Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder

Abstract

Significance This study shows that the myeloid immune response in isolated rapid-eye-movement sleep behavior disorder (iRBD) patients involves both brain and periphery, and that these responses are related, supporting a cross-talk between the brain and the peripheral immune system. Furthermore, these immune events were correlated with dopaminergic neuronal changes, strongly supporting a role for the immune system in the neuronal process associated with iRBD and putatively with Parkinson’s disease. These findings support monocytes as biomarkers and potential targets. Future studies should address possible association between monocytic changes and disease progression in longitudinal cohorts and the use of monocytes as accessible prognostic markers of brain events in synucleinopathies. Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson s disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients’ blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.