The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations

Abstract

Multiple system atrophy (MSA) has varying clinical (MSA-P versus MSA-C) and pathological [striatonigral degeneration (SND) versus olivopontocerebellar atrophy (OPCA)] phenotypes. To investigate the spectrum of clinicopathological correlations, we performed a semi-quantitative pathological analysis of 100 MSA cases with well-characterized clinical phenotypes. In 24 areas, chosen from both the striatonigral (StrN) and olivopontocerebellar (OPC) regions, the severity of neuronal cell loss and gliosis as well as the frequency of glial (oligodendroglial) cytoplasmic inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs) were determined. Clinical information was abstracted from the patients' medical records, and the severity of bradykinesia in the first year of disease onset and in the final stages of disease was graded retrospectively. The degree of levodopa responsiveness and the presence or absence of cerebellar ataxia and autonomic symptoms were also recorded. We report that 34% of the cases were SND- and 17% were OPCA-predominant, while the remainder (49%) had equivalent SND and OPCA pathology. We found a significant correlation between the frequency of GCIs and the severity of neuronal cell loss, and between these pathological changes and disease duration. Our data also suggest that GCIs may have more influence on the OPC than on the StrN pathology. Moreover, we raise the possibility that a rapid process of neuronal cell loss, which is independent of the accumulation of GCIs, occurs in the StrN region in MSA. There was no difference in the frequency of NCIs in the putamen, pontine nucleus and inferior olivary nucleus between the SND and OPCA subtypes of MSA, confirming that this pathological abnormality is not associated with a particular subtype of the disease. In the current large post-mortem series, 10% of the cases had associated Lewy body pathology, suggesting that this is not a primary process in MSA. As might be expected, there was a significant difference in the severity of bradykinesia and the presence of cerebellar signs between the pathological phenotypes: the SND phenotype demonstrates the most severe bradykinesia and the OPCA phenotype the more frequent occurrence of cerebellar signs, confirming that the clinical phenotype is dependent on the distribution of pathology within the basal ganglia and cerebellum. Putaminal involvement correlated with a poor levodopa response in MSA. Our finding that relatively mild involvement of the substantia nigra is associated clinically with manifest parkinsonism, while more advanced cerebellar pathology is required for ataxia, may explain why the parkinsonian presentation is predominant over ataxia in MSA.