Paramagnetic rim lesions and the central vein sign: Characterizing multiple sclerosis imaging markers.

BACKGROUND AND PURPOSE: Paramagnetic rims and the central vein sign (CVS) are proposed imaging markers of multiple sclerosis (MS) lesions. Using 7 tesla magnetic resonance imaging, we aimed to: (1) characterize the appearance of paramagnetic rim lesions (PRLs); (2) assess whether PRLs and the CVS are associated with higher levels of MS pathology; and (3) compare the characteristics between subjects with and without PRLs in early MS. METHODS: Prospective study of 32 treatment-naïve subjects around the time of diagnosis who were assessed for the presence of PRLs and the CVS. Comparisons of lesion volume and macromolecular pool size ratio (PSR) index, a proxy of myelin integrity, between PRLs and non-PRLs, and CVS-positive and CVS-negative lesions were carried out. Differences in clinical/demographic characteristics between patients with PRLs and those without were tested. RESULTS: Fifteen subjects had ≥1 PRL for a total of 36 PRLs, of which two-thirds had a full rim. PRLs predicted a larger lesion size and decreased PSR signal. Lesion volume and presence of cervical spine lesions were significantly different between subjects with PRLs and those without, although neither remained significant after adjusting for multiple comparisons. One hundred and eighty-one lesions with CVS were identified with no differences between CVS-positive and CVS-negative lesions in volume (p = .27) and PSR values (p = .62). CONCLUSIONS: PRLs, but not CVS-positive lesions, are larger and have lower myelin integrity. Our findings indicate that PRLs are associated with higher levels of lesion-specific pathology prior to the start of disease-modifying therapy.

Cervical spinal cord susceptibility-weighted MRI at 7T: Application to multiple sclerosis.

BACKGROUND: Susceptibility-weighted imaging (SWI) has been extensively studied in the brain and in diseases of the central nervous system such as multiple sclerosis (MS) providing unique opportunities to visualize cerebral vasculature and disease-related pathology, including the central vein sign (CVS) and paramagnetic rim lesions (PRLs). However, similar studies evaluating SWI in the spinal cord of patients with MS remain severely limited. PURPOSE: Based on our previous findings of enlarged spinal vessels in MS compared to healthy controls (HCs), we developed high-field SWI acquisition and processing methods for the cervical spinal cord with application in people with MS (pwMS) and HCs. Here, we demonstrate the vascular variability between the two cohorts and unique MS lesion features in the cervical cord. METHODS: In this retrospective, exploratory pilot study conducted between March 2021 and March 2022, we scanned 12 HCs and 9 pwMS using an optimized non-contrast 2D T2*-weighted gradient echo sequence at 7 tesla. The overall appearance of the white and gray matter as well as tissue vasculature were compared between the two cohorts and areas of MS pathology in the patient group were assessed using both the magnitude and processed SWI images. RESULTS: We show improved visibility of vessels and more pronounced gray and white matter contrast in the MS group compared to HCs, hypointensities surrounding the cord in the MS cohort, and identify signal changes indicative of the CVS and paramagnetic rims in 66 % of pwMS with cervical spinal lesions. CONCLUSION: In this first study of SWI at 7T in the human spinal cord, SWI holds promise in advancing our understanding of disease processes in the cervical cord in MS.

Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis.

BACKGROUND: Magnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). OBJECTIVES: To identify the relationship between SELs and PRLs in MS, and their association with disability. METHODS: 61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs. RESULTS: The median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients. CONCLUSION: SELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression.

Advanced spinal cord MRI in multiple sclerosis: Current techniques and future directions.

Spinal cord magnetic resonance imaging (MRI) has a central role in multiple sclerosis (MS) clinical practice for diagnosis and disease monitoring. Advanced MRI sequences capable of visualizing and quantifying tissue macro- and microstructure and reflecting different pathological disease processes have been used in MS research; however, the spinal cord remains under-explored, partly due to technical obstacles inherent to imaging this structure. We propose that the study of the spinal cord merits equal ambition in overcoming technical challenges, and that there is much information to be exploited to make valuable contributions to our understanding of MS. We present a narrative review on the latest progress in advanced spinal cord MRI in MS, covering in the first part structural, functional, metabolic and vascular imaging methods. We focus on recent studies of MS and those making significant technical steps, noting the challenges that remain to be addressed and what stands to be gained from such advances. Throughout we also refer to other works that presend more in-depth review on specific themes. In the second part, we present several topics that, in our view, hold particular potential. The need for better imaging of gray matter is discussed. We stress the importance of developing imaging beyond the cervical spinal cord, and explore the use of ultra-high field MRI. Finally, some recommendations are given for future research, from study design to newer developments in analysis, and the need for harmonization of sequences and methods within the field. This review is aimed at researchers and clinicians with an interest in gaining an overview of the current state of advanced MRI research in this field and what is primed to be the future of spinal cord imaging in MS research.

Paramagnetic rims are a promising diagnostic imaging biomarker in multiple sclerosis.

BACKGROUND: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). OBJECTIVE: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. METHOD: This retrospective international study reviewed MRI scans of patients with MS (n = 254), MS mimics (n = 91) and older healthy controls (n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. RESULTS: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%-99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%-36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion (n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%-100.0%) but equally low sensitivity (21.3%, CI = 16.4%-26.81%). CONCLUSION: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS.

Transcallosal and Corticospinal White Matter Disease and Its Association With Motor Impairment in Multiple Sclerosis.

Purpose: In this cross-sectional, proof-of-concept study, we propose that using the more pathologically-specific neurite orientation dispersion and density imaging (NODDI) method, in conjunction with high-resolution probabilistic tractography, white matter tract templates can improve the assessment of regional axonal injury and its association with disability of people with multiple sclerosis (pwMS). Methods: Parametric maps of the neurite density index, orientation dispersion index, and the apparent isotropic volume fraction (IVF) were estimated in 18 pwMS and nine matched healthy controls (HCs). Tract-specific values were measured in transcallosal (TC) fibers from the paracentral lobules and TC and corticospinal fibers from the ventral and dorsal premotor areas, presupplementary and supplementary motor areas, and primary motor cortex. The nonparametric Mann-Whitney U test assessed group differences in the NODDI-derived metrics; the Spearman's rank correlation analyses measured associations between the NODDI metrics and other clinical or radiological variables. Results: IVF values of the TC fiber bundles from the paracentral, presupplementary, and supplementary motor areas were both higher in pwMS than in HCs (p ≤ 0.045) and in pwMS with motor disability compared to those without motor disability (p ≤ 0.049). IVF in several TC tracts was associated with the Expanded Disability Status Scale score (p ≤ 0.047), while regional and overall lesion burden correlated with the Timed 25-Foot Walking Test (p ≤ 0.049). Conclusion: IVF alterations are present in pwMS even when the other NODDI metrics are still mostly preserved. Changes in IVF are biologically non-specific and may not necessarily drive irreversible functional loss. However, by possibly preceding downstream pathologies that are strongly associated with disability accretion, IVF changes are indicators of, otherwise, occult prelesional tissue injury.

Assessment of 2D conventional and synthetic MRI in multiple sclerosis.

PURPOSE: To qualitatively and quantitatively compare synthetic and conventional MRI sequences acquired on a 1.5-T system for patients with multiple sclerosis (MS). METHODS: Prospective study that involved twenty-seven consecutive relapsing-remitting MS patients scanned on a 1.5-T MRI scanner. The MRI protocol included 2D transverse conventional spin-echo sequences: proton density-weighted (PD), T2-weighted, T2-FLAIR, and T1-weighted. Synthetic images were generated using 2D transverse QRAPMASTER and SyMRI software with the same voxel size, repetition, echo, and inversion times as the conventional sequences. Four raters performed a crosstab qualitative analysis that involved evaluating global image quality, contrast, flow artefacts, and confidence in lesion assessment introducing the concepts of predominance, agreement, and disagreement. A quantitative analysis was also performed and included evaluating the number of lesions (periventricular, juxtacortical, brainstem, and cerebellum) and the contrast-to-noise ratio between regions (CSF, white matter, grey matter, lesions). RESULTS: The global image quality assessment showed predominance for better scores for conventional sequences over synthetic sequences, whereas contrast, confidence in lesion assessment, and flow artefacts showed predominance for agreement between sequences. There was predominance for disagreement between all pairs of raters in most of the evaluated qualitative parameters. Synthetic PD and T2-FLAIR images showed higher contrast-to-noise ratios than the corresponding conventional images for most comparison between regions. There were no significant differences in the number of lesions detected for most of the study regions between conventional and synthetic images. CONCLUSION: Synthetic MRI can be potentially used as an alternative to conventional brain MRI sequences in the assessment of MS.

CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event.

BACKGROUND: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis. OBJECTIVE: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event. METHODS: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (ß = 1.41; 95% confidence interval (CI) = 1.10-1.79; p < 0.01) and serum NfL levels (ß = 2.30; 95% CI = 1.47-3.60; p < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (ß = 1.45; 95% CI = 1.11-1.90; p < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses. CONCLUSION: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.

Perilesional neurodegenerative injury in multiple sclerosis: Relation to focal lesions and impact on disability.

BACKGROUND: Axonal injury is the primary source of irreversible neurological decline in persons with multiple sclerosis (pwMS). Identifying and quantifying myelin and axonal loss in lesional and perilesional tissue in vivo is fundamental for a better understanding of multiple sclerosis (MS) outcomes and patient impairment. Using advanced magnetic resonance imaging (MRI) methods, consisting of selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment diffusion MRI with the spherical mean technique (SMT), we conducted a cross-sectional pilot study to assess myelin and axonal damage in the normal appearing white matter (NAWM) surrounding chronic black holes (cBHs) and how this pathology correlates with disability in vivo. We hypothesized that lesional axonal transection propagates tissue injury in the surrounding NAWM and that the degree of this injury is related to patient disability. METHODS: Eighteen pwMS underwent a 3.0 Tesla conventional clinical MRI, inclusive of T1 and T2 weighted protocols, as well as SIR-qMT and SMT. Regions of interests (ROIs) were manually delineated in cBHs, NAWM neighboring cBHs (perilesional NAWM), distant ipsilateral NAWM and contra-lateral distant NAWM. SIR-qMT-derived macromolecular-to-free pool size ratio (PSR) and SMT-derived apparent axonal volume fraction (Vax) were extracted to infer on myelin and axonal content, respectively. Group differences were assessed using mixed-effects regression models and correlation analyses were obtained by bootstrapping 95% confidence interval. RESULTS: In comparison to perilesional NAWM, both PSR and Vax values were reduced in cBHs (p < 0.0001) and increased in distant contra-lateral NAWM ROIs (p < 0.001 for PSR and p < 0.0001 for Vax) but not ipsilateral NAWM (p = 0.176 for PSR and p = 0.549 for Vax). Vax values measured in cBHs correlated with those in perilesional NAWM (Pearson rho = 0.63, p < 0.001). No statistically relevant associations were seen between PSR/Vax values and clinical and/or MRI metrics of the disease with the exception of cBH PSR values, which correlated with the Expanded Disability Status Scale (Pearson rho = -0.63, p = 0.03). CONCLUSIONS: Our results show that myelin and axonal content, detected by PSR and Vax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This finding is indicative of an ongoing anterograde/retrograde degeneration and suggests that treatment prevention of cBH development is a key factor for preserving NAWM integrity in surrounding tissue. It also suggests that measuring changes in perilesional areas over time may be a useful measure of outcome for proof-of-concept clinical trials on neuroprotection and repair. PSR and Vax largely failed to capture associations with clinical and MRI characteristics, likely as a result of the small sample size and cross-sectional design, however, longitudinal assessment of a larger cohort may unravel the impact of this pathology on disease progression.

Single Test to ARrive at Multiple Sclerosis (STAR-MS) diagnosis: A prospective pilot study assessing the accuracy of the central vein sign in predicting multiple sclerosis in cases of diagnostic uncertainty.

BACKGROUND: Misdiagnosis is common in multiple sclerosis (MS) as a proportion of patients present with atypical clinical/magnetic resonance imaging (MRI) findings. The central vein sign has the potential to be a non-invasive, MS-specific biomarker. OBJECTIVE: To test the accuracy of the central vein sign in predicting a diagnosis of MS in patients with diagnostic uncertainty at disease presentation using T2*-weighted, 3 T MRI. METHODS: In this prospective pilot study, we recruited individuals with symptoms unusual for MS but with brain MRI consistent with the disease, and those with a typical clinical presentation of MS whose MRI did not suggest MS. We calculated the proportion of lesions with central veins for each patient and compared the results to the eventual clinical diagnoses. The optimal central vein threshold for diagnosis was established. RESULTS: Thirty-eight patients were scanned, 35 of whom have received a clinical diagnosis. Median percentage of lesions with central veins was 51% in MS and 28% in non-MS. A threshold of 40.7% lesions with central veins resulted in 100% sensitivity and 73.9% specificity. CONCLUSION: The central vein sign assessed with a clinically available T2* scan can successfully diagnose MS in cases of diagnostic uncertainty. The central vein sign should be considered as a diagnostic biomarker in MS.

Evaluation of the Central Vein Sign as a Diagnostic Imaging Biomarker in Multiple Sclerosis.

Importance: The central vein sign has been proposed as a specific imaging biomarker for distinguishing between multiple sclerosis (MS) and not MS, mainly based on findings from ultrahigh-field magnetic resonance imaging (MRI) studies. The diagnostic value of the central vein sign in a multicenter setting with a variety of clinical 3 tesla (T) MRI protocols, however, remains unknown. Objective: To evaluate the sensitivity and specificity of various central vein sign lesion criteria for differentiating MS from non-MS conditions using 3T brain MRI with various commonly used pulse sequences. Design, Setting, and Participants: This large multicenter, cross-sectional study enrolled participants (n = 648) of ongoing observational studies and patients included in neuroimaging research databases of 8 neuroimaging centers in Europe. Patient enrollment and MRI data collection were performed between January 1, 2010, and November 30, 2016. Data analysis was conducted between January 1, 2016, and April 30, 2018. Investigators were blinded to participant diagnosis by a novel blinding procedure. Main Outcomes and Measures: Occurrence of central vein sign was detected on 3T T2*-weighted or susceptibility-weighted imaging. Sensitivity and specificity were assessed for these MRI sequences and for different central vein sign lesion criteria, which were defined by the proportion of lesions with central vein sign or by absolute numbers of lesions with central vein sign. Results: A total of 606 participants were included in the study after exclusion of 42 participants. Among the 606 participants, 413 (68.2%) were women. Patients with clinically isolated syndrome and relapsing-remitting MS (RRMS) included 235 women (66.6%) and had a median (range) age of 37 (14.7-61.4) years, a median (range) disease duration of 2 (0-33) years, and a median (range) Expanded Disability Status Scale score of 1.5 (0-6.5). Patients without MS included 178 women (70.4%) and had a median (range) age of 54 (18-83) years. A total of 4447 lesions were analyzed in a total of 487 patients: 690 lesions in 98 participants with clinically isolated syndrome, 2815 lesions in 225 participants with RRMS, 54 lesions in 13 participants with neuromyelitis optica spectrum disorder, 54 lesions in 14 participants with systemic lupus erythematosus, 121 lesions in 29 participants with migraine or cluster headache, 240 lesions in 20 participants with diabetes, and 473 lesions in 88 participants with other types of small-vessel disease. The sensitivity was 68.1% and specificity was 82.9% for distinguishing MS from not MS using a 35% central vein sign proportion threshold. The 3 central vein sign lesion criteria had a sensitivity of 61.9% and specificity of 89.0%. Sensitivity was higher when an optimized T2*-weighted sequence was used. Conclusions and Relevance: In this study, use of the central vein sign at 3T MRI yielded a high specificity and a moderate sensitivity in differentiating MS from not MS; international, multicenter studies may be needed to ascertain whether the central vein sign-based criteria can accurately detect MS.

Abnormal task driven neural oscillations in multiple sclerosis: A visuomotor MEG study.

Multiple sclerosis (MS) is a debilitating disease commonly attributed to degradation of white matter myelin. Symptoms include fatigue, as well as problems associated with vision and movement. Although areas of demyelination in white matter are observed routinely in patients undergoing MRI scans, such measures are often a poor predictor of disease severity. For this reason, it is instructive to measure associated changes in brain function. Widespread white-matter demyelination may lead to delays of propagation of neuronal activity, and with its excellent temporal resolution, magnetoencephalography can be used to probe such delays in controlled conditions (e.g., during a task). In healthy subjects, responses to visuomotor tasks are well documented: in motor cortex, movement elicits a localised decrease in the power of beta band oscillations (event-related beta desynchronisation) followed by an increase above baseline on movement cessation (post-movement beta rebound (PMBR)). In visual cortex, visual stimulation generates increased gamma oscillations. In this study, we use a visuomotor paradigm to measure these responses in MS patients and compare them to age- and gender-matched healthy controls. We show a significant increase in the time-to-peak of the PMBR in patients which correlates significantly with the symbol digit modalities test: a measure of information processing speed. A significant decrease in the amplitude of visual gamma oscillations in patients is also seen. These findings highlight the potential value of electrophysiological imaging in generating a new understanding of visual disturbances and abnormal motor control in MS patients. Hum Brain Mapp 38:2441-2453, 2017. © 2017 Wiley Periodicals, Inc.

The Central Vein Sign in Multiple Sclerosis Lesions Is Present Irrespective of the T2* Sequence at 3 T.

BACKGROUND AND PURPOSE: Previous T2*-weighted magnetic resonance imaging (MRI) studies have used white matter lesion (WML) central veins to distinguish multiple sclerosis (MS) from its mimics. To be clinically applicable, the "central vein sign" needs to be detectable across different T2* sequences. Our objective was to determine if the central vein sign is reliably present in MS and absent in patients with ischemic small vessel disease (SVD) across different T2* sequences at 3T MRI. METHODS: Ten patients with MS and 10 with SVD were each scanned on a 3 T Philips and GE scanner. The MRI protocol included 3-dimensional (3D) T2* GRE, T2* with high echo planar imaging (EPI) factor and susceptibility-weighted angiography (SWAN). Total WML numbers, central vein numbers, and proportion of WMLs with central veins were calculated using each sequence. Three blinded raters identified a subset of six WMLs with central veins to diagnose MS or SVD. RESULTS: Irrespective of the sequence, MS patients were identified based on a higher proportion of WMLs with central veins. This proportion was dependent on the T2* sequence used. T2* with high EPI allowed the highest median proportion (69.6%) in MS patients; 6.1% in SVD patients (P < .0004). Rater reproducibility varied depending on the T2* sequence used. T2* with high EPI produced good agreement with the clinical diagnosis (Cohen's kappa range; .78-.89), as did SWAN imaging with some raters; ĸ = .69. CONCLUSIONS: The central vein sign can diagnose MS in the clinical setting of modern 3T scanners. However, variations in the T2* sequences need to be considered when defining a threshold for diagnosis.