Background

Background: Diffusely abnormal white matter (DAWM) is associated with decreased axonal and myelin density, fibrillary gliosis, and inflammatory cell activation on histopathology, and has been linked to progression in secondary progressive MS (SPMS). However, few studies have focused on assessing DAWM in primary progressive MS exclusively. Hence, we aimed to characterize the longitudinal evolution of DAWM and its relationship with focal white matter lesions (FWML) and confirmed disability progression (CDP) in a PPMS population.

Objectives

Objectives: 1) To automatically segment and characterize the longitudinal evolution of FWML and DAWM in PPMS. 2) To assess associations of voxels of DAWM that transform into FWML at last visit with CDP (CDP=sustained increase in EDSS that persisted for 24 weeks).

Methods

Methods: The data included 1753 MRI scans of 376 PPMS participants, followed for 122 weeks, scanned at screening, weeks 06, 48, 96, and 122. FWML and DAWM were automatically segmented using a previously validated automated 2-weighted-intensity thresholding technique. All gadolinium enhancing and new white matter lesion voxels were excluded from the FWML mask, to capture the chronic component of FWML. DAWM voxels at screening, weeks 06, 48 and 96 that transformed into FWML at the last MRI scan (w122) were segmented.

Results

Results: As disease duration increased, PPMS participants showed volumes of chronic FWML that significantly increased (t=7.3; p<0.0001) but no significant changes in DAWM volumes. The voxels of DAWM in subsequent scans that transformed to FWML at the last visit significantly decreased as disease duration progressed (t=-8.8; p<0.0001) and were not significantly associated with CDP.

Conclusions

Conclusions: DAWM voxels show a dynamic transformation into FWML over time, with volumes of DAWM-to-FWML transformation in PPMS decreasing progressively as disease duration increases. These dynamic changes are similar to those observed in SPMS. However, unlike SPMS, where previous studies have shown an association between DAWM-to-FWML transformation and CDP, this group of PPMS participants did not show such an association. This finding would suggest that other factors, other than DAWM evolution, might have a stronger weight in disease progression in PPMS, compared to SPMS.

Background

It was suggested that slow-burning inflammation isassociated with lesion expansion and leads to progressive loss of axons and disability worsening. However, in vivo evidence linking lesion expansion with biomarkers of disease progression, particularly during relapsing-remitting stage of the disease, is lacking.

Objectives

To examine the incidence and extent of chronic white matter lesion expansion in relapsing-remitting MS (RRMS) patients followed for 5 yearsand to evaluate its relationship with clinical and imaging biomarkers of disease progression.

Methods

Pre- and post-gadolinium T1, FLAIR and diffusion tensor images were acquired from 33 patients. Lesion expansion was analysed between baseline and 48 months using custom-designed software written in Phyton. Percentage brain volume change (PBVC) was calculated using SIENA/FSL. Progression of clinical disability was assessed by EDSS. Progressive tissue damage inside chronic lesions was measured as an increase of Mean Diffusivity (MD).

Results

There were 569 lesions identified as chronic at baseline, of which 261 (46%) were expanding (total volume change:31320 mm³), 236 (42%) were stable (total volume change:1380 mm³) and 72 (12%) were shrinking (total volume change: -2664 mm³). In addition, 139 new free-standing and confluent lesions were detected (total volume:13867).

No association was found between change of volume in chronic lesions and the volume of new lesions (p=0.4). There was a significant increase in total brain lesion volume during the follow-up period (6680+/-5509 vs 7951+/-6315 mm³), the bulk of which was accounted for by an increase of chronic lesions group volume (67.3% or 855+/-1066 mm³), while only 32.7% (or 420+/-633 mm³) was attributable to new lesions.

There was significant negative correlation of chronic lesion volume change with the rate of brain atrophy (r=-0.57, p=0.001) and change of EDSS during the follow-up period (r=0.38, p=0.03). A strong positive correlation was also observed between the rate of chronic lesion volume change and an increase of MD inside the lesions during the follow-up period (r=0.75, p<0.001).

Conclusions

In RRMS patients the expansion of chronic white matter lesions dominates the process of total lesion load accumulation and is a significant contributing factor to the disease progression. Furthermore, our results suggest that low-grade inflammation at the lesion rim associated with significant degree of axonal loss both inside chronic lesions (MD increase) and in NAWM (brain atrophy). In addition, lack of correlation between an expansion of chronic lesion and volume of newly appearing lesions supports the notion that different mechanisms underpin the development of the new lesions and progressive changes in chronic pre-existing lesions.

Background

Conventional Magnetic Resonance Imaging (MRI) has a high sensitivity for detecting inflammatory disease activity of the brain, but is time-consuming, only semi-quantitative and rely on subjective assessments. On the contrary, the technique called ‘synthetic MRI’ (SyMRI) uses a single pulse sequence, can create contrast-weighted images from quantitative maps based on relaxometry and simultaneously provides automatic brain volume and myelin measurements. All this information is delivered after a single 6-minute scan and software with post-processing time less than 1 minute. Measuring the change in brain volume and myelin content in vivo could provide new insights into the relationship between two main pathological processes in multiple sclerosis (MS), demyelination and neurodegeneration and the impact of disease modifying treatments (DMTs) on these processes.

Objectives

The aim was to assess brain volume and myelin content over time in patients with newly diagnosed MS and in healthy control persons.

Methods

We prospectively included 116 patients newly diagnosed with relapsing-remitting (RR) MS, and 51 healthy control subjects (HC). All patients initiated DMT and were dichotomized into those with disease activity (relapse and/or new or enlarging lesions on MRI) (n=74) and those without disease activity (n=42) at follow up. The MRI was performed at baseline in both groups and in patients at 6, 12, 24 and 36 months, and in HC only at 24 months. Brain parenchymal fraction (BPF) and myelin parenchymal fraction (MyPF) of the brain were calculated via SyMRI software.

Results

At baseline, there was no significant difference between HC and newly diagnosed MS in BPF (89% and 89.1%, respectively, p=0.97), but HC had significantly lower MyPF than patients (14.1% and 14.9%, respectively, p<0.001). At 36 months follow-up, the mean change of BPF and MyPF in patients was -0.9% (±1.6) p<0.001 and 0.3 % (±1.3) p=0.022, respectively. Patients without disease activity had significantly higher MyPF compared with patients with disease activity during follow-up time (15.7% and 14.9%, respectively, p=0.009). At 24 month follow-up, BPF and MyPF were unchanged in HC compared to baseline (p=0.94 and p=0.44, respectively).

Conclusions

SyMRI showed the development of significant brain atrophy in RRMS after 3 years of follow-up and signs of increased demyelination in patients with disease activity. However, patients had unexpectedly higher MyPF than controls at baseline and the MyPF increased in stable RRMS at follow-up. This might indicate increased remyelination. However, the sensitivity of SyMRI to quantify the myelin fraction of the brain deserves further validation.

Background

Progressive multiple sclerosis (MS) phenotypes are associated with important clinical disability. Yet, moderate lesion burden is usually reported using conventional magnetic resonance imaging (MRI), suggesting other mechanisms at the basis of disability (e.g., motor cortical lesions, alteration of corticospinal tract (CST) function and integrity). Transcranial magnetic stimulation (TMS) permits a noninvasive exploration of corticospinal function. MRI allows a precise assessment of cortical (double inversion recovery (DIR) sequence) and CST structural integrity (diffusion tensor imaging (DTI)).

Objectives

This work aimed to assess the correlation between TMS and MRI-derived measures of CST and motor cortex. This might give complementary insight on neurophysiological and neuroanatomical characteristics of CST.

Methods

Adult patients with progressive MS were included. Patients were not included if they had a relapse in the last three months, change in MS treatments in the last two months, absence of motor evoked potentials, presence of contraindications for TMS/MRI performance, or presence of other neuropsychiatric diagnoses. TMS measures included short interval intracortical inhibition and facilitation. MRI protocol included DTI and DIR sequences to generate measures of CST integrity (volume, fractional anisotropy, apparent diffusion coefficient (ADC), axial diffusivity and radial diffusivity (RD)) and motor cortical lesions load. Correlation analysis was performed.

Results

Twenty-five patients completed the evaluations (13 females, mean age: 56 ± 11 years). Significant inverse correlations between percentages of intracortical facilitation and each of CST RD (p<0.01) and CST ADC (p<0.05) were observed.

Conclusions

High ADC and RD have been previously found among patients with MS and reflect high structural damage of the CST (demyelination as reflected by high RD, or both axon/myelin pathology as reflected by high ADC). In addition, low intracortical facilitation was previously suggested to reflect a deficient synaptic transmission and would hint towards an exhaustion of the compensatory mechanisms that are usually deployed to overcome the MS-related functional decline. The current findings would suggest a concomitant impairment of CST and intracortical facilitatory circuits that takes place at an advanced stage of MS. Intracortical facilitation and RD/ADC could constitute potential biomarkers to monitor disease evolution and response to interventions.

Background

The thalamus is a key gray matter structure, and a sensitive marker of neurodegeneration in multiple sclerosis (MS). Previous reports have indicated that thalamic volumetry on clinical-quality T2-FLAIR images alone is fast and reliable, using artificial intelligence (AI).

Objectives

To investigate the feasibility of thalamic atrophy measurement using AI in patients with MS, in a large multi-center, clinical routine study.

Methods

DeepGRAI (Deep Gray Rating via Artificial Intelligence) is a multi-center (31 USA sites), longitudinal, observational, real-word, registry study that will enroll 1,000 relapsing-remitting MS patients. Brain MRI exams previously acquired at baseline and at follow-up on 1.5T or 3T scanners with no prior standardization are used, in order to resemble real-world situation. Thalamic volume measurement is performed at baseline and follow-up on T2-FLAIR by DeepGRAI tool and on 3D T1-weighted image (WI) and 2D T1-WI by using FIRST software.

Results

In this pre-planned interim analysis, 515 RRMS patients were followed for an average of 2.7 years. There were 487 (94.6%) T2-FLAIR, 342 (66.4%) 2D T1-WI and 176 (34.2%) 3D T1-WI longitudinal pair of MRI exams available for analyses. Estimation of thalamic volume by DeepGRAI on T2-FLAIR correlated significantly with FIRST on 3D-T1-WI (r=0.733 and r=0.816, p<0.001) and with FIRST on 2D-T1-WI (r=0.555 and r=0.704, p<0.001) at baseline and at follow-up. The correlation between thalamic volume estimated by FIRST on 3D T1-WI and 2D T1-WI was r=0.642 and r=0.679, p<0.001, respectively. The thalamic volume % change over the follow-up was similar between DeepGRAI (-0.75) and 3D T1-WI (-0.82), but somewhat higher for 2D T1-WI (-0.92). Similar relationship was found between the Expanded Disability Status Scale (EDSS) and thalamic volume by DeepGRAI on T2-FLAIR and by FIRST on 3D T1-WI at baseline (r=-0.214, p=0.01 and r=-0.287, p=0.001) and at follow-up (r=-0.298, p=0.001 and r=-0.291, p=0.001).

Conclusions

DeepGRAI provides feasible thalamic volume measurement on multi-center clinical-quality T2-FLAIR images. The relationship between thalamic atrophy and physical disability is similar using DeepGRAI T2-FLAIR and standard high-resolution research approaches. This indicates potential for real-world thalamic volume monitoring, as well as quantification on legacy datasets without research-quality MRI.

Background

Multiple sclerosis (MS) is a disease characterized radiologically by the accumulation of lesions in grey and white matter over time throughout the CNS. Accumulating evidence has demonstrated abnormal patterns of brain functional connectivity (FC) in MS patients as compared to healthy controls (HCs). A longitudinal approach that accounts for all alterations in FC following structural damage in MS is warranted to better understand the complex interplay between disease progression and FC reorganization.

Objectives

1) To assess fMRI-based FC anomalies in early MS 2) To determine the relation between FC changes and structural brain damage due to disease progression 3) To study the association between FC changes and cognitive and physical disability.

Methods

Structural MRI and resting-state fMRI were acquired from 76 early relapsing-remitting MS patients at baseline (average disease duration 71.7 months ± 63) and after five years. Ninety-four HCs matched for age and sex were included at baseline. Independent component analysis (ICA) and network modelling were used to measure FC. FC variation was related to expanded disability status scale, timed 25-foot walk test, 9 hole peg test and neuropsychological outcomes. Brain and lesion volumes were quantified using standard methods. We used the 25 independent components obtained from ICA to estimate the longitudinal stability of the brain functional connectome as a proxy for functional reorganization over time. We computed the stability of the brain functional connectome for each MS patient by vectorizing each participant’s whole-brain connectivity matrix. Then, we calculated the within subjects Spearman correlation coefficient between fMRI at baseline and follow-up, obtaining a measure of whole-brain connectome stability that is sensitive to all changes in FC in the follow-up period.

Results

The MS subjects (71% females, mean age 35.3 ± 7.3) were clinically and cognitively stable. Compared to HCs, FC abnormalities were detected within networks and in single connections, mainly in the default mode network and frontoparietal areas, in patients with early MS at baseline. Over time, FC was relatively invariable, but changes in FC were associated with progression of brain atrophy (ρ = 0.39, p = .06). No significant relationship with clinical and cognitive measures or lesion load was detected.

Conclusions

We used the stability of the brain functional connectome as a proxy for FC reorganization. Patients with MS showed altered FC in the early stages of the disease, with FC abnormalities being bidirectional (i.e. increased and decreased FC). Over time, changes in FC, independent of direction, could be related to progression of brain atrophy, which is associated with changes in clinical and cognitive functioning. Connectome stability enables fMRI data to be condensed into a proxy as a cross-sectional and longitudnal individual imaging marker.

Background

MRI assessment in MS focuses on the presence of typical white matter (WM) lesions. Neurodegeneration characterised by brain atrophy is recognised in the research field as an important prognostic factor. It is not routinely reported clinically, in part due to difficulty in achieving reproducible measurements. Automated MRI quantification of WM lesions and brain volume could provide important clinical monitoring data. In general, lesion quantification relies on both T1 and FLAIR input images, while tissue volumetry relies on T1. However, T1-weighted scans are not routinely included in the clinical MS protocol, limiting the utility of automated quantification.

Objectives

We address this important translational challenge by assessing the performance of FLAIR-only lesion and brain segmentation, against a conventional approach requiring multi-contrast acquisition. We explore whether FLAIR-only grey matter (GM) segmentation yields more variability in performance compared with two-channel segmentation; whether this is related to field strength; and whether the results meet a level of clinical acceptability demonstrated by the ability to reproduce established biological associations.

Methods

We used a multicentre dataset of subjects with a CIS suggestive of MS scanned at 1.5T and 3T in the same week. WM lesions were manually segmented by two raters, ‘manual 1’ guided by consensus reading of CIS-specific lesions and ‘manual 2’ by any WM hyperintensity. An existing brain segmentation method was adapted for FLAIR-only input. Automated segmentation of WM hyperintensity and brain volumes were performed with conventional (T1/T1+FLAIR) and FLAIR-only methods.

Results

WM lesion volumes were comparable at 3T between ‘manual 2’, T1+FLAIR and FLAIR-only methods. For cortical GM volume, linear regression measures between conventional and FLAIR-only segmentation were high (1.5T: α=1.029, R²=0.997, standard error (SE)= 0.007; 3T: α=1.019, R²=0.998, SE=0.006). Age-associated change in cortical GM volume was a significant covariate in both T1 (p=0.001) and FLAIR-only (p=0.005) methods, confirming the expected relationship between age and GM volume for FLAIR-only segmentations.

Conclusions

FLAIR-only automated frameworks for segmentation of WM lesions and brain volumes were consistent with results obtained through conventional methods and had the ability to demonstrate biological effects in our study population. This could facilitate the integration of automated WM lesion volume and brain atrophy analysis as clinical tools in radiological MS reporting.

Background

The pathogenesis of neurodegeneration in multiple sclerosis (MS) is multifactorial and the determinants of brain atrophy rates are not completely understood.

Objectives

To investigate the association between annualized atrophy rate (AAR) of multiple brain measures (regional cortical thickness (CTh), volumes of basal ganglia, thalamus, white matter, gray matter, brain and brain parenchymal fraction (BPF)) and: (1) annualized rate of new and enlarging white matter lesions (WMLs); (2) annualized rate of resolved WMLs; (3) occurrence of progression independent of relapse activity (PIRA) during follow-up.

Methods

We included 1573 1.5T or 3T brain MRI scans from 378 patients of the Swiss MS Cohort Study (331 relapsing-remitting MS (RRMS), 27 clinically isolated syndrome (CIS), 11 secondary-progressive MS (SPMS), 9 primary-progressive MS (PPMS); 70% female; median age: 41.9 yrs; disease duration: 8.3 yrs; EDSS: 2.0; follow-up time: 4.0 yrs). Longitudinal changes in WMLs were obtained using an automated prototype (LeMan-PV). Brain volumes and CTh AARs were obtained using FreeSurfer longitudinal pipeline (v6.0) after WMLs filling. In patients fulfilling PIRA an EDSS progression had to be confirmed ≥6 months after the index event. Multivariable generalized linear models were used to model the association between AAR (dependent variable) and independent variables (1-3), correcting for age, sex, disease duration and baseline EDSS. p-values were adjusted for Bonferroni multiple comparison correction; for vertex-wise CTh analysis, Monte Carlo Z simulation was performed (cluster threshold p<0.05).

Results

We found positive associations between annualized rate of new and enlarging WMLs and (i) CTh AAR of 8 extensive clusters (bilateral frontal, temporal and occipital regions and right insula, all p<0.01) and (ii) AAR of: caudate bilaterally (p=0.02), white matter volume, brain volume and BPF (p<0.001 for all).

We also found a negative association between annualized rate of resolved WMLs and CTh AAR in 3 cortical clusters (right insula, precentral area and anterior cingulate region, all p<0.05); no associations with AAR of volumes emerged.

57 patients fulfilled PIRA whereas 295 experienced no EDSS progression events: no significant differences in AAR measures were found between these two groups.

Conclusions

In a large cohort of MS patients, with a median follow-up of 4 years, local radiological inflammatory and reparative activity were associated with AAR in multiple brain regions. PIRA did not seem to be related to increased AAR in any of the regions studied.

Background

Diagnostic criteria for multiple sclerosis (MS) have undergone several iterations in the past 20 years, resulting in increased sensitivity and earlier diagnosis, but also increased misdiagnoses due to reduced specificity. Biomarkers are needed to distinguish MS from its mimics and between MS subtypes. MS lesions in white matter (WM) typically form around a central vein, which can be visualized with FLAIR* imaging (Sati, et al, 2012). Central vein sign (CVS) presence on MRI can help differentiate MS from other diseases with WM T2-weighted hyperintensities and may increase the sensitivity and specificity of MS diagnosis.

Objectives

To apply MRI-based gradient echo plural contrast imaging (GEPCI) approach (Luo, et al, 2012) to generate FLAIR*-like images and detect CVS in patients with progressive MS (PMS) and relapsing remitting MS (RRMS). To quantitatively evaluate tissue damage in lesions with and without CVS using tissue-specific GEPCI R2t* metric (Xiang, et al, 2019).

Methods

MRI scans of PMS (n=39) and RRMS subjects (n=30) were analyzed for the CVS within WM lesions. Presence of CVS, lesion volume, and anatomic location were determined. To quantitatively evaluate the severity of brain-tissue damage in MS lesions, mean R2t* was calculated. R2t* is a quantitative measure that correlates with brain tissue cellular density and is decreased in areas of reduced tissue integrity. The proportion of total lesions with CVS was calculated, excluding confluent lesions and lesions with more than 1 central vein. Median proportions in PMS and RRMS subjects were compared using the Wilcoxon sign rank test. Individual lesion CVS status was examined using generalized linear models. Linear mixed models adjusted for age were used to evaluate predictors of mean R2t* in nonconfluent lesions with only one central vein of sufficient size. Associations of CVS and clinical data from time of MRI scan, including Expanded Disability Status Scale (EDSS), symbol digit modality test (SDMT), and multiple sclerosis functional composite (MSFC) were made using Spearman correlations.

Results

The PMS group had significantly higher EDSS scores and poorer performance on SDMT and MSFC than the RRMS group. There were no significant differences in total CVS and percentage of CVS per lesion between MS subtypes. Controlling for age, EDSS, and lesion volume did not increase the odds of either group having CVS. Lesions with CVS had lower R2t* (greater tissue damage). However, accounting for MS type, age, and lesion count reduced significance (p = 0.09). Mean R2t* was significantly lower in PMS than RRMS (p = 0.027) and declined with age (p = 0.023).

Conclusions

This study did not find that the presence of CVS could distinguish between patients with RRMS and PMS. Our data suggest that lesions with CVS have more tissue damage. Due to reduced significance after accounting for additional variables, further studies with more patients are needed.

Background

In multiple sclerosis (MS) upper and lower limbs can be affected, but impairments only moderately relate to each other. Previous motor task studies have focussed predominantly on imaging hand function at clinical field strengths, preventing the detection of subtle changes and differentiation of mechanisms underlying subtle motor impairment.

Objectives

To investigate functional brain changes related to upper and/or lower limb motor task performance in minimally disabled MS patients using ultra-high field MRI.

Methods

Twenty-eight MS patients and seventeen healthy controls underwent visually-guided force-matching fMRI tasks using either hand or foot. Task performance (force error and lag) and activation level during upper and lower limb movements were compared between groups. Correlations were assessed between task activation and behavioural performance.

Results

During lower limb force tracking, MS patients showed significantly (p<0.01) longer lag, higher force error, higher primary motor and premotor cortex activation and lower cerebellar Crus I/II activation, compared to controls. No differences were seen in upper limb performance or activation. Upper and lower limb task performance was related to the level of activation in cerebellar, visual and motor areas in MS patients.

Conclusions

Altered lower limb movements and brain activation with preserved upper limb function and activation in minimally disabled patients suggests partially divergent functional mechanisms underlying upper and lower limb disability.

Background

Automated multiple sclerosis lesion counts and volumes are poised to be salient clinical biomarkers of disease progression; however, algorithmic variability and low expert agreement prevents widespread adoption in clinical practice. Because every method has a non-negligible error rate, visual quality control (QC) is required before a clinical decision can be made. QC is a bottleneck to the use of automated lesion count and volume metrics in the clinic. A method is needed to 1) quickly evaluate experts and non-experts to understand and resolve disagreements, and 2) quickly QC the output of automated lesion segmentation methods.

Objectives

To evaluate the feasibility of a web application called braindr (Keshavan et al., 2019) for high-throughput QC of automated lesion segmentation by measuring the 1) intra-rater reliability, 2) the inter-rater reliability, and 3) to characterize the types of lesions that are disagreed upon.

Methods

3D T1 and FLAIR images from 32 subjects were registered, N4 bias field corrected, and z-scored. Subtraction images (Z_FLAIR-Z_T1) were thresholded at varying levels. A triplanar image of each resulting segmentation (called a potential lesion, PL) was generated, resulting in over 80,000 individual PL’s needing QC, which simulates a high-throughput scenario with a high error rate. Expert and non-expert raters were asked to pass or fail PLs based on the 2D triplanar image on the app. We measured variability between and within raters by calculating the intraclass correlation coefficients (ICC).

Results

1) Feasibility: 14,973 PLs were labelled by 5 raters. The raters were a neuroradiologist (MI), a general neurologist (BD), 2 experienced technicians (AK, KL), and 1 beginner (MB). 2) Intra-rater reliability (ICC(1,1)) : a) neuroradiologist: 0.97, b) beginner: 0.90, c) experienced techs: 0.87, 0.85, and d) neurologist: 0.84. 3) Inter-rater reliability for an average rating ICC(2,k) = 0.92, and individual ICC(2,1) = 0.74. 4) Disagreements occurred more frequently on PL’s in the brainstem, cerebellum, hippocampal, and basal ganglia.

Conclusions

We simultaneously evaluated raters, and QC’d lesions from an automated method using a quick, scalable, web application. This enables us to 1) improve expert agreement on lesion identification, 2) develop better quality education materials for experts and non-experts alike, 3) train new raters quickly, and 4) ensure the quality of the measurements at scale.

Background

Slowly expanding lesions (SELs) can be detected on conventional in vivo brain magnetic resonance imaging (MRI). Previous studies suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. Histopathological characterization of SELs are still not fully investigated.

Objectives

To characterize SEL regions using in vivo MRIs and postmortem brain tissue, and compare the difference between SEL and non-SEL regions.

Methods

We identified an autopsy case with secondary progressive MS (male, age=51 years, disease duration=23 years), who had standardized in vivo MRIs. The interval between the last in vivo MRI and death was 7 weeks. From the last two years of in vivo MRIs, T2 lesions were segmented, and the Jacobian determinants of nonlinear registration between baseline and follow-up scans were calculated. SELs were identified as regions with small local constant and concentric expansion from baseline lesions. We identified 11 regions-of-interest (ROI): 10 T2 lesions (3 SELs and 7 non-SEL) and 1 normal-appearing white matter (NAWM). Using a custom brain cutting box with MRI-visible markers, the in vivo ROIs were localized on the corresponding brain slice. The ROIs were blocked and stained for proteolipid protein, SMI-31/32, and MHC class II. We then evaluated myelin status, axonal diameter, axonal loss, and inflammatory activity in ROIs.

Results

The NAWM region was myelinated, the axonal diameter was 0.74 um, and axonal density was 23.4%. In the SEL regions, the mean axonal diameter was 1.11 um, and mean axonal density was 17.5%. In non-SEL regions, the mean axonal diameter was 0.84 um, and mean axonal density was 15.7%.

Two SEL and 4 non-SEL regions were demyelinated. The demyelinated SEL regions had activated microglia at the lesion edge and were compatible with chronic active lesions. Three demyelinated non-SEL regions also had activated microglia at the edge. One demyelinated non-SEL region was a chronic inactive lesion. No microglia activity was observed in any of the myelinated non-SEL regions. In the myelinated SEL region, the density of activated microglia was higher compared to NAWM.

Conclusions

Not all SEL regions in T2 lesions were demyelinated. SEL also had greater axonal diameters suggesting of axonal swelling. In this case report, all of the demyelinated SEL regions had activated microglia at the lesion edge.

Background

Hurst Exponent (HE) is a scalar measurement of long-term temporal memory of a time series. The HE has been found in previous studies to be an effective means of measuring the long-range temporal dependence of brain activity as measured by fMRI. We hypothesize that the HE can be associated with impairment in Multiple Sclerosis (MS), therefore can be an imaging biomarker of MS.

Objectives

The primary goal of the study is to assess how well HE measurements can distinguish MS patients from healthy controls (HC), as well as MS patients with impairment from those without impairment. The second objective was to identify which brain regions’ HE alterations are associated with impairment in MS.

Methods

Fifteen HC (age: 43.66±8.64, 53% female) and 76 MS patients (age:45.28±11.46 years, 65% female, disease duration:12.29±7.25 years) were included in our study; 23 had EDSS2 at study baseline. Logistic ridge regression (LR) was used to classify two groups: (1) HC vs MS patients and (2) MS patients with vs without impairment. The classification tasks were performed using HE measurements in 86 cortical and subcortical regions. Five-fold cross-validation was used to train, validate, and test the model, with 10 outer loop repetitions. Area Under ROC curve (AUC) over the folds was used to assess classification performance.

Results

HE was found to be significantly higher in the non-impaired group compared to the impaired group in the right superior frontal gyrus (corrected p-value=0.025). The classification of HC vs MS had an AUC of 0.65 (IQR:0.18), while the task of classifying MS patients by impairment level had an AUC of 0.63 (IQR: 0.12). For the classification of HC vs MS, the regions that were the most predictive were in deep gray matter. Lower HE in the left amygdala, left thalamus and left putamen, and higher HE in the left hippocampus was associated with MS. For the classification of impairment level in MS, deep gray matter regions were also important, as were HE in the frontal lobe. Lower HE in the left caudate, right and left amygdala, and left superior frontal and higher HE in the right ventral DC were associated with more impairment in MS.

Conclusions

HE was found to be moderately discriminative between HC and MS and within impairment levels in MS. HE in subcortical and superior frontal regions were found to be important biomarkers of impairment severity in MS, as well as in distinguishing MS patients from HC. Further research is necessary to identify the mechanism driving these differences.

Background

Brain volumetry is an accepted monitoring tool for the diffuse, not relapse-related inflammatory activity in MS. As thalamus volume turned out to be most affected by the atrophic process in MS, a special focus is put on this region.

Objectives

We present first data from our ongoing study, addressing the effect of Cladribine Tablets on global and regional brain atrophy.

Methods

45 consecutive patients with highly active MS from our observational study are presented (mean age 39 y, mean EDSS 2.1, 31 female, 14 male). Clinical and brain MRI evaluations were carried out at baseline prior to Cladribine treatment and repeated after 6 and 12 months following Cladribine treatment initialization. All images were acquired with the same 3T Philips Achieva scanner using the same 3D MPRAGE protocol. Global and regional brain volumes were derived using a previously described atlas based volumetry approach implemented in SPM12 in cooperation with jung diagnostics. Quantified parameters include brain parenchymal volume (BPV), grey matter volume (GMV), white matter volume (WMV), Corpus callosum volume (CCV) and thalamus volume (THV). All atrophy parameters of the single subjects were tested against the normative database. All volumes were tranformated to age-corrected z-volumes. Z<-1.96 means significant atrophy. 0.0 equals the mean of the normative database.

Results

As expected, at baseline the regional brain volumetry revealed the highest pretreatment mean loss in THV, e.g. the highest sensitivity for the atrophic process in thalamus (z= -1.64), followed by CCV (z=-1.22), WMV (z=-1.67) and GMV (z=-0.54). 6 and 12 months after Cladribine initialization the z-differences from baseline to first visit and second visit to third visit were for BPV +0.21, -0.11; GMV +0.18, +0.01; WMV +0.07, -0.18; THV +0.21, +0.06; CCV +0.13, +0.02. GMV, THV and CCV are fully protected by Cladribine tablets for the entire first treatment year. For WMV and BPV respectively there is a slight trend to volume reduction. The z-difference in the second half of the first treatment year equals an estimated annual volume loss of age-corrected 0.2% which is still an excellent effect.

Conclusions

From the first data of this ongoing study can be concluded that the first treatment period with Cladribine tablets fully protects GMV including the highly sensitive thalamus. With the exception of CCV with good protection, the effect of Cladribine on WMV seems to decrease in the second half of the first treatment year.

Background

Changes in magnetization transfer ratio (MTR) are a marker of changes in myelin density and associated tissue integrity in the brain. Siponimod improved MTR recovery in lesions and demonstrated a significant effect on MTR decrease in normal-appearing brain tissue (NABT) and cortical grey matter (cGM) with a more pronounced effect on normal-appearing white matter (NAWM) in the overall EXPAND secondary progressive multiple sclerosis (SPMS) population, as reported previously.

Objectives

To investigate the effect of siponimod vs placebo (PBO) on MTR changes in NABT, cGM, and NAWM in subgroups of SPMS patients.

Methods

This prospective MTR substudy assessed the effect of siponimod versus PBO on median normalized MTR (nMTR) in NABT, cGM and NAWM assessed by absolute change from baseline (BL) to Month (M) 24 using repeated measures models. Patient subgroups were defined by: disease history and severity (age [≤45/>45 years], disease duration [≤15/>15 years], Expanded Disability Status Scale (EDSS) score [≤5.5/≥6.0], Symbol Digit Modalities Test score (≤43/>43); and inflammatory disease activity (active/non-active SPMS, with/without relapse in 2 years before screening, with/without gadolinium-enhancing lesions). Data from the per-protocol set (n=443) are presented.

Results

The subgroup analysis indicated that absolute changes from BL in median nMTR for NAWM ranged from –0.124 to –0.034 in the PBO group and from –0.016 to 0.040 in the siponimod group, which corresponds to 79–198% attenuation in median nMTR decrease versus PBO across all the subgroups studied (all p<0.05 except EDSS≥6 subgroup, p=0.064). The results were consistent for NABT (70–170%) and cGM (44–188%) although slightly less pronounced (p>0.05 for some subgroups). In the active SPMS subgroup, siponimod attenuated median nMTR decrease across NABT, cGM and NAWM by 91–109% (p<0.01 all); and in the non-active SPMS subgroup by 170–198% (p=0.0151 for NAWM, p>0.05 for NABT, cGM).

Conclusions

Over 24 months, siponimod attenuated the decrease in median nMTR in brain tissues across the patient subgroups characterized by disease activity and severity. The effect of siponimod was most pronounced in NAWM. These data support preclinical studies of siponimod, showing direct beneficial CNS effects on myelination.

Background

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines.

Objectives

The goal is to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination and implementation.

Methods

The CMSC convened an expert panel in October 2019 to update the standardized MRI protocol. Conference attendees included neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Representatives from CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocol, gadolinium, diffusion weighted imaging, and the central vein sign.

Results

95 neurologists completed the survey. 34% use the CMSC protocol. 48% use a standardized MRI protocol but are uncertain if it is similar to CMSC guidelines. 51% continue to use gadolinium for routine imaging. 58% wanted the central vein sign to be included in the diagnostic work up of MS. 87% were interested in monitoring brain volume and 10% were doing it routinely. The panel worked to harmonize CMSC and MAGNIMS MRI protocols so the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences and exam cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use.

Conclusions

The international expert group developed revised clinical MRI guidelines with the vision and action plans for them to be universally useful and useable and become the standard of care for patients with MS.

Background

To assess the connectome disruption in patients with multiple sclerosis (MS), methods have been developed that utilise connectomes derived from healthy controls (HC) which require the accurate registration of white matter structures from patients with MS onto HCs whole brain streamline tractograms.

MRI T1 based image registration may be inaccurately mapped to HC derived tractograms due to the lack of information within the relatively homogenous T1 signal of white matter.

Fibre orientation distributions (FODs), created by the constrained spherical deconvolution (CSD) model of white matter diffusion data, have the potential to improve white matter registration as it holds information of all fibre directions for each voxel.

Objectives

Here we compare the accuracy and utility of FOD-based, T1-based and FA-based registration of white matter tracts in MS.

Methods

10 MS patients and 10 age matched healthy controls underwent 3T MRI scanning including 1mm 3D T1 and single shell diffusion weighted imaging. FOD maps were created using CSD algorithm designed for single shell data. Tensor and FA maps were created.

Non-linear registration was undertaken directly from each patient to each control (ie. 100 warps) with ANTs using T1 and FA images, and through an MNI template intermediary.

Registration was performed directly from each patient to controls using FOD maps using MRtrix3 FOD-based registration, as well as through a custom population FOD template.

Each registration method was assessed in transforming three white matter tracts, corticospinal tracts (CST), anterior thalamic radiations (ATR) and optic radiations (OR), from patients to controls. The resultant transformed segmentations from each registration method was compared to the control segmentation by calculating its Dice coefficient.

Further to this each method was assessed using a tract segmentation that had the cortical ribbon and juxtacortical tract removed.

Statistically significant differences were assessed by non-parametric Kruskal-Wallis test with Dunn’s post hoc testing.

Results

For combination of all tracts, the highest Dice coefficients were with direct FA (median = 0.727, IQR 0.06215) and direct T1 (median = 0.72185, IQR 0.056525) with no significant difference found.

For combination of all cropped tracts, the highest Dice coefficients were with FOD population template (median = 0.7673, IQR 0.0468), direct FOD (median = 0.76565, IQR 0.050175) and direct FA registration (median = 0.7626, IQR 0.060025) with no significant difference found.

When utilising an intermediary template, both T1 and FA based methods performed worse, whereas the FOD population template performed similarly.

Conclusions

FA and T1 based registration outperformed FOD based, despite more white matter information. This was driven by poorer juxtacortical registration in the FOD based method. This is important in the analysis of MS due to the high prevalence of juxtacortical lesional pathology.

Background

Quantitative metrics such as lesion count and brain volume can provide objective data of disease progression in Multiple Sclerosis (MS). However, implementing FDA-approved quantitative software in clinical practice requires significant effort and investment. It has not yet been established if quantitative software can consistently improve the detection of clinically relevant MRI findings in MS-specific radiology reports.

Objectives

To characterize clinically relevant findings in MS-specific radiology reports generated by a neuroradiologist after visual interpretation of images alone and with FDA-approved software.

Methods

26 patients with MS who had MRIs performed between 2013-2017 were retrospectively selected from an anonymized database. Each patient had 2 MRIs (average 1 year apart) consisting of 3D T1 and T2 FLAIR sequences. Images were processed using FDA-approved software (NeuroQuant and LesionQuant 3.0.1) to generate lesion count and brain volume data and a color-coded map that highlighted lesion changes between MRI timepoints.

A neuroradiologist visually compared MRIs in each patient and reported the number of new, enlarging, shrinking, and enhancing lesions, and provided an assessment of brain atrophy in a qualitative report (qual). To avoid recall bias, cases were randomized and re-anonymized, and one month later, the neuroradiologist used the post-processed data and images to generate a second quantitative report (quant). Interpretation time was recorded during both sessions. Two neuroimaging experts coded differences in the reports and verified lesion accuracy.

Results

Upon review of qual reports, a total of 44 new, 10 enlarging, and 5 shrinking T2 lesions and 3 enhancing lesions were reported, compared with 50 new, 15 enlarging, 8 shrinking, and 3 enhancing lesions on quant reports. Of the 13 cases that reported differences in lesion counts, one additional new lesion, on average, was detected in quant reports (SD= 2.4). Brain atrophy descriptions changed with the addition of quantitative metrics in 7 cases, where 5 cases were upgraded and 2 cases were downgraded in severity. No significant difference (p=.16, paired t-test) was found in interpretation time (qual 12.3 minutes; quant 11.4 minutes).

Conclusions

The use of FDA-approved quantitative software improved the detection of clinically relevant neuroimaging findings in MS patients, without adding time to image interpretation, suggesting its potential value in clinical practice.

Background

Ultra-high field MRI highlighted the crucial role of cortical injury in multiple sclerosis (MS). Cortical pathology is frequent in MS, and seems to be more pronounced in progressive stages of the disease. One aspect of cortical pathology is represented by focal cortical lesions (CL).

Pioneering studies demonstrated the high frequency of CL in MS, their independence from white matter injury and their clinical relevance, particularly for cognitive impairment. Nevertheless, very few is known about their presence from the onset of the disease, their dynamics of apparition, neither the differential impact of intracortical (IC) and leukocortical (LC) lesions in early MS.

Objectives

The present study aims to assess the prevalence, the topography and the clinical counterpart of cortical lesions in patients included in the first year of MS.

Methods

16 MS patients in the first year of their disease course and 12 matched controls were included. All subjects underwent a 7T brain MRI scan designed to maximize the accuracy of CL detection (sequences: MP2RAGE, FLAIR, FLAWS with 600μm³ isotropic resolution and T2*/QSM with 600μm² in-plane resolution and thickness of 600μm, total acquisition time 58 min). EDSS and MSFC were performed by rated physicians.

Radiological analysis: a cortical lesion was considered in case of signal change with identifiable boundaries compared to adjacent cortex on MP2RAGE, confirmed by at least one other sequence (FLAIR, FLAWS and T2*/QSM), excluding anatomical structure (eg vessels). CL were divided into two groups according to their location: leukocortical when the lesion extended across both white matter (WM) and grey matter (GM) and intracortical when the lesion is exclusively located within the GM. WM lesions were depicted on MP2RAGE and FLAIR sequences with a 3 mm minimal size.

Statistical analysis: patients and lesions descriptive data were presented with means and standard deviation (SD). Spearman correlations were performed between cortical and WM lesions count and clinical evaluations.

Results

Patients' caracteristics: 13 females, 3 males; mean age = 33 yo (SD = 9); mean disease duration = 6 months (SD = 3); mean EDSS = 0.28 (SD=0.51); mean relapse = 1.68 (SD = 1.01).

399 cortical lesions were detected in 14 patients (mean = 11.68, SD = 12.32). Among them 211 LC lesions were seen in 11 patients and 187 IC lesions in 14 patients. Mean number of WM lesions was 27 (SD = 27.45), mean volume was 2.15 mL (SD = 2.75). LC lesions were significantly correlated with WM lesions (ρ=0.91, p<.001). In opposite, IC lesions were not correlated with WM lesions (ρ=0.49, p=0.05) nor LC lesions (ρ=042, p=0.09). No lesions were seen in controls.

No correlations were found between cortical lesions and EDSS nor MSFC.

Conclusions

We evidenced that the prevalence of cortical lesions is very high at the earliest stage of MS and is not correlated with white matter impairment. This study confirms the accuracy of MP2RAGE to depicit these lesions.

Background

Automated and reproducible measures of MS severity and subclinical inflammatory activity and neurodegeneration in routine practice could support therapeutic decisions and accelerate research. Toward this goal, we developed and validated a software prototype, MSPie (MS PATHS Image Evaluation). MSPie runs on syngo.via Frontier (Siemens Healthcare, Erlangen, Germany) and processes standardized T2 FLAIR and T1-weighted MRIs to quantify brain parenchymal fraction (BPF), T2 lesion volume, and #new/enlarging T2 lesions (NET2L). Results are reviewable by radiologists through an interface that displays current, prior, and subtraction images, as well as overlays of brain and lesion segmentations, and allows +/- corrections of NET2L.

Objectives

To assess an image analysis prototype integrated into radiological practice to generate quantitative brain volume and lesion measurements at the point of care.

Methods

MSPie was installed at 2 MS Partners Advancing Technology and Health Solutions (MS PATHS) institutions. 3 neuroradiologists per institution used MSPie to review 40 longitudinal pairs of routine MS PATHS MRIs. For each case, radiologists performed a visual assessment of the brain segmentation used for BPF, manually corrected NET2L if needed, approved or rejected the results, and completed a performance evaluation survey.

Results

MSPie performance was assessed in 240 cases. Radiologists accepted MSPie-generated BPF and lesion results for 230/240 cases (96%). 38.8% of cases required corrections of false positive (FP) or false negative (FN) NET2L, with a mean of 2.5 (FP+FN) NET2L per case. In 94% of cases, NET2L FP+FN was £3, a prespecified design target based on radiologists’ input. MSPie detected 221/229 true NET2L, yielding a sensitivity of 96.2%. In 18% of cases, radiologists reported MSPie-detected NET2L they would have missed. Mean performance ratings on a scale of 1(poor) to 5(excellent) were: 3.9 for overall performance; 3.9 for brain segmentation; 3.9 for T2 lesion segmentation.

Conclusions

Incorporation of brain volume and T2 lesion quantification into MS imaging practice is feasible. MSPie demonstrated a high sensitivity for disease activity, detecting some NET2L that might have been missed by radiologists. MSPie achieved the prespecified target rate of acceptable false positive NET2L. MSPie might allow neuroradiologists to provide quantitative brain atrophy and T2 lesion metrics in clinical practice and to increase their diagnostic precision.

Disclosures: MS PATHS is sponsored by Biogen.

Background

Microstructural alterations in the Normal-Appearing White Matter (NAWM) preceeding the onset of a new lesion have been described using advanced MRI in patients with MS. However, the biological substrate of these alterations remains poorly understood due to the lack of specificity of the MRI signal. We have previously shown that Positron Emission Tomography (PET) with 11C-PIB has the potential to quantify myelin content changes in WM lesions. Interestingly, dynamic 11C-PIB PET acquisitions, including early frames, enable the estimation of regional brain perfusion too.

Objectives

To characterize whether perfusion changes, microstructural damage and demyelination could precede lesion appearance on T2-weighted (T2-w) MRI images.

Methods

Longitudinal dynamic 11C-PIB PET and 3T MRI, including diffusion weighted and magnetization transfer imaging, were acquired in 19 active patients with relapsing-remitting MS. Following baseline scans, patients underwent a second evaluation after 1-2 month (n= 10) or after 3-4 months (n=9). Prelesional areas were defined as the baseline NAWM areas which became hyperintensities on the second T2-w image. Logan reference graphical analysis and simplified reference tissue model were respectiveley used to generate voxelwise maps of Distribution Volume Ratio (DVR), and relative delivery (R1) from 11C-PIB images. Myelin content, reflected by DVR, and perfusion, measured by R1, were extracted for each prelesional area and the corresonding contralateral area in the NAWM. Magnetization transfer ratio (MTR), fractional anisotropy (FA), radial and axial diffusivity (RD and AD) were calculated in the same areas. Paired t-test were used to test differences in DVR, R1, MTR, FA, RD and AD between the prelesional and its contralateral areas.

Results

We identified 77 prelesional areas. In the subgroup of patients with a 1-2 months follow-up, prelesional areas (45 out of 77) showed a higher perfusion (8.5%, p=0.03), increased RD (4.2%, p=0.003), lower MTR (-1.2%, p=0.008) and reduced FA (-6.2%, p=0.008), compared to contralateral NAWM areas, while no difference was detected in DVR (p=0.4). No statistical differences were found in the subgroup of patients with a follow-up of 3-4 months.

Conclusions

One-two months before becoming hyperintense on T2-w MRI, prelesional areas are characterized by an increased perfusion associated with microstructural changes, but not by demyelination.

Background

Mean rates of brain atrophy in healthy controls range from 0.05-0.5%, depending on age and technical factors, including scanner, acquisition sequences, and image analysis techniques. In MS PATHS (MS Partners Advancing Technology for Health Solutions), standardized MRIs are analyzed using a software prototype (MSPie, MS PATHS Image Evaluation) that incorporates a novel approach to calculate BPF. Normative ranges measured using MSPie are needed to distinguish age- and disease-related changes.

Objectives

To establish a normative reference for interpretation of brain parenchymal fraction (BPF) in individual MS patients relative to age-matched healthy volunteers (HV).

Methods

HV aged 21-60 were recruited at 6 MS PATHS sites to be age-, race-, and gender-matched to the MS PATHS cohort. HVs were imaged at baseline and once/year using 3T scanners (Siemens Healthcare, Erlangen, Germany) and standardized acquisitions (3DFLAIR and 3DT1), as in routine MRIs in MS PATHS. MRIs from UK Biobank supplemented the normative dataset past the age of 60. All MRIs were analyzed with MSPie to calculate BPF. BPF normative percentile were calculated for each age using quantile regression. Mean annualized rate of brain atrophy was estimated from HVs with follow-up MRIs. BPF percentiles were applied to the MS PATHS cohort. Mean Processing Speed Test (PST) z-scores were compared in MS patients stratified based on BPF percentiles.

Results

209 HVs were enrolled, 590 UKBiobank HVs were selected, and 9479 MS patients had at least one MRI. HV BPF values ranged from 0.855-0.895 in the 21-30 age group to 0.796-0.882 in the 61-73 age group, demonstrating accelerating and more variable atrophy with increasing age. For MS patients age 21-73 years (n=6791), mean age-adjusted BPF percentile was 27.8%, where BPF values fell above the 50^th%-ile in 23.4% (“mild MS”) and below the 25^th%-ile in 57.6% (“severe MS”). Mean PST z-scores differed in BPF-based mild MS vs. severe MS groups (-0.15 and -0.83; p<0.001). Mean annualized BPF change in HV was -0.08% (range: -0.71% to +0.57%) based on 71 subjects (mean age: 41.1 years) with >2 MRIs.

Conclusions

Incorporating normative reference data into MSPie will aid clinicians with interpretation of individual patients’ BPF in clinical practice and may enable patient stratification based on BPF and other predictors. Additional longitudinal normative data are being collected to contextualize disease progression as measured by BPF change over time.

Disclosures: MS PATHS is sponsored by Biogen.

Background

Neurofilament light polypeptide (NfL) is a neurofilament protein highly expressed in myelinated axons. Increased serum NfL (sNfL) concentration indicates the presence of axonal damage in patients with multiple sclerosis (MS). Until now, the potential effects of this axonal damage on brain connectivity have never been investigated.

Objectives

We studied the relationship between active inflammation measured by sNFL and structural connectivity alterations detectable by global network metrics estimated with diffusion MRI.

Methods

Diffusion MRI, T1-weighted and FLAIR sequences were acquired on 74 patients (44F, 44.9±14.6yrs, 50 relapsing-remitting and 24 progressive) and sNfL levels were measured from blood samples in the same session. Volume of white-matter lesions was computed on FLAIR with an automatic in-house tool. To build the connectomes we 1) performed deterministic tractography on diffusion MRI, 2) segmented the grey matter in 85 regions using T1 images, and 3) quantified the connection strength of each pair of regions by counting the streamlines between them. From each connectome we extracted 5 global metrics: Density (ratio between actual and possible connections), Efficiency (capability of transferring and processing information); Modularity (network segregation); Clustering Coefficient (degree to which nodes tend to cluster together); Mean Strength (average of the sum of the edge weights connected to a node). Since discrepancies in density may affect other metrics, we first tested its correlation with sNFL, then we performed partial correlations of the last 4 metrics with sNFL using age, sex and density as covariates.

Results

We found negative correlation between density and sNfL (R=-0.252 p=0.05) indicating that high axonal damage is associated with reduced number of connections. Efficiency and mean strength showed a strong anti-correlation with sNfL (R=-0.325 p=0.011 and R=-0.475 p<0.001), while modularity and clustering coefficient seemed not related to axonal damage (R=0.183 p=0.162 and R=-0.215 p=0.099). Finally, a positive association with sNfL was found for both the lesions volume and the Expansion Disability Status Scale (p=0.011 R=0.323 and p=0.038 R=0.267), confirming previous results.

Conclusions

We showed that high values of sNfL are associated with global connectivity damage (reduced number of connections, efficiency and mean strength) confirming the utility of network-based connectivity metrics to assess MS disease impact.

Background

Chronic active lesions (‘smoldering lesions’) in MS patients have recently gained increasing interest as possible markers of MS activity. Yet there is no in vivo marker to detect these lesions and characterize their structural dynamics.

Objectives

Our objective was to detect chronic active lesions in MS patients and characterize their intraindividual volume dynamics over time.

Methods

581 MRI datasets in 200 relapsing-remitting MS patients (2 - 5 per individual) from a 3-year multi-centre observational INSPIRATION-MRI study were investigated using Voxel-Guided-Morphometry (VGM), a method for intraindividual detection and quantification of structural changes in volumetric MRI scans (T1 – weighted MPRAGE-sequence) over time. Chronic active lesions were identified and differentiated into chronic shrinking vs. chronic enlarging lesions.

Results

Intervals between consecutive scans varied between 53 and 1199 days, mean = 443 days. Overall, individual MRI scan intervals varied between 53 (2 scans) and 1360 (3 scans) days. In total, 2419 active lesions were identified, characterized and quantified, corresponding to a mean active lesion load of 12 lesions per patient. In chronic shrinking lesions, mean volume change was -33% (from -11% to -59%), in chronic enlarging lesions mean volume change was +53% (from 29% to 425%). We found a mean annual volume decrease for white matter of 0.17% and gray matter of 0.12%. 31 patients exclusively demonstrated chronic enlarging lesions, in 16 patients only chronic shrinking lesions were detected, and 119 patients were found to have a mixture of both types of active lesions. In 34 patients, no active lesions were identified.

Conclusions

Chronic active lesions were detected in 83% of the investigated patients using Voxel-Guided-Morphometry in longitudinal 3D-MRI datasets. As these chronic active lesions are supposed to represent MS activity with corresponding brain tissue damage also in patients who do not demonstrate new contrast-enhancing lesions, they might be regarded as an additional biomarker for MS activity. The relationship between chronic active brain tissue lesions and clinical MS progression needs to be further investigated.

Background

In multiple sclerosis (MS), pathological changes are not limited to lesions, but extensively involve normal-appearing tissues, being more pronounced in perilesions. Histological studies have shown that the pathological changes affecting perilesions mainly result from the ongoing damage in demyelinating lesions. Similarly, the structural integrity of perilesions could depend on the extent of myelin repair at the lesional level, which can be explored in vivo by positron emission tomography (PET) with 11C-PiB.

Objectives

To assess in a longitudinal study whether myelin content changes in white matter lesions, measured with 11C-PiB PET, influence the microstructural integrity of the surrounding perilesions over time, explored by diffusion tensor imaging and magnetization transfer (MT)-derived metrics.

Methods

Nineteen patients with MS underwent a longitudinal PET/MRI study. Voxel-wise maps of 11C-PiB distribution volume ratio, reflecting myelin content, were used to calculate for each patient in each non-enhancing lesion 3 indices of myelin content change: the percentage of demyelinated voxels at baseline, and the percentage of demyelinating and remyelinating voxels over the follow-up. From each 3 mm-thick perilesional area surrounding lesions, the change over time (delta) of fractional anisotropy (FA), mean diffusivity (MD) and MT ratio (MTR), reflecting microstructural damage, was calculated. Associations between the indices of myelin content change and the delta FA, MD, and MTR in perilesions were assessed using multivariate linear regressions. Perilesions were classified in “improving” or “worsening” according to the sign of the change of the microstructural parameters and a multivariate logistic regression was used to test which PET-derived index was independently associated with perilesion class.

Results

A higher percentage of demyelinated voxels at baseline and of demyelinating voxels over the follow-up inside lesions were associated with a more severe microstructural damage developing over time in perilesions (p<0.001). Conversely, a higher percentage of remyelinating lesional voxels correlated with a more preserved perilesional microstructure at the follow-up (p<0.001). The percentage of remyelinating voxels inside lesions was the only independent predictor of perilesion improvement (p=0.001). We found that at least 43% of the demyelinated volume had to remyelinate to predict a favorable evolution of the microstructure of perilesional tissue (AUC=0.8).

Conclusions

Lesional remyelination effectively protects the integrity of surrounding tissues over time, possibly by reducing the extent of Wallerian degeneration and rescuing damaged axons.

Background

Quantitative measurements of lesion volume, lesion count, distribution of lesions and brain atrophy have a potentially significant value for evaluating disease progression in multiple sclerosis (MS).

Objectives

We wanted to investigate whether utilizing a software designed for evaluating MRI data in MS would be more sensitive and clinically useful compared to the visual neuro-radiological evaluation.

Methods

A group of 56 MS patients (mean age 35 years, 70 % females and 96 % relapsing-remitting MS) was examined with brain MRI one and five years after being diagosed with MS. The T1 and FLAIR brain MRI sequences for all patients were analyzed using the LesionQuant (LQ) software. The resulting LQ output was compared with data from structured visual evaluations of the MRI scans performed by a neuro-radilogist, includning assessements of atrophy and lesion count. Correlations with clinical tests, like the timed 25- foot walk test (T25-FW), were performed to explore additional value of LQ analyses compared to visual assessments.

Results

Lesion count assessments by LQ and by the neuro-radiologist were significantly correlated one year (cor=0.92, p=2.2x10¯¹⁶) and five years (cor=0.84, p=2.7x10¯¹⁶) after diagnosis. LQ detected a reduction in whole brain percentile >10 in 10 patients across the time-points, whereas the neuro-radiologist assessment identified six of these. The neuro-radiologist additionally identified five patients with increased atrophy in the follow-up period, all of them displayed decreasing low whole brain percentiles (median 11, range 8-28) in the LQ analysis. A significant positive correlation was identified between lesion volume measured by LQ and test performance of T25-FW both at one year (t=3.08, p=3.2x10¯³) and five years (t=3.72, p=4.8x10¯⁴) after diagnosis, while we found no association between visual inspection and the clinical tests.

Conclusions

For the number of MS lesions at both time-points, we demonstrated strong correlations between the assessments done by LQ and the neuro-radilogist. Lesion volume evaluated with LQ correlated with T25-FW performance. LQ-analyses were more sensitive in capturing brain atrophy than the visual neuro-radiological evaluation. In conclusion, LQ seems like a promising supplement to the evaluation performed by neuro-radiologists, providing an automated tool for evaluating lesions and brain volume in MS patiens in both a longitudinal and cross-sectional setting.

Background

Motor skills are commonly impaired in patients with multiple sclerosis (MS) as a consequence of gray (GM) and white matter (WM) pathology and cortical excitability abnormalities.

Objectives

We hypothesized that microstructural characteristics of motor regions as assessed with the neurite orientation dispersion and density imaging (NODDI) model predict motor cortical excitability that is frequently altered in MS. Further, we evaluated pathological microstructure alterations in motor WM tracts of MS patients compared to healthy controls (HC) using NODDI in comparison to the diffusion tensor imaging (DTI) parameter fractional anisotropy (FA).

Methods

We applied advanced diffusion imaging in 50 MS patients and 49 age-matched HC. As excitability maker, we assessed resting motor thresholds using non-invasive transcranial magnetic stimulation. For quantification of microstructural integrity of the motor system, neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (IVF) and FA averaged within left primary motor cortex as the stimulation site were considered. We applied hierarchical regression modeling to evaluate the prediction of the resting motor threshold by NDI, ODI, IVF and FA in MS patients and HC. Cognitive-motor performance quantified by the Nine Hole Peg Test and Trail Making Test part A (TMT-A) and part B (TMT-B) was regressed on the diffusion parameters in a subsample of 44 MS patients. In the WM, we applied tract-based spatial statistics with the threshold-free cluster enhancement (TFCE) method within motor tracts comparing MS patients and HC. We tracked contributions of NDI and ODI to FA and evaluated if the NODDI model detects additional pathological alterations.

Results

A hierarchical regression revealed that lower NDI suggestive for axonal loss in the GM significantly predicted higher motor thresholds, i.e. reduced excitability in MS patients (F(1,48) = 7.493, p = .009). Lower NDI was indicative for decreased performance in TMT-A (F(1,42) = 8.102; p = .007) and TMT-B (F(1,42) = 7.390; p = .009). Microstructural abnormalities of the interconnected WM tracts were characterized by lowered FA, decreased NDI and increased ODI in MS (all TFCE-corrected p < .05). NDI exclusively (56%) and in overlap with FA (19%) accounted for the largest amount of differences, followed by ODI alone (9%).

Conclusions

Our work shows that lower neurite density in primary motor cortex is linked to decreased motor cortical excitability and decreased cognitive-motor performance in MS patients. Lower neurite density and higher orientation dispersion are characteristic in the WM of MS patients compared to HC. Our results suggest that these markers are more sensitive to pathological alterations than the classical DTI measure FA. This work outlines the potential of microstructure imaging using advanced biophysical models to forecast neurodegeneration and excitability alterations in neuroinflammation.

Background

Cortical lesions (CLs) have recently acquired a great relevance in multiple sclerosis (MS), both at diagnosis and during the monitoring of the disease, because of their impact on long-term prognosis. However, there is still limited knowledge about the evolution of CLs in time.

Objectives

The aim of the present observational study was to investigate, retrospectively, the longitudinal evolution of CLs number in comparison to FLAIR-T2 hyperintense white matter lesions (WMLs) in a cohort of MS patients in a single MS centre.

Methods

We included all consecutive patients with a relapse-onset MS referred to MS centre of Parma (Italy) who performed at least two MRI scans including double inversion recovery sequences from 2014 to 2019, collecting demographic, clinical and MRI data.

Results

We included 140 MS patients, 67.9% female, with the following characteristics at first MRI: relapsing-remitting (RR) course in 84.3% and secondary progressive (SP) in 15.7% of cases, mean age 40.1±10.49 years, mean disease duration 169.7±100.75 months, mean EDSS 2.5±1.30, mean number of WMLs 24.8±16.50 and of CLs 2.5±2.87. After a mean follow-up of 51.8±8.32 months we observed a conversion to SP phase in 2.1% and a 3-mo-confirmed EDSS progression in 13.6% of patients, with a mean EDSS of 2.6±1.48 and mean number of relapses of 1.1±1.95. During the follow-up only 3.6% of patients did not take any therapy, while 47.1% and 49.3% were on a first-line and a second-line disease-modifying treatment (DMT), respectively. Occurrence of ≥1 new WML or CL appeared in 37.9% and 12.9% of cases, respectively, with a mean number of new WMLs of 1.8±5.58 and new CLs of 0.2±0.6. New CLs never appeared without concomitant WMLs, but 44.4% of cases with new CLs occurred in patients with 1-2 new WMLs and 26.7% of patients with 1-2 new WMLs had ≥1 new CL. At multivariate analysis the risk of occurrence of new CLs was higher in patients with a higher number of new WMLs at last MRI (OR 1.44, CI95% 1.17-1.78, p=0.001) and lower in those who remained RR (OR 0.04, CI95% 0.002-0.76, p=0.03).

Conclusions

In our cohort we observed an overall low MRI activity, probably related to the high percentage of patients on DMT. New CLs appeared in a small percentage of patients and were strictly related to new WMLs. Nevertheless, they added clinical relevance to a consistent proportion of cases characterised by otherwise minimal MRI activity, with important implications for therapeutic switch.

Background

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), one of its pathophysiological hallmarks is demyelination, which is known to be involved in neurodegenerative mechanisms.

Objectives

Modular architecture and its dynamic adaptation could play a critical role in achieving flexible alterations of cerebral network architecture during de- and remyelination which is still not fully elucidated.

Methods

We address dynamic adaptation to cuprizone model of general de- and remyelination and ask if network community organization can relate to the longitudinal time events. To start with baseline and then by introducing cuprizone into the diet of mice we induced full CNS demyelination by targeting oligodendrocytes, over a period of 5 weeks (two time points). A subsequent myelin synthesis was allowed over reintroduction of normal food (two time points). To identify the modular organization the resting state fMRI within the graph theory framework was analyzed from each of the five time points. The dynamic network reconfiguration was estimated by flexibility as parameter of modularity allegiance and effective connectivity analyses were applied to test the causality of network dynamics between the identified modules.

Results

We found six modules namely default mode network (DMN), hippocampus, thalamus, lateral cortical network, basal forebrain and ventral mid brain. Interestingly the dynamics of de- and remyelination was mirrored by an initial significant increase in flexibility values and a return to baseline in the hippocampus (F_{(4, 80)} = 22.8, p < 0.001), DMN (F_{(4, 80)} = 36.5, p < 0.001) and thalamus (F_{(4, 80)} = 24.5, p < 0.001). The other three networks showed a reversed pattern. The strength of connections from the hippocampus to DMN was associated with the behavioral indicators of memory novel object recognition (NOR) (r² = 0.3854, p < 0.001) and thalamus to hippocampus to locomotor activity (r² = 0.3144, p < 0.001).

Conclusions

Taken together, our fMRI modular analyses showed that global modularity and flexibility partially compensate for demyelination. Dynamics of compensation could be identified as modular specific (i.e. hippocampus, thalamus and DMN) at different intermediate time points, supporting the hypothesis that altered thalamocortical connectivity is an early pathological hallmark of the disease. Causality dynamics also provide biomarkers for evaluating the course of MS and disease dynamics.

Background

The brain's ability to adapt in response to damage is debated in multiple sclerosis (MS) literature. In a previous work, we have shown that following the acute damage caused to the visual system by an episode of optic neuritis (ON), the functional visual network experiences changes that are associated with the specific neurologic deficit, all within the limits of the underlying disease pathophysiology.

Objectives

To examine whether the changes associated with ON in the structural and functional networks, can still be discerned in progressive MS patients, even years after the acute insult.

Methods

Forty-eight progressive MS patients, with and without prior ON (MS-ON and MS-nON, respectively; n_MS-ON = 21, n_MS-nON = 27), underwent structural and functional magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and resting state fMRI (RS-fMRI). Anatomical and functional visual networks were defined using 50 visual regions-of-interest. Data were analyzed using graph theory-based methods and weighted network metrics were extracted, including density, strength, global and local efficiency, and modularity.

Results

Preliminary results have shown that while no functional metrics were significantly different between the two groups, anatomical global efficiency and density were significantly higher for the MS-nON group, despite no significant difference in lesion load between the groups.

Conclusions

The anatomical networks of the MS-ON group appear to be more damaged than those of the MS-nON group, while the functional networks appear to function to the same degree. Anatomical connectivity seems influenced by the long- standing distal damage to the optic nerve, suggesting trans-synaptic effects. However, despite our previous study having shown possibly-adaptive functional changes in the visual network following acute ON, our current results suggest that even if the MS brain has the ability to respond and adapt to insult in the early stages of the disease, this ability is nullified in progressive patients.

Background

The revised Lublin criteria (Lublin et al. 2014) provide a detailed definition of individual patient status in secondary progressive multiple sclerosis (SPMS), where patients are assessed annually based on progression and activity (MRI and/or relapse). So far, the revised criteria were applied to SPMS patients only in a small number of studies (Perez et al. EP1344 ECTRIMS 2017). The same is true for quantitative and standardized MRI analyses, which are often implemented in clinical trials, but are not part of standard routine care in patient management, although projects like QUANTUM clearly showed a benefit of quantitative and standardized MRI analysis in routine care (Schippling et al. P508 ECTRIMS 2018).

Objectives

MAGNON aims to evaluate if access to standardized quantification of MRI data and assessment of MS patients based on the Lublin criteria provides additional benefit for neurologists working in day-to-day MS patient management.

Methods

Approximately 3.600 MRI studies of patients with transitioning relapsing remitting MS (RRMS) or SPMS will be provided by 100 centers in Germany. Physicians are asked to categorize their patients according to the revised Lublin criteria. Standardized MRI data (3D T1 gradient-echo sequence and 2D/3D FLAIR) are analysed by means of a centralised automatic processing pipeline (Biometrica MS®, jung diagnostics GmbH). The analysis comprises a volumetric quantification of brain and thalamic volumes as well as T2 lesion volume and number. Percentage brain volume change is computed (using an optimized SIENA pipeline) when follow-up scans are available. The results are visualised and provided to the participating physicians as a report. The value of standardized MRI analysis and the impact on patient assessment, including potential changes in Lublin classification, will be evaluated.

Results

MAGNON will start in the first half of 2020 and design of the project as well as the first baseline data will be presented.

Conclusions

In the near future, an increasing implementation of Lublin criteria and quantitative MRI analysis in routine clinical practice is expected. Quantification of lesion volume as well as brain and thalamic atrophy on routine MRI may facilitate the individual assessment of disease activity and progression according to the Lublin criteria and provide additional information for individual patient management.

Background

Understanding whether multiple sclerosis (MS) can have a favorable course is still challenging. However, a small group of patients who are not disabled after many years of disease can be identified. The mechanisms responsible for this ‘benign’ clinical course remain unclear, likely due to the lack of long-term studies.

Objectives

To assess brain damage in multiple sclerosis patients with no or minimal disability after a longstanding clinical course.

Methods

We compared 13 patients with long-term benign clinical course (LT-BMS, age >55 years, disease duration >30 years, Expanded Disability Status Scale [EDSS] <3.0) and 27 non-benign MS (non-BMS) patients (age >55 years, EDSS >3.0). MRI scans were retrospectively assessed (mean follow-up: 11 years, mean scan per patient: 3). Comparisons of brain volumes (BV) and total T2-lesion volume (LV) changes between the two groups were performed using a mixed effect model. Lesion probability maps (LPMs) of both groups were compared using a nonparametric permutation test.

Results

Patients with LT-BMS showed less over-time decrease in global BV (p=0.02) and grey matter (GM) volume (p<0.001) than non-BMS. Lower atrophy was seen in LT-BMS with no or mild cognitive impairment. By contrast, there was no over-time difference between patient groups in T2-LV accumulation and lesion frequency across brain.

Conclusions

Global brain and GM atrophy changes were mild in this unique patient group with long-standing and no or minimal physical and cognitive disability. These results support the relevant role of GM atrophy in characterizing MS patients who may have favorable long-term disease evolution.

Background

Cognitive impairment in multiple sclerosis (MS) is strongly related to functional network dysfunction. In the absence of MS, optimal cognitive functioning of an individual is ensured by dynamically adapting the configuration of the functional network as needed. How these dynamic patterns are altered in MS remains unclear.

Objectives

Our aim was to investigate the dynamic reconfiguration of cognitively relevant brain networks in MS, to identify specific brain network patterns related to progression of cognitive impairment.

Methods

Resting-state functional MRI (rs-fMRI) and cognitive scores were acquired from 230 patients with MS and 59 matched healthy controls, at baseline and at 5 year follow-up. Seven cognitive domains were examined with the expanded Brief Repeatable Battery of Neuropsychological tests. A sliding-window approach was used on the rs-fMRI data, for which brain regions were assigned to one of seven classic literature-based resting-state networks based on connectivity patterns at that point in time. How regions switched between networks was described using measures of promiscuity (number of networks switched to), flexibility (number of switches), cohesion (switches with another region), and disjointedness (independent switches). Linear mixed models were used for baseline and longitudinal analyses, controlling for age, sex, and education.

Results

At baseline, 42% of patients showed cognitive impairment (CI) (18% Mild CI, ≥2 tests Z<-1.5; 23% severe CI, ≥2 tests Z<-2) and 28% of patients declined over time (≥2 tests yearly reliable decline>0.25). At baseline, CI patients showed increased promiscuity, flexibility and cohesion (i.e. more switching between networks) compared to preserved patients. Patients displaying cognitive deterioration showed increases in cohesion over time. Higher baseline cohesion was related to less gray matter volume, and more white matter integrity loss and lesion volume. Within cognitive domains, cohesion was inversely related to verbal memory, information processing speed, and working memory.

Conclusions

In patients with MS, increased switching between brain networks was related to cognitive impairment and structural damage. Cohesion particularly increased over time in patients showing cognitive decline, indicating that switching together with other regions might be particularly more common. These results provide support for the hypothesis of a progressive destabilization of the functional brain network in MS.

Background

Quantitative MRI measures are proposed as biomarkers of disease course and therapeutic response. Understanding the evolution of these metrics is key for interpretation of change in clinical practice.

Objectives

To describe longitudinal changes in T2 lesion volume (T2LV), whole brain (WBF) and gray matter (GMF) fraction, and thalamic volume (TV) over the disease course in a large multiple sclerosis (MS) cohort.

Methods

Demographics, disease history, and MRI were collected from MS patients at a single site. Patients with ≥2 MRI assessments were included. T2LV, WBF, GMF, and TV annualized rate of change and raw values compared to the first available scan were analyzed. Multivariate mixed-effects models were used to evaluate longitudinal MRI changes, adjusting for age at disease onset, sex, and patient-determined disease steps category (PDDS) with a random intercept for patient and an autoregressive covariance structure. For each outcome, three models were generated: a linear model, a second-order B-spline model, and a third-order B-spline model were tested for nonlinearity in the relationship between MRI outcome and disease duration and were compared based on Akaike Information Criterion.

Results

1012 patients were included (69.2% female, 72.9% relapsing-remitting MS, mean ± SD age at disease onset 34.4±10.3, age at baseline MRI 43.8±11.1, disease duration 9.4±5.8 years, mean number of MRIs 3.1±1.2, median [IQR] PDDS 1.0 [0.0-3.0]). Male sex (B=4.9) and PDDS>3 (B=7.0) were associated with greater T2LV accumulation over the disease course (best fit: linear model). T2LV annualized rate of change peaked at 5-6 years of disease duration (rate 9%/year) (best fit: third-order B spline). Male sex, older age, and PDDS>3 were associated with lower WBF, TV (best fit: linear model), and GMF (best fit: second-order B spline), all p<0.05. No non-linear effect of disease duration on WBF, TV, and GMF were observed. There was no statistically significant change in the annualized rate of change of WBF, TV, and GMF over the disease course.

Conclusions

The dynamics of T2LV accumulation are variable throughout the disease course, whereas the rate of change of WBF, TV, and GMF were more stable. These results suggest T2LV accumulation reflecting focal lesion activity predominates early in the disease while WBF, TV, and GMF loss reflecting underlying neurodegeneration is present at disease onset and continues throughout the course.

Background

Multiple sclerosis (MS) and MOG-associated disorders (MOGad) are characterized by hyperintense white matter (WM) lesions on T₂/FLAIR MRI. Conventional imaging is sensitive but does not inform on the specific pathological substrate. Magnetization transfer saturation provides a good myelin measure, and multishell diffusion is sensitive to the axon + myelin assembly. Together, these can be modelled to estimate myelin volume fraction (MVF), axonal volume fraction (AVF) and imaging g-ratio.

Objectives

To quantify gradients of damage to axons and myelin in lesions and surrouding normal appearing white matter, in pediatric MS and MOGad.

Methods

15 MS [67% females (F), mean (range) age [years (y)]: 17y (14-18), disease duration (DD) 3y (0-6), time from last relapse (TLR) 2y (0-6)] and 7 MOGad [86% F, 13y (8-18), DD 3y (0-6), TLR 1y (0-3), 6/7 relapsing] participants received 3T brain MRI. MVF, AVF and g-ratio were computed according to established procedures. T₂ lesions were segmented according to standardized pipelines and WM masks by multi-atlas segmentation. Euclidean distance transforms labelled voxels in normal-appearing WM with the distance to the nearest lesion voxel, and voxels inside lesions with the distance to the nearest non-lesional WM voxel. Mean MVF, AVF and g-ratio were computed on each isodistant surface. Data were modeled using linear mixed models with distance, diagnosis, and their interaction. Knots were used at 0 and 2mm distance.

Results

MVF decreased towards the center of lesions (MOGad: -0.03/mm; MS: -0.05/mm; p values (ps)<0.002; difference n.s.) as did AVF (MOGad: -0.03/mm; MS: -0.01/mm; ps<0.0002; difference p=0.02); this graded damage extended to 2mm outside lesions. Beyond this, AVF continued to increase (MOGad: 0.001/mm; MS: 0.0003/mm; ps<10^-6; difference p<10^-6). Inside lesions, g-ratio increased towards the center in MS (0.03/mm, p<10^-6) and decreased in MOGad (p=0.15; MOGad-MS difference p<10^-4). G-ratio rose with distance outside lesions (MOGad: 0.001/mm; MS: 0.0004/mm; ps<10^-4; difference p<10^-5). AVF and g-ratio were similar between groups (within 2%) at 20mm from lesions; MVF was higher in MS (14%, p=0.08).

Conclusions

MS and MOGad showed myelin and axonal loss of decreasing severity with distance from lesion center, and this damage extended outside visible lesions. However, MOGad exhibited more severe axonal loss within and near lesions. The corresponding decreasing g-ratio relative to MS may indicate preferential loss of small axons in MS, or relatively better remyelination in MOGad.

Background

Multiple sclerosis (MS) patients have heterogeneous clinical manifestations, natural history, and treatment response, due to heterogeneous underlying pathophysiological differences.

Objectives

To find clusters of MS patients with homogeneous underlying pathophysiology, as determined by advanced MRI techniques.

Methods

One-hundred-and-fifteen MS (57 relapsing-remitting, 12 primary- and 46 secondary-progressive) patients, and 44 age- and sex-matched healthy controls (HC) underwent brain and cervical cord 3T MRI with pulse sequences for assessing lesions, atrophy, and microstructural damage (with diffusion-tensor metrics). A complete neurological assessment, with rating of Expanded Disability Status Scale (EDSS) was also performed. Clusters of MS patients were identified with hierarchical clustering on age- and sex-adjusted MRI variables.

Results

Five clusters of MS patients were identified: “early”; “intermediate-cord”, “intermediate-cortical”, “intermediate-late-lesion”; and “late”. “Early” patients showed similar MRI metrics vs HC (except lesions), low EDSS and short disease duration (DD). “Intermediate” groups had altered MRI metrics, higher EDSS and longer DD, compared to “early” (p<0.01). “Intermediate-cord” patients were characterized by high cord T2-lesion volume (LV) (p<0.001 vs all but “late” groups), and “intermediate-cortical” by low cortical thickness (p<0.001 vs all but “intermediate-late-lesion” and “late” groups). “Intermediate-late-lesion” patients showed higher brain T2-LV and deep grey matter (GM) atrophy, but also a longer DD, compared to all but “late” groups (p<0.01). “Late” patients had higher EDSS and DD, compared to “intermediate-cord” and “intermediate-cortical” (p<0.01); and worst corticospinal-tract diffusion-tensor metrics and cord/brain atrophy (p<0.01 vs all). “Intermediate-cord” patients could be divided into 2 groups with similar DD characterized by different cord GM atrophy and cortical thickness (p<0.01), the more impaired one including mostly progressive phenotypes and higher EDSS.

Conclusions

MRI-based clustering of MS patients is feasible. It contributes to demonstrate disease heterogeneity and in the future it may be useful for personalized medicine. “Intermediate-cord” patients may be the best target to study neuroprotective and regenerative strategies.

Funding: Partially supported by grants from Fondazione Italiana Sclerosi Multipla (FISM/2018/R/16).

Background

One of the challenges in multiple sclerosis (MS) research is to improve prediction of disease progression. While information from conventional MRI of the brain is essential in the diagnosis of MS, it only allows prognosis to some extent. Given the complexity of the disease, a combined analysis of structural and functional MRI changes appears more promising to identify markers associated with disease progression.

Objectives

We thus investigated how multimodal MRI can contribute to predicting disease progression in a single-centre cohort of patients with MS (PwMS).

Methods

We analyzed multimodal MRI-data from 123 PwMS (71 women; age (years): M=37.2, SD=10.4; n_CIS=16; n_RRMS=98; n_PMS=9). All patients had undergone clinical and 3T MRI evaluations between 2015 and 2016 (baseline, BL) and clinical re-evaluations 2 years later (SD=1.0; follow-up, FU). Brain-volume, T2 lesion load, fractional anisotropy (FA) and resting-state functional connectivity (rsFC) of the default-mode (DMN) and sensorimotor network (SMN) at BL were correlated with the patients’ disease severity score progression (absolute Expanded Disability Status Scale (EDSS) score change from BL to FU).

Results

Across the entire cohort, median EDSS scores were significantly higher at FU (Med=1; IQR=2.5) than at BL (Med=1; IQR=2; p=0.04), with a low rate of disease severity score progression (assessed by EDSS BL – EDSS FU/ FU duration; Med = 0; IQR = 0.5). Neither normalized brain volume (NBV) nor T2 lesion load, extracted mean scores of whole brain FA or rsFC within DMN or SMN significantly correlated with disease severity score progression. Whole brain voxel-based analyses (controlled for age and disease duration) indicated trends for decreased FA within the corpus callosum (CC) and the corticospinal tract (CST) and decreased rsFC within the anterior cingulate cortex (ACC) and the hand motor area to be associated with disease progression. Subsequent ROI analyses revealed a significant decrease in mean FA in the CC genu (p=0.024), the CC forceps minor (p=0.020) and right CST (p=0.020) related to disease progression. Moreover, ROI analyses showed a decrease in mean rsFC in the left hand motor area (p=0.012) and the ACC (p=0.005) with increased disease progression.

Conclusions

Our results show that even within a relatively low rate of clinical disease progression over short term FU, subtle microstructural and functional changes may represent more sensitive predictors compared to gross morphological measures obtained from conventional MRI.

Background

Background: After cessation of contrast enhancement MS lesions may show enlargement or shrinkage on T1w MRI. The presence of hypointense lesion rims on susceptibility weighted MRI may be associated with ongoing inflammation and tissue damage/rearrangement. The relationship of enlarging and shrinking MS lesions on T1w MRI to hypointense rims on SWI is therefore of interest.

Objectives

Objective: To investigate enlarging and shrinking non-enhancing multiple sclerosis (MS) lesion characteristics using a novel multimodal magnetic resonance imaging (MRI) approach.

Methods

Methods: Two high-resolution 3 D T1-weighted 3T MRI datasets obtained 12 months apart were analyzed in 67 MS patients. Non-enhancing enlarging and shrinking lesions were identified by voxel guided morphometry (VGM) demonstrating regional volume changes as compared to stable lesions without volume change. In addition the presence of hypointense lesion rims on susceptibility-weighted imaging (SWI) was evaluated. In order to estimate tissue damage within lesions, T1 signal intensity (SI) ratios and the apparent diffusion coefficient (ADC) were analyzed.

Results

Results: Forty-three patients demonstrated chronic enlarging and/or shrinking lesions (active T1 lesions), while in 24 patients exclusively stable lesions were seen. Overall, we identified 444 chronic MS lesions (109 enlarging, 67 shrinking, 268 stable lesions). Chronic-enlarging/shrinking lesions were more frequently associated with hypointense rims compared to stable lesions (p < 0.05). Both, chronic-enlarging/shrinking lesions showed a stronger decrease of the T1 SI ratio and, conversely, an increase in ADC values at follow-up in comparison to stable lesions. Patients with enlarging or shrinking lesions had longer disease durations, higher EDSS scores, larger T2 lesion volumes and lower normalized brain volumes than patients without such lesions (p < 0.05).

Conclusions

Conclusion: Enlarging and shrinking lesions on T1w MRI frequently show hypointense rims on SWI. Those lesions are linked to progressive white matter damage and may indicate sustained inflammation and may therefore indicate low grade inflammatory changes, that could be a valuable marker of disease activity.

Background

Cortical damage is clinically relevant in multiple sclerosis (MS), however reliable MRI markers for its monitoring are still an unmet need. Ratio of T1-weighted (T1w) and T2-weighted (T2w) sequences (i.e., T1w/T2w-ratio) has been suggested as a feasible MRI measure to assess cortical abnormalities in patients with MS (PwMS), but its histopathological substrate has yet to be definitively elucidated.

Objectives

To define the histopathological substrate of T1w/T2w-ratio in normal-appearing and demyelinated cortices of PwMS by performing a combined post-mortem MRI/histopathology study.

Methods

Fifteen PwMS and ten age- and sex-matched non-neurological controls (nNC) underwent post-mortem in situ 3T MRI with 3D T1w and T2w sequences, followed by brain dissection.

One hundred and five paraffin embedded tissue blocks (49 from PwMS, 56 from nNC) were collected. Tissue regions were matched to T1w/T2w-ratio maps to obtain regional cortical T1w/T2w-ratio. Using immunohistochemistry and silver staining, cortical density of myelin, microglia, neurons, glial cells and neurites were evaluated. Correlates of T1w/T2w-ratio alterations with histological markers were assessed through linear mixed-effects models.

Results

Twenty-six cortical lesions (85% subpial) were found in 24/49 (51%) cortical regions from PwMS. Compared to nNC’s cortex, both PwMS’ normal-appearing and demyelinated cortices had a significantly lower T1w/T2w-ratio (p=0.045 and 0.001). In PwMS, demyelinated cortex showed a significant lower T1w/T2w-ratio compared to normal-appearing cortex (p=0.007). In PwMS, neurite density was significantly lower in both normal-appearing and demyelinated cortices compared to nNC (p=0.041 and 0.001), and in demyelinated vs. normal-appearing cortex (p=0.048). Demyelinated cortex showed also significant lower myelin density compared to normal-appearing cortex in both nNC and PwMS (p<0.001). Regarding the pathological substrate, T1w/T2w-ratio was positively associated with neurite density (β=3.464×10^-2, p=0.004), whereas only a trend for myelin density was found (p=0.082).

Conclusions

Both demyelination and neurite loss were found in the cortex of PwMS. By evaluating several histopathological markers in nNC and PwMS (in normal-appearing and demyelinated cortices), T1w/T2w-ratio was found to be sensitive to MS cortical damage and more specific to neurite than myelin density. T1w/T2w-ratio could be useful to investigate cortical damage in MS.

Background

Cortical lesions are common and often extensive in MS, and have been associated with worse disability and progressive disease. There is limited evidence that cortical lesions continue to form in progressive phases of the disease, when new white matter lesion formation is minimal, perhaps offering an explanation for worsening disability in progressive MS.

Objectives

We longitudinally characterized cortical lesions in an MS cohort with stable white matter lesion burden in the year prior to enrollment to determine whether new cortical lesions are more frequent in people with worsening disability.

Methods

45 adults with MS (30 relapsing remitting (RR), 13 secondary progressive (SP), and 2 primary progressive (PP)), underwent 7T brain MRI (T2*w and MP2RAGE, each with 0.5mm isometric resolution), 3T brain and spine MRI, and clinical evaluation annually for 1 year. Cortical lesions were segmented manually on 7T images and categorized as leukocortical, intracortical, or subpial. White matter and spinal cord lesion burden were also determined.

Results

At baseline, 93% of individuals (42/45) had at least 1 cortical lesion. Median cortical lesion number was higher in progressive MS (median 55, interquartile range (IQR) 96, range 2–177) than RRMS (median 15, IQR 21, range 0–108; p<0.01). Cortical lesion volume correlated with physical and cognitive measures of disability. There was only a weak correlation between subpial and white matter lesion volume (r=0.35, p<0.05). During 1 year of follow-up, 6 people (4 RR, 2 SP) developed 1 new cortical lesion each. 4 of the 6 new cortical lesions were leukocortical, 1 was intracortical, and 1 was subpial. 5 people developed new white matter lesions, none of whom developed a new cortical lesion. In 2 people, we observed white matter lesions expand into the cortex. 3/6 people with new cortical lesions were on highly effective disease-modifying therapy during the follow up period. There was no difference in new cortical lesion or new white matter lesion number in people with stable vs worsening disability.

Conclusions

Using sensitive 7T MRI techniques, cortical lesions are detected in almost all MS cases. Cortical lesions are associated with worse and progressive disability and may form independently from white matter lesions. New cortical lesions appear to form infrequently in people with stable white matter lesions, however current disease-modifying therapies may not be completely effective at stopping cortical lesion formation.

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS). It has been reported that OCR reduces brain atrophy in MS patients, however, a voxel-based approach has never been reported.

Objectives

To identify brain regions where atrophy is modified by the OCR treatment in Relapsing MS (RMS), using a fully automatic, voxel-based approach.

Methods

We applied longitudinal deformation-based morphometry (L-DBM) using the Advanced Normalization Tools (ANTs) to T1-weighted 3D MPRAGE brain MRI (voxel=1x1x3 mm3​ ​) from two clinical trials of OCR for RMS (Opera I: NCT01247324 and Opera II: NCT01412333). For each MRI visit, a Jacobian map was derived based on the deformation generated by registering the scan to a Single-Subject Template (SST) constructed for the same patient. Jacobian maps in patient SSTs were mapped to a population brain template for group analysis. Patients were included if MRI data were available for all visits (baseline, Weeks 24, 48, and 96) and the images were of sufficient quality to be successfully processed through the L-DBM pipeline (683 in the OCR arm, 580 in the active control arm of Interferon beta-1a). Voxelwise ANOVA was iterated over the whole brain to detect an interaction between Treatment and Time (​p​<0.01 with familywise error correction). Post-hoc analysis was done with mean Jacobian of identified regions, including Linear Mixed Effect (LME) analysis.

Results

Voxelwise ANOVA identified one cluster of voxels in the brain (besides the ventricles) that were contained within parts of thalamus, brainstem, and cerebellum. From the analysis of mean Jacobian of this cluster region, the percent volume reduction from baseline was significantly smaller in the treatment arm than the control arm at every follow-up visit (​p​<0.0001, ​t​>8.0, relative difference>75%). LME analysis of the mean Jacobian of the cluster region confirmed that there was a strong interaction between Treatment and Time (​F​=18.35), for which age and sex were controlled.

Conclusions

L-DBM has identified several brain structures where atrophy was modified by the OCR treatment in RMS. The L-DBM analysis was performed at the voxel level and these regional findings are consistent with previous reports. Localization of the treatment-responsive brain structures may have an implication for future assessment of clinical outcomes in MS.

Background

Chronic black holes (cBHs), characterized by severe myelin and axonal loss, are associated with higher disability levels in patients with multiple sclerosis (MS). However, whether cBHs impact perilesional tissue via retrograde and/or antegrade degeneration and how this remote pathology affects patient disability has not been investigated in vivo. Novel MRI techniques, such as selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment microscopic diffusion MRI spherical mean technique (SMT) have the potential to more accurately assess myelin and axonal injury in vivo, thus allowing us to measure remote tissue injury and its impact on patient clinical disability.

Objectives

To compare the macromolecular-to-free pool size ratio (PSR), derived from SIR-qMT, and apparent axonal volume fraction (V_ax), from SMT, values among cBHs, perilesional normal-appearing white matter (NAWM) and contra-lateral (distant) NAWM and test associations of these measures with disability in vivo.

Methods

Eighteen MS patients underwent 3T MRI consisting of clinical protocols, SIR-qMT and SMT. Regions of interest (ROIs) were manually placed on CBHs, perilesional NAWM and distant NAWM areas; PSR/V_axwere calculated and compared using a mixed effects model. Pearson correlation analyses tested the associations between PSR/V_ax values and patient clinical and MRI metrics.

Results

Compared to perilesional NAWM, both PSR (-43.3%, p<0.001) and V_ax (-29.7%, p<0.001) values were reduced in cBHs and increased in distant NAWM (10.2%, p<0.001 for PSR and 20%, p<0.001 for V_ax). A strong correlation was seen for cBH and perilesional NAWM V_axvalues (rho=0.63 p<0.001). No significant associations were seen between PSR/V_axvalues and other clinical or MRI metrics of disease apart from cBHs PSR, which correlated with the EDSS score (rho=-0.63, p=0.03). There was a trend for decreasing PSR and V_axvalues in all regions with worsening disease phenotype.

Conclusions

Our results show that myelin and axonal integrity, detected by PSR and V_ax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This is indicative of an ongoing anterograde and retrograde degeneration and suggests that preventing cBH development is a key factor for preserving NAWM integrity in surrounding tissue. PSR and V_axlargely failed to capture associations with clinical and MRI characteristics. However, the trends observed with disease phenotypes suggest that longitudinal assessment of a larger cohort may indeed unravel the impact of this pathology on disease progression.

Background

Clinical disability in multiple sclerosis (MS) is insufficiently explained by structural damage as measured with standard magnetic resonance imaging (MRI) measures. More advanced measures of brain network atrophy and functional network changes might better explain symptoms and clinical deterioration.

Objectives

To investigate the relevance of functional network alterations in addition to network atrophy for explaining physical disability in MS.

Methods

In this cross-sectional study 143 MS patients and 36 healthy control participants underwent resting-state magnetoencephalography (MEG) and structural MRI. Functional connectivity between regions was estimated using the phase lag index, from which the minimum spanning tree (MST) was constructed, representing the backbone of the functional network. The topology of the MST was described using the so-called tree hierarchy (MST-Th). Gray matter (GM) volume was calculated within literature-based resting-state network maps (i.e. visual, sensorimotor, dorsal attention, ventral attention, limbic, fronto-parietal, default mode, deep gray matter, and cerebellar networks). Physical disability was quantified with the Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (9HPT) and Timed 25-Foot Walk Test (TWT). Network atrophy and topology were compared between groups and related to disability.

Results

Atrophy was apparent in all resting-state networks. All volumes correlated positively (p<.001) with EDSS and 9HPT: Spearman’s ρ between .289 and .567, highest correlations for sensorimotor, default mode, fronto-parietal and dorsal attention networks. EDSS correlated negatively with MST-Th in the lower alpha band (α1) (p < 0.008), while 9HPT correlated negatively with MST-Th in the upper and lower alpha, gamma, delta and theta bands (p <0.05), indicating a less efficient network relating to worse disability. TWT was related to atrophy in all networks, but not network topology. Together, MST-Th-α1, age, cerebellar and fronto-parietal atrophy explained 36% of EDSS variance, while 19% of 9HPT variance was explained by deep GM atrophy and MST-Th-α1. Lesion volume had no added significant effect on variance.

Conclusions

These results suggest that more advanced measures of network atrophy and functional network topology can explain a significant degree of disability variance in MS. In addition, mobility scores were not related to network changes, which could imply different underlying pathological substrates compared to those that underlie upper limb dexterity.

Background

Myelin water imaging can isolate the magnetic resonance imaging (MRI) signal from myelin water, providing a quantitative measure associated with myelin, termed the myelin water fraction (MWF), which has been validated in histopathologic studies. The amyloid tracer ¹¹C Pittsburg compound B (PiB) also has an affinity for myelin and its binding can be reduced in MS lesions compared to normal-appearing white matter (NAWM). We sought to determine whether these myelin-sensitive techniques provide overlapping or complementary information in MS.

Objectives

To determine (1) whether MWF and PiB binding are decreased in lesions compared to NAWM and (2) if there is a correlation between MWF andPiB binding.

Methods

Eleven participants (5 relapsing-remitting MS, 3 secondary progressive MS, 3 primary progressive MS) were scanned on a 3T Philips MRI scanner, and on a Siemens HRRT PET scanner with an injection of 18 mCi ¹¹C PiB. Two RRMS participants were treated with glatiramer acetate 40 mg subcutaneously three times per week. MRI scans included structural scans for tissue segmentation and a myelin water sequence for MWF calculation. PIB binding was quantified with the Logan method-derived non-displaceable binding potential (BP_ND) using healthy grey matter from cerebellum as reference region. Lesion masks included all lesions within the imaging volume. Regional mean values of MWF and BP_ND were determined for NAWM and lesions.

Results

Lesions showed a 38% decreased MWF and a 23% decreased BP_ND compared to NAWM (MWF: lesions=0.08±0.01 vs NAWM=0.13±0.02, p<0.0001; BP_ND: lesions=0.91±0.08 vs NAWM=1.18±0.07, p<0.0001). A correlation was found between MWF and BP_ND when including both NAWM and lesions (r=0.73, p=0.0001). However, there was no correlation when fitting for NAWM or lesions alone (NAWM: r=-0.51, p=0.06; lesions: r=0.39, p=0.23).

Conclusions

In this pilot study, lesions showed a decrease in both myelin water and PiB binding as expected in demyelinated tissue. The partial correlation between MWF and PIB BP_ND suggests that each technique might have different sensitivity for detecting the severity of demyelination in heterogeneously affected tissue. PIB BP_ND values in NAWM were relatively homogenous. PIB BP_ND was good at discriminating between NAWM and lesions. MWF showed more subtle differences in myelination in NAWM and lesions. PET-PiB imaging and MWF appear to provide reliable measures of myelin abnormality in MS lesions. MWF may be able to provide additional information on the heterogeneity of demyelination in lesions and NAWM.

Background

Although quantitative measures from research-quality MRI relate well to clinical outcomes in persons with multiple sclerosis (PwMS), these metrics are largely unavailable in clinical settings.

Objectives

To determine how well a quantitative snapshot of brain pathology, measured on routine clinical T2-FLAIR MRI, relates to standard research-quality MRI, clinical disability, and clinical progression over mid-term.

Methods

This retrospective study of prospectively collected data was approved by the local Institutional Review Board. 3T MRI was acquired for 172 PwMS at baseline and neurologic disability was assessed at baseline and five-years later. Five measures (thalamus volume, lateral ventricle volume, medulla oblongata volume, lesion volume, and network efficiency) for quantifying disparate aspects of brain pathology from low-resolution T2-FLAIR were applied to predict similar measures obtained from research-quality MRI and associated with neurologic disability and disease progression over five years.

Results

The combination of the five T2-FLAIR measures explained most of the variance in standard research-quality MRI, including T2-lesion volume (R²=0.97, p<0.001) and thalamus volume (R²=0.90, p<0.001). T2-FLAIR measures (R²=0.279, p<0.001; R²=0.382, p<0.001) were associated with neurologic disability and cognitive function five-years later, similar to standard research-quality MRI (R²=0.279, p<0.001; R²=0.366, p<0.001). They also similarly predicted disability progression over five years (%-correctly-classified=69.8, R²=0.145, p=0.034), compared to standard research-quality MRI (%-correctly-classified=72.4%, R²=0.196, p=0.022) in relapsing-remitting MS.

Conclusions

T2-FLAIR measures explained considerable variance of standard research-quality MRI, correlated with neurologic disability, and predicted progression of disability over five years. Quantifying brain pathology at a single time-point with clinical-quality T2-FLAIR can be useful in clinical settings.

Background

Steroid treatment is a first-line therapy in acute multiple sclerosis (MS) episodes. While it is well-established that there is an inverse relationship between serum steroid-levels and decreases of cortical thickness (CT), little is known about the effects of steroid treatment during MS relapses on CT.

Objectives

In this study, we investigated whether CT changes occur in MS patients following steroid treatment after the first clinical episode in MS in a retrospective design. Additionally, we aimed to assess whether such effects were sustained.

Methods

T1-weighted magnetic resonance (MR) images were acquired from 8 MS patients during their first clinical episode (7 females, median age 27 years). At the time of that baseline scan, all patients were within 5 days of onset of prednisolone treatment (1000mg/day i.v.; steroid treatment was stopped after these 5 days). A first follow-up scan was acquired 4 weeks later. To check for sustained effects on CT (post-hoc), a second follow-up scan, 8 weeks after baseline, was acquired. Additionally, data from 8 age- and sex-matched healthy controls (HC) was acquired (baseline and 4 weeks later).

CT maps from all subjects were generated individually and parceled into 68 regions using the Desikan-Killiany atlas. We used a repeated measures analysis of variance to test for significant differences of CT changes between MS and HC over time. Family-wise error-corrected p-values (p_FWER) were calculated using a Monte-Carlo permutation procedure. Since the ANOVA yielded a significant interaction for one region, we investigated post-hoc whether that effect was still observable another four weeks after the first follow-up. To test for this effect, we used a paired t-test to compare mean CT levels of that region within the patient group between 4 and 8 weeks after treatment, as well as baseline vs. 8 weeks after treatment.

Results

The ANOVA showed a significant interaction of group x time for the medial orbitofrontal cortex (mOFC) of the right hemisphere (F = 21.956 , p_FWER = 0.011), with MS patients showing a decrease of mean CT within that region over time. No main effects were observed. A post-hoc paired t-test comparing the CT means within the mOFC at a second follow-up scans eight weeks after baseline revealed no significant difference between follow-up 1 and follow-up 2 (t₇ = -0.9841, p = 0.3578) and approached significance for the comparison between baseline and follow-up 2 (t₇ = 2.3513, p = 0.0510).

Conclusions

Our results provide first evidence that steroid treatment during the first acute episode in MS was associated with cortical thinning in the mOFC, which tended to reverse after eight weeks of steroid-free treatment. Although these results need to be further validated in a larger cohort, our results suggest that steroid treatment potentially associates to atrophy in the medial orbitofrontal cortex; an effect which – if validated – should be taken into account for MS therapy.

Background

Cognitive processing speed deficits are common in multiple sclerosis (MS). Despite this, the exact neural mechanism underlying slowed information processing speed remains unknown. Furthermore, functional magnetic resonance imaging (fMRI) using only blood-oxygen-level-dependent signal may not be sensitive to MS-related metabolic changes affecting processing speed ability. Previous work has shown that cerebral metabolism in motor and visual areas are associated with performance on motor and visual tasks, however, it is unknown if task-based metabolism in the dorso-lateral prefrontal cortex (dlPFC), a region known to be involved in processing speed, is related to the slowed processing speed observed in MS.

Objectives

We aim to assess whether metabolism in the dlPFC, a processing speed region, is associated with MS-related processing speed deficits.

Methods

MS and healthy control (HC) participants who met inclusion criteria were scanned using a 3T MRI scanner with a dual­echo calibrated fMRI (cfMRI) sequence which provided near­simultaneous measures for both cerebral blood flow (CBF) and BOLD signal. During imaging, participants performed a block-design digit-symbol substitution task (DSST) that required the viewing of a digit-symbol pairing key and responding as to whether a probe digit-symbol pair matched the key as fast as they could using button boxes. A hypercapnia gas challenge involving periodic inhalation of room air (4 min) and 5% CO2 (6 min) permitted measures of cerebral metabolic rate of oxygen (CMRO2). Data were preprocessed and average percent signal change from baseline was calculated in each voxel providing BOLD and CBF time series. The anatomical region of interest (ROI) was defined as dlPFC after Freesurfer cortical parcellation. Regression analyses were performed controlling for ROI size to assess whether BOLD, CBF, or CMRO2 could explain variability in processing speed ability.

Results

An independent-samples t-test showed that the MS group had a significantly higher response time (RT) for the DSST (t[50]=3.12, p=.003) compared to HCs. Within the MS group, regression analyses using RT for correct trials as the dependent factor were not significant for BOLD and CBF PSC but was significant for CMRO2 (R²=.170, p=.053) after controlling for number of voxels within the ROI. No regression analyses were significant within the HC group.

Conclusions

Our analyses suggest that metabolism, not BOLD or CBF, in dlPFC, a region known to involved in processing speed, explains MS-related slowed processing speed.

Background

Chronic active multiple sclerosis (MS) lesions, characterized by a hyperintense rim (rim+) on quantitative susceptibility mapping (QSM), have been shown to contain iron-enriched, activated microglia and macrophages. QSM is a potential biomarker to monitor treatments directed toward the CNS inflammation. Studies have suggested that dimethyl fumarate (DMF) may reduce the pro-inflammatory innate immune response in the CNS. A comparison to other disease modifying therapies (DMTs) is warranted to evaluate this potential benefit.

Objectives

To determine if dimethyl fumarate (DMF) reduces the iron load, as measured on QSM, in chronic active MS lesions at a greater rate than glatiramer acetate (GA) treatment.

Methods

Sixty-one patients (41 female, 20 male, mean age: 42.1 years +/- 10.9 and EDSS 0.82 +/- 1.2), were considered for this analysis. Fifty-six patients had relapsing-remitting MS and 5 had clinically-isolated syndrome; 37 patients were treated with DMF and 24 with GA. The two treatment groups had similar baseline clinical characteristics; however, DMF patients had less time on treatment as compared to GA (3.86 +/- 1.75 years vs 5.99 +/- 2.67 years, p<0.001). Patients had a QSM scan prior to treatment and a minimum of two on-treatment QSM MRIs. Lesions were classified as rim+ or rim- negative based upon a review of two independent reviewers. To compare longitudinal QSM change in the rim+ lesions among treatment groups, a linear mixed effects model was utilized.

Results

At baseline, patients treated with GA had more QSM rim+ lesions (9.4%) as compared to those starting DMF (4.5%), p=0.0004, however the number of patients having at least one rim+ lesion was similar (16 vs 18 patients) among the treatment groups. DMF patients with rim+ lesions had a longer disease duration as compared to rim+ GA patients (8.15 +/- 6.82 vs 3.55 +/- 4.85 years, p= 0.032). In the subset of patients with QSM rim+ lesions, there was a significantly larger decrease in susceptibility in rim+ lesions with DMF treatment as compared to GA, p< 0.0009. There was minimal reduction of susceptibility in rim- lesions, which was similar among treatment groups; all patients (p=0.92) and QSM rim+ only patients (p=0.11).

Conclusions

This study suggests that DMF reduces the iron load in rim+ MS lesions at a greater rate than GA. These results support QSM to evaluate the effectiveness of various DMTs on the CNS innate immune response in chronic active MS lesions.

Background

[Background]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). However, there is a lack of appropriate methods to monitor CNS myelin in daily practice. We successfully developed a novel imaging method, titled q-space Myelin Map (qMM). The qMM accurately depicted myelin status in a pilot clinical study of patients with MS, suggesting that it may be useful in detecting remyelinated lesions.

Dimethyl fumarate (DMF) has demonstrated its sustained efficacy on relapses and disability progression in patients with relapsing-remitting MS (RRMS). However, limited reports exist to indicate the potential for remyelination with DMF.

Objectives

[Objective]

To report the interim results of the efficacy of DMF on qMM recovery, which suggests remyelination activity, in patients with RRMS.

Methods

[Methods]

Nineteen RRMS patients were registered and 14 of those were evaluated as of February 2020. After initiating DMF, a longitudinal analysis of qMM was performed with 3-12 month intervals to detect q-MM supported remyelination and demyelination. The expanded disability status scale (EDSS) assessment and the qMM analysis were performed independently by board-certified neurologists. The study was approved in advance by the ethics committee of Keio University School of Medicine (#20170311).

Results

[Results]

A total of 14 patients were included in the analysis. The age and EDSS at baseline (mean ± standard deviation) were 37.6±10.2 years and 1.9±1.5, respectively. Prior disease-modifying therapies included glatiramer acetate (n=1), fingolimod (n=10) and natalizumab (n=1); two patients were treatment-naïve. Mean time to start DMF after MS onset was 80.1±95.9 months and DMF treatment duration was 23.1±9.4 months. Three patients discontinued DMF: reasons were disability progression (n=1), new MRI lesion (n=1) and entry of another clinical trial (n=1). One patient interrupted DMF due to pregnancy (n=1). Out of the 14 patients, 6 (42.9%) had presence of remyelination. Of those 6 patients, 3 had presence of remyelination only while 3 also had presence of demyelination. No patients were detected with demyelination only. In all 6 cases of remyelination, the remyelination was detected in the first year of DMF treatment.

Conclusions

[Conclusions]

The qMM successfully visualized remyelination activity in MS patients treated with DMF. The association between qMM-supported remyelination and disease progression should be further investigated in a larger population.

Background

Within multiple sclerosis (MS) lesions, T1 weighted hypo-intensity correlates with pathological markers of irreversible damage, including axonal degeneration. Studies have found that T1 “black holes” have a higher correlation with clinical disability than do T2 weighted lesions, and that measurable T1 signal drop out occurs within slowly enlarging lesions or chronic active lesions, as opposed to inactive lesions, suggestive of ongoing axonal degeneration.

To perform this quantitative analysis two pre-processing steps are necessary. The first is correction of low frequency intensity nonuniformity present in image data, also known as bias fields. The second is normalisation of the signal between subjects and timepoints. Both of these steps need to maintain representative contrast between pathological and normal appearing white matter (NAWM) to provide accurate results. Validation of these methods within the MS context is needed to support their use as a biomarker in MS.

Objectives

To assess the accuracy N3⁴ bias correction on maintaining accurate MS lesion contrast

To assess the accuracy of Freesurfer normalization tool⁶ in maintaining accurate relative signal intensity

Methods

21 relapsing MS and 26 progressive MS subjects had MRI brain scans with 1mm³ 3D T1 fast spoiled gradient echo (FSPGR), and 0.6 x 0.46mm2 FLAIR sequences. FLAIR images were resampled and linearly registered to the T1 using FLIRT. MS lesions were segmented from the FLAIR using JIM software.

To calculate an accurate measure of local tissue contrast between MS lesions and surrounding NAWM, the lesion segmentations were dilated and masked for white matter segmentation. The lesion mask was then subtracted from the segmentation to create an edge of NAWM surrounding the lesion. The measure of raw local tissue contrast was taken as the T1 value of

lesion core / lesion edge

N3 bias correction was done with the Freesurfer command mri_nu_correct.mni. Normalization of the T1 sequences was undertaken with Freesurfers mri_normalize which imposes a hard ceiling effect on the white matter peak found, creating an homogenous NAWM intensity of 110 and CSF intensity of ~35.

Correlations of each MS lesion between the bias field corrected and local tissue contrast was explored. Correlations between the bias field corrected and normalized values was explored.

Results

A total of 2401 lesions were analysed. N3 bias corrected T1 images correlated with local tissue contrast of the raw T1 images with an R² = 0.7556. Normalized T1 images correlated with N3 bias corrected images with an R² = 0.9415. Average MS lesion normalized T1 intensity was similar between relapsing MS and progressive MS cohorts (82.927 vs 82.793, p = 0.42).

Conclusions

In this analysis T1 intensity was able to be corrected for bias fields and normalized to a set range with reasonable accuracy in maintaining lesion contrast. This supports the use of these methods as a biomarker in quantifying the T1 signal within MS lesions.

Background

Spinal cord atrophy contributes to disability in multiple sclerosis (MS), and its quantification along the entire spinal cord may be important to fully characterize the disease.

Objectives

We sought to characterize atrophy of the entire spinal cord in various multiple sclerosis phenotypes and determine its clinical correlates in a cross-sectional study. Further, we sought to evaluate its evolution in a longitudinal study of relapsing remitting MS (RRMS).

Methods

Axial T₁-weighted images perpendicular to cord edge were automatically reformatted at each point along the cord. Spinal cord cross‐sectional area (SCCSA) were calculated from C1-T10 vertebral body levels and profile plots were compared across phenotypes. Average values from C2-3, C4-5, and T4-9 regions were compared across phenotypes and correlated with clinical scores, then categorized as atrophic/normal based on z-scores derived from controls, to compare clinical scores between subgroups. In the subset of relapsing-remitting cases with longitudinal scans, cases showing clinical progression (progressive-disability group) were defined as those in whom change in EDSS was ≥ 1 , while all other cases were grouped as having stable-disability. A random coefficient model for longitudinal data was applied to evaluate the change of regional-SCCSA variables over time, including in the model the disability group (progressive vs. stable), age, and the interaction between disability group and age.

Results

The cross-sectional study consisted of 149 adults with RRMS, 49 with secondary-progressive MS, 58 with primary-progressive MS and 48 healthy controls. The longitudinal study included 78 RRMS cases. Compared to controls, all MS groups had smaller average regions except RRMS in T4-9 region. Measures from all regions of the RRMS cohort correlated with clinical measures, whereas the progressive cohorts had fewer clinical correlates. In the RRMS cohort, 23% of cases had at least one atrophic region, whereas in progressive MS the rate was almost 70%. Longitudinal analysis demonstrated a correlation between disability and cervical cord thinning, as the random coefficient model showed a significant interaction between groups (stable- vs. progressive-disability) and age for cervical regional-SCCSA variables, indicating that the rate of decrease in regional-SCCSA with age in the progressive disability group was significantly higher than that in the stable disability group (0.62 mm²/year vs. 0.07 mm²/year for C2–3, p=0.0015; 0.72 mm²/year vs. 0.29 mm²/year for C4–5, p=0.0038).

Conclusions

Spinal cord atrophy was demonstrated in all MS phenotypes, with SCCSA from all regions showing significant correlations with all clinical parameters in RRMS cohort. Longitudinal changes in the cervical regions were significantly higher in RRMS subjects showing clinical progression than those who did not. SCCSA is therefore a potential imaging marker for disease progression.

Background

Postmortem MRI provides precious insights into the relation of MRI metrics to pathoanatomical features of multiple sclerosis (MS) and can help to understand the basis of damage and repair.

Objectives

To investigate the respective features of MS lesions in the cortex and in the white matter using multiparametric postmortem MR imaging at 3T and identify discriminant characteristics of white matter lesion subgroups.

Methods

We scanned three fixed brains of secondary-progressive MS patients (mean disease duration 15.3 years) on a standard clinical 3T-MRI scanner with following sequences: Magnetization Transfer Saturation (MTsat), T1-relaxometry (T1-rt), Myelin Water Fraction (MWF) and Diffusion Tensor - Fractional Anisotropy (DTI-FA). We compared these metrics between (i) cortical lesions (CL, n=118) and normal-appearing grey matter (NAGM, n=186) and (ii) white matter lesions (WML, n=140) and normal-appearing white matter (NAWM, n=53) using a Mann-Whitney U test. Then, we analyzed the differences between different subgroups of WML (periventricular lesions -PVL-, n=38, WM part of leukocortical lesions -WMLCL-, n=36, subcortical lesions -SCL-, n=66, and areas of “dirty white matter” -DWM-, n=15) by performing a Kruskal-Wallis test and a Mann-Whitney U tests for direct comparison. Bonferroni correction for multiple-testing was applied.

Results

CL exhibited lower MTsat (p<0.001), higher T1-rt (p<0.001) and MWF (p<0.01) than normal appearing cortical tissue. WML showed lower MTsat (p<0.001), higher T1-rt (p<0.001), and lower MWF (p<0.001) than normal appearing white matter. DTI-FA did not differ between CL/WML and NAWM/NAGM. MTsat values were lower in the PVL (p<0.001) and higher in the DWM (p<0.001) in comparison to all other lesion subgroups. T1-rt were higher in PVL (p<0.001) compared to the other lesion subgroups. MWF values were higher in DWM and SCL (p<0.01), not statistically different between PVL and WMLCL. DTI-FA values were lower in WMLCL in comparison to all other subgroups (p<0.01) and did not differ between the other categories.

Conclusions

Postmortem MRI metrics in WML/CL as well as in different subgroups of WML, are compatible with myelin damage and tissue destruction. Interestingly, MWF was higher in CL than in NAGM, which might correspond to a predominance of “myelin blistering” pathology in the cortex. Ongoing work aims to directly correlate our findings with detailed histopathological characterization including electron microscopy of myelin damage.

Background

Neuropathological examinations of multiple sclerosis (MS) brains indicate sub-pial cortical grey matter (GM) demyelination and damage occurring according to a “surface-in” gradient related to elevated levels of inflammation compartmentalized in sub-arachnoid spaces and meninges. Quantitative susceptibility mapping (QSM) is an MRI technique sensitive to changes in iron or myelin.

Objectives

To test the ability of QSM to detect and localize alterations in cortical iron/myelin content in MS and to investigate possible QSM alterations possibly caused by cortical thinning.

Methods

A group of 105 RR-MS patients (40.7±10.2 y mean±std; m:f 13:92; EDSS median 2 (0 - 6)) and 21 matched healthy controls (HC; 39.5±10.5 y; m:f 8:13) were examined by using 3T MRI 3D-EPI (0.5x0.5x0.5mm), 3D T1w (1x1x1mm) and a 3D FLAIR sequence (1x1x1mm). QSM was computed using a total generalized variation algorithm. T1 lesion filled images were analyzed with Freesurfer to reconstruct WM/GM and pial surfaces. QSM was sampled across the entire cortex with steps of 25% of cortical volume (0%: WM/GM, 100%: pial surface) and projected to the 32k vertices Conte-69 template. Group-wise QSM differences were performed by a permutation-based ANOVA test employing threshold-free cluster enhancement to correct for multiple comparisons (p<0.05 FWE corrected). A vertex-wise cortical thickness (CTh) regressor was used to investigate the impact of cortical thinning on QSM alterations.

Results

Significant differences in QSM showing higher susceptibility in RR-MS than HC were present in majority in cerebral sulci (21, 55 and 55% at 25, 50 and 75%) compared to gyri (9, 37, 38% at 25, 50 and 75%) and in the outer portion of the cortex compared to the inner cortex. The percentage of vertices significantly altered was higher in the outer layer (75%) respect to the inner ones (25%) in several regions, including portions of temporal and parietal lobes, precuneus and para- and post-central sulcus. The use of the CTh regressor, showed significant alterations in the same regions, and revealed further alterations of the cingulate cortex.

Conclusions

Surface analysis of QSM exhibits the presence of increase susceptibility in the cortex of MS patients compared to HC: the alterations are more extended in the outer layers of the cortical ribbon than the inner ones, supporting the hypothesis of a “surface-in” gradient of iron/myelin alterations in the cortex of MS patients. Moreover, these differences were not entirely explained by the presence of cortical thinning.

Background

Microglia are iron-rich cells, found surrounding multiple sclerosis (MS) lesions in areas of active inflammation. Quantitative Susceptibility Mapping (QSM) can detect this increased iron and thus could be a novel MRI biomarker for microglia-associated inflammation in the brain. The proportion of patients with active inflammation is currently unknown, as is the proportion of MS lesions seen on conventional MRI sequences that are active across patients. Ultra-high field MRI (7 Tesla +) provides superior signal to noise and susceptibility contrast making it the optimal method for detecting iron in MS lesions and tracking active inflammation.

Objectives

To compare the number of lesions with positive QSM signal indicating active inflammation with lesion size and number in patients with relapsing-remitting MS (RRMS) using 7T MRI.

Methods

21 people with RRMS (mean ± SD age = 42 ± 11 yrs; sex: 2m/19f; mean ± SD disease duration = 5.5 ± 3.2 yrs; all EDSS < 4; no relapses in previous 12 months) were scanned using MP2RAGE anatomical and multi-echo gradient echo sequences on a Siemens 7T MAGNETOM MRI scanner. MP2RAGE was used to identify lesions and then co-registered to QSM (calculated from gradient echo phase images using an in-house pipeline). The number of lesions with an average QSM value over 0 (QSM+), indicating the presence of iron associated with active inflammation, were compared to the total number and total volume (log₁₀ transformed) of lesions across patients using linear regression.

Results

The number of lesions in patients ranged from 3 to 92 (mean ± SD = 33 ± 25) and volumes ranged from 26 to 14505 mm³ (mean ± SD = 2554 ± 3445 mm³). Across all patients, the average proportion of QSM+ lesions was 0.61 (95% CI = 0.50-0.72, R²=0.87, p<0.0001), and for each log₁₀ cubic millimeter change in the lesion volume, there were an additional 15 QSM+ lesions (95% CI = 7.0-24, R²=0.43, p=0.0012). There were no associations between the proportion of QSM+ lesions and any disease or demographic variables.

Conclusions

Irrespective of disease severity or duration, the proportion of QSM+ lesions was highly consistent. Based on the assumption that QSM+ lesions are undergoing active inflammation, our results indicate that around ~60% of lesions in RRMS patients could be active.

Background

The presence of infratentorial lesions early in the disease has been shown to have prognostic value for future disability in multiple sclerosis (MS). Quantitative imaging metrics such as T1 relaxometry might contribute to understanding the relationship between supratentorial (ST), infratentorial (IT), and spinal cord (SC) pathology.

Objectives

Our aim was to explore the association between ST, IT and SC pathology and microstructural tissue alterations assessed with T1 relaxometry in T2-hyperintense lesions as well as cerebral and cerebellar normal-appearing white matter (NAWM) in patients with recently diagnosed MS with- and without IT lesions.

Methods

Microstructural tissue alterations were assessed in 42 patients (mean age 33.6±8.0 years, median MS duration 0.2 years (0-2.3)) as deviations from normative T1 times, both obtained from the MP2RAGE sequence at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The normative T1 values were voxel-wise modelled via a study-specific atlas based on spatially normalized data from 102 healthy individuals (21-59 years). Relationship between normalized IT volumes (mesencephalon, pons, medulla oblongata, cerebellum), SC volume, ST and IT lesion loads estimated by the Morphobox prototype, Scanview and LemanPV prototype, respectively and the deviations from normative T1 times expressed as z-score-derived metrics (volumes and means of voxels with z-scores above z-score 2 and below z-score 2) in lesions, cerebral and cerebellar NAWM were studied by partial correlations adjusted for age and brain lesion volume.

Results

Patients with IT lesions (n=23, 33.0±8.5 years) had larger lesion load, higher volumes of voxels with positive z-scores (> 2), higher mean of z-scores above 2 in lesions, and larger thalami than patients without IT lesions (n=19, 34.3±7.7 years). The remaining volumes and z-scores derived metrics did not differ between groups. Cerebellar volume correlated negatively with volume of voxels with negative z-scores (< 2) in cerebellar NAWM (partial correlation coefficient r=-.437, p=.005) only in patients with IT lesions. In patients without IT lesions, SC and pons volumes correlated negatively with volume of voxels with positive z-scores corresponding to areas of supratentorial T2 lesions (SC: r=-.669, p=.003, pons: r=-0.606, p=0.01).

Conclusions

Microstructural alterations identified as T1 z-scores relate differently to IT and SC volumes in MS patients with and without IT lesions. In the presence of IT lesions, changes in cerebellar NAWM (T1 shortening relative to healthy controls) are associated with lower cerebellar volume. In the absence of IT lesions, the association of cerebellar NAWM and cerebellar volume is not present. In patients without IT lesions, microstructural alterations in ST lesions (T1 prolongation) that might indicate the extent of tissue damage in lesions, are associated with lower pontine and SC volumes regardless of the T2 lesion load.

Background

Although conventional MRI acquisitions are of essence in the monitoring of MS, they show low specificity towards the microstructural nature of tissue alterations and exhibit rather low correlations with clinical metrics (“clinico-radiological paradox”). Conversely, recent advances in brain relaxometry allow characterizing microstructural alterations on a single-subject basis; the question yet remains whether such quantitative measurements can help bridging the gap between radiological and clinical findings.

Objectives

This study investigates whether automatically assessed alterations of T₁ relaxation times in brain lesions and normal-appearing white matter (NAWM) improve clinico–radiological correlations in early MS with respect to conventional measures.

Methods

102 healthy controls (65% female, [21-59] y/o) and 50 early-MS patients (76% female, [19-52] y/o) underwent MRI at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The employed 3D protocol comprised MPRAGE, FLAIR (both used for lesion segmentation as in [Fartaria et al., 2017, MICCAI]), and MP2RAGE for T₁ mapping.

After the healthy controls’ data were spatially normalized into a study-specific template, reference T₁ values in healthy tissues were established by linear, voxel-wise modelling of the T₁ inter-subject variability [Piredda et al., MRM, 2020]. In the MS cohort, T₁ deviations from the established references were calculated as z-score maps.

Correlations between the EDSS and conventional measures, i.e. lesion volume and count, were compared against correlations with z-score-derived metrics in lesions and NAWM, namely the volume of voxels exceeding a given z-score threshold.

Results

Correlations between EDSS and lesion volume and count were found to be 0.23 and 0.18, respectively. Higher correlations were found between EDSS and the volume of voxels exceeding an absolute z-score threshold of 2, both in lesions and NAWM, with ρ=0.3 and ρ=0.33, respectively. Correlation further improved when considering only negative z-scores, ρ=0.36 for lesions and ρ=0.39 for NAWM. The highest correlation was found when considering absolute z-scores in the occipital lobe NAWM, ρ=0.47.

Conclusions

Microstructural alterations identified as T₁ z-scores were found to improve clinico–radiological correlation in comparison to conventional measures (lesion volume and count). Of notice, negative z-scores (i.e. abnormal T₁ shortening), which may be due to an increase in iron content, appear to be a potential predictor for the clinical state of an early MS patient.

Background

Magnetic resonance imaging (MRI) analyses play a key role both in treatment monitoring of patients with multiple sclerosis (MS). In MS clinical trials MRI analyses are carried out based on highly standardized protocols, comparable standards are yet to be implemented in routine clinical practice.

Objectives

To evaluate whether standardization of MRI acquisition, volumetric quantification and computerized lesion evaluation of MRI data provides an additional benefit to neurologists working in day-to-day MS patient management.

Methods

From July 2016 until December 2019 297 neurological centers across Germany participated in the QUANTUM project. In total 9,000 MRI data sets from 6.718 MS patients were acquired from 183 radiological centers which all underwent a qualification procedure. Standardized MRI data (3D T1 gradient-echo sequence and 2D/3D FLAIR) were analyzed by a centralized automatic processing pipeline (Biometrica MS®, jung diagnostics GmbH). The analysis comprises volumetric quantification of brain volume, as well as T2 lesion load and number. Percentage brain volume change (using an optimized SIENA pipeline) and T2 lesion activity were computed if follow-up scans were available. The results were visualized and provided to the participating physicians as a report. The benefit and feasibility were evaluated using questionnaires.

Results

Analysis of 8087 questionnaires revealed a good acceptance and usability of the QUANTUM reports. 70% of neurologists reported a strong/very strong correlation between the quantitative MRI parameters and the clinical evaluation of MS patients. More than 74% of neurologists were able to use the report to better classify the patient's disease activity. They rated the additional benefit of the quantitative MRI parameters as high/very high in terms of achieving all four NEDA criteria. 24.4% of the neurologists weighted MRI as more important for therapy decision making than at the beginning of the project. The full data set will be available for presentation.

Conclusions

With QUANTUM standardization of MRI acquisition and MRI evaluation was transferred into daily clinical practice. Volumetric quantification and computerized lesion evaluation can be provided reliably if standardized MRI protocols are used. Quantification of lesion load and volume and visualization of MRI abnormalities might be beneficial for the use of MRI data by neurologists in general and support the individual patient management.

Background

Magnetic resonance imaging (MRI)-based measures have been established as robust, non-invasive, in vivo biomarkers of disease. Although the relationship between quantitative regional MRI volume measures and selected aspects of clinical disability in MS has been described, characterization of specific trends by race/ethnicity is lacking.

Objectives

To characterize racial disparities in disability-specific patterns of MRI-based volumetric measures between Hispanic and non-Hispanic Caucasian individuals with MS and explore the relevance of regional brain volumetric measures as predictors of clinical disability progression.

Methods

MRI from 94 Hispanic and 94 Caucasian MS patients was analyzed using automatic and manual brain segmentation techniques. Scans were done between January 2010 and December 2019 on a single 3.0-Tesla scanner using a standardized imaging protocol. Whole brain, cortex, white matter, basal ganglia, thalamus, corpus callosum, lateral ventricular, and T2 lesion volumes were measured and compared with the extent of neurological impairment as measured by Expanded Disability Status Scale (EDSS) scores at baseline and in subsequent follow-up visits. Cox proportional hazard regression models determined the predictive value of baseline MRI metrics for sustained EDSS progression in a time-to-event analysis.

Results

At baseline, Hispanic patients had a higher median EDSS score (median [IQR], 2.0; [1.0–3.5]) compared to Caucasians (median [IQR], 1.0 [0.0–2.0]). In addition, Hispanics were found to develop more rapid accumulation of clinical disability and an increased risk of requiring assistance to ambulate (hazard ratio (HR), 9.7; 95% confidence interval (CI), 2.8–32.5). T2 lesion volume was associated with EDSS in Hispanics (r_s = .38, p < .001), and white matter volume was moderately correlated with disability in Caucasians only (r_s = -.41, p < .001). The association between normalized thalamic volume and EDSS scores was moderate in both (r_s = -.42, P < .001 in Hispanics and r_s = -.32, P = .002 in Caucasians). Baseline thalamic volume was the best predictor of sustained disability worsening in both. Patients with thalamic volumes below the mean had a higher risk for progression, with greater risk in Hispanics (HR, 7.9; 95% CI, 3.5–17.9) compared to Caucasians (HR, 3.0; 95% CI, 1.5–6.4).

Conclusions

Quantitative MRI assessment of brain and lesion volume is a useful tool to explore the influence of race on clinical disease expression in multiple sclerosis. Racial disparities in baseline volumetric MRI correlates of clinical disability suggest a burgeoning trend of possibly differentially regulated pathophysiologic processes through which race-dependent disparities may manifest. The confounding impact of race and ethnicity on brain volumetric measures may affect the interpretation of outcome measures in clinical MS studies and should be controlled in randomized clinical trials.

Background

Magnetic resonance imaging (MRI) is widely used for the diagnosis and follow-up of patients with multiple sclerosis (MS). It is considered the most reliable and accurate paraclinical tool to evaluate disease activity and progression due to the high sensitivity to detect demyelinating lesions. Coordination between Neurology and Neuroradiology departments is essential to ensure that radiological studies are effectively performed and interpreted. However, in clinical practice, this coordination can be improved to maximize MS management and care.

Objectives

To establish a set of organizational recommendations focused on the coordination between neurologists and neuroradiologists to improve MS management in clinical practice.

Methods

A panel of 17 experts, including neurologists and neuroradiologists, from eight Spanish academic hospitals participated in the study. The Consensus Recommendation Guideline was conducted in four phases: 1) definition of the scope and methodology of the study; 2) review of the literature on good practices or recommendations in the use of MRI in MS; 3) discussion of drafted recommendations to achieve a consensus between the authors; 4) formalization and validation of the contents in a set of recommendations.

Results

We provide nine recommendations to improve the coordination between Neurology and Neuroradiology departments, which can be summarized as follows: 1) standardize the MRI requests, reports and schedules, 2) create shared protocols for MRI studies, 3) establish multidisciplinary working committees and coordination sessions, and 4) generate formal communication channels to improve the coordination between professionals from both departments. These recommendations are based on the available scientific evidence, international good practice guidelines and the experience of the panel experts.

Conclusions

We propose a series of recommendations expected to serve as a functional guide to implement improvements in the coordination between neurologists and neuroradiologists that will ultimately lead to improve the diagnosis and follow-up of MS patients.

Background

In multiple sclerosis, the interplay of neurodegeneration, demyelination and inflammation leads to changes in neurophysiological functioning.

Objectives

This study aims to characterise the relation between reduced brain volumes and spectral power in multiple sclerosis patients and matched healthy subjects.

Methods

During resting-state eyes closed, we collected magnetoencephalographic data in 67 multiple sclerosis patients and 47 healthy subjects, matched for age and gender. Additionally, we quantified different brain volumes (white matter, cortical and deep grey matter, FLAIR lesion load and volume of black holes) and calculated the power spectral density. Instead of using the traditionally used frequency bands, we calculated the source reconstructed power spectral density in frequency bins of 0.25 Hz (range: 0-40 Hz) and corrected for multiple comparisons through permutation testing.

Results

First, a principal component analysis (PCA) of brain volumes demonstrates that atrophy can be largely described by two components: one overall degenerative component that is indicative of brain integrity and correlates strongly with different cognitive tests, and one component that mainly captures degeneration of the cortical grey matter that strongly correlates with age. As the first PC was observed both when performing the PCA on the full cohort and on the two subcohorts, we denote this component as an index of brain integrity. Logically, this component was more strongly expressed in the MS cohort.

Next, a multimodal correlation analysis indicates that reduced brain integrity is accompanied by increased alpha1 power in the temporoparietal junction (TPJ). Patients showing this local increase in alpha-peak also scored significantly worse on different cognitive tests and reduced thalamic volumes. The increase in alpha1-power comes from both a slowing of the main alpha-peak and an increase in power.

Conclusions

MS patients with reduced brain integrity demonstrated increased alpha1 power in the TPJ and impaired cognitive functioning.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and can impair processing speed, episodic memory, and executive function. Magnetic resonance imaging (MRI) studies have demonstrated associations between several MRI metrics and cognitive functioning in MS, including thalamic volume and brain parenchymal fraction. Fingolimod is an MS therapy that demonstrated reduced brain volume loss across several clinical trials.

Objectives

Determine the relationship between cognitive function in fingolimod-treated relapsing-remitting MS patients and 7 tesla (7T) MRI measures.

Methods

We recruited fingolimod-treated MS patients and healthy controls to be followed for 12 months. Participants underwent 7T brain MRI and cognitive testing including the symbol digit modalities test (SDMT), selective reminding test (SRT), and the trail making, color, and verbal subtests of the Delis-Kaplan Executive Function System (DKEFS) at baseline, 6 months, and 12 months. Mixed effects linear regression models were used to determine the relationship between MRI metrics and neurometric test performance, fitting values from all 3 time points. Rates of change in MRI metrics and neurometric test performance were compared between patients and controls using two-sample t-tests.

Results

We enrolled 15 MS patients with mean age 42.4 years (SD=5.6), mean disease duration 8.5 years (SD=4.1), and median expanded disability status scale 3 (IQR=1.5-3.5). Five controls were enrolled with mean age 41.5 (SD=6.6) years. Controls performed better than patients on all psychometric tests, but this was only significant for tests of orthographic knowledge (DKEFS letter fluency) and long-term storage (SRT). When MRI metrics were used to predict neuropsychological test performance over time in patients, thalamic volume was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and inhibitory control (DKEFS Color Inhibition). Thalamic myelin density was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and semantic knowledge (DKEFS Verbal Category Fluency). When changes in neuropsychological testing performance and MRI metrics were compared for patients and controls from 0-6 months, and from 0-12 months, none of the differences between patients and controls were significant.

Conclusions

Thalamic volume and myelin density are associated with measures of cognitive function. 7T MRI of the thalamus may be useful as a clinical trial measure to predict cognitive effects.

Background

Recent examinations of the cerebellum have found relationships to higher level processes (i.e., cognition, mood). Mood disturbance is highly prevalent in multiple sclerosis (MS), yet, most studies examining the role of the cerebellum in MS have focused on disability or cognitive functioning, despite cerebellar changes being linked to mood disturbance (e.g., depression) in other clinical populations.

Objectives

The aim of the current study is to examine the relationship between cerebellar gray matter volume and white matter connectivity and mood in persons with MS.

Methods

Forty-eight participants were divided into three groups: MS with depression (MS+D; N=22), MS without depression (MS-D; N=11), and Depression without MS (D-MS; N=15). Each participant completed self-report mood questionnaires (Beck Depression Inventory-Fast Screen; Chicago Multiscale Depression Inventory; Apathy Evaluation Scale; Depression Proneness Rating Scale). Multi-shell diffusion MRI and structural data (T1, T2 FLAIR) were collected. Deterministic tractography was performed and structural connectivity (i.e., graph theory) analyses were conducted within the cerebellum. Five graph theory metrics were calculated- density, clustering coefficient, path length, small worldness, global efficiency- for number of normalized streamlines and quantitative anisotropy (QA). Gray matter volume (mm3) was calculated for the anterior and posterior cerebellum and 16 separate cerebellar lobules. Whole brain lesion volume was also calculated. Analyses of variance (ANOVA) determined group differences for self-report and brain measures. The two MS groups were also combined to conduct ridge regression analyses for brain metrics vs. mood severity.

Results

Significant differences were observed between groups on all mood measures. MS+D and MS-D had significantly greater whole brain lesion volumes than D-MS. After correcting for multiple comparisons, MS+D had significantly lower streamline clustering coefficients and global efficiency compared to MS-D. MS+D showed significantly decreased volume in lobules I-IV, Vermis Crus II, and lobule VIIIb when compared to MS-D or D-MS, though they did not survive Bonferroni correction. The combined MS group showed less efficient connectivity (clustering, global efficiency) to be related to greater depression severity/proneness and apathy. Similarly, greater atrophy within the anterior cerebellum, Vermis Crus II, I-IV, lobule VIIIb, Vermis IIIb, and Vermis IX were related to depression severity/proneness and apathy.

Conclusions

This study is among the first to examine mood in persons with MS through a cerebellar volumetric and structural connectivity lens. Results provide evidence for the contribution of cerebellar atrophy and structural network disruption to the presence and severity of mood disturbance in MS. These results have important implications for future research and clinical interventions.

Background

To date, no studies have explored the relationship between brain atrophy and MS disability using differing MRI protocols and scanners at multiple sites.

Objectives

To assess the association between brain atrophy and MS disability, as measured by EDSS and 6-month confirmed disability progression (CDP).

Methods

In this retrospective study at 4 MS centres, a total of 1300 patients had brain MRI imaging assessed by icobrain. Relapse-onset MS patients were included if they had two clinical MRIs 12 (±3) months apart and ≥2 EDSS scores post MRI-2, the first ≤3 months from MRI-2, with ≥6 months between first and last EDSS. Volumetric data were analysed if the alignment similarity between two images was as good as that of same-scanner scan-rescan images (normalised mutual information ≥0.2). The percentage brain volume change (PBVC), percentage grey matter change (PGMC), FLAIR lesion volume change, whole brain volume, grey matter volume, FLAIR lesion volume and T1 hypointense lesion volume at MRI-2 were calculated. Ordinal mixed effect models were used to determine the association between these volumetric MRI measures and all EDSS scores post MRI-2. Cox proportional hazards models were used for the 6-month CDP outcome, using a subset of patients with ≥3 EDSS. Models were adjusted for proportion of time spent on disease-modifying therapy during MRIs ± whole brain/grey matter volume at baseline MRI.

Results

Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. During the follow-up period (median 3.8 years, range 1.3-8.9), 29 of 244 (12%) patients experienced 6-month CDP. There was no evidence for association between annualised PBVC or PGMC and CDP or EDSS (p>0.05). Cross-sectional whole brain and grey matter volume (at MRI-2) tended to associate with CDP (HR 0.99, 95% CI 0.98-1.00, p=0.06). Every 1ml of whole brain or grey matter volume lost represented a 1% higher chance of reaching 6-month CDP. Only whole brain volume (at MRI-2) was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the slope of EDSS change over time (β -0.001, SE 0.0003, p=0.02). On average, every 33ml reduction of brain volume was associated with a 1 step increase in EDSS.

Conclusions

In this real-world clinical setting where a fifth of the brain atrophy analysis were performed on different scanners, we found no association between individual brain atrophy and MS disability. However, there was an association between cross-sectional whole brain volume with EDSS and slope of EDSS change.

Background

In multiple sclerosis (MS), cortical damage is a relevant predictor of clinical disability, but MRI measures more specific to cortical pathology are needed. Neurite orientation dispersion and density imaging (NODDI) model is a multi-compartment diffusion model to better evaluate the complexity of brain microarchitecture.

Objectives

To characterize, using NODDI, the microstructural abnormalities of normal-appearing cortex (NA-cortex) and cortical lesions (CLs) and their relations with disease phenotypes and clinical disability in a relatively large cohort of MS patients.

Methods

Brain 3D T1-weighted, FLAIR, double inversion recovery (DIR) and diffusion-weighted (DW) sequences were acquired from 164 MS patients (94 relapsing-remitting [RR], 70 progressive [P] MS) and 51 healthy controls (HC). The cortex was segmented from 3D T1-weighted sequence, whereas CLs were quantified on DIR. CLs and NA-cortex masks were then transformed into DW space. Using NODDI, intracellular volume fraction (ICV_f), representing neurite density, extracellular volume fraction (ECV_f) and orientation dispersion index (ODI), reflecting neurite orientation variability, were assessed in NA-cortex and CLs. Between-group comparisons and correlations with clinical and structural MRI measures were investigated.

Results

One hundred and twelve (68.3%) MS patients had ≥1 CL. MS NA-cortex had a significant lower ICV_f vs HC NA-cortex (p=0.001). CLs showed a significant increased ECV_f (p<0.001) and decreased ICV_f and ODI compared to NA-cortex of HC (p<0.001) and MS (p=0.035 and <0.001). Compared to RRMS, PMS had a significant decreased NA-cortex ICV_f (p=0.024). Higher burden of CLs (p<0.001) were found in PMS vs RRMS, without microstructural differences. In MS patients, NA-cortex ICV_f, ECV_f and ODI were significantly correlated with disease duration, EDSS, white matter lesion volumes, CL volumes and whole brain and gray matter atrophy (r from -0.37 to 0.71, p from <0.001 to 0.048).

Conclusions

A significant neurite loss occurs in MS NA-cortex, being more severe with longer disease duration, higher disability and PMS. CLs show a further reduction of neurite density, together with an increased extracellular space, possibly due to inflammation and gliosis, and a reduced ODI suggestive of increased tissue coherence and simplification of neurite complexity. NODDI is reliable and clinically relevant to investigate in vivo the heterogeneous pathological processes affecting MS cortex.

Funding. This study is supported by a senior research fellowship FISM – Fondazione Italiana Sclerosi Multipla – cod. 2019/BS/009 and financed or co-financed with the ‘5 per mille’ public funding.

Background

Gadolinium (Gd)-based contrast agents are widely used to assess disease activity and treatment response by MRI in multiple sclerosis (MS). There is, however, increasing concern about their safety as their repeated administration may lead to brain parenchymal accumulation, while preclinical models suggest that they induce mitochondrial toxicity and neuronal cell death. Moreover, recent reports have demonstrated that three-dimensional (3D) T2-weighted Fluid-Attenuated-Inversion-Recovery (FLAIR) is highly sensitive in detecting new or enlarging MS lesions.

Objectives

To explore whether the presence of contrast enhancing lesions (CEL) based on Gd injection is more sensitive in detecting lesional activity in clinically stable MS patients in comparison to the analysis of new or enlarging MS lesions by 3D FLAIR.

Methods

MS patients being part of the observational, multicenter Swiss Multiple Sclerosis Cohort Study (SMSC) with contrast enhanced T1-weighted (T1w) images were included. Clinical stability was defined as no relapse and no Expanded Disability Status Scale (EDSS) increase during at least twelve months prior to MRI. Presence of CEL was assessed on contrast enhanced T1w images. Presence of new or enlarging T2w lesions was assessed manually on 3D FLAIR in an independent analysis by a different investigator in clinically stable MS patients presenting with CEL.

Results

3930 MRI scans (3.0 Tesla n=1497 (38%)) in 1057 participants (685 women, median age 42.0 years, 941 with relapsing MS, 116 with progressive MS, median EDSS 2.0 (range 1.5-3.5), median disease duration 7.4 years) were included.

Of 2620 MRI scans (66.7%) acquired in clinically stable conditions 46 (1.8%) demonstrated CEL. In all of these, new or enlarging T2w lesions were detectable by 3D FLAIR when a previous MRI was available for comparison (previous MRI available in 29/46; median number of new or enlarging T2w lesions: 3 (range 1-41, total number 176); median number of CEL: 1 (range 1-4, total number 47)).

Conclusions

In our large cohort from clinical practice, the assessment of new or enlarging lesions by 3D FLAIR was equally sensitive as the quantification of CEL to detect disease activity in clinically stable MS patients, challenging current practice of the use of Gd-enhanced MRI for monitoring of MS in clinical routine.

Background

The cerebellum plays a relevant role in both motor and cognitive function due to the high number of cerebellar connections with the brain and spinal cord. Alterations in cerebellar functional connectivity may modulate the relationship between brain structural damage and clinical impairment in multiple sclerosis.

Objectives

To investigate whether resting-state functional connectivity changes of the sensorimotor cerebellum represent adaptive neuroplastic mechanisms to reduce the effects of structural damage on physical disability in patients with multiple sclerosis and no disability.

Methods

A total of 144 multiple sclerosis patients with a score of ≤1.5 on the Expanded Disability Status Scale and 98 healthy subjects were selected from the Italian Neuroimaging Network Initiative database and included in this study. Both patients and healthy subjects underwent multimodal 3T-MRI including functional MRI at rest. After parcellation of the cerebellum, the sensorimotor cerebellum (lobules I-V + VIII) was identified and used as a seed for resting-state functional connectivity analysis.

Results

In patients, brain areas with decreased and increased sensorimotor cerebellar functional connectivity were found to coexist with respect to healthy subjects. Areas of decreased cerebellar functional connectivity, i.e. the lingual gyrus, insula, and precentral and postcentral gyri, negatively correlated with T2 lesion load and white matter atrophy. Areas of increased cerebellar functional connectivity, i.e. the posterior cerebellum, nucleus accumbens, prefrontal cortex, cingulate/paracingulate gyri, and precuneus, positively correlated with T2 lesion load and cerebellar and thalamic atrophy. Areas of increased cerebellar functional connectivity with the cingulate gyrus and precuneus negatively correlated with global grey and white matter atrophy.

Conclusions

In patients with multiple sclerosis, the sensorimotor cerebellum extensively reorganizes its functional links with other brain regions. Areas of decreased cerebellar functional connectivity related to white matter damage are present even in the absence of clinical manifestations and may represent a preclinical condition. Areas of increased cerebellar functional connectivity related to both lesion burden and thalamic or cerebellar atrophy likely represent a compensative reorganization of brain circuits. Lastly, global atrophy may influence functional connectivity changes in posterior cortical areas.

Background

Both upper and lower limb disability is common in multiple sclerosis (MS), but do not always occur together, suggesting partially independent underlying mechanisms. Physical disability strongly relates to brain network disturbances in MS, yet network mechanisms underlying upper and lower disability progression remain unclear.

Objectives

To investigate the relationship between upper and lower limb progression and functional sensorimotor network changes in MS.

Methods

Longitudinal data was included from a prospectively acquired cohort, with baseline data collected between 2008 and 2012 and follow-up assessments between 2014 and 2017. Participants underwent MRI and dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) tests at baseline and after 5 years. Patients were stratified into progressors (>20% decline) or non-progressors for both tests. Measures of network efficiency were calculated from resting-state functional MRI data using both static (i.e. calculated on the entire scan) and dynamic (i.e. fluctuations during the scan) approaches and compared between patient groups. Multiple logistic regression was used to identify independent predictors of upper and lower limb progression and baseline connectivity patterns.

Results

This study included 214 people with MS (age 47±11; 149 women) and 58 healthy controls (age 46±10; 31 women). Compared to respective non-progressors, upper limb progression (n=24) was related to higher dynamic efficiency of the right premotor cortex, somatosensory cortex and thalamus, while lower limb progression (n=37) was related to higher dynamic efficiency of the right supplementary motor area at baseline (p<0.05). Logistic regression showed that dynamic efficiency of the thalamus and supplementary motor area best predicted upper and lower limb progression respectively, independent of the severity of structural damage (p<0.01). Both areas displayed widespread higher dynamic connectivity in progressing compared to non-progressing patients at baseline (p<0.05).

Conclusions

Disability progression can be predicted by the severity of fluctuations (i.e. higher dynamics) in the efficiency of the sensorimotor network. The dynamic behavior of the thalamus and supplementary motor area were respectively related to upper and lower limb progression, possibly indicating different mechanisms underlying these types of progression in MS.

Background

Both perfusion-based imaging (PWI) measures and serum neurofilament light chain levels (sNfL) have been associated with multiple sclerosis (MS) disability and different pathologies.

Objectives

To determine whether the perfusion and neurofilament biomarkers are correlated to each other or independently describe different MS processes.

Methods

3T MRI dynamic susceptibility contrast (DSC)-PWI and single molecule assay (Simoa)-based sNfL (in pg/mL) were utilized in 86 MS patients. Perfusion measures of mean transit time (MTT), cerebral blood volume (CBV) and cerebral blood flow (CBF) were derived for the regions of normal-appearing whole brain (NAWB), normal-appearing white matter (NAWM), gray matter (GM), deep GM (DGM) and thalamus. Normalized CBV and CBF (nCBV and nCBV) were adjusted with the corresponding NAWM measure. Age and sex-adjusted linear regression models determined associations between DSC-PWI measures and sNfL. False discovery rate (FDR)-adjusted p-values lower than 0.05 were considered statistically significant.

Results

After age and sex adjustment, thalamic MTT significantly and independently was associated with higher sNfL (standardized β=0.648, t-statistics=2.868, adjusted p-value=0.011) and explained additional 4.0% of sNfL variance. NAWM MTT was initially added in the model (adding additional 3.3%) but did not survive FDR correction. Similarly, after adjusting for age and sex effects, lower nCBV of the thalamus was associated with greater sNfL (standardized β=-0.221, t-statistics=-2.529, p=0.013, adjusted p-value=0.022). Correspondingly, lower nCBF of the thalamus was also associated with greater sNfL (standardized β=-0.346, t-statistics=-4.188, p<0.001, adjusted p-value=0.001).

Conclusions

Higher sNfL are associated with poorer PWI-based measures of the thalamus. Future longitudinal studies should determine their temporal relationship.

Background

Cortical lesions are of eminent clinical relevance in patients with multiple sclerosis (MS), since they have been associated with clinical decline and disease progression. Heretofore, cortical lesions were commonly assessed at a whole-brain level, and were found to correlate with EDSS. However, there is no evidence on correlations between the spatial distribution of cortical lesions and cognition. We hypothesize that the distribution of cortical lesions contributes to explaining the variance of both clinical and cognitive decline.

Objectives

To further elucidate the spatial distribution of cortical lesions and assess their association with clinical and cognitive decline.

Methods

One-hundred-fourteen patients (59 RRMS, 37 SPMS, 16 PPMS, mean age 54.49 ±8.99, 76 female) underwent MRI (double inversion recovery (DIR) and 3D-T1), and neuropsychological assessment (BRB-N, Stroop, Memory comparison task). Raw cognition data were converted to Z-scores based on the control scores, and averaged over the domains. For each patient, cortical lesions were identified and delineated on DIR. The extent of lesioned cortex was measured and cortical lesion maps were generated to enable vertex-wise cortical lesion probability maps and correlations using FreeSurfer.

Results

Cortical lesions were preponderantly situated in frontal and temporal lobes, as well as in the motor and anterior cingulate cortex. Significant clusters of vertex-wise correlations between cortical lesions and EDSS were primarily found for the motor cortex. Significant clusters of vertex-wise correlations between cortical lesions and cognition were primarily found for the frontal and temporal lobe.

Conclusions

The presence of frontal and temporal cortical lesions specifically predicted cognitive decline, while cortical lesions in the motor cortex were related to physical functioning. This confirms the hypothesis that the spatial distribution of cortical lesions contributes to explaining the variance of both clinical and cognitive decline. Further studies should investigate whether the location of cortical lesions is relevant to specific cognitive functions (e.g., memory or executive functioning).

Background

Spinal cord atrophy is a common feature of multiple sclerosis (MS), can be detected in vivo using MRI, and is one of the main substrates of disease progression. In our previous studies, we have adapted the boundary shift integral (BSI) technique developed for the brain, to be applied to the spinal cord, obtaining the first registration-based method for longitudinal assessment of spinal cord atrophy.

Objectives

We aim to 1) compare spinal cord atrophy measurements using segmentation- and registration-based methods, with possible implications for clinical trial design (e.g., measurement variability, image noise floor); 2) compare spinal cord atrophy measurements obtained from routine brain (C1-2) and dedicated spinal cord MRI (C1-2 and C2-5), using segmentation- and registration-based methods; 3) explore possible clinical correlates, also in relation to conventional brain MRI measures; and 4) explore possible treatment effect.

Methods

We included 220 primary-progressive multiple sclerosis patients from a phase 2 clinical trial, with baseline and week-48 3DT1-weighted MRI of the brain and spinal cord (1x1x1mm³), acquired separately. We obtained segmentation-based cross-sectional spinal cord area (CSA) at C1-2 (from both brain and spinal cord MRI) and C2-5 levels (from spinal cord MRI) using DeepSeg, and, then, we computed corresponding GBSI.

Results

Depending on the spinal cord segment, we included 67.4-98.1% patients for CSA measurements, and 66.9-84.2% for GBSI. Spinal cord atrophy measurements obtained with GBSI had lower measurement variability, than corresponding CSA. Looking at image noise floor, the lowest median standard deviation of the MRI signal within the cerebrospinal fluid surrounding the spinal cord was found on brain MRI at C1-2 level. Spinal cord atrophy derived from brain MRI was related to corresponding measures from dedicated spinal cord MRI, more strongly for GBSI than CSA. Spinal cord atrophy measurements using GBSI, but not CSA, were associated with upper and lower limb motor progression. No treatment effect was detected for any spinal cord atrophy measurements.

Conclusions

Notwithstanding reduced measurement variability, clinical correlates, and possibility of using brain acquisitions, spinal cord atrophy using GBSI should remain a secondary outcome measure in MS studies, until further advancements increase the quality of acquisition and reliability of processing.

Background

SC pathology occurs early in the course of MS. However, few studies have investigated the relationship between lesions, diffuse changes and mean upper cervical cord area (MUCCA) in MS patients with different levels of disability in detail.

Objectives

To explore spinal cord (SC) pathology in multiple sclerosis (MS) patients with different levels of disability and MS phenotypes.

Methods

638 MS patients with different degrees of disability and 102 healthy controls (HC) underwent MRI on a 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The MRI protocol comprised transversal 3D-T2WI for MUCCA, sagittal T2WI-Fat-Sat and PDWI for SC pathology, and 3D-MPRAGE for regional brain volume (BV). MUCCA was measured automatically between the C3 and C4 vertebra (ScanView.cz). Global and regional BVs were estimated by the fully automated MorphoBox prototype (Siemens Healthcare, Erlangen, Germany). Diffuse changes, number and location of SC lesions were assessed manually. Patients and HC were matched by sex and age using propensity scores. MUCCA, regional BVs and SC pathology were compared among matched subgroups of: 54 patients with mild disability (EDSS=<1.5), 54 patients with mild-to-moderate disability (EDSS 2-3.5), 54 patients with severe disability (EDSS 4-4.5), 54 patients with very severe disability (EDSS>=5), 18 primary progressive (PP) patients, and 54 controls from the HC group. ANOVA test was used for between-group comparison.

Results

There was a trend of lower MUCCA with higher disability level. Mean MUCCA was 76.5±10.8 mm² invery severe, 80.1±9.6 mm² in severe, 85.7±8.0 mm² in moderate, 85.6±8.5 mm² in mild disability, and 90±7.7 mm² in HC groups. There was a significant difference in MUCCA between HC and mild disability group (p<0.001). SC pathology was prominent in 64.1% of the patients with mild disability, compared to 90.4% patients with very severe disability. The percentage of diffuse changes varied greatly between the groups, with prevalence increasing almost four times between patients with mild and very severe disability.

Conclusions

SC pathology is present in all disability MS groups. MUCCA differentiated between patients with mild disability and healthy controls, suggesting that it may be promising for the implementation in diagnostic protocols. The evaluation of diffuse changes can help to predict disability. Low MUCCA together with prominent diffuse changes could help differentiate PP MS from other MS phenotypes.

Background

Multiple sclerosis (MS) is associated with brain dysconnectivity that leads to changes in network organisation. However, given the inconsistent results obtained by studies of structural and functional connectivity, the relationship between the structural and functional deficits in MS is unclear.

Objectives

This study explored structure-function relationships during the early stages of MS and their role in cognitive performance.

Methods

Patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years. Healthy controls matched for age, sex and level of education were followed-up in parallel.

The evolution of structural and functional brain networks was investigated, and structural-functional coupling was assessed. Clinical and cognitive status was determined at each follow-up visit. The association between brain network parameters and cognitive performance was assessed using linear mixed-effects models.

Results

The study included 32 patients (25 females) and 10 healthy controls. The mean (SD) age of the patients was 37.7 (10.4) years. Both structural and functional reorganisation was observed during the disease course. Structural clustering coefficient was significantly increased after 5 years whereas characteristic path length decreased, indicating strengthened short-distance connections and the loss of long-range connections. By contrast, functional connections and related path lengths were decreased after 5 years, suggesting stronger local short-distance connections. Structural-functional coupling had increased significantly after 5 years, indicating greater constraint of functional connectivity by direct anatomical connections. This structural-functional coupling was the only parameter associated with cognitive and clinical status, with stronger coupling associated with a decline in both domains.

Conclusions

Our findings provide novel biological evidence that MS leads to less dynamic brain function in relation to the underlying anatomy of the brain. The collapse of this network leads to both cognitive impairment and clinical disability.

Background

Advanced diffusion-weighted MRI (DW-MRI) sequences, in combination with biophysical models, provide new information on the microstructural properties of the tissue.

Objectives

To investigate the differences in intra-axonal signal fraction (IASF) between perilesional normal-appearing white matter (pl-NAWM), white matter lesions (WML) without (rim-) and with paramagnetic rim (rim+) comparing eight biophysical diffusion models.

Methods

The study included 102 MS patients: RRMS: 66%, SPMS: 18%, PPMS: 16%, mean age 46±14; female 64%, disease duration 12.16±18.18 yrs, median EDSS: 2.5.

DW-MRI data were acquired with 1.8mm isotropic resolution and b-values [0, 700, 1000, 2000, 3000] s/mm².

Lesion masks were generated with a deep-learning-based method and manually corrected if required; pl-NAWM was defined as a region of 3-voxels around each WML; 225 paramagnetic rim lesions were manually identified based on 3D EPI and 2330 were labelled as rim-.

The following microstructural models were applied: Ball and Stick, Ball and Rockets, AMICO-NODDI, SMT-NODDI, MCMDI, NODDIDA, CHARMED, Microstructure Bayesian approach.

Delta (WML - pl-NAWM) was calculated for each WML, and one-side Mann Whitney U was used to compare the delta between models, followed by Bonferroni to correct for multiple testing.

Mean difference and Cohen's d was used to assess differences between lesions with extensive axonal damage (rim+) and other WML (rim-).

Results

All models applied in this study reported low IASF in rim+ WML, medium IASF in rim- WML and relatively high IASF in pl-NAWM. However, a broad spectrum of IASF values was identified from the different models: relatively simple models such as Ball and Stick and CHARMED, showed low delta IASF within lesions, while MCMDI models reported the highest significant difference compared to other models (p<0.0001). The comparison between WML and pl-NAWM mean IASF across models showed that MCDMI exhibited the highest difference (mean 0.13, Cohen’s d 1.34). AMICO-NODDI and SMT-NODDI showed close results (mean difference 0.12/0.12 and Cohen’s d 1.46/1.51).

The models best discriminating IASF between rim+ and rim- lesions were MCMDI and NODIDDA (mean 0.08/0.07, Cohen’s d -0.69/-0.70).

Conclusions

We compared eight WM diffusion models for assessment of intralesional axonal damage in MS patients. The comparison between WML and pl-NAWM showed that robustness of the method, identified with SMT-based and NODDI-based models, it is crucial. For the comparison between lesions with a high level of damage (rim +) and other WML, the diffusivity estimation appeared to play an important role. The method which appeared both robust and able to estimate the diffusivity of the tissue was MCMDI, which performed best in both cases.

Background

The central vein sign (CVS) is a novel imaging biomarker for the differential diagnosis of multiple sclerosis (MS). In studies at 7.0 tesla MRI, the percentage of supratentorial white matter lesions (WMLs) with CVS vary between 80% to 100% in MS patient brains. Similar results were reported at 3.0 tesla (3T) MRI in optimized sequences, such as T2*-weighted 3D echo-planar-imaging sequence and SWAN-venule. The value of the CVS for infratentorial brain remains unknown.

Objectives

The aim of this study was to determine the proportion of WMLs positive for the CVS in the brainstem and cerebellum of MS patients.

Methods

We included subjects with clinically defined MS, that showed at least one infratentorial lesion larger than 3 mm in 3D-FLAIR. Patients were scanned in a 3T MRI system (GE Medical Systems, discovery MR750) using a 32-channel coil array. MRI included 3D T2-weighted FLAIR and post-contrast SWAN-venule: [FOV = 22 cm x 16 cm; number of slices= 126; voxel resolution, 0.4 mm x 0.4 mm x 0.8 mm; TR = 47 msec; TE = 28 msec; flip angle (FA) = 8 degrees; ETL = 9; AT = 7.38 min]. The CVS, defined as a thin hypointense line or a hypointense small dot visualized in two planes, was recorded on SWAN-venule by two trained raters.

Results

Thirty MRIs were analyzed, three were excluded for motion artefacts. A total of 91 focal lesions were detected in FLAIR, 22 in the cerebellum and 69 in brainstem. Out of 91 lesions, 83 (91%) were visible in SWAN-venule and 83% were positive for the CVS.

Conclusions

The infratentorial brain is a cardinal compartment for MS diagnosis, SWAN-venule detects infratentorial WMLs and highlights the CVS in most plaques at 3.0 T MRI. The CVS could be used to discriminate MS lesions from its radiological infratentorial mimics.

Background

The “central vein sign” (CVS) in white matter lesions (WMLs) is a current radiological biomarker of multiple sclerosis (MS). Using magnetic susceptibility-based sequences, the CVS was observed in 80-100% of lesions at 7.0 tesla Magnetic Resonance Imaging (MRI) in the research setting. Recently, similar detection rate was reported at 3.0 Tesla (3T) MRI in the clinical setting using susceptibility-weighted angiography (SWAN)-venule sequence. Some data suggest that using 3D T2*EPI/ FLAIR*, the CVS may be useful to differentiate MS from other neurological diseases with focal WMLs.

Objectives

The objective of our study was to determine if the CVS detected in SWAN-venule at 3T MRI discriminates MS from its radiological mimics.

Methods

Subjects were scanned on a 3T MRI system (Discovery MR750, GE, Milwaukee, USA) using a 32-channel head coil. We performed post-contrast 3D-FLAIR and SWAN-venule sequences [FOV = 22 cm x 16 cm; number of slices= 126; voxel resolution, 0.4 mm x 0.4 mm x 0.8 mm; TR = 47 msec; TE = 28 msec; flip angle = 8° ; ETL = 9; AT = 7.38 min]. MRIs with focal supratentorial WMLs visible in FLAIR, larger than 3 mm and smaller than 15 mm, were included. The CVS, defined as a thin hypointense line or a hypointense small dot centering a WML, was recorded blinded to the diagnosis on SWAN-venule by one junior neuroradiologist and two trained MS raters.

Results

Twenty people with MS and 24 subjects with non-MS WMLs: 9 migraine, 6 Neuromyelitis Optica spectrum disease (NMOs), 5 Susac Syndrome (SS), and 4 with other vascular diseases (2 primary angiitis of the central nervous system, 1 small vessels disease, and 1 Lupus), were included. A total of 380 WMLs were detected in the MS group, and 427 WMLs in the non-MS group (215 migraine, 52 NMOs, 83 SS, and 77 in other vascular diseases). The CVS was detected in 86% of MS WMLs compared to 23% of WMLs of other diseases (25% of migraine, 21% of NMOs, 22% of other vascular diseases).

Conclusions

The use of SWAN-venule sequence for the identification of CVS on 3T MRI helps differentiate MS WMLs from other WMLs that mimic MS.

Background

Despite the high prevalence and debilitating nature of fatigue and depression in Relapsing-Remitting Multiple Sclerosis (RRMS), the underlying pathophysiology is still far from being fully understood. While several findings highlighted the contribution of white matter lesion load (WMLL) and brain atrophy, the role of cortical lesions (CL) has been only marginally assessed.

Objectives

To investigate: i) the contribution of CL volume to fatigue and depression; ii) the relative role of total CL volume (tCLV), intracortical lesion volume (ICLV) and juxtacortical lesion volume (JCLV).

Methods

Sixty-five RRMS patients underwent: i) clinical evaluation including the Expanded Disability Status Scale (EDSS), ii) assessment of fatigue and depression trough the Modified Fatigue Impact Scale (MFIS) and the Beck Depression Inventory (BDI), iii) a 3T–MRI protocol including Double-Echo (DE) and 3D–Double Inversion Recovery (DIR) imaging to identify WMLL and CL. Correlation analyses were run between WMLL, CL and MFIS, and BDI. A multiple linear regression model was applied to evaluate the contribution of CL to MFIS and BDI, controlling for clinico-demographic data and WMLL.

Results

The correlation analysis showed that tCLV and JCLV correlated with MFIS (rho= 0.31, p=0.007; rho= 0.28, p=0.01 rispectively) and BDI (rho= 0.24, p=0.03 and rho= 0.23, p=0.04, rispectively), while ICLV or WMLL did not correlate with neither MFIS nor BDI. Regression analysis did not reveal any CL volume as a significant predictor of fatigue or depression.

Conclusions

Although CL volume is not a significant independent predictor of fatigue and depression, our study shows a significant role of CL volume in determining these symptoms in RRMS.

Background

MS-SMART is a recently reported phase 2b randomised placebo controlled multi-arm study of the neuroprotective potential of amiloride, fluoxetine and riluzole in secondary progressive multiple sclerosis [NCT01910259]. No change in atrophy rate was observed in any arm compared to placebo. We obtained brain metabolic data using proton magnetic resonance spectroscopic imaging (MRSI) at baseline and 96 weeks to explore postulated candidate drug mechanisms of action for the three interventions. Fluoxetine has previously shown an increase in total N-acetyl aspartate plus N-acetyl aspartyl glutamate [tNAA]; myoinositol was also examined as a marker of astrogliosis. Amiloride blocks the acid sensing ion channel-1 receptor that mediates sodium and calcium and therefore could increase neuroaxonal integrity (tNAA). It is known that riluzole decreases glutaminergic transmission.

Objectives

MRSI data at baseline and then 96 weeks was used to interrogate drug specific effects of fluoxetine on tNAA and myoinositol (mIns); riluzole on Glx (glutamate + glutamine); and amiloride on tNAA levels, all compared to placebo.

Methods

108 participants from the MS-SMART trial were included and had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR =35/2000ms) at 3T. Metabolite levels and ratios to creatine (tCr) were determined for normal appearing white matter (NAWM) and grey matter (GM) with LCModel using an unsuppressed water scan as the internal reference. Multiple regression models adjusting for age, sex and baseline Expanded Disability Status Scale (EDSS) were used.

Results

Mean age of the entire cohort was 55 (sd 7.1) years, 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (range 4.0-6.5) and median T2 lesion volume 9.0mL (IQR 6.0).

In the fluoxetine arm, there was no significant change in tNAA (or tNAA/Cr) in NAWM or GM; mIns/tCr (but not mIns) was lower at 96 weeks (β = -0.21, 95% CI [-0.40 to -0.02], p = 0.03) in NAWM (but not GM).

In the riluzole arm, there was a reduction in GM Glx (β = -0.25, 95% CI [-0.47 to -0.04], p = 0.02) and Glx/tCr (β = -0.29, 95% CI [-0.50 to -0.08], p = 0.007), but no change was seen in NAWM.

In the amiloride arm, there was no change in tNAA (or tNAA/tCr) in NAWM or GM.

Conclusions

Neither fluoxetine nor amiloride had any effect on proposed measures of neuroaxonal integrity in NAWM or GM as reflected in tNAA levels. There was a fluoxetine reduction in NAWM mIns/tCr perhaps reflecting some decrease in astrogliosis. Riluzole decreased GM Glx levels as anticipated. However, despite these target effects for these drugs, ultimately they did not translate into a reduction in atrophy rate in the trial.

Background

Meningeal inflammation is a progressively recognized finding in multiple sclerosis (MS). The real prevalence of leptomeningeal enhancement (LME) in different stages of MS and its association with neurodegeneration is still a matter of debate.

Objectives

To assess the in-vivo prevalence of LME in relapsing-remitting MS (RRMS) and to evaluate the association with clinical/radiological activity and cerebrospinal fluid (CSF) markers.

Methods

This is an ongoing observational study. LME was assessed by two blinded neurologists on a 3D 1x1x1 mm³ Fluid-Attenuated-Inversion-Recovery (FLAIR) acquired 20 minutes post gadolinium (TR 6000 ms; TE 356 ms; Fat suppressed). LME was defined as signal intensity within the subarachnoid space greater than that of brain parenchyma and brighter on postcontrast scans. MRI activity was defined as at least 1 gadolinium enhancing and/or new/enlarging T2 lesions. Differences in terms of clinical, radiological, CSF metrics between patients with and without LME were tested with ANOVA, chi square and binary logistic regression analysis as appropriate.

Results

38 RRMS patients were included in the analysis: [65,2% female, mean age 37,8±10.1 years mean disease duration 10,1±9.2 years, median Expanded-Disability-Status-Scale (EDSS) 2 (0-6,5)]. 78,3% of patients had MRI activity in the previous 2 years: among them 17,4% had uniquely radiological activity and 60,9% had clinical relapses (experiencing disease progression in 17,4 % of cases), 26.1% had ongoing MRI activity. LME was found in 37% of patients, median number 1 (range 1-3). No difference in EDSS, age and disease duration was found between patients with or without nodules. LME prevalence was higher in patients with previous MRI activity (P=0.047). Multivariable models adjusted for baseline EDSS exploring predictive value of clinical progression, previous MRI activity, ongoing MRI activity show that previous MRI activity was the only variable associated with LME (p=0.002). CSF parameters had no predictive value for LME development nor any association was found between presence of oligoclonal bands and LME.

Conclusions

LME was found in a discrete proportion of RRMS patients and it was associated with previous, but not ongoing, radiological activity. A prospective clinical evaluation is needed in order to assess the prognostic value of our findings.

Background

Conventional MRI has limitations when it comes to characterizing the grey matter pathology of MS. PET (positron emission tomography) imaging, on the other hand, can provide more precise information at the cellular level. [¹¹C]PK11195 is a first generation translocator protein (TSPO) radioligand that has been used to study innate immune cell activation status in multiple sclerosis brain in vivo.

Objectives

Our aim was to analyse the MRI volumes and [¹¹C]PK11195 signal of MS brain grey matter regions and to investigate how these variables connect with disability progression.

Methods

MRI (3 or 1.5 tesla) and [¹¹C]PK11195 PET data from 71 MS patients and 18 healthy controls were examined for regional grey matter BPF (brain parenchymal fraction) and [¹¹C]PK11195 DVR (distribution volume ratio). The following regions of interest were chosen: cerebral cortex, thalamus, caudate, putamen and pallidum. EDSS (Expanded Disability Status Scale) was available at baseline and after 3.4 ± 1.1 (mean ± SD) years of follow-up. The imaging variables were compared between MS patients and healthy controls, and forward type stepwise logistic regression was used to assess the best variables predicting disease progression.

Results

MS patients had lower BPF in the cortex, thalamus and caudate (P < 0.05) compared to controls. MS patients had higher [¹¹C]PK11195 DVR in the thalamus and pallidum (P = 0.01 and P = 0.0099 respectively) compared to controls. Patients with EDSS progression (EDSS increase ≥ 1.0 at follow-up; or ≥ 0.5, if EDSS at baseline was ≥ 6.0) had lower BPF in the thalamus and caudate (P = 0.045 and P = 0.034 respectively) and higher DVR in the thalamus (P = 0.014) compared to patients with no EDSS progression. In the forward type stepwise logistic regression model DVR in the thalamus was the only measured imaging variable that remained a significant predictor of disease progression.

Conclusions

There are regional differences in [¹¹C]PK11195 binding and atrophy in grey matter areas of the MS brain. [¹¹C]PK11195 signal in the thalamus seems to have potential in predicting future MS disease course.

Background

Multiple sclerosis (MS) is frequently associated with memory impairment. Nevertheless, the pathophysiology of memory impairment in MS is still unclear. Most studies now agree on hippocampal involvement. However, whether functional reorganization could help compensate and mitigate memory deficit is a matter of debate.

Objectives

This study aimed to identify the patterns of functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances at the early stage of MS. We hypothesized that functional reorganization could compensate for structural damage, allowing a delay in memory impairment appearance.

Methods

Patients were enrolled after their first neurological episode suggestive of MS in a prospective longitudinal study, along with matched healthy controls, and followed over 5 years. Verbal and visual memory scores were assessed. We used a multimodal approach, combining in vivo structural measures – i.e. hippocampal volume and connectivity – and functional measures – i.e. rs-fMRI connectivity. The association between network parameters and cognitive performance was assessed using linear mixed-effects models.

Results

This study included 32 patients and 10 healthy controls. The mean (SD) age of the patients was 37.7 (10.4) years. Verbal memory scores decreased significantly over time, whereas visuospatial memory performances were maintained.

Hippocampal volume of patients decreased significantly over time, indicating an increase in tissue alteration with the evolution of the pathology. Structural shortest path length of the hippocampus significantly decreased after 5 years along with an increase in hippocampus’ connections, indicating strengthened short-distance connections.

As for the functional network, the hippocampus showed a significant increase in the number of connections after 5 years, with a decrease of its shortest path length, suggesting stronger local short-distance connections.

Hippocampal volume loss was associated with worse verbal memory, while the hippocampus functional shortest path length significantly explained visual memory performances.

Conclusions

Our study demonstrated an important interplay between hippocampal-related structural and functional networks in explaining cognitive performances in the early stages of MS. As the structural damage increases, functional reorganization is able to maintain visual memory performances with strengthened short-distance connections.

Background

Recent imaging data in multiple sclerosis (MS) suggests that chronic-active lesions and inactive lesions can be differentiated based on the presence of paramagnetic rims on gradient-echo (GRE). At autopsy, chronic-active lesions show significant demyelination, oligodendrocyte loss, and outer rims of iron laden macrophages and activated microglia. Confirmation of the destructive nature of these lesions on MRI would provide in vivo evidence of their consequences. Further, evidence of local blood-brain barrier (BBB) breakdown in these lesions would provide further validation of their chronic-active state, along with suggesting a possible opportunity for therapeutic intervention.

Objectives

We aimed to determine if white matter lesions (WMLs) with paramagnetic rims show greater alterations in multiple signal characteristics, including our novel metric for BBB breakdown, Magnetization prepared 2 rapid gradient echo (MP2RAGE) ΔT1 mapping.

Methods

MP2RAGE and GRE images of the brain were acquired on 36 participants with MS on a 7T MRI before and after contrast. GRE images were processed for R2* and quantitative susceptibility maps (QSM). MP2RAGE was processed for T1 mapping and all images were registered to the pre-contrast T1-weighted (T1-w) image. ΔT1 maps were created by subtracting pre and post-contrast T1 maps. All WMLs were masked on T1-w and masks were separately created for lesions with visible paramagnetic rims on QSM. T1, ΔT1, χ (from QSM), and R2* values were compared across lesion types using a linear mixed effects model and Wilcoxon rank sum testing.

Results

Mean pre-contrast T1 was significantly higher in rimmed lesions (2.323, SE = 0.03964) compared to non-rimmed lesions (2.113, SE = 0.05791; p<0.001). Mean and median ΔT1 values were not significantly different in non-rimmed lesions versus rimmed lesions. Median pre-contrast χ values were significantly smaller in rimmed lesions (-0.00581, SE = 0.00277) versus non-rimmed lesions (-0.01298, SE = 0.003332; p = 0.011). Pre-contrast median R2* was significantly lower in rimmed lesions (24.55, SE = 0.8378) versus non-rimmed lesions (28.04, SE = 0.8919; p<0.001).

Conclusions

Elevated T1 and reduced χ and R2* in rimmed lesions in this study are confirmatory of greater demyelination and tissue destruction in this lesion subtype. The lack of significant difference in ΔT1 values suggests that there is no evidence of additional BBB breakdown in chronic-active lesions as measured on MRI.

Background

Modifications of magnetic susceptibility, seemingly reflecting iron accumulation/depletion, have been consistently demonstrated in subcortical gray matter (GM) of MS patients, but some questions remain unanswered regarding the underlying neurobiological processes and their clinical relevance.

Objectives

to disentangle the contribution of atrophy, iron and myelin changes to deep GM (DGM) damage in MS, simultaneously exploring their relationship with clinical disability through the application of quantitative susceptibility mapping (QSM) and longitudinal relaxation rate (R1) relaxometry.

Methods

In this cross-sectional study, 91 patients and 55 healthy controls were imaged with 3T MRI to compute QSMs and R1 maps, from which iron and myelin concentration maps were estimated by applying an external model. Modifications of DGM iron and myelin (mean concentration-dependent from atrophy and total content-independent from atrophy) were investigated at both global and regional levels. Significantly altered MRI features were tested as disability predictors in hierarchical linear regression models.

Results

Compared to controls, MS patients showed reduced thalamic(p<0.001) and increased pallidal(p<0.001) iron concentrations. No differences emerged regarding total myelin or iron content in the basal ganglia, while actual iron depletion was found in the thalamus(p<0.001). At the voxel-based analysis, patients showed increased iron concentration in the basal ganglia(p≤0.001) and reduced iron and myelin local content in thalamic posteromedial regions(p≤0.004), corresponding to reduced iron and myelin content in the pulvinar(p≤0.001) at the subnuclei analysis. Thalamic volume(B=-0.341,p=0.02), iron concentration(B=-0.379,p=0.005) and content(B=-0.406,p=0.009) significantly predicted disability, as well as pulvinar iron(B=-0.415,p=0.003) and myelin(B=-0.406,p=0.02) content, independently of atrophy.

Conclusions

Quantitative MRI suggests an atrophy-related iron increase within the basal ganglia of MS patients, along with an absolute reduction of thalamic iron and myelin, which correlates with disability. Atrophy-independent depletions of thalamic iron and myelin may represent clinically relevant, sensitive markers of subcortical GM damage.

Background

Magnetic resonance imaging (MRI) is frequently utilized to assess activity of disease in multiple sclerosis (MS). Repeated gadolinium-based contrast agent use has been shown to deposit in the brain by a dose-dependent fashion. As a result, the Food and Drug Administration issued a warning regarding gadolinium use and has prompted the reexamination of its utility in clinical practice.

Objectives

To evaluate gadolinium utility in brain MRIs for routine monitoring of asymptomatic MS in an academic neurology clinic.

Methods

Retrospective chart review identified patients diagnosed with MS seen at the Landon Center of the University of Kansas Health System who had a MRI brain performed from December 16, 2016 to December 16, 2017. Data was collected regarding demographics, MS history, MRI ordered (with and/or without gadolinium), MRI results, and treatment decisions.

Results

Two-hundred forty charts were reviewed to date, identifying 124 completed MRIs in the study timeframe. All but 2 were ordered with gadolinium. Average age was 41.0 with 69.0% female and 85.2% with relapsing remitting MS. MRIs were then subdivided into the following indications: asymptomatic monitoring (n=85), diagnostic (n=15), and symptomatic (n=15). Of the monitoring MRIs, 79 (93%) had prior MRIs available for comparison, 19 (22.4%) had a new nonenhancing lesion, 10 (11.8%) had an enhancing lesion, and 22 (25.9%) had either a new nonenhancing or enhancing lesion. Of those who had radiographic progression of MS, 59% had a change in MS disease modifying therapy at follow up visit (RR 34.4, 95% CI 5.9-196.7; p=0.001). There were 17 (26.2%) enhancing lesions identified of 65 new nonenhancing or enhancing lesions. By direct comparison of unenhanced sequences, only 4.7% (n=3) of new lesions were not apparent without the aid of contrast, though each of these MRIs had other evidence of progression (total of 4 enhancing, 3 new nonenhancing lesions). In those without an available prior comparison MRI (n=6), none had enhancing lesions.

Conclusions

Preliminary results show gadolinium was useful in identifying only 4.7% additional lesions on asymptomatic monitoring MRIs and was not of additional benefit in identifying overall radiographic progression by MRI study nor in those without a prior comparator. Further data collection is planned to verify these initial trends.

Background

VDRF, such as hyperlipidemia, hypertension, obesity, diabetes, and heart disease, appear to significantly increase the risk of disability progression in MS, however the underlying mechanisms are not well understood.

Objectives

To determine if the presence of VDRF affects the disease progression and brain phosphate metabolism in people with MS.

Methods

This is a 3-year prospective, observational, single-site, study with two arms (MS subjects with and without VDRF). We collect 7T MRI brain data at baseline, 12, 24 and 36 months (V1, V2, V3 and V4 visits, respectively) and clinical and biomarkers data every 6 months. Outcome measures include changes in: 1) high energy phosphate metabolites in cerebral gray matter assessed by ³¹P 7T MR imaging (MRSI) and 2) brain parenchymal volume, 3) clinical impairment, disability, and quality of life.

Results

We preformed cross-sectional and longitudinal analyses of MRI data (52 V1 and 37 V3 subjects). Mean age/gender was 54.6 years with 71% female) (+VDRF, N=29, mean age 56.3 years, 83% female) and -VDRF, N=23, mean age 52.4 years; 57% female) at baseline. We analyzed a volume of interest in the occipital region for changes in phosphate metabolites (V1 and V3) using 7T MRSI. We observed decrease in Adenosine triphosphate (ATP) to total phosphate signal ratio in +VDRF subjects by 3.3% (P<0.05) compared with -VDRF. +VDRF subjects showed a larger reduction in parenchymal volume fraction (0.01544, P=0.025) over time (between V1 and V3) compared to ‑VDRF (0.00423). No significant group differences in temporal changes in phosphate metabolites are seen. Additional analyses are underway.

Conclusions

This is the first study to assess brain metabolism and volume in MS patients with and without VDRF. +VDRF MS subjects have significantly reduced brain ATP compared with -VDRF. ATP depletion may reflect mitochondrial dysfunction and contribute to MS disease progression as suggested by the increased brain atrophy in those with VDRF.

Background

The thalamus and the putamen, highly-connected brain areas (hubs), are vulnerable to MS-induced atrophy. Here we investigate if white matter (WM) tracts that pass through hubs have different susceptibility to MS pathology, due to anterograde and retrograde neurodegeneration, compared to tracts do not pass through these hubs. We use the apparent intra-axonal volume fraction (V_ax) derived from the multi-compartment diffusion MRI spherical mean technique (SMT) as well as the neurite density index (NDI) and isotropic volume fraction (IVF) derived from the neurite orientation dispersion and density imaging (NODDI) coupled with high-resolution tractography to assess the degree of tract-specific axonal integrity.

Objectives

(1) To compare tract-specific lesion burden, V_ax, NDI and IVF between WM tracts that overlap with either the thalamus or the putamen (hub+ tracts) and those that do not (hub- tracts); and (2) to assess the relationship between these MRI metrics and those of physical impairment, as measured by the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW).

Methods

EIghteen patients underwent 3T MRI inclusive of T1- and T2-weighted sequences, SMT and NODDI. Using probabilistic tractography, we reconstructed 49 WM tracts, 12 hub+ tracts and 37 hub- tracts. Using T-tests, we compared the following MRI metrics between hub+ and hub- tracts: T1 and T2 lesion burden (calculated as percentage of tracts occupied by T1 and T2 lesions) as well as whole tract and normal-appearing WM (NAWM) average NDI, IVF and V_ax values. Spearman correlation assessed the relationship between these MRI metrics and those of clinical impairment.

Results

Hub+ tracts had a lower mean %T1 lesions (0.86 vs. 1.99) and %T2 lesions (2.90 vs. 5.42), as well as higher whole tract NDI (0.61 vs. 0.57), NAWM NDI (0.61 vs. 0.58), whole tract V_ax (0.49 vs 0.44) and NAWM Vax (0.50 vs. 0.44), all significant at the p<0.001 level. Stronger correlations were seen between clinical measures and hub+ tracts compared to hub- tracts, with the strongest correlation for %T1 lesions and the T25FW (r= -0.59, p<0.0001).

Conclusions

WM tracts that overlap with the thalamus and the putamen have a higher degree of axonal integrity and lower lesional burden, suggesting a protective role of hubs. However, given the ramifications of disease present at the level of hub+ tracts, disease here retains a major impact on disability. If confirmed, our data suggest the role of disease location in relation to hubs as guidance for treatment personalization, considering more aggressive approaches for patients presenting with MRI changes in hub+ fiber tracks.

Background

Periodic brain magnetic resonance imaging (MRI) monitoring is recommended to assess subclinical disease activity in patients with multiple sclerosis (MS) who are on disease modifying therapies (DMTs). However, it is unclear whether spinal cord MRI surveillance is also useful.

Objectives

To determine how frequently follow-up MRI of the cervical or thoracic spine revealed asymptomatic new (T2 hyperintense or T1 gadolinium-enhancing) lesions in patients with MS on DMTs.

Methods

This was a retrospective medical record review. Patients with relapsing MS aged 18–60 years, on DMT, with MRI of the brain, cervical and thoracic spine, seen in our MS clinic in the past 5 years were included.

Results

One hundred and ten patients were included. Seventy-four percent were female and 92% were Caucasian. Median age at MS diagnosis was 37 years (range 19-56) and the median disease duration at the time of first MRI in the study was 0.7 years (range 0-20). Median follow up time was 3 years (range 1- 10). At least one new asymptomatic lesion was detected in the brain MRI in 31% of the patients. Nine patients (8%) developed at least one new asymptomatic cervical cord lesion. None developed asymptomatic new lesions in the thoracic spine.

Conclusions

A small proportion of patients developed asymptomatic cervical cord lesions and none of the patients developed asymptomatic thoracic lesions. Given that spinal cord lesions are associated with worse prognosis in the first years after MS diagnosis, cervical spine MRI might be useful in surveying asymptomatic new lesions, but thoracic spinal cord MRI does not appear to add significant value to MS monitoring.

Background

Early treatment in MS is a complex concept to convey to a naïve audience as it often needs to be considered in the absence of symptoms. There are risks involved and other life priorities to contemplate.

Objectives

To address the importance of early intervention, a film was created conveying the results of non-action. The film was produced to appeal to a broad, modern audience: short duration (164 seconds), conceptual, without dialogue and accessible across multi-formats. We assessed its success at delivering the message to people with MS (pwMS) and a general population (GP).

Methods

Three populations were included: pwMS from the UK MS Register, pwMS from outpatient clinics and a GP (Ethical approval ref: 19/LO/0282). Based upon industry standard, pre-specified outcomes were 50% viewer retention (viewing for ≥30 seconds) and 50% understanding of the concepts. The film was embedded into a website, participants were asked to review the film and the four concepts were explained. Participants answered questions about the concepts and were asked for their opinion utilising free commentary and evaluated using thematic analysis.

Results

In the MS Register population 757/959 (78.9%) pwMS had total self-perceived understanding (4/4 concepts) versus 29/42 (69%) in pwMS from outpatients and 136/149 (91%) in the GP. Understanding in all cohorts were significantly above the expected outcomes (p<0.0001) and was highest in the GP compared to pwMS (p>0.0001) In the total population 714/1150 (62%) watched ≥30 seconds with an average viewing duration of 156/164 seconds (95%), significantly above the pre-specified outcome percent (p<0.0001). Nine-hundred and eighteen of 959 (96%) provided optional free text commentary about the film. Six-hundred and ten of 918 (66%) acknowledged the role of early intervention and of taking action. In a multivariate analysis with understanding as the factor, pwMS without degree-level education and who commentated neutrally/positively, were independently associated with increased understanding of the film.

Conclusions

As part of a preventative medicine strategy, a short duration, targeted film can successfully convey the importance of early intervention to both pwMS and a GP.

Background

The internet and social media have become an increasingly accessible source of information for MS patients; allowing them to not only expand their knowledge of MS but also connect with fellow sufferers and hence feel part of a community.

Objectives

To assess how use of online information and social media impacts patients’ MS management, in the 5EU (UK/Germany/France/Italy/Spain) and the United States (US).

Methods

The Ipsos MS syndicated Patient Community gathered qualitative patient perceptions via an online community platform; collected via a PC, tablet or app in the 5EU (UK/ Germany/ France/ Italy/ Spain) and US in 9/2019. Patients were recruited from a specific MS patient panel and were taking a range of disease-modifying treatments (DMTs) of varying treatment status and MS types.

Results

229 MS patients participated in the MS syndicated Patient Community (n=178/51 5EU/US). Patients typically use official MS specific websites to search for facts seeing these as credible sources whilst Facebook groups are the main social media platform used to engage with other patients, gain first-hand experiences and share support. Patients typically research only at key milestones in their journey; primarily when they are waiting for a diagnosis, when first starting or switching DMT or when suffering from a significant symptom or relapse. Additionally, patients are more likely to research if they feel listened to by their Healthcare Professionals (HCPs) as being able to discuss their online findings provides an incentive to be proactive in their MS management. Patient awareness of the European/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) is low; 63.1% of patients have never heard of ECTRIMS/ACTRIMS and many are not aware of key topics and new developments presented, although most have a strong interest to learn.

Conclusions

Patients are less proactive in researching about MS if they feel they are stable on treatment or if there is little HCP engagement to discuss what they have read online. The low awareness of ECTRIMS/ACTRIMS suggests that HCPs are not sharing what they have learned as well there being a lack of patient-friendly conference news. Whilst there is a lot of focus on both pharma and HCPs having a patient-centric approach, additional investigation is needed to identify how to promote an active patient researcher mindset thereby empowering patients to take charge of their MS management.

Background

Classic health care (HC) models are currently being challenged by the ‘coronavirus disease of 2019’ (COVID-19) pandemic for which social isolation and unprecedented mobility restrictions have been deployed as essential measures of constrain. Digital communication services have the potential to preserve and improve access to specialized medical facilities in a cost- and time-efficient manner. Nonetheless, studies on live interaction between patients with multiple sclerosis (MS) and HC providers for neurological follow-up are still scarce. In a recent pilot project, we have shown that individual real-time audiovisual teleconsultations (TCs) over the internet are feasible and highly appreciated in patients with MS, but compliance and technical reliability over time remain to be demonstrated.

Objectives

To evaluate feasibility of real-time audiovisual TCs over the internet for neurological follow-up of patients with MS.

Methods

Thirty patients with MS presenting at a specialized center in Belgium were recruited for this ongoing study, and scheduled to receive 4 TCs over the course of 12 months. Patients were provided a unique hyperlink by mail in advance, leading them automatically and directly to the virtual waiting room, where they could accept or decline our incoming call. All TCs are performed by a trained HC professional with the intention to keep the conversation similar to what is usually discussed during a classic face-to-face MS consultation. The approach will be considered feasible if at least 80% of the planned TCs can be successfully completed at the foreseen moment. We present the results of an interim analysis (July 8, 2020), when at least 2 TCs were executed in each participant. Patient satisfaction (technical quality, convenience, quality of care and added value) was evaluated via telephone by means of 5-point Likert scales containing the categories very unsatisfied, unsatisfied, neutral, satisfied and highly satisfied.

Results

Three participants dropped out of the study due to loss of interest (2) or a broken device (1). Sixty of the 75 scheduled TCs were successfully completed (80%). Failures were due to patients not responding (7/56) or technical issues (8/56). Out of the 27 active participants, 24 responded to the telephone call for satisfaction analysis. Rates of patients declaring themselves satisfied or highly satisfied regarding the TCs were 19/24 for technical quality, 23/24 for convenience, 22/24 for quality of care and 21/24 for added value.

Conclusions

Real-time audiovisual TCs over the internet appear to be feasible and well-received in patients with MS. Full completion of this trial is expected early next year. Incorporation of digital communication services in routine MS practice is expected to improve access to specialized care, particularly in dire times such as the current COVID-19 crisis.