Original Investigation
November 2015

Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis

Author Affiliations
  • 1Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
  • 2Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia
  • 3Department of Neurology, Royal North Shore Hospital, Sydney, New South Wales, Australia
  • 4Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia
  • 5Disciplines of Medicine and Pathology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

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JAMA Neurol. 2015;72(11):1268-1274. doi:10.1001/jamaneurol.2015.1872

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.