Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis.

Keywords: ALS; TMS; cortical hyperexcitability; glutamate excitotoxicity.

Figure 1

(A) The three theories for ALS onset are illustrated. The dying forward hypothesis proposes that ALS is primarily a disorder of the corticomotoneurons (red colour), which connect monosynaptically with the anterior horn cells, and mediate anterograde motor neuron degeneration via glutamate excitotoxicity. In contrast, the dying back hypothesis proposes that ALS begins within muscles or at the neuromuscular junction, with noxious factors transported retrogradely from the periphery to the axon cell body, where they exert toxic effects. The independent degeneration hypothesis proposed that upper and lower motor neuron degeneration occurs independently. (B) Transcranial magnetic stimulation excites neurons in the underlying motor cortex, with motor evoked potentials (MEP) recorded over the contralateral muscle. It is a sensitive measure of cortical excitability.

Figure 2

Amyotrophic lateral sclerosis (ALS) appears to be mediated by a complex interaction between molecular and genetic pathways. Reduced uptake of glutamate from the synaptic cleft, leading to glutamate excitotoxicity, is mediated by dysfunction of the astrocytic excitatory amino acid transporter 2 (EAAT2). The resulting glutamate-induced excitotoxicity induces neurodegeneration through activation of Ca²⁺-dependent enzymatic pathways. Mutations in the c9orf72, TDP-43 and fused in sarcoma (FUS) genes result in dysregulated RNA metabolism leading to abnormalities of translation and formation of intracellular neuronal aggregates. Mutations in the superoxide dismuates-1 (SOD-1) gene increases oxidative stress, induces mitochondrial dysfunction, leads to intracellular aggregates, and defective axonal transportation. Separately, microglia activation results in secretion of proinflammatory cytokines and neurotoxicity.

Figure 3

Dissociated muscle atrophy is a specific feature of ALS, characterized by preferential wasting of the (A) abductor pollicis brevis and (B) first dorsal interosseous muscles, when compared to the hypothenar group of muscles.

Figure 4

(A) A tracking target of 0.2 mV (± 20%), which lies in the steepest portion of the stimulus response curve, is tracked. As such, larger variations in the motor evoked potential (MEP) amplitude translate to smaller variations in transcranial magnetic stimulation (TMS) intensity. (B) When the MEP amplitude is larger than the tracking target (a) the intensity is reduced on subsequent stimulus, while when MEP is smaller (b) than the TMS, intensity is increased. (C) Short interval intracortical inhibition (SICI) is reflected by conditioned-test stimulus intensity being greater than zero (red dotted line), while the converse is true for intracortical facilitation (ICF). In amyotrophic lateral sclerosis (ALS), there is a significant reduction in SICI and an increase in ICF, indicative of cortical hyperexcitability.