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Back to the Drawing Board: Evidence that Advanced Motor Cortex Pathology in Amyotrophic Lateral Sclerosis causes Whole Brain Systemic Effects


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Objective: To examine intracranial CNS iron accumulation outside the motor system in amyotrophic lateral sclerosis (ALS) and its impact on white matter (WM) microstructural integrity. Background: Recent studies have demonstrated that excessive oxidative stress in motor neurons due to iron accumulation in the motor cortex (MC) results in loss of WM microstructural integrity along the pyramidal tract in ALS. While ALS is classically considered a disease restricted to the motor system, we examine potential systemic manifestations by measuring WM integrity and iron accumulation using diffusion tensor imaging (DTI) and quantitative susceptibility mapping (QSM) throughout the brain to provide greater insights into ALS pathophysiology. Design/Methods: ALS and age/sex-matched controls MRI exams were identified in a preexisting institutional database. WM integrity was estimated from DTI fractional anisotropy (FA) values in 23 regions throughout the brain using the Reproducible Objective Quantification Scheme. Iron deposition was measured on QSM using manual tracing in all 23 regions and bilateral MC. Control FA values were used to compute Z-scores. Associations between FA Z-scores and iron concentrations were performed using non-parametric Spearman-Rho correlations. Results: 40 ALS (mean age 639, 16 F) and 35 controls were obtained. Increasing MC iron deposition was significantly associated with increased iron deposition in 20 regions after controlling for multiple comparisons (p<0.002, all 23 regions p<0.005). In the centrum semiovale, decreased WM integrity was associated with iron concentration (right p=0.124 R=0.434, left p=0.007 R=0.520). Additionally, increased FA in the presence of increased iron deposition was identified in frontal WM pathways (right uncinate fasciculus p=0.009, R=0.407, genu of corpus callosum, p=0.008, R=0.412). Conclusions: Iron accumulation outside the MC may reflect unrecognized systemic effects of ALS. Decreased WM integrity in motor neurons and increased WM integrity in frontal WM pathways may reflect pathologic mechanisms from oxidative stress and preservation of higher order cognitive domains.


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© Copyright 2019 Morressier GmbH.
All rights reserved.