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

TY - JOUR

T1 - An MND/ALS phenotype associated with C9orf72 repeat expansion

T2 - Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline

AU - Troakes, Claire

AU - Maekawa, Satomi

AU - Wijesekera, Lokesh

AU - Rogelj, Boris

AU - Siklos, Laszlo

AU - Bell, Christopher

AU - Smith, Bradley

AU - Newhouse, Stephen

AU - Vance, Caroline

AU - Johnson, Lauren

AU - Hortobagyi, Tibor

AU - Shatunov, Aleksey

AU - Al-Chalabi, Ammar

AU - Leigh, Nigel

AU - Shaw, Christopher E.

AU - King, Andrew

AU - Al-Sarraj, Safa

N1 - © 2011 Japanese Society of Neuropathology.

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - Age of Onset

KW - Amyotrophic Lateral Sclerosis

KW - Blotting, Western

KW - Brain

KW - Cerebellum

KW - Cerebral Cortex

KW - Cognition Disorders

KW - DNA

KW - DNA-Binding Proteins

KW - Female

KW - Fluorescent Antibody Technique

KW - Hippocampus

KW - Humans

KW - Immunohistochemistry

KW - Inclusion Bodies

KW - Male

KW - Microscopy, Electron

KW - Middle Aged

KW - Motor Neuron Disease

KW - Proteins

KW - Proto-Oncogene Proteins c-myc

KW - Spinal Cord

KW - Tissue Banks

KW - Trinucleotide Repeat Expansion

U2 - 10.1111/j.1440-1789.2011.01286.x

DO - 10.1111/j.1440-1789.2011.01286.x

M3 - Article

C2 - 22181065

SN - 0919-6544

VL - 32

SP - 505

EP - 514

JO - Neuropathology

JF - Neuropathology

IS - 5

ER -