Beyond the Motor Cortex: Thalamic Iron Deposition Accounts for Disease Severity in Amyotrophic Lateral Sclerosis

Abstract

ObjectivePrevious studies have reliably identified iron deposition in the motor cortex as potential pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we intended to investigate iron deposition, gray matter (GM) atrophy, and their associations with disease severity in the motor cortex and the thalamus in patients with ALS.MethodsA total of 34 patients with ALS (age 51.31 ± 8.24 years, 23 males) and 34 nonneurological controls (age 50.96 ± 9.35 years, 19 males) were enrolled between 2018 and 2020. The Revised ALS Functional Rating Scale (ALSFRS-R) and the Penn upper motor neuron (UMN) score were measured. MRI data included quantitative susceptibility mapping (QSM) for iron deposition and three-dimensional (3D) T1 for gray matter volume. After a between-group comparison, Pearson's correlation coefficient was used for identifying correlations of iron deposition, GM volume, and clinical measurements.ResultsThe two-sample t-tests revealed increased iron deposition in the left precentral gyrus (peak voxel T = 4.78, PSVC = 0.03) and the thalamus (peak voxel: right: T = 6.38, PSVC < 0.001; left: T = 4.64, PSVC = 0.02) in patients with ALS. GM volume of the precentral gyrus (T = −2.42, P = 0.02) and the bilateral thalamus (T = −4.10, P < 0.001) were reduced. Negative correlations were found between the increased QSM values and the decreased GM volume (P < 0.04, one-tailed) in patients with ALS. Iron deposition in the left precentral gyrus was positively correlated with the UMN score (R = 0.40, P = 0.02) and the GM volume was negatively correlated with the UMN score (R = −0.48, P = 0.004). Negative correlation between thalamic iron deposition and the ALSFRS-R (R = −0.36, P = 0.04) score was observed.DiscussionIron deposition in the thalamus, in addition to the motor cortex, is accompanied by GM atrophy and is associated with disease severity in patients with ALS, indicating that the thalamus is also a pathological region in patients with ALS.

Iron quantification in basal ganglia using quantitative susceptibility mapping in a patient with ALS: a case report and literature review

“…Our QSM analysis found that the ALS patient exhibited higher magnetic susceptibility values in the bilateral putamen compared to controls, indicating increased iron accumulation. Several studies have reported increased magnetic susceptibility in the motor cortex and other regions, which could be indicative of iron accumulation (Schweitzer et al, 2015 ; Costagli et al, 2016 ; Acosta-Cabronero et al, 2018 ; Donatelli et al, 2019 ; Bhattarai et al, 2020 ; Li et al, 2022 ). Our results are consistent with these findings, providing further evidence for the potential role of iron dysregulation in the pathophysiology of ALS.…”

“…The study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical Code: IR.TUMS.MEDICINE.REC.1400.1173). The QSM was reconstructed from the SWI sequence data acquisition using the following steps based on methodological studies: (1) phase unwrapping using the Laplacian-based method (Li et al, 2014 , 2022 ; Acosta-Cabronero et al, 2018 ); (2) background field removal using the V-SHARP method (Fang et al, 2017 ; Kan et al, 2018 ; Wang et al, 2020 ; Li et al, 2022 ); and (3) field-to-susceptibility inversion using streaking artifacts reduction QSM (STAR-QSM) method (Wei et al, 2015 ; Wang et al, 2020 ; Conte et al, 2021 ; Yaghmaie et al, 2021 ). QSM calculations were performed using MATLAB, STI Suite (a MATLAB toolbox) (Li et al, 2014 ).…”

Basal ganglia alterations in amyotrophic lateral sclerosis

“…Several studies assessing gray matter (GM) loss in patients with sporadic ALS reported alterations of caudate head ( Agosta et al, 2009 ; Bede et al, 2013 , 2016 , 2018 ; Menke et al, 2014 ; Machts et al, 2015 ; Masuda et al, 2016 ; Senda et al, 2017 ; Alruwaili et al, 2018 ; Christidi et al, 2018b ; Tae et al, 2020 ; Ahmed et al, 2021 ; Canna et al, 2021 ), both in patients with slow and fast disease progression ( Agosta et al, 2009 ; Senda et al, 2017 ), putamen ( Agosta et al, 2009 ; Machts et al, 2015 ; Buhour et al, 2017 ; Kim et al, 2017 ; Bede et al, 2018 ; Christidi et al, 2018a , b ; Tae et al, 2020 ; Ahmed et al, 2021 ; Canna et al, 2021 ), globus pallidus ( Machts et al, 2015 ; Bede et al, 2018 ; Tae et al, 2020 ; Ahmed et al, 2021 ; Canna et al, 2021 ; Castelnovo et al, 2021 ; Leoni et al, 2022 ), accumbens ( Bede et al, 2013 , 2016 , 2018 ; Machts et al, 2015 ; Finegan et al, 2019 ), and thalamus ( Chang et al, 2005 ; Thivard et al, 2007 ; Bede et al, 2013 , 2016 ; Machts et al, 2015 ; Masuda et al, 2016 ; Senda et al, 2017 ; Branco et al, 2018 ; Christidi et al, 2018a ; Menke et al, 2018 ; Tu et al, 2018 ; Finegan et al, 2019 ; Chipika et al, 2020 ; Ahmed et al, 2021 ; Liu et al, 2021 ; Li et al, 2022 ). A recent cross-sectional study, which stratified ALS patients in different disease stages based on the...…”

“…The analysis demonstrated that the involvement of bilateral motor cortex, bilateral caudate, right hippocampus, right putamen, right globus pallidus, and right amygdala differentiated ALS patients and controls with a mean accuracy of 0.68, and specifically right and left caudate, right putamen and right globus pallidus showed a range of accuracy between 0.66 and 0.69 ( Canna et al, 2021 ). Another study showed reduced GM volume and increased iron deposition in the bilateral thalamus in ALS patients compared to controls, and a positive relationship between increased iron deposition and disease severity ( Li et al, 2022 ).…”

“…As such, given BG involvement in voluntary movement and high-order aspects of motor control ( Groenewegen, 2003 ), structural and functional changes in BG were often associated with greater disease severity ( Sharma et al, 2013 ; Menke et al, 2018 ; Abidi et al, 2020 ; Bharti et al, 2022 ; Li et al, 2022 ), worsening of clinical symptoms, including greater disability and motor decline ( Sharma et al, 2013 ; Bharti et al, 2022 ), as well as faster disease progression ( Basaia et al, 2020 ; Tae et al, 2020 ), and shorter survival ( Westeneng et al, 2015 ; Zhang J. Q. et al, 2017 ).…”