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Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein

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Abstract

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically characterized by cerebellar signs, parkinsonism, and autonomic dysfunction. Pathologically, MSA is an α-synucleinopathy affecting striatonigral and olivopontocerebellar systems, while neocortical and limbic involvement is usually minimal. In this study, we describe four patients with atypical MSA with clinical features consistent with frontotemporal dementia (FTD), including two with corticobasal syndrome, one with progressive non-fluent aphasia, and one with behavioral variant FTD. None had autonomic dysfunction. All had frontotemporal atrophy and severe limbic α-synuclein neuronal pathology. The neuronal inclusions were heterogeneous, but included Pick body-like inclusions. The latter were strongly associated with neuronal loss in the hippocampus and amygdala. Unlike typical Pick bodies, the neuronal inclusions were positive on Gallyas silver stain and negative on tau immunohistochemistry. In comparison to 34 typical MSA cases, atypical MSA had significantly more neuronal inclusions in anteromedial temporal lobe and limbic structures. While uncommon, our findings suggest that MSA may present clinically and pathologically as a frontotemporal lobar degeneration (FTLD). We suggest that this may represent a novel subtype of FTLD associated with α-synuclein (FTLD-synuclein).

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Acknowledgments

We are grateful to all patients, family members, and caregivers who agreed to brain donation; without their donation these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau and Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry. This research was supported in part by a research grant from the Uehara Memorial Foundation, as well as NIH P50 NS072187, P50 AG16574 and P30 AG12300, as well as the CurePSP: Foundation for PSP|CBD and Related Disorders, The Mangurian Foundation, and The Robert E Jacoby Professorship in Alzheimer’s Disease Research.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Naoya Aoki, Wen-Lang Lin, Shunsuke Koga, Owen A. Ross & Dennis W. Dickson

  2. Department of Pathology, University of Colorado, Denver, CO, USA

    Philip J. Boyer

  3. Department of Anesthesiology, Venice Regional Hospital, Venice, FL, USA

    Cheryl Lund

  4. Department of Psychiatry and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Myron Weiner & Anne Lipton

  5. Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA

    James M. Powers

  6. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Charles L. White III

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  1. Naoya Aoki
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Correspondence to Dennis W. Dickson.

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Aoki, N., Boyer, P.J., Lund, C. et al. Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein. Acta Neuropathol 130, 93–105 (2015). https://doi.org/10.1007/s00401-015-1442-z

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  • DOI: https://doi.org/10.1007/s00401-015-1442-z

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