Brief communicationInflammatory markers in AD and MCI patients with different biomarker profiles
Introduction
Immunopathological and experimental evidence supports the hypothesis that inflammatory mechanisms are involved in the aetiology of Alzheimer's disease (AD), even before fibrillar amyloid deposits are present (Akiyama et al., 2000, Veerhuis et al., 2003).
Activated microglia and astrocytes that accumulate in amyloid beta (Aβ) plaques express pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), or tumour necrosis factor α, as well as acute phase proteins C-reactive protein (CRP) and α1-antichymotrypsin (ACT) (Akiyama et al., 2000, Yasojima et al., 2000). Microglial activation and clustering most prominently occur in Aβ deposits that have bound and accumulated complement activation products and other amyloid associated factors, and precedes the neurodegenerative changes in AD neocortex (Veerhuis et al., 2003).
To date, different inflammatory markers have been studied in CSF and serum of AD patients with conflicting results (for a review see Teunissen et al. (2002)). Only a few studies on CRP in serum have been published (Licastro et al., 2000), whereas several studies regarding IL-6 and ACT have been performed. Some CSF studies on IL-6 and ACT demonstrated no differences between controls and AD patients (Engelborghs et al., 1999, Pirttila et al., 1994, Tarkowski et al., 1999), while others found increased IL-6 or ACT levels in AD compared to control subjects (Blum-Degen et al., 1995, Martinez et al., 2000). The observed differences might partly be explained by differences in the study population such as inclusion criteria or the number of subjects. In addition, an association between plasma levels of the inflammatory markers CRP, IL-6 and ACT and cognitive decline, many years before onset of dementia, has been demonstrated in a few longitudinal population-based studies (Dik et al., 2005, Schmidt et al., 2002, Yaffe et al., 2003).
To study the role of inflammation in the preclinical stage of AD further, we selected a large cohort of patients with mild cognitive impairment (MCI), which is considered to be a preclinical stage of AD (Petersen et al., 1999). Follow-up studies show a conversion rate to AD of 12–41% per year in MCI patients (Geslani et al., 2005, Petersen et al., 1999, Petersen et al., 2005). The aim of the present study was to examine the involvement of inflammatory markers early in the pathology process of AD. Therefore, we studied the inflammatory markers CRP, IL-6 and ACT in both serum and CSF in a cohort of established MCI and AD patients.
Section snippets
Patients
Between November 2000 and April 2004 67 patients with MCI and 145 patients with probable AD were enrolled at the Alzheimer Center of the VU University Medical Center (VUMC), Amsterdam. Diagnoses of MCI and probable AD were according to Petersen et al. (1999) and NINCDS-ADRDA criteria (McKhann et al., 1984), respectively. MCI patients, were divided in MCI patients at high or low risk for AD, according to their Aβ42 and tau levels in CSF (Schoonenboom et al., 2004, Schoonenboom et al., 2005). The
Results
Spearman rank correlations between CSF and serum inflammatory markers were 0.16 for IL-6, 0.85 for CRP, and 0.36 for ACT. In CSF, correlations between IL-6 and CRP were 0.20, between IL-6 and ACT 0.16, and between CRP and ACT 0.38. In serum, correlations between IL-6 and CRP were 0.53, between IL-6 and ACT 0.11, and between CRP and ACT 0.16.
To assess the levels of cytokines in patients with different Aβ42/tau biomarker profiles (high-risk and low-risk CSF profiles), MCI patients were stratified
Discussion
In the present study significantly higher CRP levels were observed in both CSF and serum of MCI cases compared to AD patients. This was seen in the MCI group as a whole, as well as in subcohorts of MCI patients with a high- and low-risk profile. After adjustment for age, ApoE ɛ4, cardiovascular diseases, white matter lesions and brain infarcts, this significant difference persisted only in the low-risk MCI subgroup. For IL-6 and ACT no differences between MCI and AD patients were found in the
Disclosure statement
The authors have no actual or potential conflicts of interest to disclose.
Acknowledgements
The Alzheimer Center is supported by Stichting VUmc Fonds; the database structure is funded by Stichting Dioraphte and this study by grants from Internationale Stichting Alzheimer Onderzoek (ISAO; grants # 03509 (R.V.) and # 04519 (M.A.B.)). We thank Astrid Kok, Department of Clinical Chemistry, for technical support and Wiesje van der Flier, Department of Neurology, for the development of the database. In VUmc the departments of Clinical Chemistry, Genetics, Neurology, Molecular Cell Biology
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