Cortical hyperexcitability evolves with disease progression in ALS

Abstract

Objective: Cortical hyperexcitability has been established as an early feature of amyotrophic lateral sclerosis (ALS). The evolution of cortical hyperexcitability with ALS progression remains to be fully elucidated. This study aims to investigate changes in cortical function in ALS with disease progression. Methods: Cortical function assessed by threshold tracking transcranial magnetic stimulation (TMS) along with clinical phenotyping was prospectively undertaken on 444 patients presenting with suspected ALS (345 ALS; 99 neuromuscular mimics). Disease stage was defined as follows: (1) King's clinical staging system and (2) proportion of disease duration statistically categorized into tertials. Results: Cortical hyperexcitability was evident across all ALS stages, being more prominent in later stages of ALS as indicated by increased motor-evoked potential amplitude (P < 0.05), as well as longer disease duration as reflected by reduced short-interval intracortical inhibition (P < 0.05). Prolonged central motor conduction time was evident with disease progression. These changes were accompanied by reduction in neurophysiological index (P < 0.001) and compound muscle action potential amplitude (P < 0.01), progressive muscle weakness (P < 0.001), and decline in the ALS functional rating scale (P < 0.001). Interpretation: This study established an increase in cortical hyperexcitability with increased disease duration in ALS, mediated by cortical disinhibition and direct increase in corticomotoneuronal excitability.

TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

“…GO term analyses identified pathways such as Membrane Potential Stability and Transmembrane Transport—K+ (Fig. 3 g–j, Additional file 3 : Table S3-4) comprising genes related to membrane excitability, a process known to be altered in ALS [ 74 ]. We note that although GO term analysis is useful to identify translational alterations affecting multiple components of the same pathway, the genes encompassed by these GO terms represent only a fraction of genes enriched and translationally dysregulated in the context of TDP-43 (Fig.…”

TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

“…These analyses that approximately 1/3 of the genes depleted from ribosomes were also enriched in TDP-43 complexes (Figure 3a, Supplemental Table 3-1, TDP-43 WT 30.6%, TDP-43 G298S 37.6%) suggesting that these may be direct targets of translation inhibition. GO term analyses of these TDP-43 enriched, TRAP depleted genes using David 6.8 49,50 identified pathways that have previously been associated with ALS including GPCR signaling 65,66 , NMJ Development 65,66 , Autophagy 67,68 , ER Organization 69 , Immune Respone 70 and Oxidation Reduction 71 Table 3-4) comprising genes related to membrane excitability, a process known to be altered in ALS 72 . We note that although GO term analysis is useful to identify translational alterations affecting multiple components of the same pathway, the genes encompassed by these GO terms represent only a fraction of genes enriched and translationally dysregulated in the context of TDP-43 ( Figure 3a, f, TDP-43 WT = 13.7%, TDP-43 G298S = 12.4%).…”

Intuitive Staging Correlates With King’s Clinical Stage

“…Biomarkers of disease stage are being investigated in ALS (9)(10)(11), but until a robust biomarker of disease stage is found, clinical staging is an alternative. King's clinical ALS staging (7) has been proposed for use as a staging method for ALS and has been validated in various studies (12)(13)(14)(15), and some biomarkers have been mapped to King's stage (16)(17)(18). Recently, we used King's staging to estimate the clinical stage at which Riluzole, a treatment for ALS, showed greatest effect (13).…”