Pathophysiological and diagnostic implications of cortical dysfunction in ALS

Key Points

  • Cortical hyperexcitability is an early pathophysiological feature of amyotrophic lateral sclerosis (ALS)

  • Cortical hyperexcitability potentially mediates motor neuron degeneration in ALS via a dying-forward, trans-synaptic, glutaminergic mechanism

  • The identification of the C9orf72 hexanucleotide repeat expansion as a major cause of familial and apparently sporadic ALS, as well as frontotemporal dementia, underscored the importance of cortical dysfunction

  • Cortical hyperexcitability is an important diagnostic biomarker of ALS, and could enable more-definitive diagnosis at an earlier stage of the disease process

Abstract

Cortical dysfunction — specifically, the development of hyperexcitability — seems to be an early and intrinsic feature of sporadic and familial amyotrophic lateral sclerosis (ALS) phenotypes, preceding the onset of lower motor neuron dysfunction and correlating with ensuing lower motor neuron dysfunction and degeneration. In fact, cortical dysfunction could provide a pathogenic basis for ALS, with corticomotor neuronal hyperexcitability mediating motor neuron degeneration via a trans-synaptic, glutamate-mediated, excitotoxic mechanism. The recent identification of C9orf72 repeat expansion as an important genetic risk factor for both ALS and frontotemporal dementia has underscored the importance of cortical function in ALS pathogenesis, and has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. Changes in cortical function that develop in ALS could prove useful as diagnostic biomarkers, potentially enhancing the diagnosis of ALS at an early stage of the disease process. Pathophysiological and diagnostic biomarkers of cortical function might also provide insights to guide the development of future therapeutic approaches, including stem cell and genetic interventions, thereby providing potential for more-effective management of patients with ALS.

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Figure 1: Disease onset and progression in amyotrophic lateral sclerosis.
Figure 2: GABAergic inhibitory circuits in the motor cortex.
Figure 3: Pathophysiological mechanisms in amyotrophic lateral sclerosis.
Figure 4: Apical dendrite defects and spine loss in mouse models of motor neuron disease.
Figure 5: Threshold tracking transcranial magnetic stimulation.
Figure 6: Loss of cortical inhibition in amyotrophic lateral sclerosis.

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Acknowledgements

The authors gratefully acknowledge research support from the Motor Neuron Disease Research Institute of Australia (awarded to N.G.), and the National Health and Medical Research Council of Australia (project grants 510233, 1024915 and 1055778 awarded to M.C.K. and S.V, and Program Grant #1037746 awarded to M.C.K.). S.V. had full access to all the data reviewed in the article, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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N.G, P.M., P.H.Ö. and S.V. researched data for the article. All authors made substantial contributions to discussions of the content. N.G, P.M. and S.V. wrote the article, and P.H.Ö. and M.C.K. reviewed and edited the manuscript before submission.

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Correspondence to Steve Vucic.

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Geevasinga, N., Menon, P., Özdinler, P. et al. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol 12, 651–661 (2016). https://doi.org/10.1038/nrneurol.2016.140

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