Microglial Markers are Elevated in the Prodromal Phase of Alzheimer's Disease and Vascular Dementia

Article type: Research Article

Authors: Olsson, Bob^{a; *} | Hertze, Joakim^b | Lautner, Ronald^a | Zetterberg, Henrik^a | Nägga, Katarina^b | Höglund, Kina^c | Basun, Hans^d | Annas, Peter^c | Lannfelt, Lars^d | Andreasen, Niels^e | Minthon, Lennart^b | Blennow, Kaj^a | Hansson, Oskar^b

Affiliations: [a] Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden | [b] Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden | [c] AstraZeneca R&D, Södertälje, Sweden | [d] Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden | [e] Memory Clinic, M51, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden

Correspondence: [*] Correspondence to: Bob Olsson, PhD, Department of Psychiatry and Neurochemistry, University of Gothenburg, V-house, Sahlgrenska University Hospital Mölndal, 431 80 Mölndal, Sweden. Tel.: +46 31 343 24 06; Fax: +46 31 343 24 26; E-mail: [email protected].

Abstract: Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p = 0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p = 0.029 and p = 0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and Aβ42, YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p = 0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r = 0.94, p = 3.4 × 10−25; r = 0.77, p = 2.0 × 10−11) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI to AD and those that convert to AD and VaD.

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, dementia, microglia, vascular dementia

DOI: 10.3233/JAD-2012-120787

Journal: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 45-53, 2013