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- 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.
- Authors
Troakes, Claire; Maekawa, Satomi; Wijesekera, Lokesh; Rogelj, Boris; Siklós, László; Bell, Christopher; Smith, Bradley; Newhouse, Stephen; Vance, Caroline; Johnson, Lauren; Hortobágyi, Tibor; Shatunov, Aleksey; Al-Chalabi, Ammar; Leigh, Nigel; Shaw, Christopher E.; King, Andrew; Al-Sarraj, Safa
- 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.
- Subjects
MOTOR neuron diseases; AMYOTROPHIC lateral sclerosis; DNA-binding proteins; DEMENTIA patients; CEREBRAL cortex; BASAL ganglia; HIPPOCAMPUS (Brain)
- Publication
Neuropathology, 2012, Vol 32, Issue 5, p505
- ISSN
0919-6544
- Publication type
Article
- DOI
10.1111/j.1440-1789.2011.01286.x