An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline

Authors

  • Claire Troakes,

    Corresponding author
    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Satomi Maekawa,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Lokesh Wijesekera,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Boris Rogelj,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • László Siklós,

    1. Laboratory of Molecular Neurobiology, Institute of Biophysics, Biological Research Center, Szeged, Hungary
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  • Christopher Bell,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Bradley Smith,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Stephen Newhouse,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Caroline Vance,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Lauren Johnson,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Tibor Hortobágyi,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Aleksey Shatunov,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Ammar Al-Chalabi,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Nigel Leigh,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Christopher E. Shaw,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
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  • Andrew King,

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
    2. Department of Clinical Neuropathology, King's College Hospital, Denmark Hill, London, UK
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    • These authors contributed equally to the study.

  • Safa Al-Sarraj

    1. King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park
    2. Department of Clinical Neuropathology, King's College Hospital, Denmark Hill, London, UK
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    • These authors contributed equally to the study.


Claire Troakes, PhD, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, PO65, De Crespigny Park, London SE5 8AF, UK. Email: claire.troakes@kcl.ac.uk

Abstract

The transactive response DNA binding protein (TDP-43) proteinopathies describe a clinico-pathological spectrum of multi-system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD-TDP, showed high p62 levels and low TDP-43 levels with no high molecular weight smearing. MND/ALS-associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked MND/ALS and FTLD. We conclude that these chromosome 9-linked MND/ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.

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