Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis.
OBJECTIVE
The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS).


OBJECTIVE
To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique.


METHODS
Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants.


METHODS
Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants.


RESULTS
Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2% [1.8%]; F = 16.1; P < .001) and healthy control participants (11.8% [1.0%]; F = 16.1; P < .001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P < .01) and motor-evoked potential amplitude (P < .05) as well as a reduction in the resting motor threshold (P < .05) and cortical silent period duration (P < .001).


CONCLUSIONS
This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.
Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.
Nimeshan
N
Geevasinga
Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.
Parvathi
P
Menon
Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.
Garth A
GA
Nicholson
Department of Neurology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
Karl
K
Ng
Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia.
James
J
Howells
Disciplines of Medicine and Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Jillian J
JJ
Kril
Department of Neurology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
Con
C
Yiannikas
Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia.
Matthew C
MC
Kiernan
Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.
Steve
S
Vucic
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000503:physiopathology*; D042622:DNA Repeat Expansion; D019054:Evoked Potentials, Motor / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009433:Neural Inhibition / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D050781:Transcranial Magnetic Stimulation
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins