Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type

Aims To identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). Methods We analyzed 70 μm thick sections of 10 cases with MSA-C and 24 normal controls. Results MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells (PC) increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia, and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. Conclusions Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the CNS and neurodegeneration with disease progression. This article is protected by copyright. All rights reserved.