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Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease: a comparative study of eight disorders

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Abstract

Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer’s disease, Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the ‘fused in sarcoma’ (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400–800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders.

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Acknowledgments

We thank the families of patients whose generosity made this research possible. Support for this work was provided by grants from the National Institute on Aging of the National Institutes of Health (P50-AG05681 and P01-AG03991), the Hope Center for Neurological Disorders, the Charles F. and Joanne Knight Alzheimer’s Disease Research Centre, University School of Medicine, St. Louis, MO, USA. We thank the following for making tissue sections available for this study: Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA, Brain Bank, Institute of Psychiatry, King’s College London, London, UK, William Ellis (Department of Pathology, University of California, Davis, Sacramento, CA, USA), Ronald L. Hamilton (Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA), Ian R. A. Mackenzie (Department of Pathology, Vancouver General Hospital, Vancouver, Canada), E. Tessa Hedley-Whyte (Massachusetts General Hospital and Harvard Brain Tissue Resource Center, Belmont, MA, USA), Marla Gearing (Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA), Robert Perry Department of Neuropathology, Newcastle General Hospital, Newcastle-upon-Tyne, NE4 6BE, UK), Charles Duyckaerts, Laboratoire de Neuropathologie, Hôpital de la Salpêtrière, AP-HP, 75651, Paris, France), Felix Cruz-Sanchez (Institute of Neurological and Gerontological Sciences, International University of Catalonia, Barcelona, Spain), Kari Skullerud (Department of Pathology, Rikshospitalet, N-0027, Oslo, Norway), Eileen Bigio (Department of Pathology, Northwestern University Medical School, Chicago, Illinois, USA), and Hideaki Yokoo (Department of Pathology, Gunma University School of Medicine, Maebashi, Japan).

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  1. Vision Sciences, Aston University, Birmingham, B4 7ET, UK

    Richard A. Armstrong

  2. Departments of Neurology and Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, 63108, USA

    Nigel J. Cairns

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Correspondence to Richard A. Armstrong.

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Armstrong, R.A., Cairns, N.J. Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease: a comparative study of eight disorders. J Neural Transm 119, 1551–1560 (2012). https://doi.org/10.1007/s00702-012-0838-3

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