Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild–moderate Alzheimer's disease patients

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Abstract

Cognitive functions display a progressive impairment with ageing, and this is thought to be due to the accumulation of neuronal loss or acute and/or repeated microvascular accidents. Chronic damage to the brain cortex lead to decreasing ability of elderly subjects to cope with daily events and ultimately result in loss of self-sufficiency. Since proinflammatory cytokines have been implicated both in cerebrovascular injury due to atherosclerosis and in Alzheimer's disease (AD), we investigated 70 elderly subjects with neurocognitive and functional impairment. Diagnosis was established in 54, the others were included in the ‘mixed’ group. Sera were collected and stored at −70°C until measurement of IL-1β and TNF-α, performed by commercial ELISA kits. Data obtained were analysed with respect to other socio-demographic, psychoneurological and clinical variables.

The results show that serum TNF-α was lower in mild–moderate AD compared to severe AD and dementias due to vascular disease, as well as the TNF-α/IL-1β ratio. Both cytokines showed a significant relationship with age.

Our study suggests that proinflammatory cytokines serum profiles seem to discriminate between mild–moderate AD and vascular or mixed forms of dementia. Furthermore, it offers new evidence of a strong implication of inflammatory mechanisms in atherosclerosis, more than in less severe AD.

Introduction

Cognitive functions display a progressive impairment with ageing (Polvikoski et al., 2001), and this is thought to be due to either chronic neurodegenerative events with neuronal loss due to oxidative stress, as in Alzheimer's dementia (AD), or acute, subacute and/or repeated microvascular accidents (Snowdon et al., 1997, Marx et al., 1998, Marx et al., 1999, Di Iorio et al., 1999, Farkas et al., 2000a, Perl, 2000). Diagnosis of either types of dementia requires costly and cumbersome exams as well as deep psychoneurological tests (Erkinjuntti et al., 1987, Erkinjuntti et al., 1997). In the common form of AD, neuroimageing is required for assessing the contribution of cerebrovascular disease (CVD). Still, many cases fall into the intermediate category of mixed-type dementia.

The inflammatory pathogenesis of both AD and atherosclerotic changes leading to CVD has been recently advocated, mainly based on the genetic associations of proinflammatory cytokines regulatory elements, and the finding of raised levels of TNF-α, IL-1β and IL-6 in either disease (Lombardi et al., 1999). Despite the heterogeneous nature of both AD and atherosclerosis, inflammatory aspects are prominent in some phases of their natural history. However, to our knowledge, there is little evidence reported on in vivo differences of these cytokines, able to discriminate primary vs. secondarily induced inadequate or excessive production.

We selected four groups of elderly with neurocognitive and functional impairment described as vascular dementia, mixed diseases, and mild–moderate or severe AD, including 70 non-institutionalized persons, and measured serum levels of TNF-α and IL-1β by high sensitivity methods. The results were analysed by univariate and multivariate statistics for influence of socio-demographic, psychoneurological and functional tests, as well as clinical variables. Our preliminary data demonstrate that in mild–moderate AD these proinflammatory cytokines are lower than in patients with vascular-dependent dementia.

Section snippets

Study design and patients

From the local Registry for the study of Cognitive Disorders in the Elderly (ReCoDE), 70 patients were selected on the basis of clinical symptoms, neuropsychological examination and by means of computed tomography (CT) and/or magnetic resonance imageing (MRI).

A cross-sectional analysis was carried-out comparing the levels of IL-1β and TNF-α in these patients affected by dementia; they were also clustered in the following groups: (1) Vascular dementia (VaD); (2) Mixed dementia (MD); (3) severe

Results

We selected 70 elderly patients affected by different types of dementia: 18 were diagnosed as pure VaD, 36 as AD and 16 included in the MD group. Among those with AD, 25 belonged to the mild–moderate and 11 to the severe type. In this latter subgroup, only three cases (27.3%) at the time of sampling were treated with cholinesterase inhibitors, compared to one in the MD group (6.3%) and none of the VaD patients, who were all treated with antiaggregating drugs.

Sex distribution was almost

Discussion

AD is a progressive neurodegenerative disease with heterogeneous genetic and phenotypic features. Consensus criteria for diagnosis (NINCDS-ADRDA Work Group, 1985) include the exclusion of major CVD features, revealed by CT or MRI, although the precision of these procedures is disputed, and brain infarctions have been detected in the Nun Study also in cases who met the neuropathological criteria for AD (Snowdon et al., 1997). The diagnosis therefore relies on clinical grounds, although 10–20% of

Acknowledgements

This work was funded by grants of the Faculty of Medicine of the University ‘G. d'Annunzio’ for 2000 and 2001 to RP and GA, by Cofin 2000 from the Italian Ministry of Education and University to RP, by a grant from the Italian Ministry of Research to the Center of Excellence on Ageing of the University of Chieti, and it has been performed in the framework of the ImAginE project (EC grant QLK6-CT1999-02031). We thank Dr E.J. Remarque (Leiden, The Netherlands) for sharing with us his data.

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