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Original Investigation |

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

Nimeshan Geevasinga, MBBS1; Parvathi Menon, PhD1; Garth A. Nicholson, PhD2; Karl Ng, PhD3; James Howells, PhD4; Jillian J. Kril, PhD5; Con Yiannikas, MBBS3; Matthew C. Kiernan, DSc4; Steve Vucic, PhD1
[+] 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
JAMA Neurol. 2015;72(11):1268-1274. doi:10.1001/jamaneurol.2015.1872.
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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.

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Figure 1.
Reduced Mean Short-Interval Intracortical Inhibition (SICI) in C9orf72 Familial Amyotrophic Lateral Sclerosis (FALS)

A, SICI was significantly reduced in patients with c9orf72 FALS when compared with asymptomatic c9orf72 expansion carriers and control participants. The reduction of SICI was comparable with that evident in patients with sporadic ALS (SALS). B, The mean SICI between interstimulus intervals of 1 to 7 milliseconds was significantly reduced in patients with FALS and patients with SALS. Error bars indicate SD values.

aP < .001.

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Figure 2.
Reduced Peak Components of Short-Interval Intracortical Inhibition (SICI) in C9orf72 Familial Amyotrophic Lateral Sclerosis (FALS)

The peak SICI interstimulus interval at 1 millisecond and 3 milliseconds was significantly reduced in patients with FALS and patients with sporadic ALS (SALS) compared with asymptomatic c9orf72 expansion carriers and control participants.

aP < .001.

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Figure 3.
Cortical Hyperexcitability as a Feature of C9orf72 Familial Amyotrophic Lateral Sclerosis (FALS)

A, Intracortical facilitation was significantly increased in patients with FALS and patients with sporadic ALS (SALS). B, Motor-evoked potential was significantly increased in patients with FALS and SALS when compared with asymptomatic c9orf72 expansion carriers and control participants. C, The cortical silent period duration was significantly reduced in patients with FALS and patients with SALS when compared with asymptomatic c9orf72 expansion carriers and control participants. D, Central motor conduction time was significantly increased in patients with FALS and patients with SALS. All P values were corrected for multiple comparisons using post hoc Bonferroni testing.

aP < .05.

bP < .01.

cP < .001.

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