TY - JOUR
T1 - Pathophysiological and diagnostic implications of cortical dysfunction in ALS
AU - Geevasinga, Nimeshan
AU - Menon, Parvathi
AU - Ozdinler, Pembe Hande
AU - Kiernan, Matthew C.
AU - Vucic, Steve
N1 - Funding Information:
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.
Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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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U2 - 10.1038/nrneurol.2016.140
DO - 10.1038/nrneurol.2016.140
M3 - Review article
C2 - 27658852
AN - SCOPUS:84988603515
VL - 12
SP - 651
EP - 661
JO - Nature Clinical Practice Neurology
JF - Nature Clinical Practice Neurology
SN - 1759-4758
IS - 11
ER -