Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid

Gustaf Boström, Eva Freyhult, Johan Virhammar, Daniel Alcolea, Hayrettin Tumani, Markus Otto, Rose-Marie Brundin, Lena Kilander, Malin Löwenmark, Vilmantas Giedraitis, Alberto Lleó, Christine A F von Arnim, Kim Kultima, Martin Ingelsson, Gustaf Boström, Eva Freyhult, Johan Virhammar, Daniel Alcolea, Hayrettin Tumani, Markus Otto, Rose-Marie Brundin, Lena Kilander, Malin Löwenmark, Vilmantas Giedraitis, Alberto Lleó, Christine A F von Arnim, Kim Kultima, Martin Ingelsson

Abstract

Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.

Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.

Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.

Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).

Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

Keywords: Alzheimer’s disease; frontotemporal dementia; mild cognitive impairment; neuroinflammation; proteomics.

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-1565r2).

Figures

Fig. 1
Fig. 1
Principal component analysis (PCA) of cerebrospinal fluid protein levels. The PCA is divided into (A) patient groups, (B) medical centers, and (C) number of plate sent for analysis. Each ellipse represents 95% of respective group’s samples. D) The detected proteins’ contribution to principal component 1 (PC1) and 2 (PC2). AD, Alzheimer’s disease dementia; C, healthy controls; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease.
Fig. 2
Fig. 2
Volcano plots of group differences in cerebrospinal fluid proteins. The plots show fold change and p-values of inflammatory proteins in cerebrospinal fluid from (A) patients with AD and MCI/AD compared with healthy controls, (B) patients with MCI/AD compared with patients with MCI, and (C) patients with FTD compared with healthy controls. The proteins were analyzed using ANOVA F-tests, adjusting for age, sex, plate ID, and study site (A, C), and age, sex, and plate ID (B), respectively. Proteins with a false discovery rate below 0.05 are labeled. AD, Alzheimer’s disease dementia; C, healthy controls; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease.
Fig. 3
Fig. 3
Box plot of MMP-10 levels stratified by patient group and medical center. AD, Alzheimer’s disease dementia; C, healthy controls; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease; MMP-10, matrix metalloproteinase-10; NPX, normalized protein expression.

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