Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis

Abstract

Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.

Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons

“…Axonal hyperexcitation by increased I NaP might even play a causal role for neuronal damage and, hence, for the progression of some of these diseases (Waxman ; Iwai et al . ). Indeed, riluzole appears to be efficient in clinical studies on spinal cord injury (Grossman et al .…”

“…), axonal hyperexcitability in motor neuron disease (Iwai et al . ; Shibuya et al . ), neurodegeneration in multiple sclerosis (Trapp and Stys ), and spasticity following spinal cord injury (Brocard et al .…”

“…Indeed, the lateral diffusion or enhanced efficacy of I NaP in demyelinated axons causes hyperexcitability and increased propensity for eAP (Hamada and Kole 2015). This mechanism may underlie several pathophysiological phenomena, including dysfunctional information processing in demyelinated fiber tracts (Hamada and Kole 2015), neuropathic pain (Lachance et al 2014;Nicholson et al 2014), axonal hyperexcitability in motor neuron disease (Iwai et al 2016;Shibuya et al 2016), neurodegeneration in multiple sclerosis (Trapp and Stys 2009), and spasticity following spinal cord injury (Brocard et al 2016). Axonal hyperexcitation by increased I NaP might even play a causal role for neuronal damage and, hence, for the progression of some of these diseases (Waxman 2008;Iwai et al 2016).…”

“…This mechanism may underlie several pathophysiological phenomena, including dysfunctional information processing in demyelinated fiber tracts (Hamada and Kole 2015), neuropathic pain (Lachance et al 2014;Nicholson et al 2014), axonal hyperexcitability in motor neuron disease (Iwai et al 2016;Shibuya et al 2016), neurodegeneration in multiple sclerosis (Trapp and Stys 2009), and spasticity following spinal cord injury (Brocard et al 2016). Axonal hyperexcitation by increased I NaP might even play a causal role for neuronal damage and, hence, for the progression of some of these diseases (Waxman 2008;Iwai et al 2016). Indeed, riluzole appears to be efficient in clinical studies on spinal cord injury (Grossman et al 2014;Fehlings et al 2016) and has been used for many years to treat amyotrophic lateral sclerosis (Bellingham 2011).…”

Early Axonal Dysfunction of the Peripheral Nervous System Influences Disease Progression of ALS: Evidences From Clinical Neuroelectrophysiology

“…The amplitude of compound muscle action potential (CMAP) is widely used in clinical practice as an important electrophysiological index to detect motor axonal damage [13]. It was found that the decrease in the CMAP amplitude of the motor nerve in early stage was signi cantly related to motor axonal hyperexcitability, as increased persistent sodium currents and reduced potassium currents in motor axons [5,6,14]. To explore the relationship between motor axonal dysfunction in early stage and disease progression in patients with ALS, we studied the CMAP amplitude within 12 months of symptom onset (CMAP-12 amplitude) in these patients.…”