The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here we review clinical, imaging, neuropathologic and genetic features of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration (FTLD). The terms CBD and FTLD refer to pathologically confirmed cases of corticobasal syndrome (CBS) and frontotemporal dementia (FTD). FTLD clinically presents as behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non‐fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While PSP and CBS have been called Parkinson‐plus syndromes in the past, they are now classified as FTD‐related disorders, reflecting that they pathologically differ from α‐synucleinopathies like MSA and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau PET imaging, are being investigated. Multimodal magnetic resonance imaging (MRI) approaches and automated MRI volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.
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