Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.

Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study.

OBJECTIVES: To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients. METHODS: Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8-5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years. RESULTS: At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing-remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (ß)=0.97), higher EDSS (ß=0.41), higher cord lesion number (ß=0.41), lower normalised cortical volume (ß=-0.15) and lower cord area (ß=-0.28) (C-index=0.81). Older age (ß=0.86), higher EDSS (ß=1.40) and cord lesion number (ß=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (ß=1.49), cord lesion number (ß=1.02) and lower normalised cortical volume (ß=-0.56) (C-index=0.88). Baseline age (ß=0.30), higher EDSS (ß=2.03), higher cord lesion number (ß=0.66) and lower cord area (ß=-0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (ß=1.87) and cord lesion number (ß=0.54) predicted EDSS=6.0 (C-index=0.91). CONCLUSIONS: Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.

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.

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.

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

BACKGROUND: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. OBJECTIVE: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. METHODS: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). RESULTS: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability (r = -0.40/-0.62, p < 0.05, corrected). CONCLUSIONS: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

Association of iron rim lesions with brain and cervical cord volume in relapsing multiple sclerosis.

OBJECTIVES: In multiple sclerosis (MS), iron rim lesions (IRLs) are indicators of chronic low-grade inflammation and ongoing tissue destruction. The aim of this study was to assess the relationship of IRLs with clinical measures and magnetic resonance imaging (MRI) markers, in particular brain and cervical cord volume. METHODS: Clinical and MRI parameters from 102 relapsing MS patients (no relapses for at least 6 months, no contrast-enhancing lesions) were included; follow-up data obtained after 12 months was available in 49 patients. IRLs were identified on susceptibility-weighted images (SWIs). In addition to standard brain and spinal cord MRI parameters, normalised cross-sectional area (nCSA) of the upper cervical cord was calculated. RESULTS: Thirty-eight patients had at least one IRL on SWI MRI. At baseline, patients with IRLs had higher EDSS scores, higher lesion loads (brain and spinal cord), and lower cortical grey matter volumes and a lower nCSA. At follow-up, brain atrophy rates were higher in patients with IRLs. IRLs correlated spatially with T1-hypointense lesions. CONCLUSIONS: Relapsing MS patients with IRLs showed more aggressive MRI disease characteristics in both the cross-sectional and longitudinal analyses. KEY POINTS: • Multiple sclerosis patients with iron rim lesions had higher EDSS scores, higher brain and spinal cord lesion loads, lower cortical grey matter volumes, and a lower normalised cross-sectional area of the upper cervical spinal cord. • Iron rim lesions are a new lesion descriptor obtained from susceptibility-weighted MRI. Our data suggests that further exploration of this lesion characteristic in regard to a poorer prognosis in multiple sclerosis patients is warranted.

Characterization of chronic active multiple sclerosis lesions with sodium (23 Na) magnetic resonance imaging-preliminary observations.

BACKGROUND AND PURPOSE: There has been an increasing interest in chronic active multiple sclerosis (MS) lesions as a new magnetic resonance imaging (MRI) marker of disease progression. Chronic active lesions are characterized by progressive tissue matrix damage, axonal loss and chronic inflammation. Sodium (23 Na) MRI provides a biochemical marker of cell integrity and tissue viability in a quantitative manner. The aim of this study was to investigate with 23 Na MRI tissue abnormalities in chronic active lesions as indicators of tissue destruction. METHODS: To identify chronic active lesions, two 3D magnetization-prepared rapid acquisition gradient-echo datasets obtained 12 months apart were processed using the voxel-guided morphometry algorithm. Cross-sectional 23 Na MRI was performed during the 12-month follow-up period. Total sodium concentration was calculated in chronic active lesions compared to shrinking, chronic stable and acute contrast-enhancing lesions. RESULTS: Overall, 70 MS lesions (21 chronic active, 10 shrinking, 29 chronic stable lesions, 10 acute contrast-enhancing lesions) in 12 patients were included. Total sodium concentration in chronic active lesions (49.57 ± 8.47 mM) was significantly higher than in shrinking (42.16 ± 3.9 mM; p = 0.03) and chronic stable lesions (39.92 ± 4.82 mM; p < 0.001). Chronic active lesions showed similar sodium values compared to acute contrast-enhancing lesions (48.06 ± 6.65 mM; p = 0.97). No differences between shrinking and chronic stable lesions were observed (p = 0.89). CONCLUSION: High sodium values in chronic active MS lesions may be an indicator of ongoing inflammation and tissue damage.

Acute Corticonuclear Tract Ischemic Stroke with Isolated Central Facial Palsy.

OBJECTIVE: The clinical distinction between habitual facial asymmetry, early stage peripheral facial palsy, and isolated central facial palsy is sometimes difficult. The diagnosis of acute central facial palsy is of importance to identify patients for stroke work-up and appropriate treatment. We aimed to evaluate the prevalence and localization of acute ischemic lesions associated with isolated central facial palsy. METHODS: We screened our stroke database for patients presenting with isolated central facial palsy related to ischemic stroke between 2012 and 2017. All identified patients were comprehensively characterized including magnetic resonance (MR) diffusion-weighted imaging (DWI). RESULTS: We identified four out of 5169 patients (one male; 62-83 years) with isolated facial palsy as a result of acute ischemic stroke (NIHSS 1-2). All four had circumscribed DWI lesions in different regions of the corticonuclear tract in different areas with different etiologies. CONCLUSION: Isolated central facial palsy is a rare manifestation of acute ischemic stroke and may be missed if clinical suspicion is not raised. MR-DWI identifies small ischemic lesions in the corticonuclear tract, which results in appropriate diagnostic work-up and secondary prophylaxis.

[Treatment-associated neurological symptoms of cancer patients and their treatment]. / Therapieassoziierte neurologische Symptome onkologischer Patienten und deren Behandlung.

With the increasing understanding of the specific molecular and cellular pathogenesis of cancer, systemic cancer treatment has become much more targeted and in part substantially more effective. The increased number of long-term survivors and the number of highly specific targeted therapies have resulted in a wide range of neurological complications. Neurologists are increasingly confronted with previously unknown neurological complications of cancer treatment. A profound understanding of the molecular and cellular mechanisms of action of anticancer drugs is the key for a prompt diagnosis and appropriate treatment of these treatment-associated neurological complications.

Arterial Spin Labeling Cerebral Perfusion Magnetic Resonance Imaging in Migraine Aura: An Observational Study.

BACKGROUND: Changes in cerebral perfusion during migraine with aura (MA) have been assessed mainly using dynamic susceptibility contrast (DSC) magnetic resonance perfusion imaging. A contrast agent-free method to assess these changes would be desirable. We assessed changes in cerebral perfusion during MA using arterial spin labeling (ASL) perfusion magnetic resonance imaging. METHODS: We investigated 4 patients with a standardized protocol including ASL perfusion imaging during MA (n = 2) or early headache phase (n = 2) and asymptomatic follow-up. Semiquantitative evaluation was done using a region of interest (ROI) within hypoperfused or hyperperfused areas and corresponding ROIs in the contralateral hemisphere. Relative ratios of mean perfusion in the corresponding ROIs were calculated. DSC imaging was done at initial time points and compared visually with ASL findings. RESULTS: In all patients, regional perfusion changes were detected in the acute phase. These abnormalities did not respect the boundaries of major cerebral vascular territories but overlapped onto adjoining regions. During MA, adjacent hypoperfused and hyperperfused areas were found, whereas during headache, regional hyperperfusion only was observed. Perfusion abnormalities normalized on follow-up. CONCLUSIONS: ASL perfusion imaging is a contrast agent-free method suitable for assessment of reversible perfusion changes during or immediately after MA.

Heterogeneity of acute multiple sclerosis lesions on sodium (23Na) MRI.

BACKGROUND: Advanced magnetic resonance imaging (MRI) techniques provide a window into pathological processes in multiple sclerosis (MS). Nevertheless, to date only few studies have performed sodium MRI in MS. OBJECTIVES: We analysed total sodium concentration (TSC) in hyperacute, acute and chronic lesions in MS with (23)Na MRI. METHODS: (23)Na MRI and (1)H MRI were performed in 65 MS patients and 10 healthy controls (HC). Mean TSC was quantified in all MS lesions with a diameter of >5 mm and in the normal appearing white and grey matter (NAWM, NAGM). RESULTS: TSC in the NAWM and the NAGM of MS patients was significantly higher compared to HC (WM: 37.51 ± 2.65 mM versus 35.17 ± 3.40 mM; GM: 43.64 ± 2.75 mM versus 40.09 ± 4.64 mM). Acute and chronic MS lesions showed elevated TSC levels of different extent (contrast-enhancing lesions (49.07 ± 6.99 mM), T1 hypointense lesions (45.06 ± 6.26 mM) and remaining T1 isointense lesions (39.88 ± 5.54 mM)). However, non-enhancing hyperacute lesions with a reduced apparent diffusion coefficient showed a TSC comparable to the NAWM (37.22 ± 4.62 mM). CONCLUSIONS: TSC is not only a sensitive marker of the severity of chronic tissue abnormalities in MS but is also highly sensitive to opening of the blood-brain barrier and vasogenic tissue oedema in contrast-enhancing lesions.

Individual Assessment of Brain Tissue Changes in MS and the Effect of Focal Lesions on Short-Term Focal Atrophy Development in MS: A Voxel-Guided Morphometry Study.

We performed voxel-guided morphometry (VGM) investigating the mechanisms of brain atrophy in multiple sclerosis (MS) related to focal lesions. VGM maps detect regional brain changes when comparing 2 time points on high resolution T1-weighted (T1w) magnetic resonace imaging (MRI). Two T1w MR datasets from 92 relapsing-remitting MS patients obtained 12 months apart were analysed with VGM. New lesions and volume changes of focal MS lesions as well as in the surrounding tissue were identified by visual inspection on colour coded VGM maps. Lesions were dichotomized in active and inactive lesions. Active lesions, defined by either new lesions (NL) (volume increase > 5% in VGM), chronic enlarging lesions (CEL) (pre-existent T1w lesions with volume increase > 5%), or chronic shrinking lesions (CSL) (pre-existent T1w lesions with volume reduction > 5%) in VGM, were accompanied by tissue shrinkage in surrounding and/or functionally related regions. Volume loss within the corpus callosum was highly correlated with the number of lesions in its close proximity. Volume loss in the lateral geniculate nucleus was correlated with lesions along the optic radiation. VGM analysis provides strong evidence that all active lesion types (NL, CEL, and CSL) contribute to brain volume reduction in the vicinity of lesions and/or in anatomically and functionally related areas of the brain.

Cerebrospinal fluid pleocytosis in multiple sclerosis patients with lesions showing reduced diffusion.

In multiple sclerosis (MS) occasionally acute lesions show a reduced apparent diffusion coefficient (ADC) on magnetic resonance imaging (MRI); however, the underlying mechanism of this phenomenon is not known. We compared cerebrospinal fluid (CSF) findings with diffusion MRI signal characteristics of acute lesions in 25 patients with MS or a clinically isolated syndrome (CIS) later confirmed as MS. In nine of 25 patients investigated between days 1 and 4 after symptom onset, a reduced intralesional ADC value (-15% to -51%) was accompanied by a marked CSF pleocytosis (11-46 leukocytes/µl). Our results suggest that ADC reduction in acute MS lesions is a phenomenon that is possibly related to an aggressive inflammatory milieu as indirectly indicated by CSF pleocytosis. Furthermore, the ADC reduction and CSF pleocytosis were observed only early after symptom onset, which suggests that both are typically early and transient phenomena.

A generalizable deep voxel-guided morphometry algorithm for the detection of subtle lesion dynamics in multiple sclerosis.

Introduction: Multiple sclerosis (MS) is a chronic neurological disorder characterized by the progressive loss of myelin and axonal structures in the central nervous system. Accurate detection and monitoring of MS-related changes in brain structures are crucial for disease management and treatment evaluation. We propose a deep learning algorithm for creating Voxel-Guided Morphometry (VGM) maps from longitudinal MRI brain volumes for analyzing MS disease activity. Our approach focuses on developing a generalizable model that can effectively be applied to unseen datasets. Methods: Longitudinal MS patient high-resolution 3D T1-weighted follow-up imaging from three different MRI systems were analyzed. We employed a 3D residual U-Net architecture with attention mechanisms. The U-Net serves as the backbone, enabling spatial feature extraction from MRI volumes. Attention mechanisms are integrated to enhance the model's ability to capture relevant information and highlight salient regions. Furthermore, we incorporate image normalization by histogram matching and resampling techniques to improve the networks' ability to generalize to unseen datasets from different MRI systems across imaging centers. This ensures robust performance across diverse data sources. Results: Numerous experiments were conducted using a dataset of 71 longitudinal MRI brain volumes of MS patients. Our approach demonstrated a significant improvement of 4.3% in mean absolute error (MAE) against the state-of-the-art (SOTA) method. Furthermore, the algorithm's generalizability was evaluated on two unseen datasets (n = 116) with an average improvement of 4.2% in MAE over the SOTA approach. Discussion: Results confirm that the proposed approach is fast and robust and has the potential for broader clinical applicability.

H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient.

H3K27M, a driver mutation with T and B cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient treated with an H3K27M peptide vaccine who subsequently entered complete remission. The vaccine robustly expanded class II human leukocyte antigen (HLA)-restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their complementarity-determining region 3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ and HLA-DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II-restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.

[Acute ischemic stroke and troponin elevation: update of the Mannheim clinical algorithm]. / Akuter ischämischer Schlaganfall und erhöhter Troponinwert ­ Update des Mannheimer Algorithmus.

Elevated high-sensitivity cardiac troponin (hs-cTn) levels should be expected in about half of all patients with acute ischemic stroke (AIS). Since those patients are at risk of increased morbidity and mortality, often attributable to cardiac causes, an adequate work-up of the underlying etiology is required. This can only be achieved by a team of cardiologists and neurologists. Since underlying causes of hs-cTn elevation in AIS patients are diverse, often atypical or silent in their clinical presentation and some, such as an accompanying myocardial infarction, can be acutely life-threatening, the work-up should follow a standardized clinical algorithm. The vast majority of hs-cTn elevations are caused by non-ischemic myocardial injury associated with AIS. This work presents a practice-oriented approach to differential diagnosis with the update of the Mannheim clinical algorithm for acute ischemic stroke and troponin elevation.

Brain atrophy and lesion load predict long term disability in multiple sclerosis.

OBJECTIVE: To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). DESIGN: From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1-2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing-remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0-3.5, n=111) or moderately impaired (EDSS=4-6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. RESULTS: In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R(2)=0.74 in the whole group and R(2)=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R(2)=0.68), lesion volumes in moderately impaired relapse onset patients (R(2)=0.21) and whole brain atrophy in primary progressive MS (R(2)=0.34). CONCLUSIONS: This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.

Short-term brain atrophy evolution after initiation of immunotherapy in a real-world multiple sclerosis cohort.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), brain atrophy measurements have emerged as an important biomarker reflecting neurodegeneration and disability progression. However, due to several potential confounders, investigation of brain atrophy in clinical routine and even in controlled clinical studies can be challenging. The aim of this study was to investigate the short-term dynamics of brain atrophy development after initiation of disease-modifying therapy (DMT) in a "real-world setting." METHODS: In this retrospective study, we included MS patients starting DMT (natalizumab, fingolimod, dimethyl fumarate, or interferon-ß1a) or without DMT, availability of a baseline MRI, and two annual follow-up scans on the same MRI system. Two-timepoint percentage brain volume changes (PBVCs) were calculated. RESULTS: Fifty-five MS patients (12 patients starting DMT with natalizumab, 7 fingolimod, 14 dimethyl fumarate, 11 interferon-ß1a, and 11 patients without DMT) were included. We found the highest PBVCs in the first 12 months after initiation of natalizumab treatment. Furthermore, the PBVCs in our study were very much comparable to the results observed by other groups, as well as for fingolimod, dimethyl fumarate, and interferon-ß1a. CONCLUSION: We found PBVCs that are comparable to the results of previous studies, suggesting that brain atrophy, assessed on 3D MRI data sets acquired on the same 3T MRI, provides a robust MS biomarker.

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

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.