Widespread microglial activation in multiple system atrophy

Abstract

Background The pattern and role of microglial activation in multiple system atrophy is largely unclear. The objective of this study was to use [ 11 C] (R) ‐PK11195 PET to determine the extent and correlation of activated microglia with clinical parameters in MSA patients. Methods Fourteen patients with the parkinsonian phenotype of MSA (MSA‐P) with a mean disease duration of 2.9 years (range 2‐5 years) were examined with [ 11 C] (R) ‐PK11195 PET and compared with 10 healthy controls. Results Patients with the parkinsonian phenotype of MSA showed a significant ( P ≤ 0.01) mean increase in binding potentials compared with healthy controls in the caudate nucleus, putamen, pallidum, precentral gyrus, orbitofrontal cortex, presubgenual anterior cingulate cortex, and the superior parietal gyrus. No correlations between binding potentials and clinical parameters were found. Conclusions In early clinical stages of the parkinsonian phenotype of MSA, there is widespread microglial activation as a marker of neuroinflammatory changes without correlation to clinical parameters in our patient population. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

CSF-1 controls cerebellar microglia and is required for motor function and social interaction

“…Due to their important role in brain development and homeostasis, microglia are involved in virtually all pathological conditions affecting the CNS (Hickman et al, 2018;Li and Barres, 2018). Accordingly, imaging as well as post-mortem studies show that microglia are activated in both multisystem atrophy and bipolar disorder (Watkins et al, 2014;Vieira et al, 2015;Kübler et al, 2019), which affected the microglia donors analyzed here (Fig. 1, A and B).…”

T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

“…Now in the CNS, these Olig001-SYN associated CD4 T cells are reactivated by an MHCII + microglia displaying the same CNS antigen. This interaction induces a signal cascade that includes the secretion of IFN-γ which can primarily serve to further push microglia to a proinflammatory phagocytic state [41], support the chemotaxis of peripheral inflammatory monocytes to the CNS [15], and cause damage to surrounding neurons or OPCs [31,32,41] (Fig. 8).…”

MSA: From basic mechanisms to experimental therapeutics

“…However, based on pathological and molecular evidence from MSA human studies and animal models, several factors seem to be definitely associated with the disease and may serve as therapeutic targets for disease modification (Fig. 1), including the abnormal accumulation of α-syn [30][31][32][33]43,44], microglial activation and neuroinflammation [52,[54][55][56][57][58][59][60][61]89], autophagy disturbances [64][65][66][67], mitochondrial dysfunction [12,15,66,[68][69][70][71][72][73][74] and oxidative stress [76]. Yet the primary event which triggers the whole pathogenic cascade is still unknown.…”

“…Microglial activation and neuroinflammation constitute important features of MSA according to PET and pathological studies of MSA brains [52,[54][55][56][57][58][59][60][61]. Histopathological findings in MSA showed activated microglia in the main brain areas affected by the disease, which paralleled system degeneration and was associated with the presence of α-syn inclusions [48,55,56,60,168]. The role of microglia in MSA and other neurodegenerative disorders is not completely understood and a matter of debate, however, it is thought that α-syn species activate microglial cells, which would lead to increased cell death and α-syn aggregation, thus potentiating neurodegeneration [55,58].…”

“…Moreover, the possible pathogenic role of GCIs and αsyn aggregation and accumulation has been experimentally confirmed in transgenic animal models overexpressing α-syn specifically in oligodendrocytes [43,44]. Besides the presence of GCIs, other prominent microscopic features of MSA are selective neuronal loss and axonal degeneration [45][46][47], demyelination [48][49][50], astrogliosis [38,[51][52][53], microglial activation and neuroinflammation [52,[54][55][56][57][58][59][60][61].…”