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Neuropathology underlying clinical variability in patients with synucleinopathies

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Abstract

Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer’s disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.

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Acknowledgments

GH is supported by a Senior Principal Research Fellowship of the National Health and Medical Research Council of Australia. The Queen Square Brain Bank, UCL Institute of Neurology is supported by the Reta Lila Weston Institute of Neurological Studies and the Progressive Supranuclear Palsy (Europe) Association. TR and JLH are supported by research grants from the Multiple System Atrophy Trust, Alzheimer’s Research UK and Parkinson’s UK. JLH is supported by the Reta Lila Weston Institute for Neurological Studies. This work was supported in part by the Wellcome/MRC Parkinson’s Disease Consortium grant to UCL Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. This work was partly undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centers funding scheme. DWD is supported by Grants from the National Institutes of Health (R01-AG15866, P50-AG16574, P50-NS72187), Robert E. Jacoby Professorship in Alzheimer’s Research and Mayo Foundation for Research and Education. We would like to thank Dr. Zeshan Ahmed and Heidi Cartwright for assistance with the figure work.

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  1. Neuroscience Research Australia and the University of New South Wales, Barker Street, Randwick, Sydney, 2031, Australia

    Glenda M. Halliday

  2. Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    Janice L. Holton & Tamas Revesz

  3. Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL, 32224, USA

    Dennis W. Dickson

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  1. Glenda M. Halliday
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Correspondence to Glenda M. Halliday.

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Halliday, G.M., Holton, J.L., Revesz, T. et al. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122, 187–204 (2011). https://doi.org/10.1007/s00401-011-0852-9

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