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The severity of parkinsonism and response to levodopa vary in patients with multiple system atrophy (MSA) because of the heterogeneity of nigrostriatal neuropathology. To investigate the difference in clinical features between MSA patients with predominantly pre-synaptic nigrostriatal dysfunction and those with trans-synaptic nigrostriatal dysfunction. We retrospectively analyzed clinical data of 61 patients with MSA who underwent both [18F]FP-CIT-PET and [18F]FDG-PET within 3 months of clinical evaluation, and who had ≤3 years of disease duration. Tracer uptake of the striatum on [18F]FP-CIT-PET and glucose metabolism of the striatum on [18F]FDG-PET were analyzed using eight striatal subregional volumes-of-interest templates. The patients were classified into two subgroups according to the predominant pre-synaptic tracer uptake loss of the posterior putamen on [18F]FP-CIT-PET (MSA-SNpc, n = 21) and trans-synaptic dopaminergic dysfunction reflected by both [18F]FP-CIT-PET and [18F]FDG-PET (MSA-STR, n = 40). Parkinsonian features were significantly more severe in the MSA-STR group than in the MSA-SNpc group (P =.005) and cerebellar ataxia was significantly more severe in the MSA-SNpc group (P =.036). The cerebellar type of MSA was significantly more common in the MSA-SNpc group (P =.001). There was no difference in age at onset, disease duration at the time of study, or Mini-Mental Status Examination scores between the groups. Patients with MSA showed distinct clinical features depending on whether the pattern of nigrostriatal dysfunction was predominantly pre-synaptic or trans-synaptic. • Brain [18F]FP-CIT- and [18F]FDG-PET is useful to understanding the features of MSA. • Parkinsonism is more severe in MSA with trans-synaptic nigrostriatal dysfunction. • Cerebellar ataxia is more severe in MSA with presynaptic nigrostriatal dysfunction. • MSA shows distinct features depending on the pattern of nigrostriatal dysfunction. [ABSTRACT FROM AUTHOR]