Longstanding Multiple System Atrophy-Parkinsonism with Limbic and FTLD-type α-Synuclein Pathology.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically marked by autonomic failure and variable degrees of parkinsonism and cerebellar ataxias. The average age of onset is in the sixth decade of life with a five-year survival, although fulminant and more benign courses have been described (1). The pathologic hallmark of MSA is abundant α-synuclein-positive protein aggregates within oligodendrocytes (glial cytoplasmic inclusions, GCI) and neurons (neuronal cytoplasmic inclusions, NCI, and neuronal nuclear inclusions, NNI). The density of GCIs has been correlated with disease duration and severity of neuronal loss (2). Here, we present an unusual case of MSA clinically characterized by rapid decline followed by a 20-year disease duration in a severely affected state. At autopsy, the brain showed severe gliosis and neuronal loss in a pattern characteristic of MSA. Additionally, there were atypical Pick body-like and ring-shaped α-synuclein inclusions, most prominent in limbic regions, consistent with a recently described subtype of MSA designated "atypical MSA" (3). Four different α-synuclein antibodies highlighted only scant α-synuclein-positive pathology; however, Gallyas and Campbell-Switzer silver stains identified additional GCIs most prominent in subcortical white matter. Interestingly, many of the α-synuclein-positive limbic inclusions were Gallyas-negative, while many of the Gallyas-positive inclusions were α-synuclein-negative (4). This observation of markedly disparate α-synuclein immunohistochemical versus Gallyas reactivity of MSA inclusions is unusual and could support the possibility that MSA inclusions have variable compositions, something which has been recently suggested (5).