Cerebral Astrocytic Phosphorylated-α-Synuclein Accumulation in Multiple System Atrophy With Long Clinical Course

Multiple system atrophy (MSA) is characterized by neuronal loss with gliosis in the striatonigral and olivopontocerebellar structures, along with phosphorylated α-synuclein accumulation in oligodendroglias and neurons. Although subpial and subependymal astrocytic α-synuclein accumulation has been reported in cases of long-duration MSA, little is known regarding cerebral cortical astrocytic α-synuclein pathology in MSA. A 61-year-old woman developed dizziness and dysarthria at 38 years of age. She was diagnosed with MSA-C based on the typical neurological and imaging findings of MSA. Tracheostomy was performed at 48 years of age. Voluntary movement disappeared completely at 49 years of age. The patient died at age 61. The overall clinical course of the MSA was 22 years. The brain, weighing 780 g after fixation, showed severe atrophy, with discoloration of the brainstem, cerebellum, basal ganglia, cerebral cortex, and cerebral white matter. The substantia nigra and locus ceruleus had severe depigmentation. Microscopically, the frontotemporal regions of the cerebral cortices, striatum, pontine nucleus, inferior olivary nuclei, cerebellar white matter, and Purkinje cells had severe degeneration. The widespread occurrence of phosphorylated α-synuclein-positive neuronal and oligodendroglial inclusions, such as glial cytoplasmic inclusions, is noteworthy, leading to a definite diagnosis of MSA. Regarding astrocytic lesions, astrocyte processes-dominant α-synuclein accumulation in the cerebral cortices and amygdaloid nucleus was observed. Furthermore, several astrocytes in the cerebral white matter showed α-synuclein-positive inclusions in the periphery of the cytoplasm and proximal parts of the processes besides α-synuclein-positive subpial astrocytes in the ventral part of the brainstem. The atypical form of α-synuclein and advanced propagation of the pathogenic protein induced by a long clinical course can be implicated in the astrocytic cytopathology of MSA.