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. 2019 Feb 21;16(1):46.
doi: 10.1186/s12974-019-1399-2.

Glial activation and inflammation along the Alzheimer's disease continuum

Kaja Nordengen  1 , Bjørn-Eivind Kirsebom  2   3 , Kristi Henjum  4 , Per Selnes  5 , Berglind Gísladóttir  5   6 , Marianne Wettergreen  5   6 , Silje Bøen Torsetnes  5   6 , Gøril Rolfseng Grøntvedt  7 , Knut K Waterloo  2 , Dag Aarsland  8   9 , Lars N G Nilsson  4 , Tormod Fladby  5   10
Affiliations

Glial activation and inflammation along the Alzheimer's disease continuum

Kaja Nordengen et al. J Neuroinflammation. .

Abstract

Background: Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer's disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation.

Methods: We included healthy controls (n = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n = 19), mild cognitive impairment (MCI, n = 39), or AD dementia (n = 27). The following CSF markers were measured: a microglial activation marker-soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction-monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers-chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker-fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn's pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score.

Results: Compared to healthy controls, sTREM2 was increased in SCD (p < .01), MCI (p < .05), and AD dementia cases (p < .001) and increased in AD dementia compared to MCI cases (p < .05). MCP-1 was increased in MCI (p < .05) and AD dementia compared to both healthy controls (p < .001) and SCD cases (p < .01). YKL-40 was increased in dementia compared to healthy controls (p < .01) and MCI (p < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T-N+ and A+T+N+), compared to subjects without neurodegeneration (A-T-N- and A+T-N-).

Discussion: Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored.

Keywords: Apolipoprotein J; CX3CL1; Cerebrospinal fluid; Chitinase-3-like protein 1; Clusterin; ELISA; Early diagnosis; Fractalkine; MCP-1; Microglia; Monocyte chemoattractant protein-1; Neuroinflammation; YKL-40; sTREM2.

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Conflict of interest statement

Ethics approval and consent to participate

The project has been considered by the Norwegian Regional Ethics Committee (approval number for the DDI project: 2013/115, approval number for the genetic analysis (APGEM): 2014/1164, approval number for the biobank: 2011/1051). The local data protection officer at Akershus University Hospital has also approved the study with the according approval number 13-056, 14-156 and 13-088. Data handling was in accordance with local and national regulations, with security precautions for storage and regulated biobank facilities. Both sexes are equally included, patients and controls give informed consent to participate in the study. The DDI has a patient and caregiver representative in the steering group. User participation is ensured with open meetings and written information.

Consent for publication

Not applicable.

Competing interests

Dr. Aarsland has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, and GE Health and serves as paid consultant for H. Lundbeck, Eisai, Heptares, and Axovant. Dag Aarsland is a Royal Society Wolfson Research Merit Award Holder and would like to thank the Wolfson Foundation and the Royal Society for their support. Dr. Fladby is inventor and co-founder of Inventor Pre Diagnostics A/S. All other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Between-group CSF immune marker comparisons based on clinical staging. Fig. text: The Y-axis with sTREM2 (a), MCP-1 (b), fractalkine (d), and clusterin (e) reported as CSF concentration in nanograms per milliliter, while the Y-axis for YKL-40 (c) are residuals standardized for age. Error bars are shown as mean and 95% confidence interval (CI). Abbreviation: Ctr: healthy controls (n = 36), SCD: CSF Aβ42+ subjects with subjective cognitive decline (n = 19), MCI: CSF Aβ42+ subjects with mild cognitive impairment (n = 39), Dem: Aβ42+ subjects with Alzheimer’s disease dementia (n = 27). Statistically significant differences are marked with asterisks, where * indicates p < .05, ** indicates p < .01, and *** indicates p < .001
Fig. 2
Fig. 2
Between-group CSF immune marker comparisons based on ATN staging. Fig. text: The association with ATN groups. Y-axis shows concentration of inflammatory markers in CSF in nanograms per milliliter. A+ indicating CSF Aβ42 below the reference range, T+ indicating CSF p-tau above the reference range and N+ here indicating T-tau above the reference range for age. Minus (−) indicating normal values within the reference range. Error bars are shown as mean and 95% confidence interval (CI). Statistically significant differences are marked with asterisks, where * indicates p < .05, ** indicates p < .01, and *** indicates p < .001
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