Abstract for presentation at The Australian and New Zealand Association of Neurologists Annual Scientific Meeting 2007

Cortical hyperexcitability precedes the development of familial amyotrophic lateral sclerosis

  • Dr Steve Vucic, Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Australia
  • A/Prof Garth Nicholson, ANZAC Research Institute, University of Sydney, Concord Hospital., Australia
  • A/Prof Matthew Kiernan, Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Australia

    • Purpose: Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. Although 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the mechanisms underlying neurodegeneration in FALS has not been established. The dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation (TMS) techniques to investigate the mechanisms underlying neurodegeneration in FALS.
    Methods: Studies were undertaken in 16 pre-symptomatic carriers of the SOD-1 mutation and 6 SOD-1 positive FALS patients, and the results were compared to 40 sporadic ALS (SALS) patients and 55 normal controls. Threshold tracking TMS was performed using a 90 mm circular coil connected to a BiStim stimulator. Peripheral nerve excitability studies were performed in the same sitting, with responses recorded from the abductor pollicis brevis muscle.
    Results: Short-interval intracortical inhibition (SICI) was significantly reduced in clinically affected SOD-1 FALS and SALS patients compared to the presymptomatic ALS carriers and controls (SICI clinically affected FALS -1.2 ± 0.6%; SALS -0.7 ± 0.3%; pre-symptomatic SOD-1 mutation carriers 8.3 ± 1.8%; controls 8.5 ± 1.0%, P < 0.00001) and was accompanied by an increase in intracortical facilitation, motor evoked potential amplitude and magnetic stimulus-response curve gradient, all indicative of cortical hyperexcitability. In 14 asymptomatic SOD-1 carriers cortical excitability was normal. In two pre-symptomatic SOD-1 mutation carriers SICI was markedly reduced (SICI patient 1, -3.2%; patients 2, -1.3%). These two individuals subsequently developed clinical features of ALS within 3 months of neurophysiological testing.
    Conclusions: Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, suggesting that cortical hyperexcitability appears to drive neurodegeneration in FALS.

    Conference Organiser - ICMS Pty Ltd