC) is associated with the occurrence of thromboembolic complications. Assuming that thrombosis may underlie manifestations of the central nervous system (CNS) in patients with systemic lupus erythematosus (SLE), we studied 20 patients with SLE and CNS manifestations for the presence of LAC. In 8 patients (40%) including 4 with overt cerebral infarction, LAC was demonstrated. The 4 patients with LAC and cerebral infarction all had thrombocytopenia, 2 had a history of peripheral thrombosis, and one recurrent abortion. In the 4 LAC-positive patients without overt cerebral infarction, thrombocytopenia was present in 3, a history of thrombosis in 2, and fetal wastage in one. We conclude that LAC identifies within the CNS-SLE group a subpopulation of patients in whom CNS manifestations are caused by cerebral infarction. This subpopulation is further characterized by increased prevalence of thrombocytopenia, peripheral thrombosis and fetal wastage. A possible pathogenetic role of LAC may be related to a hypercoagulable state occurring in this subgroup of SLE patients.
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Twelve patients with chorea from a population of 500 patients with SLE and "lupus-like" disease were reviewed. Clinical histories, including time relationships of chorea to the systemic illness and other neurologic manifestations, are reported. Chorea appeared early in the course of disease in most patients, but the development of cerebral infarctions or TIAs occurred subsequently in seven of nine patients demonstrating antiphospholipid antibodies. The relationship of chorea to the presence of these antibodies in nine of 12 patients and the therapeutic outcome are briefly discussed.