Fitz-Gibbon, Patrick D

ObjectiveMultiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.MethodsWe used synchrotron X‐ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.ResultsImmunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17–127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3–64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = −40 to −14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X‐ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron.InterpretationIron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron‐sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498–510

ABSTRACTPURPOSETo determine interobserver spatial variability in language area localization using three commonly employed language tasks.MATERIALS AND METHODSWith institutional review board approval, 125 fMRI time series from 50 different clinical language cases were retrospectively reviewed by three blinded readers who selected 3‐dimensional points representing the perceived center of Wernicke's and Broca's areas using three language tasks (semantic decision, SD; sentence comprehension, SC; and silent word generation, WG). Point dispersion values were then calculated using the perimeter of the 3‐dimensional triangle defined by the three readers’ selections.RESULTSAfter resolving interobserver laterality disagreements, there was no difference in spatial variability between the three tasks (P = .069). The SD task had the fewest interobserver laterality disagreements (P = .028) and the SC task had fewer failed localizations for Broca's area (P = .050) and Wernicke's area (P = .013).CONCLUSIONWhile there were no differences between interobserver spatial variability in language area localization between the three tasks, language task choice impacts the accuracy of fMRI language area identification because tasks vary in their rates of interobserver laterality disagreements and failed localizations. A combination of tasks including one with low laterality disagreements (eg, SD) and one with few failed localizations (eg, SC) may offer the best combination.