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Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS
  1. M R Turner1,2,
  2. A D Osei-Lah3,
  3. A Hammers2,4,
  4. A Al-Chalabi1,
  5. C E Shaw5,
  6. P M Andersen6,
  7. D J Brooks2,4,
  8. P N Leigh1,
  9. K R Mills3
  1. 1Department of Neurology, PO Box 41, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
  2. 2MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
  3. 3Department of Clinical Neurophysiology, Guy’s, King’s & St. Thomas’s School of Medicine, Academic Neuroscience Centre, King’s College Hospital, London SE5 9RS, UK
  4. 4Institute of Neurology, Queen Square, London WC1N 3BG, UK
  5. 5Department of Neurology, Guy’s, King’s & St. Thomas’s School of Medicine, Academic Neuroscience Centre, King’s College Hospital, London, SE5 9RS, UK
  6. 6Department of Neurology, Umeå University Hospital, Umeå, Sweden
  1. Correspondence to:
 Dr M R Turner
 PO Box 41 (ANC), Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK; m.turneriop.kcl.ac.uk

Abstract

Background: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABAA receptor, and 11C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms.

Methods: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. 11C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical 11C-flumazenil binding that might explain differences in cortical excitability seen using TMS.

Results: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical 11C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS.

Conclusions: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. 11C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

  • ALS, amyotrophic lateral sclerosis
  • ALSFRS-R, ALS functional rating scale
  • CMAP, compound muscle action potential
  • CMCT, central motor conduction time
  • FDI, first dorsal interosseous
  • GABA, gamma aminobutyric acid
  • ICF, intracortical facilitation
  • ICI, intracortical inhibition
  • ISI, interstimulus intervals
  • MEP, motor evoked potentials
  • PET, positron emission tomography
  • PSTH, peristimulus time histogram
  • RMT, resting motor threshold
  • sALS, sporadic amyotrophic lateral sclerosis
  • SOD1, superoxide dismutase-1
  • SP, silent period
  • S-R, stimulus response
  • TMS, transcranial magnetic stimulation
  • UMN, upper motor neurone
  • VD, volume of distribution
  • amyotrophic lateral sclerosis
  • transcranial magnetic stimulation
  • D90A

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Footnotes

  • Competing interests: none declared