Calcium accumulation or iron deposition: Delving into the temporal sequence of amyotrophic lateral sclerosis pathophysiology in the primary motor cortex

Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, but an in vivo understanding of its early pathology remains limited. A recent study used topographic layer imaging to investigate iron and calcium accumulation in the primary motor cortex (M1) of patients with ALS compared with controls. Despite the preserved cortical thickness, ALS patients showed increased iron in layer 6 and calcium accumulation in layer 5a and the superficial layer. Calcium accumulation was particularly prominent in the low-myelin borders, potentially preceding the demyelination. This study reveals a novel in vivo pathology in ALS, suggesting that calcium dysregulation may precede iron accumulation and contribute to early M1 cell degeneration. Further investigation using quantitative susceptibility mapping and complementary techniques, such as diffusion kurtosis imaging, along with ultrahigh-field magnetic resonance imaging, into the role of calcium and early intervention strategies is warranted.