Short CommunicationEarly decrease in intermediate monocytes in peripheral blood is characteristic of multiple system atrophy-cerebellar type
Introduction
In multiple system atrophy (MSA) patients, massive infiltration of activated microglia/macrophages was observed in autopsied brain tissues, particularly in early lesions (Ishizawa et al., 2004; Yokoyama et al., 2007). We reported significant increases in the levels of granulocyte-macrophage colony-stimulating factor, interleukin (IL)6, IL12, and IL13 in cerebrospinal fluid (CSF) of MSA cerebellar-type (MSA-C) patients (Yamasaki et al., 2017). Moreover, these cytokine levels had significant negative correlations with anteroposterior diameters of the pontine base, vermis, or medulla oblongata, while C
C motif chemokine ligand (CCL)2/monocyte chemoattractant protein (MCP)1 was significantly negatively correlated with disease duration. Based on these observations, we hypothesized that early recruitment of macrophage-lineage cells, particularly intermediate monocytes (IMs) with proinflammatory functions (Shapouri-Moghaddam et al., 2018), from peripheral blood to central nervous system (CNS) tissues may worsen MSA-C. To test this hypothesis, we characterized macrophage/monocyte changes in the peripheral blood of MSA-C patients and determined their associations with clinical and laboratory findings.
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Participants
We enrolled 29 MSA-C and 5 MSA-P patients who satisfied the criteria of probable MSA (Gilman et al., 2008), 20 hSCD patients [three with spinocerebellar ataxia (SCA) type 3, six with SCA type 6, one with SCA type 31, one with SCA type 36, one with dentatorubral-pallidoluysian atrophy, and eight with unknown mutations], and 24 healthy controls (HCs) (Table 1). All hSCD patients were diagnosed according to the established diagnostic criteria (Gilman et al., 2008; Muzaimi et al., 2004). Disease
Comparison of monocyte subsets
The percentages of CMs and NCMs among total monocytes did not differ significantly among the four groups, while the percentage of IMs was significantly lower in MSA-C (2.8 ± 0.2%) and MSA-P (2.0 ± 0.1%) patients compared with hSCD patients (5.7 ± 1.1%) and HCs (5.5 ± 0.7%; MSA-C vs. HCs, p < 0.01; MSA-C vs. hSCD, p < 0.05; MSA-P vs. HCs, p < 0.05; Fig. 1 and Supplementary Table 2). Among IMs, the percentage of CD62L+ cells was significantly lower in MSA-C patients (13.9 ± 3.5%) compared with
Discussion
In the present study, we found a significant decrease in the percentage of IMs in the peripheral blood of MSA-C patients compared with that in hSCD patients and HCs. Importantly, the decrease in IM percentages was more prominent in patients with lower UMSARS scores, shorter disease duration, and milder brainstem atrophy. These findings indicate that decrease of peripheral blood IMs in the early stage is characteristic of MSA-C.
In the early phase of MSA, a heavy burden of glial cytoplasmic
Author contributions
DM, RY, HY, and JK designed and conceptualized the study. DM, GM, YM, KM, NI, and TM collected and analyzed the data. DM and KJ drafted the manuscript. All authors approved submission of the manuscript for publication.
Acknowledgments
This study was supported by Health and Labour Sciences Research Grants on Comprehensive Research on Disability, Health and Welfare, Japan (H29 Nanchi-Ippan-0009). The authors thank the patients for their participation. We also thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Funding
This study was supported by grants from JSPS KAKENHI, Grant Nos. 18K07501 (DM), 19K07963 (RY), 19H01045 (JK), and 19H05562 (JK), and by Health and Labour Sciences Research Grants on Comprehensive Research on Disability Health and Welfare, Japan (H29 Nanchi-Ippan-009).
Declaration of Competing Interest
RY received grants and personal fees from the Japan Society for the Promotion of Science, Biogen Japan, and the Japan Blood Products Organization. NI received grant support from Mitsubishi Tanabe Pharma, the Osoegawa Neurology Clinic, Bayer Yakuhin Ltd. and the Japan Blood Products Organization. TM received speech honoraria payments from Biogen Japan, the Takeda Pharmaceutical Company. JK received grants and personal fees from Biogen Japan, Bayer Healthcare, Novartis Pharma, Mitsubishi Tanabe
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