Markers of endothelial dysfunction in older subjects with late onset Alzheimer's disease or vascular dementia

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Abstract

A consistent amount of evidence suggests that vascular factors might be involved in the pathogenesis of late onset Alzheimer's disease (LOAD). We evaluated the presence of endothelial dysfunction by measuring the plasma levels of soluble E-selectin and vascular cell adhesion molecule 1 (VCAM-1) in a sample of patients affected by LOAD (n. 60) or vascular dementia (VD: n. 80). They were compared with a sample of older patients with cerebrovascular disease but not-dementia (CDND: n. 40), and with a sample of healthy older controls (n. 30).

sVCAM-1 plasma levels were higher in LOAD and VD compared with controls. Among patients (LOAD, VD, and CDND), sE-selectin levels were higher in individuals with most severe cerebrovascular disease on CT scan. At multivariate regression analysis, fasting glucose (p < 0.05) and TNF-α levels (p < 0.02) were positively correlated with sE-selectin levels (adjusted r2: 20%), while sVCAM-1 was positively correlated with age (p < 0.01), and alcohol consumption (p: 0.03), and negatively associated with HDL-C levels (p: 0.005), (p < 0.01; adjusted r2: 44%), independent of possible confounders.

Increased sVCAM-1 plasma levels in LOAD and VD suggest the existence of endothelial dysfunction in both types of dementia. The possible role of E-selectin in the pathogenesis of cerebrovascular disease is also supported by our data.

Introduction

Late onset Alzheimer's disease (LOAD) and vascular dementia (VD) are the most common forms of dementia in older individuals living in Western societies [1]. Although Alzheimer's disease is considered a neurodegenerative disorder, in the last ten years a consistent amount of evidence has suggested that vascular factors might be involved also in the pathogenesis of LOAD [2], [3], [4].

Epidemiological studies have shown that most of risk factors for VD are also risk factors for LOAD [3]; interestingly, it has been suggested that many of them (e.g. hypertension, diabetes, aging) share the potential ability of producing an impairment or a reduction in cerebral blood perfusion [5]. Furthermore, it has been demonstrated that the vast majority of brains affected by Alzheimer's disease display micro-vessels degeneration and periventricular white matter lesions [6], [7]. Of consequence, it is reasonable to hypothesize that an impairment in the normal endothelial function (the so-called “endothelial dysfunction”: ED) might contribute not only to the pathogenesis of VD, but also to the pathogenesis and/or progression of LOAD, even in the absence of manifest cerebrovascular disease.

In the presence of noxious molecules in the blood, such as reactive oxygen metabolites or inflammatory cytokines, endothelial cells express different adhesion molecules (AM) that are responsible for the adhesion and activation of circulating leukocytes before their transmigration into sub-endothelial space; this is considered one of the first steps in the development of the atherosclerotic plaque [8]. In fact, endothelial dysfunction has been related to cerebrovascular disease, as suggested by the finding of an association of elevated levels of AM with the presence or progression of cerebral small–large vessels disease, and white matter hyper intensities [9], [10], [11], [12].

Data about the possible activation of the adhesion molecules cascade in patients affected by LOAD are much less consistent. Interestingly, inflammatory mechanisms have been involved in the pathogenesis of LOAD and VD [13], and we have recently confirmed the presence of a systemic low-grade inflammation in both these types of dementia [14]. Since an increase in the expression of adhesion molecules is associated to the presence of systemic inflammation, we have evaluated the possible activation of the adhesion cascade, by measuring the plasma levels of soluble E-selectin and vascular cell adhesion molecule 1 (sVCAM-1), in a sample of older individuals affected by LOAD or VD.

Section snippets

Subjects

On the whole, 210 consecutive subjects referring to the Day Hospital Services (Ferrara and Treviso, Italy) were enrolled into the study. Data were collected during a three-year period. The sample included:

  • 1)

    Sixty patients with LOAD (mean age: 78.5 ± 7.6 SD years; females: 65%) by the NINCDS-ADRDA criteria [15]. Only patients with “probable” Alzheimer's disease (AD) were included; patients with “possible” LOAD or with LOAD and cerebrovascular disease on CT scan were excluded in order to increase

Results

The principal characteristics of the sample are reported in Table 1.

Patients affected by LOAD and VD were older and characterized by a higher prevalence of female gender compared to CDND and to controls. As expected, the MMSE score was pathological in LOAD and VD, while it was in the normal range in CDND and C. Hypertension and diabetes were more frequent in VD and CDND compared with LOAD and with C, while smoking was more frequent in CDND compared with the three other groups. HDL-C was lower

Discussion

It has been proposed that vascular pathology might contribute to LOAD development in about 50% of cases [17]; with regard to this phenomenon, the possible role of endothelial cells in the pathogenesis and/or progression of the disease has not been clarified. Endothelial dysfunction is strictly associated with increased expression of plasma adhesion molecules and cytokines, and we have recently reported the presence of a “low-grade” systemic inflammation in older subjects affected by dementia,

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