Quantitative susceptibility mapping for investigating brain iron deposits in amyotrophic lateral sclerosis: correlations with clinical phenotype and disease progression.

Objective: Perturbation of iron homeostasis is a potential key mechanism involved in neurodegeneration across many neurological disorders, including amyotrophic lateral sclerosis (ALS). We hypothesized that changes in quantitative susceptibility mapping (QSM) could capture perturbations in brain iron concentration in subgroups of ALS patients stratified by clinical phenotype and disease progression. Method: We enrolled 38 ALS patients (23 males - mean age: 58.7 ± 9.8), screened by clinical (ALS functional rating scale-revised, ALSFRS-R) and neuropsychological scales. Patients were a posteriori classified as fast (n = 16) or slow (n = 22) progressors. Two subgroups were also considered: pyramidal (or upper motor neuron+, UMN+) patients (n = 18), and patients with other phenotypes (n = 20). Results: Comparing fast vs. slow progressors, significant differences in iron deposits were observed in the left (p = 0.028) and right amygdala (p = 0.022), and in susceptibility distribution on the right hippocampus (p = 0.0011). Comparing UMN+ vs. other phenotypes, significant susceptibility differences emerged in the left thalamus (p = 0.0014) and right amygdala (p = 0.001). QSM changes were associated with baseline ALSFRS-R (rho = 0.36, p = 0.026) in the left paracentral cortex, and iron concentration with UMN score (rho = 0.35, p = 0.034). Moreover, the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) was associated with iron deposits in the left thalamus (rho=-0.46, p = 0.0041). Conclusions: We confirmed that QSM alterations in extra-motor areas and subcortical regions may be distinctive hallmarks of neurodegeneration in pure/dominant UMN phenotypes of ALS. Moreover, we showed that QSM could be a valuable tool to differentiate patients with different progression rates and phenotypes, suggesting that QSM may support a prognostically useful early stratification of ALS patients.