title: 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.
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.
authors.affiliation: King's College London, MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, De Crespigny Park, London, UK. claire.troakes@kcl.ac.uk
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Satomi
authors.initials: S
authors.lastname: Maekawa
authors.forename: Lokesh
authors.initials: L
authors.lastname: Wijesekera
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: László
authors.initials: L
authors.lastname: Siklós
authors.forename: Christopher
authors.initials: C
authors.lastname: Bell
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.forename: Stephen
authors.initials: S
authors.lastname: Newhouse
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Lauren
authors.initials: L
authors.lastname: Johnson
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Nigel
authors.initials: N
authors.lastname: Leigh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
mesh_terms: D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000523:psychology*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology*; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics* / Q000523:psychology*; D011506:Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology; D014015:Tissue Banks; D019680:Trinucleotide Repeat Expansion
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA