Cortical changes in amyotrophic lateral sclerosis: comparing biomarkers of glymphatic flow and cortical excitability

The pathogenesis of amyotrophic lateral sclerosis (ALS) involves a multistep process, with a central role for cortical hyperexcitability and misfolded protein accumulation. The glymphatic system mediates clearance of misfolded proteins, yet its role in modulating cortical excitability is unknown. This study aims to determine whether glymphatic dysfunction is associated with cortical hyperexcitability, thereby linking impaired protein clearance to excitotoxic neurodegeneration in ALS.

Glymphatic function was assessed using diffusion tensor imaging analysis along perivascular spaces (DTI-ALPS) and correlated with measures of corticomotoneuronal function assessed by transcranial magnetic stimulation (TMS). The DTI-ALPS index and cortical excitability testing were performed in 35 ALS patients and compared to 25 age-matched controls. The DTI-ALPS index was correlated with TMS and clinical measures.

A significant reduction in the DTI-ALPS index was observed in ALS (p = 0.016), along with cortical hyperexcitability evident as shortened cortical silent period (CSP) duration (p = 0.001) and reduced short interval intracortical inhibition (p < 0.001). The DTI-ALPS index significantly correlated with CSP duration (R = 0.48, p = 0.027). The DTI-ALPS index was significantly reduced in ALS participants with mild functional impairment. The possibility that reduced DTI-ALPS index represents an epiphenomenon of tract degeneration cannot be completely excluded.

This study identified a potential association between impaired glymphatic clearance and disrupted GABA_B-mediated cortical inhibition, suggesting that glymphatic dysfunction may play a role in the neurodegenerative cascade in ALS.

Glymphatic dysfunction may be associated with impaired cortical inhibition, thereby contributing to cortical hyperexcitability in ALS and providing further mechanistic insight.