Iron Rim Research Articles

Enlarged choroid plexus related to iron rim lesions and deep gray matter atrophy in relapsing-remitting multiple sclerosis.

Choroid plexus (CP) is considered to be linked to inflammation of multiple sclerosis (MS), but its connection with markers of inflammation in vivo in MS is unclear, the markers such as lesions load and brain atrophy, particularly the white matter lesions (WMLs) edge surrounded by an iron rim, termed as iron rim lesions (IRLs). To investigate the association between CP volume and brain lesions load, especially IRLs load and atrophy in MS, and its relationship with clinical characteristics. 3.0 T brain MRI images were acquired from 99 relapsing-remitting MS (RRMS) and 60 healthy controls (HCs) to obtain the volumes of CP, whole brain and lesions. Volumes were expressed as a ratio of intracranial volume. Expanded Disability Status Scale (EDSS), Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) were used to assess the severity of disability and cognitive function. Student's t-test and Multivariable regression analyses were performed to evaluate the difference of CP volumes between RRMS and HC and the association between CP volume and lesions load, brain volumes and clinical scale scores in RRMS. CP volume was 30% larger in patients with RRMS than HCs (p < 0.001) and was 20% larger in patients with IRLs than those without IRLs (p=0.007). Moreover, the larger CP volume was related to greater WMLs volume in the whole RRMS (r=0.46, p < 0.001). Further analysis in patients with IRLs showed a positive correlation between CP volume and WMLs volume (r=0.45, p=0.003), and IRLs volume (r=0.51, p < 0.001). Meanwhile, enlarged CP was related to lower volumes in the whole brain (r=-0.30, p=0.006), deep gray matter (r=-0.51, p < 0.001) and most regional deep gray matter nuclei (except amygdala), but no correlation with cortical lesions or cortex volume (both p > 0.05). In addition, CP volume was significantly higher in patients with cognitive impairment than those with cognitive preservation by MoCA scores (p=0.011); the larger CP volume was associated with higher EDSS scores (r=0.25, p=0.014) and lower SDMT Z scores in RRMS (r=-0.26, p=0.014). The enlargement of CP in RRMS had close correlations with inflammatory lesions, especially IRLs and deep gray matter atrophy, but not the cortex. Meanwhile, the larger CP volume was associated with higher disability and lower cognitive scores. CP volume may be a surrogate imaging marker for MS disease activity.

Iron Rim Lesions as a Specific and Prognostic Biomarker of Multiple Sclerosis: 3T-Based Susceptibility-Weighted Imaging.

This study aimed to identify the clinical significance of iron rim lesions (IRLs) in distinguishing multiple sclerosis (MS) from other central nervous system (CNS) demyelinating diseases, determine the relationship between IRLs and disease severity, and understand the long-term dynamic changes in IRLs in MS. We retrospectively evaluated 76 patients with CNS demyelinating diseases. CNS demyelinating diseases were classified into three groups: MS (n = 30), neuromyelitis optica spectrum disorder (n = 23), and other CNS demyelinating diseases (n = 23). MRI images were obtained using conventional 3T MRI including susceptibility-weighted imaging. Sixteen of 76 patients (21.1%) had IRLs. Of the 16 patients with IRLs, 14 were in the MS group (87.5%), indicating that IRLs were significantly specific for MS. In the MS group, patients with IRLs had a significantly higher number of total WMLs, experienced more frequent recurrence, and were treated more with second-line immunosuppressive agents than were patients without IRLs. In addition to IRLs, T1-blackhole lesions were observed more frequently in the MS group than in the other groups. IRLs are specific for MS and could represent a reliable imaging biomarker to improve the diagnosis of MS. Additionally, the presence of IRLs seems to reflect more severe disease progression in MS.

Longitudinal stability of progression-related microglial activity during teriflunomide treatment in patients with multiple sclerosis.

The aim was to study brain innate immune cell activation in teriflunomide-treated patients with relapsing-remitting multiple sclerosis. Imaging with 18-kDa translocator protein positron emission tomography (TSPO-PET) using the [11 C]PK11195 radioligand was employed to assess microglial activity in the white matter, thalamus and areas surrounding chronic white matter lesions in 12 patients with relapsing-remitting multiple sclerosis who had been treated with teriflunomide for at least 6 months before inclusion. Magnetic resonance imaging (MRI) was used to measure lesion load and brain volume, and quantitative susceptibility mapping (QSM) was used to detect iron rim lesions. These evaluations were repeated after 1 year of inclusion. Twelve age- and gender-matched healthy control subjects were imaged for comparison. Half of the patients had iron rim lesions. In TSPO-PET, the proportion of active voxels indicating innate immune cell activation was slightly greater amongst patients compared with healthy individuals (7.7% vs. 5.4%, p = 0.033). The mean distribution volume ratio of [11 C]PK11195 was not significantly different in the normal-appearing white matter or thalamus amongst patients versus controls. Amongst the treated patients, no significant alteration was observed in positron emission tomography distribution volume ratio, the proportion of active voxels, the number of iron-rim-positive lesions, lesion load or brain volume during follow-up. Compared to controls, treated patients exhibited modest signs of diffuse innate immune cell activity, which was unaltered during follow-up. Lesion-associated smoldering inflammation was negligible at both timepoints. To our knowledge, this is the first study applying both TSPO-PET and QSM-MRI to longitudinally evaluate smoldering inflammation.

Evaluating the effects of space weathering on magnetite on airless planetary bodies

Magnetite is a relevant mineral component of asteroids as it has been identified in carbonaceous chondrites, on the surface of asteroid Bennu through remote sensing observations, and in samples returned from asteroid Ryugu. However, the effects of space weathering processes on magnetite have not yet been explored. To investigate how this mineral phase responds to space weathering, here we simulate micrometeoroid bombardment and solar wind irradiation of magnetite using pulsed laser and ion irradiation experiments. We performed X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), and visible to near-infrared (VNIR) reflectance spectroscopy analyses to characterize the chemical, microstructural, and spectral response of magnetite to simulated space weathering. In addition, we carried out ion impact simulations using the SDTrimSP software to evaluate the calculated response of magnetite to 1 keV H+ and 4 keV He+ ions and compared these results to our XPS and TEM results. Ion irradiation simulated ∼750 years on the surface of asteroid Bennu, with a solar-wind appropriate total H:He fluence ratio (∼24). Within this time, depletion of O was observed with H+ and He+ ion irradiation, with significantly greater change via protons due to the larger fluence, where preferential sputtering promotes the formation of a metallic iron layer at the magnetite surface. This suggests that solar wind ions act as reducing agents on Fe oxides, with a fraction remaining implanted in these phases. Indeed, we observe elongated defects contained in a crystalline rim created by He+ implanted ions in the TEM. Pulsed laser irradiation, analogous to micrometeoroid impacts, generates melts on the surface of the magnetite grains. The impact melts and H+-generated metallic iron rims both result in increased VNIR spectral reflectance, but lower fluence He+ implantation has no significant spectral effect. These results suggest that space weathered magnetite could contribute to bright regions detected in remote sensing analyses of the Ryugu and Bennu surfaces by the Hayabusa2 and OSIRIS-REx missions and will contribute to the identification and interpretation of space weathered magnetite in returned samples retrieved from both asteroids.

Microstructural alterations in different types of lesions and their perilesional white matter in relapsing-remitting multiple sclerosis based on diffusion kurtosis imaging.

In multiple sclerosis (MS), contrast enhancement lesions and chronic active lesions have been demonstrated to have different degrees of inflammation. Accordingly, they exist different degrees of tissue damage, one is short and acute, and another is slow and longstanding. This study aimed to explore whether diffusion parameters can differentiate different types of lesions, and investigate the microstructural damage between different types of MS lesions by using diffusion magnetic resonance imaging (dMRI) and its correlation with clinical biomarkers of disability and cognitive states. We retrospectively identified 77 contrast enhancement lesions (CELs), 384 iron rim lesions (IRLs), 393 non-iron rim lesions (NIRLs), their corresponding perilesional white matter (PLWM), and 68 normal-appearing white matter (NAWM) from 68 relapsing-remitting MS (RRMS). Additionally, 44 white matter in healthy controls (WM in HCs) were also enrolled in this study. The DTI and DKI parameters were measured in the above white matter, including kurtosis fractional anisotropy (KFA), fractional anisotropy (FA), mean kurtosis (MK), and mean diffusivity (MD). All the patients were assessed with the Digital Span Test (DST), the Symbol Digit Modalities Test (SDMT), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Expanded Disability Status Scale (EDSS). The lowest KFA, FA, MK values and the highest MD values were found in CELs, followed by IRLs, NIRLs, NAWM, and WM in HCs. In KFA and FA values, there were significant differences between each type of lesion, as well as each type of PLWM (P < 0.05). The MK values of CELs and IRLs were significantly lower than NIRLs, but inversely for MD (P < 0.05). There were no differences between CELs and IRLs for MK (P=1) and MD (P=0.261). The results of MK and MD values in CELs-PLWM and IRLs-PLWM were similar to the CELs and IRLs. There were no significant differences between NAWM and WM in HCs in all the enrolled diffusion parameters (P >0.05) and the FA values between NIRLs-PLWM and NAWM or between NIRLs-PLWM and WM in HCs were no significant differences (P >0.05). The KFA and MD values in IRLs-PLWM (r =0.443, P =0.021; r =-0.518, P =0.006) were correlated with the DST scores and the KFA of CELs-PLWM (r =0.396, P =0.041) was correlated with SDMT scores. Our findings demonstrate that the KFA values have the potential to distinguish different types of MS white matter tissues. Furthermore, the diffusion parameters can reflect the microstructure abnormalities in different MS lesions and might help us better understand the pathological mechanism and lesion evolution.

Cerebrospinal fluid–related tissue damage in multiple sclerosis patients with iron rim lesions

Background: In multiple sclerosis (MS), iron rim lesions (IRLs) are associated with pronounced tissue damage, higher disease severity and have been suggested as an imaging marker of chronic active inflammation behind the blood–brain barrier indicating progression. Furthermore, chronic intrathecal compartmentalized inflammation has been suggested to be a mediator of a cerebrospinal fluid (CSF)–related tissue damage. Objective: To investigate CSF markers of intrathecal inflammation in patients with at least one IRL compared to patients without IRLs and to investigate tissue damage in lesions and normal-appearing white matter (NAWM) with proximity to CSF spaces. Methods: A total of 102 patients (51 with at least 1 IRL and 51 age-/sex-matched patients without IRL) scanned with the same 3T magnetic resonance imaging (MRI) and having CSF analysis data were included. Results: Patients with at least one IRL had higher disability scores, higher lesion volumes, lower brain volumes and a higher intrathecal immunoglobulin G (IgG) synthesis. Apparent diffusion coefficient (ADC) values in IRLs were higher compared to non-IRLs. We observed a negative linear correlation of ADC values in all tissue classes and distance to CSF, which was stronger in patients with high IgG quotients. Conclusion: IRLs are associated with higher intrathecal IgG synthesis. CSF-mediated intrathecal smouldering inflammation could explain a CSF-related gradient of tissue damage.

Metabolic Insights into Iron Deposition in Relapsing-Remitting Multiple Sclerosis via 7 T Magnetic Resonance Spectroscopic Imaging

ObjectiveTo investigate the metabolic pattern of different types of iron accumulation in multiple sclerosis (MS) lesions, and compare metabolic alterations within and at the periphery of lesions and newly emerging lesions in vivo according to iron deposition. Methods7 T MR spectroscopic imaging and susceptibility-weighted imaging was performed in 31 patients with relapsing-remitting MS (16 female/15 male; mean age, 36.9 ± 10.3 years). Mean metabolic ratios of four neuro-metabolites were calculated for regions of interest (ROI) of normal appearing white matter (NAWM), “non-iron” (lesion without iron accumulation on SWI), and three distinct types of iron-laden lesions (“rim”: distinct rim-shaped iron accumulation; “area”: iron deposition across the entire lesions; “transition”: transition between “area” and “rim” accumulation shape), and for lesion layers of “non-iron” and “rim” lesions. Furthermore, newly emerging “non-iron” and “iron” lesions were compared longitudinally, as measured before their appearance and one year later. ResultsThirty-nine of 75 iron-containing lesions showed no distinct paramagnetic rim. Of these, “area” lesions exhibited a 65% higher mIns/tNAA (p = 0.035) than “rim” lesions. Comparing lesion layers of both “non-iron” and “rim” lesions, a steeper metabolic gradient of mIns/tNAA (“non-iron” +15%, “rim” +40%) and tNAA/tCr (“non-iron” −15%, “rim” −35%) was found in “iron” lesions, with the lesion core showing +22% higher mIns/tNAA (p = 0.005) and –23% lower tNAA/tCr (p = 0.048) in “iron” compared to “non-iron” lesions. In newly emerging lesions, 18 of 39 showed iron accumulation, with the drop in tNAA/tCr after lesion formation remaining significantly lower compared to pre-lesional tissue over time in “iron” lesions (year 0: p = 0.013, year 1: p = 0.041) as opposed to “non-iron” lesions (year 0: p = 0.022, year 1: p = 0.231). Conclusion7 T MRSI allows in vivo characterization of different iron accumulation types each presenting with a distinct metabolic profile. Furthermore, the larger extent of neuronal damage in lesions with a distinct iron rim was reconfirmed via reduced tNAA/tCr concentrations, but with metabolic differences in lesion development between (non)-iron-containing lesions. This highlights the ability of MRSI to further investigate different types of iron accumulation and suggests possible implications for disease monitoring.

Multiple sclerosis iron rim lesions are linked to impaired cervical spinal cord integrity using the T1/T2-weighted ratio.

In multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by pronounced tissue matrix damage. The T1/T2-weighted (T1/T2w) ratio represents a postprocessing MRI approach to investigate tissue integrity, but studies investigating spinal cord pathology are missing until now. The aim of this study was to characterize tissue integrity using the T1/T2w ratio in lesions and the normal-appearing white and gray matter (NAWM, NAGM) in the spinal cord and brain in MS patients with and without brain IRLs. Forty MS patients (20 patients with at least one brain IRL and 20 age- and sex-matched patients without IRLs) were included. Normalized cross-sectional area (nCSA) of the upper cervical cord was calculated in addition to T1/T2w values and standard brain and spinal cord MRI parameters. Patients with IRLs had higher disability scores, a smaller nCSA, and a higher cervical T2 lesion volume. T1/T2w values of brain IRLs were significantly lower compared to non-IRLs (p<.001). Furthermore, T1/T2w values of lesions were significantly lower compared to the NAGM and NAWM, both in the brain and the spinal cord (p<.05 for all comparisons). T1/T2w values of the NAGM and NAWM in the brain and spinal cord did not statistically differ between the IRL group and the non-IRL group. IRLs constitute an imaging marker of disease severity. T1/T2w ratio maps represent an interesting technique to capture diffuse tissue properties. Calculation of T1/T2w ratio maps of the spinal cord might provide additional insights into the pathophysiological processes of MS.

Exploring (peri-) lesional and structural connectivity tissue damage through T1/T2-weighted ratio in iron rim multiple sclerosis lesions

ObjectiveIn multiple sclerosis (MS), iron rim lesions (IRLs) on magnetic resonance imaging (MRI) are associated with pronounced intralesional tissue damage. The aim of this study was to investigate (peri-)lesional and structural connectivity tissue damage in IRLs compared to non-IRLs. Material and methodsMRI was acquired on a 3 T system. Tissue integrity was assessed using the T1/T2-weighted (T1/T2w) ratio. Furthermore, we assessed the impact on structural network connectivity accounting for differences in lesion volumes and T1/T2w values. ResultsSeventy-six patients (38 with at least one IRL and 38 age- and sex-matched patients without IRLs) were included. In the IRL-group, T1/T2w ratios of IRLs were significantly lower compared to non-IRLs (p < 0.05). When comparing the T1/T2w ratios in non-IRLs between the IRL-group and non-IRL group, there was no significant difference (p = 0.887). We observed a centrifugal decrease in microstructural damage from lesions to the perilesional white matter. In the IRL-group, T1/T2w ratios in the perilesional white matter 3–8 mm distant to the lesion were significantly lower in IRLs compared to non-IRLs. We found no significant differences in the amount of network disruption between both lesion types (p = 0.122). ConclusionT1/T2w represents an interesting candidate to capture a pronounced intra- and perilesional tissue damage of IRLs. However, our preliminary results suggest that a pronounced tissue damage might not result in a higher disruption to structural connectivity networks in IRLs.

What is the potential of paramagnetic rim lesions as diagnostic indicators in multiple sclerosis?

ABSTRACT Introduction In multiple sclerosis (MS), paramagnetic rim lesions (PRLs) on MRI identify a subset of chronic active lesions (CALs), which have been linked through clinical and pathological studies to more severe disease course and greater disability accumulation. Beside their prognostic relevance, increasing evidence supports the use of PRL as a diagnostic biomarker. Areas covered This review summarizes the most recent updates regarding the MRI pathophysiology of PRL, their prevalence in MS (by clinical phenotypes) vs mimicking conditions, and their potential role as diagnostic MS biomarkers. We searched PubMed with terms including ‘multiple sclerosis’ AND ‘paramagnetic rim lesions’ OR ‘iron rim lesions’ OR ‘rim lesions’ for manuscripts published between January 2008 and July 2022. Expert opinion Current research suggests that PRL can improve the diagnostic specificity and the overall accuracy of MS diagnosis when used together with the dissemination in space MRI criteria and the central vein sign. Nevertheless, future prospective multicenter studies should further define the real-world prevalence and specificity of PRL. International guidelines are needed to establish methodological criteria for PRL identification before its implementation into clinical practice.

Longitudinal clinical study of patients with iron rim lesions in multiple sclerosis

Background: Iron rims (IRs) surrounding white matter lesions (WMLs) are suggested to predict a more severe disease course. Only small longitudinal cohorts of patients with and without iron rim lesions (IRLs) have been reported so far. Objective: To assess whether the presence and number of IRLs in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) are associated with long-term disability or progressive disease. Methods: Ninety-one CIS/MS patients were recruited between 2008 and 2013 and scanned with 7 T magnetic resonance imaging (MRI). Expanded Disability Status Scale (EDSS) was used to calculate Age-related Multiple Sclerosis Severity Score (ARMSS) at the time of scan and at the latest clinical follow-up after 9 years. WMLs were assessed for the presence of IRL using Susceptibility weighted imaging (SWI)-filtered phase images. Results: In all, 132 IRLs were detected in 42 patients (46%); 9% of WMLs had IRs; 54% of the cohort had no rims, 30% had 1–3 rims and 16% had ⩾4. Patients with IRL had a higher EDSS and ARMSS. Presence of IRL was also a predictor of long-term disability, especially in patients with ⩾4 IRLs. IRLs have a greater impact on disability compared to the WML number and volume. Conclusion: The presence and number of perilesional IR on MRI hold prognostic value for long-term clinical disability in MS.

The heterogeneity of tissue destruction between iron rim lesions and non-iron rim lesions in multiple sclerosis: A diffusion MRI study

ObjectivesThis study aimed to explore the microstructural heterogeneity of different white matter (WM) tissues in relapsing-remitting multiple sclerosis (RRMS) patients by diffusion magnetic resonance imaging (dMRI) and its correlation with disability and cognitive status. Materials and MethodsA total of 337 iron rim lesions (IRLs), 337 perilesional white matters of IRLs (IRLs-PLWMs), 330 non-iron rim lesions (non-IRLs), 330 non-IRLs-PLWMs, 42 normal-appearing white matters (NAWMs) in 42 RRMS patients, and 30 white matters in healthy controls (WMs in HCs) were enrolled in the lesion-wise analysis. Diffusion kurtosis imaging (DKI) parameters including kurtosis fractional anisotropy (KFA) and mean kurtosis (MK), and diffusion tensor imaging (DTI) parameters including fractional anisotropy (FA) and mean diffusivity (MD) were measured in the six types of tissues. Subgroup analysis was performed between non-IRLs with QSM hyperintense (non-IRLs-H) and non-IRLs with QSM isointense or hypointense (non-IRLs-I), as well as between non-IRLs-H-PLWMs and non-IRLs-I-PLWMs. Thirty-four out of forty-two patients were enrolled in patient-wise analysis. The relationships between these diffusion metrics of patients and their Kurtzke Expanded Disability Status Scale (EDSS) score and Symbol Digit Modalities Test (SDMT) score were analyzed separately by partial correlation analysis with age and disease duration (DD) as covariates. ResultsThe KFA, FA, MK, and MD values were significantly different among the six types of tissues. The lowest KFA, FA, and MK values and the highest MD values were revealed in IRLs. There were significant differences in all the enrolled diffusion metrics between IRLs and non-IRLs, as well as between IRLs-PLWMs and non-IRLs-PLWMs (p < 0.05). There were no significant differences between NAWMs and WMs in HCs (p = 1.000 for all enrolled diffusion metrics). For all the enrolled diffusion metrics, no significant differences were found in the subgroup analysis. The FA, MK, and MD values of total lesions (including IRLs and non-IRLs) (r = -0.420, p = 0.017; r = -0.472, p = 0.006; r = -0.475, p = 0.006) and the MK values of IRLs (r = -0.438, p = 0.012) were correlated with the EDSS scores. There was no significant correlation between the diffusion parameter values and the SDMT scores. ConclusionOur findings demonstrate that IRLs are more destructive than non-IRLs. Similarly, IRLs-PLWMs are more destructive than non-IRLs-PLWMs. Additionally, diffusion parameter values of MS lesions can reflect the disability degree. These findings contribute to a better understanding of the different evolution of MS lesions and the relationship between the disability level of patients and focal lesion damage degree.

Impact of disease-modifying therapies on evolving tissue damage in iron rim multiple sclerosis lesions

We investigated the impact of disease-modifying therapies (DMTs) on the evolving tissue damage in iron rim multiple sclerosis lesions using a novel post-processing magnetic resonance imaging (MRI) approach, the T1/T2 ratio. In this study, on baseline and 1-year follow-up, T1/T2 ratios of iron rim lesions (IRLs) in patients starting DMT (dimethyl fumarate, fingolimod, ocrelizumab) did not statistically differ compared to patients without DMT. At the second follow-up, T1/T2 ratios were significantly lower in IRLs in patients without DMT (p = 0.002), suggesting that DMTs have a beneficial delayed effect on lesion evolution and tissue matrix damage in IRLs.

Peripheral Hemolysis in Relation to Iron Rim Presence and Brain Volume in Multiple Sclerosis.

Background:Iron rim lesions (IRLs) represent chronic lesion activity and are associated with a more severe disease course in multiple sclerosis (MS). How the iron rims around the lesions arise in patients with MS (pwMS), and whether peripheral hemolysis may be a source of iron in rim associated macrophages, is unclear.ObjectiveTo determine a potential correlation between peripheral hemolysis parameters and IRL presence in pwMS.MethodsThis retrospective study included pwMS, who underwent a 3T brain MRI between 2015 and 2020 and had a blood sample drawn at ± 2 weeks. Patients with vertigo served as a control group.ResultsWe analyzed 75 pwMS (mean age 37.0 years [SD 9.0], 53.3% female) and 43 controls (mean age 38.3 years [SD 9.8], 51.2% female). Median number of IRLs was 1 (IQR 4), 28 (37.3%) pwMS had no IRLs. IRL patients showed significantly higher Expanded Disability Status Scale (EDSS) compared to non-IRL patients (median EDSS 2.3 [IQR 2.9] vs. 1.3 [IQR 2.9], p = 0.017). Number of IRLs correlated significantly with disease duration (rs = 0.239, p = 0.039), EDSS (rs = 0.387, p < 0.001) and Multiple Sclerosis Severity Scale (MSSS) (rs = 0.289, p = 0.014). There was no significant difference in hemolysis parameters between non-IRL, IRL patients (regardless of gender and/or disease type) and controls, nor between hemolysis parameters and the number of IRLs. Total brain volume was associated with fibrinogen (β= −0.34, 95% CI −1.32 to −0.145, p = 0.016), and absolute cortical and total gray matter volumes were associated with hemoglobin (β = 0.34, 95% CI 3.39–24.68, p = 0.011; β = 0.33, 95% CI 3.29–28.95, p = 0.015; respectively).ConclusionOur data do not suggest an association between hemolysis parameters and IRL presence despite a significant association between these parameters and markers for neurodegeneration.

Spatial distribution of multiple sclerosis iron rim lesions and their impact on disability

BackgroundIn multiple sclerosis (MS), iron rim lesions (IRLs) on magnetic resonance imaging (MRI) have been suggested as an imaging marker of disease progression. However, the exact mechanisms how they contribute to disability are yet not completely known. Strategic lesion location may be an important factor concerning the impact of focal lesions on clinical disability. Therefore, the aim of this study was to investigate the spatial distribution of IRLs compared to non-IRLs and their impact on disability. MethodsWe retrospectively identified 67 patients with at least one IRL on MRI and 67 age- and sex-matched patients without IRLs. We compared the spatial distribution of lesions between both groups and between IRLs and non-IRLs in patients with IRLs. Furthermore, we assessed the relationship between lesion localisation and disability on a voxel-by-voxel basis and investigated the impact on structural network disruptions. ResultsPatients with IRLs had higher disability scores (median Expanded Disability Status Scale score (range): 3.0 (0 – 8.5) versus 1.5 (0 – 6.5); p = 0.001; median pyramidal functional system score (range): 1.0 (0 – 5) versus 0 (0 – 4); p = 0.003), significantly lower brain volumes (mean normal-appearing grey matter volume: 749.66 ± 60.58 versus 785.83 ± 53.71 mL; mean normal-appearing white matter volume: 723.58 ± 60.13 versus 753.25 ± 69.61 mL; mean deep grey matter volume: 33.21 ± 4.19 versus 35.85 ± 4.89 mL; p < 0.05 for all comparisons) and a significantly higher total T2 lesion volume (mean: 9.96 ± 11.6 versus 4.31 ± 8.9 mL; p < 0.001). We found no neuroanatomical regions that were more often affected by IRLs. Furthermore, comparing the overall network disruption in the IRL group, IRLs caused less network disruption/mL lesion size compared to non-IRLs (1.54% / mL versus 2.0% / mL; p < 0.05). ConclusionIRLs are associated with higher disability scores. However, our results suggest that a higher disability is not explained by the sheer topography of IRLs or their network disruption.

MRI predictors for the conversion from contrast-enhancing to iron rim multiple sclerosis lesions

BackgroundIn multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by progressive tissue matrix damage. Therefore, early identification could represent an interesting target for therapeutic intervention to minimize evolving tissue damage. The aim of this study was to identify magnetic resonance imaging (MRI) parameters predicting the conversion from contrast-enhancing to IRLs.MethodsWe retrospective identified MS patients scanned on the same 3 T MRI system presenting at least one supratentorial contrast-enhancing lesion (CEL) and a second MRI including susceptibility-weighted images after at least 3 months. On baseline MRI, pattern of contrast-enhancement was categorized as “nodular” or “ring-like”, apparent diffusion coefficient (ADC) maps were assessed for the presence of a peripheral hypointense rim. Lesion localization, quantitative volumes (ADC, lesion volume) and the presence of a central vein were assessed.ResultsEighty-nine acute contrast-enhancing lesions in 54 MS patients were included. On follow-up, 16/89 (18%) initially CELs converted into IRLs. CELs that converted into IRLs were larger and demonstrated significantly more often a ring-like contrast-enhancement pattern and a peripheral hypointense rim on ADC maps. Logistic regression model including the covariables pattern of contrast-enhancement and presence of a hypointense rim on ADC maps showed the best predictive performance (area under the curve = 0.932).DiscussionThe combination of a ring-like contrast-enhancement pattern and a peripheral hypointense rim on ADC maps has the ability to predict the evolution from acute to IRLs. This could be of prognostic value and become a target for early therapeutic intervention to minimize the associated tissue damage.

Quantitative susceptibility mapping versus phase imaging to identify multiple sclerosis iron rim lesions with demyelination.

To compare quantitative susceptibility mapping (QSM) and high-pass-filtered (HPF) phase imaging for (1) identifying chronic active rim lesions with more myelin damage and (2) distinguishing patients with increased clinical disability in multiple sclerosis. Eighty patients were scanned with QSM for paramagnetic rim detection and Fast Acquisition with Spiral Trajectory and T2prep for myelin water fraction (MWF). Chronic lesions were classified based on the presence/absence of rim on HPF and QSM images. A lesion-level linear mixed-effects model with MWF as the outcome was used to compare myelin damage among the lesion groups. A multiple patient-level linear regression model was fit to establish the association between Expanded Disease Status Scale (EDSS) and the log of the number of rim lesions. Of 2062 lesions, 188 (9.1%) were HPF rim+/QSM rim+, 203 (9.8%) were HPF rim+/QSM rim-, and the remainder had no rim. In the linear mixed-effects model, HPF rim+/QSM rim+ lesions had significantly lower MWF than both HPF rim+/QSM rim- (p<.001) and HPF rim-/QSM rim- (p<.001) lesions, while the MWF difference between HPF rim+/QSM rim- and HPF rim-/QSM rim- lesions was not statistically significant (p=.130). Holding all other factors constant, the log number of QSM rim+ lesion was associated with EDSS increase (p=.044). The association between the log number of HPF rim+ lesions and EDSS was not statistically significant (p=.206). QSM identifies paramagnetic rim lesions that on average have more myelin damage and stronger association with clinical disability than those detected by phase imaging.

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study.

Introduction: Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, characterized by inflammatory-driven demyelination. Symptoms in MS manifest as both physical and neuropsychological deficits. With time, inflammation is accompanied by neurodegeneration, indicated by brain volume loss on an MRI. Here, we combined clinical, imaging, and serum biomarkers in patients with iron rim lesions (IRLs), which lead to severe tissue destruction and thus contribute to the accumulation of clinical disability.Objectives: Subcortical atrophy and ventricular enlargement using an automatic segmentation pipeline for 7 Tesla (T) MRI, serum neurofilament light chain (sNfL) levels, and neuropsychological performance in patients with MS with IRLs and non-IRLs were assessed.Methods: In total 29 patients with MS [15 women, 24 relapsing-remitting multiple sclerosis (RRMS), and five secondary-progressive multiple sclerosis (SPMS)] aged 38 (22–69) years with an Expanded Disability Status Score of 2 (0–8) and a disease duration of 11 (5–40) years underwent neurological and neuropsychological examinations. Volumes of lesions, subcortical structures, and lateral ventricles on 7-T MRI (SWI, FLAIR, and MP2RAGE, 3D Segmentation Software) and sNfL concentrations using the Simoa SR-X Analyzer in IRL and non-IRL patients were assessed.Results: (1) Iron rim lesions patients had a higher FLAIR lesion count (p = 0.047). Patients with higher MP2Rage lesion volume exhibited more IRLs (p <0.014) and showed poorer performance in the information processing speed tested within 1 year using the Symbol Digit Modalities Test (SDMT) (p <0.047). (2) Within 3 years, patients showed atrophy of the thalamus (p = 0.021) and putamen (p = 0.043) and enlargement of the lateral ventricles (p = 0.012). At baseline and after 3 years, thalamic volumes were lower in IRLs than in non-IRL patients (p = 0.045). (3) At baseline, IRL patients had higher sNfL concentrations (p = 0.028). Higher sNfL concentrations were associated with poorer SDMT (p = 0.004), regardless of IRL presence. (4) IRL and non-IRL patients showed no significant difference in the neuropsychological performance within 1 year.Conclusions: Compared with non-IRL patients, IRL patients had higher FLAIR lesion counts, smaller thalamic volumes, and higher sNfL concentrations. Our pilot study combines IRL and sNfL, two biomarkers considered indicative for neurodegenerative processes. Our preliminary data underscore the reported destructive nature of IRLs.

Long-term dynamics of multiple sclerosis iron rim lesions

BackgroundSeveral studies have pointed out that seemingly chronic multiple sclerosis (MS) lesions may also be in inflammatory states. In pathological studies, up to 40% of chronic MS lesions are characterized as “chronic active” or “smoldering” lesions that are characterized by a rim of iron-laden proinflammatory macrophages/microglial cells at the lesion edge with low-grade continuous myelin breakdown. In vivo, these lesions can be visualized as “iron rim lesions” (IRLs) on susceptibility-weighted imaging (SWI). The aim of this study was to investigate the long-term dynamics of IRLs in vivo for a more detailed evolution of dynamic lesion volume changes occurring over time. MethodsWe retrospectively identified patients with MS who were followed for at least 36 months (up to 72 months) and underwent at least an annual MRI on the same 3 Tsystem. Using Voxel-Guided Morphometry (VGM) we investigated regional volume changes within lesions and correlated these findings with SWI for the presence of a characteristic hypointense lesion rim. To estimate tissue damage, apparent diffusion coefficient (ADC) values for every lesion at baseline and follow-up MRIs were determined. ResultsForty-three patients were included in the study. Overall, we identified 302 supratentorial non-confluent MS lesions (52 persistent IRLs, nine transient IRLs, 228 non-IRLs and 13 acute contrast-enhancing lesions). During follow-up, persistent IRLs significantly enlarged, whereas non-IRLs showed a tendency to shrink. At baseline MRI, ADC values were significantly higher in persistent IRLs (1.23 × 10−3 mm/s2) compared to non-IRLs (1.01 × 10−3 mm/s2; p < 0.001), but not compared to transient IRLs (1.06 × 10−3 mm/s2; p = 0.15) and contrast-enhancing lesions (1.15 × 10−3 mm/s2; p = 1.0). During follow-up, ADC values significantly increased more often in persistent IRLs compared to all other lesion types (p < 0.0001). ConclusionsOur long-term data demonstrate that persistent IRLs enlarge during disease duration, whereas non-IRLs show a tendency to shrink. Furthermore, IRLs are associated with sustained tissue damage, supporting the notion that IRLs could represent a new imaging biomarker in MS.

A gene-set analysis suggests the possible involvement of iron homeostasis in neurodegeneration in progressive multiple sclerosis

Advanced neuroimaging has revealed that slowly expanding lesions with a paramagnetic iron rim are the most common lesion type in progressive multiple sclerosis (pMS) and correlate with disability. Iron accumulation in the activated microglia and macrophages at the edge of these lesions is governed by inflammatory pathways and may contribute to the pathogenesis of pMS. We investigated whether genetic variants in genes involved in iron metabolism may have an impact on pMS.