Thalamic Iron Differentiates Primary-Progressive and Relapsing-Remitting Multiple Sclerosis

Burgetová, Andrea; Dušek, Petr; Vaněčková, Manuela; Horáková, Dana; Langkammer, Christian; Krásenský, Jan; Sobíšek, Lukáš; Matras, Przemysław; Mašek, Martin; Seidl, Zdeněk

doi:10.3174/ajnr.a5166

Cited by 30 publications

(31 citation statements)

References 55 publications

(67 reference statements)

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“…The latter could be an indirect consequence of tissue loss and/or could result from an active process of iron removal from damaged oligodendrocytes, related to chronic microglia activation, ultimately leading to neurodegeneration. [14][15][16][17] When investigating the contribution of different MR imaging metrics to the development DGM atrophy in MS subgroups, we found that a global MR imaging measure of WM damage (namely, the LL) was a constant significant predictor of volume loss for all DGM structures for the patients with RRMS, with an additional, though relative, contribution of local microstructural GM changes in the development of thalamic and caudate atrophy only. This result confirms a suggested possible role of WM lesions in driving atrophy of the highly connected subcortical GM structures, most likely through axonal transection leading to disconnection, with a subsequent degeneration along axonal projections.…”

Section: Discussionmentioning

confidence: 96%

“…13,30 Finally, at the QSM analysis, patients with MS showed a significant reduction of magnetic susceptibility values in the thalamus compared with HC, in line with recent quantitative MR imaging studies. [14][15][16][17] The physiopathologic basis of this altered susceptibility could reside in the variable association of reduced paramagnetic components (ie, iron) and increased diamagnetic components (ie, myelin and/or calcium). Thus, several hypotheses have been proposed, including increased myelin density due to GM loss, calcium deposition, and, in particular, iron depletion.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Along with volume loss, a wide range of pathologic changes affecting the DGM of patients with MS has been also demonstrated using different advanced MR imaging techniques. In particular, DTI studies showed the presence of microstructural damage in these structures, [6][7][8][9] while PWI and Quantitative Susceptibility Mapping (QSM) studies described decreased cerebral perfusion [10][11][12][13] and a complex pattern of susceptibility changes [14][15][16][17] affecting the DGM of patients with MS, respectively.…”

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confidence: 99%

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Determinants of Deep Gray Matter Atrophy in Multiple Sclerosis: A Multimodal MRI Study

Pontillo

Cocozza

Lanzillo

et al. 2018

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Deep gray matter involvement is a consistent feature in multiple sclerosis. The aim of this study was to evaluate the relationship between different deep gray matter alterations and the development of subcortical atrophy, as well as to investigate the possible different substrates of volume loss between phenotypes. MATERIALS AND METHODS: Seventy-seven patients with MS (52 with relapsing-remitting and 25 with progressive MS) and 41 healthy controls were enrolled in this cross-sectional study. MR imaging investigation included volumetric, DTI, PWI and Quantitative Susceptibility Mapping analyses. Deep gray matter structures were automatically segmented to obtain volumes and mean values for each MR imaging metric in the thalamus, caudate, putamen, and globus pallidus. Between-group differences were probed by ANCOVA analyses, while the contribution of different MR imaging metrics to deep gray matter atrophy was investigated via hierarchic multiple linear regression models. RESULTS: Patients with MS showed a multifaceted involvement of the thalamus and basal ganglia, with significant atrophy of all deep gray matter structures (P Ͻ .001). In the relapsing-remitting MS group, WM lesion burden proved to be the main contributor to volume loss for all deep gray matter structures (P Յ .006), with a minor role of local microstructural damage, which, in turn, was the main determinant of deep gray matter atrophy in patients with progressive MS (P Յ .01), coupled with thalamic susceptibility changes (P ϭ .05). CONCLUSIONS: Our study confirms the diffuse involvement of deep gray matter in MS, demonstrating a different behavior between MS phenotypes, with subcortical GM atrophy mainly determined by global WM lesion burden in patients with relapsing-remitting MS, while local microstructural damage and susceptibility changes mainly accounted for the development of deep gray matter volume loss in patients with progressive MS. ABBREVIATIONS: DD ϭ disease duration; DGM ϭ deep gray matter; DMT ϭ disease-modifying treatment; EDSS ϭ Expanded Disability Status Scale; FA ϭ fractional anisotropy; HC ϭ healthy controls; LL ϭ lesion load; MD ϭ mean diffusivity; PMS ϭ progressive MS; QSM ϭ Quantitative Susceptibility Mapping; rCBV ϭ relative CBV; RRMS ϭ relapsing-remitting MS

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Determinants of Deep Gray Matter Atrophy in Multiple Sclerosis: A Multimodal MRI Study

Pontillo

Cocozza

Lanzillo

et al. 2018

AJNR Am J Neuroradiol

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“…All these data, taken together, point toward the notion that iron-related thalamic damage starts earlier in the disease course, in line with previous findings (8), and as such is more likely associated with the inflammatory environment typical of the earlier phases of the disease. Indeed, a recent study (15) comparing primary progressive relapsing-remitting MS with respect to secondary progressive MS. Khalil et al (8) showed also that whereas susceptibility changes within the basal ganglia seem to be more pronounced in patients with clinically isolated syndrome and slowed down in those with relapsing-remitting MS, atrophy follows an opposite evolution. All of these findings support the association between iron and neurodegeneration but a causal role remains speculative, although consistent with similar findings in other neurodegenerative diseases (1).…”

Section: Discussionmentioning

confidence: 99%

“…Although literature data consistently show higher iron content in other deep gray matter structures (6,(12)(13)(14), results are more contradictory with respect to the thalamus. Some studies show higher iron content (6,13), whereas others report lower iron load (4,7,8,15,16). However, comparisons between different studies are challenging because of the use of different MRI acquisition and postprocessing techniques, as well as the strong association between aging and brain iron levels (4,17).…”

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Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis

et al. 2018

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Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (β = -0.42; P = .002), higher degree of disability (β = -0.64; P = .03), and secondary-progressive course (β = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (β = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. © RSNA, 2018 Online supplemental material is available for this article.

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Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI

Schweser

Hagemeier

Dwyer

et al. 2020

Human Brain Mapping

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Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age‐ and sex‐matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing–remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease‐related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.

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Thalamic Iron Differentiates Primary-Progressive and Relapsing-Remitting Multiple Sclerosis

Cited by 30 publications

References 55 publications

Determinants of Deep Gray Matter Atrophy in Multiple Sclerosis: A Multimodal MRI Study

Determinants of Deep Gray Matter Atrophy in Multiple Sclerosis: A Multimodal MRI Study

Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis

Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI

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