Increased CCR2-immunopositive myeloid cells in the putamen and cerebellar white matter with blood–brain barrier disruption in multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. Recently, a close relationship of neuroinflammation to MSA pathogenesis was identified. Studies in mouse models of MSA have indicated that peripheral-type myeloid cells and endogenous microglia promote neuroinflammation in MSA. However, their distinct roles in MSA pathogenesis remain unknown. We performed immunohistochemical analyses of brain tissues obtained at autopsy from patients with MSA and age-matched controls to examine the putamen and cerebellar white matter with antibodies against CCR2 (a chemokine receptor expressed by monocyte-lineage cells), TMEM119 for microglia, and fibrinogen for blood-brain barrier (BBB) leakage. The CCR2-immunopositive area was significantly increased in both regions in MSA patients compared to controls (putamen, p = 0.0043; cerebellar white matter, p = 0.0438); however, the TMEM119-immunopositive area showed no significant between-group difference (putamen, p = 0.4220; cerebellar white matter, p = 0.8152). The densities of CCR2-immunopositive areas in the putamen and cerebellar white matter were positively correlated (Pearson's r = 0.7325, p = 0.0248). In the putamen, fibrinogen immunoreactivity and perivascular leakage were increased and showed a distribution similar to that of CCR2 immunostaining (p = 0.0398). These findings suggest that CCR2-immunopositive myeloid cell accumulation in regions with BBB dysfunction may involve recruitment of peripheral monocyte-lineage cells.