Quantitative Susceptibility MRI to Detect Brain Iron in Amyotrophic Lateral Sclerosis

Abstract

Purpose To investigate the whole-brain landscape of iron-related abnormalities in amyotrophic lateral sclerosis (ALS) by using the in vivo MRI technique of quantitative susceptibility mapping (QSM). Materials and Methods For this prospective study, 28 patients with ALS (mean age, 61 years; age range, 43-77 years; 18 men [mean age, 61 years; range, 43-77 years] and 10 women [mean age, 61 years; range, 47-74 years]) recruited between January 17, 2014, and September 4, 2015, and 39 matched control subjects (mean age, 61 years; age range, 39-77 years; 24 men [mean age, 62 years; range, 39-77 years] and 15 women [mean age, 59 years; range, 39-73 years]) were examined by using structural and susceptibility 3.0-T MRI techniques. Group data were cross sectionally compared with family-wise error (FWE) corrections by using voxel-based morphometry (random-field theory), cortical thickness analysis (Monte Carlo simulated), subcortical volumetry (Bonferroni-corrected Wilcoxon rank-sum testing), and QSM analysis (cluster-enhanced whole-brain permutation testing and Bonferroni-corrected rank-sum testing in regions of interest). In patients with ALS, a potential relationship between diffusion and susceptibility measurements in the corticospinal tracts (CSTs) was also examined by using Spearman rank-correlation tests. Results Conventional structural measures failed to identify atrophy in the present cohort (FWE P > .05). However, QSM identified several whole-brain abnormalities (FWE P < .05) in ALS. Regionally, higher susceptibility (expressed as means in parts per million ± standard errors of the mean) was confirmed in the motor cortex (ALS = 0.0188 ± 0.0003, control = 0.0173 ± 0.0003; P < .001), the left substantia nigra (ALS = 0.127 ± 0.004, control = 0.113 ± 0.003; P = .008), the right substantia nigra (ALS = 0.141 ± 0.005, control = 0.120 ± 0.003; P < .001), the globus pallidus (ALS = 0.086 ± 0.003, control = 0.075 ± 0.002; P = .003), and the red nucleus (ALS = 0.115 ± 0.004, control = 0.098 ± 0.003; P < .001). Lower susceptibility was found in CST white matter (ALS = -0.047 ± 0.001, control = -0.043 ± 0.001; P = .01). Nigral and pallidal QSM values were cross correlated in ALS (ρ² = 0.42, P < .001), a phenomenon visually traceable in many individual patients. QSM in the CST in ALS also correlated with diffusion-tensor metrics in this tract (ρ² = 0.25, P = .007). Conclusion Whole-brain MRI quantitative susceptibility mapping analysis is sensitive to tissue alterations in amyotrophic lateral sclerosis that may be relevant to pathologic changes. © RSNA, 2018.

Figure 1:

Summary of patient recruitment and exclusions.

Figure 2:

Images show selected regions of interest (ROIs) overlaid onto, A, T1-weighted and, B–G, quantitative susceptibility mapping study templates. A, B, Midbrain ROIs: dorsal/ventral substantia nigra subdivision and red nucleus. C, Cerebellar dentate nucleus. D, FIRST (FMRIB's Integrated Registration and Segmentation Tool) subcortical extractions. E, Precentral gyrus. F, Inferiofrontal pars opercularis. G, Corticospinal tract.

Figure 3:

Cluster-enhanced quantitative susceptibility mapping (QSM) group statistics in 28 patients with amyotrophic lateral sclerosis (ALS) versus 39 elderly control subjects. Age-corrected absolute QSM was greater in patients than in control subjects. Red/yellow clusters = statistical differences at a family-wise error (FWE) P value of less than .05, which are overlaid onto the study-wise QSM template in the Montreal Neurologic Institute I152 coordinate system. High QSM appears as hypointensity (dark areas). (Although some past studies have opted to depict high QSM values as bright, the present scheme was chosen to be consistent with the susceptibility-weighted convention of depicting strong susceptibility weighting as dark.)

Figure 4:

Bar graph shows age-adjusted signed quantitative susceptibility mapping group statistics. Summary statistics are means ± standard errors of the mean. Asterisks = the strength of the group difference—that is, * = P < .05; ** = P < .01; *** = Bonferroni-corrected P < .05; and **** = Bonferroni-corrected P < .01. ALS = amyotrophic lateral sclerosis, L = left, ppm = parts per million, R = right, SN = substantia nigra.

Figure 5:

Representative sagittal, coronal, and axial quantitative susceptibility mapping (QSM) views in standard space in, A, five control subjects and, B, five age-matched patients with amyotrophic lateral sclerosis (ALS). Arrowheads = some regions of QSM increase in ALS: precentral gyrus (all views), corpus striatum (sagittal view), and mesencephalon (coronal view). ALSFRS-R = ALS Functional Rating Scale Revised, F = female, M = male, y.o. = years old.