Cortical hyperexcitability in patients withC9ORF72mutations: Relationship to phenotype

Abstract

Introduction Patients with mutations in C9orf72 can have amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or ALS-FTD. The goals were to establish whether cortical hyperexcitability occurs in C9orf72 patients with different clinical presentations. Methods Cortical thresholds and silent periods were measured in thenar muscles in 19 participants with C9orf72 expansions and 21 healthy controls using transcranial magnetic stimulation (TMS). El Escorial and Rascovsky criteria were used to diagnose ALS and FTD. Fourteen participants with C9orf72 expansions were re-tested 6 months later. Correlations with finger-tapping speed, timed peg test, the ALS functional rating scale, and Dementia Rating Scale were examined. Results Most participants with C9orf72 expansions had normal or low cortical thresholds. Among them, ALS patients had the lowest thresholds and significantly shorter silent periods. Thresholds correlated with timed peg-test scores. TMS did not correlate with the Dementia Rating Scale. Conclusion TMS measures of cortical excitability may serve as non-invasive biomarkers of ALS disease activity.

TheC9ORF72Gene, Implicated in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia, Encodes a Protein That Functions in Control of Endothelin and Glutamate Signaling

“…Additionally, it would be informative to understand the source of intracellular glutamate accumulation; is it due mainly to GGC gene downregulation, to an increase of extracellular glutamate intake, or to a combination of both? Our findings thus provide a possible mechanism to explain the MN hyperexcitability observed specifically in C9 ALS patients (97,98).…”

Expansion of C9ORF72 in amyotrophic lateral sclerosis correlates with brain-computer interface performance

“…Four of the ALS patients in this study possessed an expansion of the C9ORF72 gene, which has been linked to the presence of electrophysiological brain abnormalities, including cortical hyperexcitability 13 , 14 , background rhythm slowing 15 , and epileptic activity 16 . While there was both a reduction in VEP quality and online BCI performance in ALS patients as a group, those with the C9ORF72 expansion demonstrated further reductions compared to those without it.…”

“…MRI studies point to structural changes common among repeat carriers that extend beyond the degeneration of the cortico-motor pathways typically involved in ALS 7 , 11 , 12 . Transcranial magnetic stimulation studies have identified a reduction in cortical inhibition attributable to this expansion found in ALS patients 13 , 14 . In an electroencephalographic (EEG) study of seven ALS/FTD patients with the repeat expansion, two showed generalized slowing of the background activity, while another two showed intermittent abnormal temporal delta-theta activity 15 .…”

Modeling the C9ORF72 repeat expansion mutation using human induced pluripotent stem cells

“…Emerging clinical functional data for symptomatic ALS patients that carry the C9ORF72 RE shows axonal hyperexcitability in lower motor neurons and the cortex . In direct contrast, cortical hyperexcitability has not been observed in FTD and ALS‐FTD patients, or asymptomatic patients, carrying C9ORF72 RE s .…”

“…Evidence for neuronal hyperexcitability has been broadly observed across the genetic spectrum of ALS and has been suggested to manifest pre‐symptomatically before potentially contributing to the degenerative process . Emerging clinical functional data for symptomatic ALS patients that carry the C9ORF72 RE shows axonal hyperexcitability in lower motor neurons and the cortex . In direct contrast, cortical hyperexcitability has not been observed in FTD and ALS‐FTD patients, or asymptomatic patients, carrying C9ORF72 RE s .…”