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

Claire Troakes, Satomi Maekawa, Lokesh Wijesekera, Boris Rogelj, László Siklós, Christopher Bell, Bradley Smith, Stephen Newhouse, Caroline Vance, Lauren Johnson, Tibor Hortobágyi, Aleksey Shatunov, Ammar Al-Chalabi, Nigel Leigh, Christopher E. Shaw, Andrew King, Safa Al-Sarraj

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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.

Original languageEnglish
Pages (from-to)505-514
Number of pages10
JournalNeuropathology
Volume32
Issue number5
DOIs
Publication statusPublished - Oct 1 2012

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Keywords

  • ALS/MND
  • C9orf72
  • Cerebellum
  • P62
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology

Cite this

Troakes, C., Maekawa, S., Wijesekera, L., Rogelj, B., Siklós, L., Bell, C., Smith, B., Newhouse, S., Vance, C., Johnson, L., Hortobágyi, T., Shatunov, A., Al-Chalabi, A., Leigh, N., Shaw, C. E., King, A., & Al-Sarraj, S. (2012). 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. Neuropathology, 32(5), 505-514. https://doi.org/10.1111/j.1440-1789.2011.01286.x