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

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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
Early online date19 Dec 2011
DOIs
Publication statusPublished - Oct 2012

Keywords

  • Age of Onset
  • Amyotrophic Lateral Sclerosis
  • Blotting, Western
  • Brain
  • Cerebellum
  • Cerebral Cortex
  • Cognition Disorders
  • DNA
  • DNA-Binding Proteins
  • Female
  • Fluorescent Antibody Technique
  • Hippocampus
  • Humans
  • Immunohistochemistry
  • Inclusion Bodies
  • Male
  • Microscopy, Electron
  • Middle Aged
  • Motor Neuron Disease
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Spinal Cord
  • Tissue Banks
  • Trinucleotide Repeat Expansion

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