Glycohistochemical characterization of vascular muscle cell destruction in CADASIL subjects by lectins, neoglycoconjugates and galectin-specific antibodies.

CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a type of small-artery stroke and vascular dementia-inducing pathology of the brain. In order to explain the molecular mechanisms behind the alterations to the blood vessels in CADASIL subjects, we scrutinized the expression of glycan and glycan-binding sites in the wall of vessels taken from five such subjects (vs. five control subjects matched for age and sex). Specimens were taken from the brain, heart, kidney, liver and lung. Although the main vessel lesions were observed in the tissues depending on the blood-brain barrier, alterations to systemic vessels were also observed despite the absence of any symptoms. The histochemical expression of a panel of 10 biotinylated neoglycoconjugates [Gal-beta(1-4)-D-Glc, Galbeta(1-3)GalNAc, alpha-D-GalNAc, beta-D-GalNAc, GalNAcalpha(1-3)-D-GalNAcalpha, GalNAcalpha(1-3)-D-GalNAcbeta, beta-D-Glc, alpha-D-Man, l-Fucose and D-Glcalpha(1-4)-D-Glc], eight plant lectins (PNA, MAA, SNA, DBA, WGA, ConA, GNA and UEA-1) and two antigalectin antibodies was monitored by means of semiquantitative and quantitative computer-assisted microscopy. The data show the altered histochemical binding of plant lectins, such as UEA-1 and ConA, in the vessel walls of CADASIL subjects. The present work, based upon staining by a panel of neoglycoconjugates, provides a biochemical characterization of the alteration of vessel walls in the brain compared to other organs including the heart, kidney, lung and liver in CADASIL as opposed to control subjects. These glycohistochemical results suggest a functional relevance of protein-carbohydrate interactions in this disease.

Peripheral inflammatory response in Alzheimer's disease and multiinfarct dementia.

Whether peripheral inflammatory molecules can be considered markers of dementia is still an open issue. We have investigated the presence of circulating cytokines and the ability of blood cells to release them in response to an inflammatory stimulus in patients with different types of dementia and in age-matched controls. A significant increase in circulating interleukin-1beta in moderate Alzheimer and in multiinfarct (145 and 224 times control concentration, respectively) dementia and in circulating tumor necrosis factor-alpha concentration in multiinfarct dementia patient group (156%) were found. Tumor necrosis factor-alpha and interleukin-6 released from blood cells after exposure to lipopolysaccharide were significantly reduced in moderate Alzheimer (60%, both cytokines) and multiinfarct patients (71 and 50%, respectively), while interleukin-10 was decreased only in multiinfarct patients (61%). The results show that patients with Alzheimer disease or multiinfarct dementia have an upregulation of circulating cytokines and a downregulation of cytokines released by blood cells.

Inflammatory markers in Alzheimer's disease and multi-infarct dementia.

Inflammation has been involved in the pathogenesis of dementia. The study evaluates the presence and the source of pro- and anti- inflammatory cytokines in the blood of patients with Alzheimer's disease (AD), multi-infarct dementia (MID) or in non-demented elderly people (controls). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor I (sTNF-RI) plasma concentrations and release from blood cells stimulated with lipopolysaccharide (LPS, 1 microg/ml) were determined. The results show that TNF-alpha released from blood cells is significantly decreased (27%) in all demented patients compared to controls. Circulating TNF-alpha is increased (400%) only in MID patients. In these patients plasma levels of sTNF-RI are increased (53%) and IL-10 from stimulated blood cells decreased (47%) compared to non-demented subjects. The results show that: (1) peripheral production of TNF-alpha is blunted in demented (both AD and MID) patients compared to non-demented age-matched subjects; (2) AD patients have a selective disregulation of the peripheral TNF-alpha system; (3) different cytokines are up- or down- regulated in MID patients showing that in this condition the pro- and anti-inflammatory peripheral cytokine system is more widely affected.

Effects of antithrombin on Binswanger's disease with antiphospholipid antibody syndrome.

The authors present a family with Binswanger's disease (BD) and antiphospholipid antibody syndrome (APAS). In one patient from this family, lupus anticoagulant and high levels of hemostatic markers were detected. The presence of BD and the clinicobiological improvements observed after antithrombin treatment in this patient are peculiar to this familial case of APAS.

Decreased immunosuppressive effect of cortisol on natural killer cytotoxic activity in senile dementia of the Alzheimer type.

Former studies have indicated alterations of the cytotoxic activity of natural killer (NK) cells in senile dementia of the Alzheimer type (SDAT). These changes may be related to the increased reactivity of NK cells with cytokines, even if an impairment of the immunosuppressive effect of glucocorticoids cannot be excluded. In the present study we have demonstrated a lower immunosuppressive effect of cortisol on NK cytolytic function in patients with SDAT than in healthy elders and in patients with dementia of multi-infarct origin (MID). This suppression is completely lacking when cortisol is employed at low concentrations (10(-7) M) and is significantly reduced after incubation at physiological (10(-6) M; p < 0.001) and supraphysiological concentrations (10(-5) M; p < 0.001). The addition of IL-2 (50 and 100 IU/ml/cells) significantly antagonizes the effects of cortisol in SDAT, whereas the cortisol-dependent immunosuppression is partially maintained in healthy elders and in patients with MID. Our data indicate that the defect of the immunosuppressive effect of cortisol may play a role in NK dysregulation in SDAT, contributing to the cytokine-mediated NK overactivity in this disease.

Excitatory pattern of gamma-interferon on natural killer cell activity in senile dementia of the Alzheimer type.

Spontaneous natural killer (NK) cell activity and NK-induced cytotoxicity after interferon-gamma (IFN-gamma) were measured in healthy elderly subjects and in patients with senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID). Normal basal and IFN-gamma-stimulated NK cytotoxicity were found in healthy old subjects and in patients with MID. On the contrary higher NK cytotoxicity after IFN-gamma (650 IU) was demonstrated in SDAT patients than in MID and healthy subjects (p < 0.001). A significant inverse correlation between the percent increase of NK cytotoxicity after IFN-gamma and the Mini Mental State Examination score (p < 0.001) was also demonstrated in patients with SDAT. Our data might suggest a cytokine-dependent mechanism of NK activation in SDAT associated with the neuroimmune hypothesis of the disease.

Association between Alzheimer's disease and bound autochthonous IgM on T cells.

OBJECTIVE: To determine whether there is an association between the number of peripheral T cells binding IgM per total T cell population (%IgM+ T cells) and dementia. DESIGN: Cross-sectional study. SETTING: Two inpatient and two outpatient sites at a university medical center. PARTICIPANTS: Fifty-three adults. MEASUREMENTS: Peripheral blood was collected from each individual, and the %IgM+ T cells was determined by flow cytometry. The data obtained by medical record chart review were analyzed to determine whether the %IgM+ T cells correlated with cognitive diagnoses, demographic variables, medical diagnoses, or prescribed medications. RESULTS: The %IgM+ T cells was negatively correlated with MMSE scores (r = -.33, P = .016). There was a significant difference in the mean %IgM+ T cells between Alzheimer's disease (AD) and non-AD patients (35.6% +/- 30.2% vs 14.6% +/- 23.9%, P < .001) but no statistically significant association between the mean %IgM+ T cells and age, sex, race, prescribed medications (except gastrointestinal (GI) medications), or medical diagnoses (except stroke). After statistically controlling for GI medications and stroke, AD remained independently associated with the %IgM+ T cells (P = .008). CONCLUSIONS: Patients with AD had significantly more of their T cells coated with IgM than did non-AD patients.

Enhanced cytotoxic response of natural killer cells to interleukin-2 in Alzheimer's disease.

Experimental data suggest an involvement of immune cellular components in the development of Alzheimer's disease (AD). Against this background, the spontaneous natural killer (NK) cell activity and the NK-induced cytotoxicity after interleukin-2 (IL-2) were studied in healthy elderly subjects and in patients with dementia of Alzheimer type (SDAT) and multi-infarct type (MID). Higher NK cytotoxicity (expressed as total lysis and percent increase) at different IL-2 concentrations (50 and 100 IU/ml/cells) was demonstrated in patients with SDAT than in healthy elderly subjects (p < 0.001) and MID patients (p < 0.001). NK cell activity of MID patients was similar to that of healthy elderly and healthy young subjects. A negative correlation between the percent increase in NK cytotoxicity after IL-2 and the Mini Mental State Examination Score was also found in SDAT patients (p < 0.01). Alterations of IL-2-mediated NK cytotoxicity may therefore support the neuroimmune hypothesis of AD.

Differences in dexamethasone-sensitivity between lymphocytes from patients with Alzheimer's disease and patients with multi-infarct dementia.

Peripheral blood mononuclear cells (PBMC) from 40 consecutive patients entering a screening program on cognitive impairment were studied in vitro with respect to their sensitivity to dexamethasone (DEX). Phytohemagglutinin-induced proliferation by PBMC from patients with senile dementia of the Alzheimer type (SDAT) was less sensitive to the inhibitory effect of DEX, compared to PBMC from patients with multi-infarct dementia (MID) and PBMC from patients with miscellaneous causes of cognitive impairment (MISC). An intermediate sensitivity was found with PBMC from patients with clinical signs of both MID and SDAT (= MIXED). These differences could not be explained by differences in the composition of the CD4(+) T cell population, interleukin (IL)-2 or IL-4 production, or quantitative differences in the expression of glucocorticoid receptors as measured by flowcytometry. However, the expression of bcl-2 was higher in PBMC from SDAT patients than in cells from MID patients or from MISC patients, whereas the MIXED group showed an intermediate expression; a high bcl-2 expression correlated with a low DEX-sensitivity. These findings suggest that characteristics of PBMC reflect related changes in the central nervous system and indicate that PBMC may be a useful and accessible tool to obtain more insight into the pathogenesis of Alzheimer's disease.

Autoantibody reactivity in serum of patients with Alzheimer's disease and other age-related dementias.

Serum antibodies against a series of antigens, including an organ-specific central nervous system (CNS) antigen and the neurotransmitter serotonin, were investigated in 22 patients with Alzheimer's Disease (n=15) and other age-related dementias (n=7) by indirect immunofluorescence assay and enzyme-linked immunosorbent assay. Patients with dementia showed an increase of antibody-positive sera against nuclear antigen, gastric parietal cells, CNS antigen, gangliosides (Gm1), laminin, and keratin. Alzheimer's Disease patients alone exhibited antibodies against CNS antigen. However, the results do not show sufficient specificity and sensitivity for use as a diagnostic indicator.

Screening psychiatric admissions for anticardiolipin antibody.

Anticardiolipin antibody (aCL) may provide an instrument for screening in neuropsychiatric syndromes due to cerebral ischemia. Thirty-five psychiatric patients, aCL-positive on admission, were matched against aCL-negative patients. Their clinical records on admission and after 2-years of follow-up were analyzed without knowledge of aCL results. An inventory was made of cerebrovascular and systemic vascular symptoms. In 13 out of 35 aCL-positive cases, vascular morbidity, suggesting ischemic causes of central nervous system pathology, could be demonstrated during follow-up and none in the comparison group. No correlation was found, however, between Hachinski ischemic scores on admission and aCL-positivity. Yet, if only on the basis of increased incidence of subsequent ischemia, the aCL-IgG/M isotype appears to be a valuable predictor of vascular neuropsychiatric symptoms.

Comparative immunohistochemical characteristics of human choroid plexus in vascular and Alzheimer's dementia.

Autoimmune alterations are indirectly supported in Alzheimer's disease by the demonstration of circulating antibodies directed to the epithelial basement membrane (BM) of the choroid plexus. We used immunohistochemical methods to compare the characteristics of choroid plexuses obtained postmortem from 15 patients. Six had a diagnosis of Alzheimer's disease, five had multi-infarct dementia (MID), and one suffered from mixed dementia. Similar tissue from three age-matched, non-demented controls was studied as well. Age-related psammoma bodies, lipofucsin, and flattened epithelial cells were present in all cases. Specific alterations were evident in Alzheimer's disease patients only. These were comprised of pseudolinear deposits of immunoglobulin (Ig)G and coarse deposits of C1q along the thickened and segmented epithelial BM, and were associated with IgM in five cases. Although no lymphoid infiltration was demonstrated, MHC Class II+ macrophages were observed in the plexus stroma, and numerous epithelial cells were class II+. These observations suggest that immune alterations, possibly of autoimmune origin, may be involved in Alzheimer's disease, leading to severe lesions of the choroid plexus. Such anomalies could be responsible for some of the alterations of cerebrospinal fluid (CSF) production or composition noted in this disease.

Cytosolic free [Ca2+] in mononuclear blood cells from demented patients and healthy controls.

There is increasing evidence that the neurodegenerative processes in Alzheimer's disease (AD) may be related to alterations in calcium homeostasis and that these metabolic changes are not necessarily restricted to the central nervous system. However, previous studies investigating [Ca2+]i in fibroblasts, lymphoblasts, platelets and lymphocytes of AD patients gave inconclusive results, since increase, decrease and no alteration in [Ca2+]i were found in AD patients compared with controls. With respect to the importance of establishing altered Ca2+ homeostasis in peripheral cells, we have investigated [Ca2+]i in circulating mononuclear cells of patients with AD, multi-infarct dementia, age-associated memory impairment and healthy controls. [Ca2+]i was evaluated using the fluorescent dye fura-2 before and during stimulation with phythaemagglutinin (PHA). In our study we failed to find major differences in resting [Ca2+]i and in response to stimulation with 25 micrograms/ml and 100 micrograms/ml PHA in cells of AD patients as compared with all other groups investigated. There was only a tendency towards a decrease in [Ca2+]i in AD after stimulation with PHA. Thus the present findings suggest that [Ca2+]i evaluation in mononuclear cells does not have diagnostic value in discriminating AD patients from other demented patients. However, there might be some difference in [Ca2+]i values between early- and late-onset AD, which could have pathophysiological importance.

Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia.

The cholinergic dysfunction present in Alzheimer's disease (AD) might be due to a specific vulnerability of cholinergic neurons linked to neurotrophic imbalance, neuroimmune impairment, and/or direct effects of beta-amyloid deposition and NFT formation in ACh neurons. The presence of abnormal epitopes exposed on neuronal membranes may contribute to the activation of resting microglia initiating a neuroimmune cascade leading to cell destruction. According to this hypothesis, a multifactorial treatment in AD should produce: 1) inhibition of beta-amyloid and NFT formation; 2) restoration of neuronal membrane integrity; and 3) control of neuroimmune auto-aggression. Since interleukin-1 (IL-1) is an APP gene promoter showing a progressive increase in body fluids in parallel with mental deterioration in AD patients, we have studied the effects of CDP-choline on cognition, several biological parameters, and IL-1 beta production in AD and multi-infarct dementia (MID) in order to elucidate whether this compound alone or in combination with other drugs is able to restore immune function and improve mental performance in senile dementia.

Circulating immune complexes in sera from patients with Alzheimer's disease, multi-infarct dementia and Down's syndrome.

Recent data suggest that immunological mechanisms may be implicated in the pathogenesis of Alzheimer's disease (AD). We tested the presence of circulating immune complexes (CIC) in the sera from dementia and Down's syndrome (DS) patients and age-matched controls using two methods: Clq-binding Elisa (ClqB-Elisa) and conglutinin-binding Elisa (KgB-Elisa). The probable AD and multi-infarct dementia (MID) patients had more frequently CIC in their sera as compared to elderly non-demented subjects (Chi-square; P < 0.05). The highest frequency of positive findings was detected for 10 DS patients (8 KgB-Elisa and 7 ClqB-Elisa positive) whereas only 1 of 10 young controls showed ClqB-positivity. In the AD patients the cognitive decline as assessed by the Mini-Mental Status test correlated significantly with CIC values. The study supports the view that systemic autoimmune mechanisms may be involved, at least partly, in dementing processes.

[Multi-infarct dementia associated with antiphospholipid antibodies. Presentation of 2 cases]. / Demencia multiinfártica asociada a anticuerpos antifosfolípido. Presentación de dos casos.

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.