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Nat Rev Neurol. 2016 Nov;12(11):651-661. doi: 10.1038/nrneurol.2016.140. Epub 2016 Sep 23.

Pathophysiological and diagnostic implications of cortical dysfunction in ALS.

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Western Clinical School, University of Sydney, Westmead Hospital, Cnr Hawkesbury and Darcy Road, Wentworthville, New South Wales, 2045, Australia.
Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, 675 North St Clair Street, Suite 20-100, Chicago, Illinois 60611, USA.
Brain and Mind Research Institute, University of Sydney, 94 Mallett Street, Camperdown, New South Wales, 2050, Australia.


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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