Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan;267(1):76-86.
doi: 10.1007/s00415-019-09552-1. Epub 2019 Sep 26.

Peripheral Inflammatory Markers and Clinical Correlations in Patients With Frontotemporal Lobar Degeneration With and Without the C9orf72 Repeat Expansion

Affiliations
Free PMC article

Peripheral Inflammatory Markers and Clinical Correlations in Patients With Frontotemporal Lobar Degeneration With and Without the C9orf72 Repeat Expansion

Kasper Katisko et al. J Neurol. .
Free PMC article

Abstract

In this study, our aim was to evaluate potential peripheral inflammatory changes in frontotemporal lobar degeneration (FTLD) patients carrying or not the C9orf72 repeat expansion. To this end, levels of several inflammatory markers (MCP-1, RANTES, IL-10, IL-17A, IL-12p, IFN-γ, IL-1β, IL-8, and hs-CRP) and blood cells counts in plasma and/or serum of FTLD patients (N = 98) with or without the C9orf72 repeat expansion were analyzed. In addition, we evaluated whether the analyzed peripheral inflammatory markers correlated with disease progression or distinct clinical phenotypes under the heterogenous FTLD spectrum. Elevated levels of pro-inflammatory RANTES or MCP-1 and decreased levels of anti-inflammatory IL-10 were found to associate with Parkinsonism and a more rapid disease progression, indicated by longitudinal measurements of either MMSE or ADCS-ADL decline. These findings were observed in the total cohort in general, whereas the C9orf72 repeat expansion carriers showed only slight differences in IL-10 and hemoglobin levels compared to non-carriers. Furthermore, these C9orf72 repeat expansion-associated differences were observed mostly in male subjects. The females in general showed elevated levels of several pro-inflammatory markers compared to males regardless of the C9orf72 genotype. Our study suggests that pro-inflammatory changes observed in the early symptomatic phase of FTLD are associated with distinct clinical profiles and a more rapid disease progression, and that the C9orf72 repeat expansion and gender may also affect the inflammatory profile in FTLD.

Keywords: C9orf72; Cytokines; Disease progression; Frontotemporal dementia; Frontotemporal lobar degeneration; Inflammation; Parkinsonism.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Peripheral blood cell counts and plasma hs-CRP concentrations in FTLD patients with or without the C9orf72 HRE. Symbols represent separate cases, and horizontal lines represent median with interquartile range. Mann–Whitney U test was used to compare groups separately. For hs-CRP, the significant p value is calculated for all males compared to all females, regardless of the C9orf72 HRE status (comparison between genders)
Fig. 2
Fig. 2
a Concentrations of MCP-1, IL-8 and IL-10 in serum of FTLD patients carrying or not the C9orf72 HRE measured using single molecule array (Simoa). The data for IL-1β is not shown due to extremely low concentrations observed in most cases. b Plasma MCP-1 and RANTES, measured using cytometric bead array (CBA). a, b Symbols represent separate cases, and horizontal lines represent median with interquartile range. Mann–Whitney U test was used to compare groups separately. For IL-8 and RANTES, the significant p value is calculated for all males compared to all females, regardless of the C9orf72 HRE status (comparison between genders). For IL-10, the difference between male C9orf72 HRE carriers and non-carriers was significant when outliers were excluded (p = 0.049)
Fig. 3
Fig. 3
Concentrations of the inflammatory cytokines MCP-1 (plasma), RANTES (plasma) and IL-10 (serum) in FTLD patients with or without Parkinsonism or psychotic symptoms. Symbols represent separate cases, and horizontal lines represent median with interquartile range. Mann–Whitney U test was used to compare the groups
Fig. 4
Fig. 4
Correlations of the levels of inflammatory cytokines (plasma RANTES, serum MCP-1 and serum IL-10) and functional or cognitive decline rates. Functional decline was assessed using ADCS-ADL and cognitive decline using MMSE examination. Higher decline ratio score indicates more rapid progression. Correlation analyses were performed with Spearman’s rank correlation test

Similar articles

See all similar articles

References

    1. Atanasio A, Decman V, White D, et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep. 2016;6(1):23204. doi: 10.1038/srep23204. - DOI - PMC - PubMed
    1. Burberry A, Suzuki N, Wang J-Y, Moccia R. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med. 2016;8(347):78. doi: 10.1126/scitranslmed.aaf6038. - DOI - PMC - PubMed
    1. O’Rourke JG, Bogdanik L, Yáñez A, et al. C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016;351:1324–1329. doi: 10.1126/science.aaf1064. - DOI - PMC - PubMed
    1. Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy AKJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JRPO, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni BP, et al. Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol. 2014;13:686–699. doi: 10.1016/S1474-4422(14)70065-1. - DOI - PMC - PubMed
    1. Pottier C, Ren Y, Perkerson RB, et al. Genome-wide analyses as part of the international FTLD–TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD. Acta Neuropathol. 2019;137(6):879–899. doi: 10.1007/s00401-019-01962-9. - DOI - PMC - PubMed

LinkOut - more resources

Feedback