University Hospital Basel and University of Basel
Medical Image Analysis Centre/MIAC

Author Of 2 Presentations

Biomarkers and Bioinformatics Oral Presentation

PS09.05 - Value of serum neurofilament light chain levels as a biomarker of suboptimal treatment response in MS clinical practice

Abstract

Background

Serum neurofilament light chain (sNfL) reflects neuro-axonal damage and may qualify as a biomarker of suboptimal response to disease modifying therapy (DMT).

Objectives

To investigate the predictive value of sNfL in clinically isolated syndrome (CIS) and relapsing-remitting (RR) MS patients with established DMT for future MS disease activity in the Swiss MS Cohort Study.

Methods

All patients were on DMT for at least 3 months. sNfL was measured 6 or 12-monthly with the NF-light®assay. The association between sNfL and age was modeled using a generalized additive model for location scale and shape. Z-scores (sNfLz) were derived thereof, reflecting the deviation of a patient sNfL value from the mean value of same age healthy controls (n=8865 samples). We used univariable mixed logistic regression models to investigate the association between sNfLz and the occurrence of clinical events (relapses, EDSS worsening [≥1.5 steps if EDSS 0; ≥1.0 if 1.0-5.5 or ≥0.5 if >5.5] in the following year in all patients, and in those fulfilling NEDA-3 criteria (no relapses, EDSS worsening, contrast enhancing or new/enlarging T2 lesions in brain MRI, based on previous year). We combined sNfLz with clinical and MRI measures of MS disease activity in the previous year (EDA-3) in a multivariable mixed logistic regression model for predicting clinical events in the following year.

Results

sNfL was measured in 1062 patients with 5192 longitudinal samples (median age 39.7 yrs; EDSS 2.0; 4.1% CIS, 95.9% RRMS; median follow-up 5 yrs). sNfLz predicted clinical events in the following year (OR 1.21 [95%CI 1.11-1.36], p<0.001, n=4624). This effect increased in magnitude with increasing sNfLz (sNfLz >1: OR 1.41 [95%CI 1.15-1.73], p=0.001; >1.5: OR 1.80 [95%CI 1.43-2.28], p<0.001; >2: OR 2.33 [95%CI 1.74-3.14], p<0.001). Similar results were found for the prediction of future new/enlarging T2 lesions and brain volume loss. In the multivariable model, new/enlarging T2 lesions (OR 1.88 [95%CI 1.13-3.12], p=0.016) and sNfLz>1.5 (OR 2.18 [95%CI 1.21-3.90], p=0.009) predicted future clinical events (n=853), while previous EDSS worsening, previous relapses and current contrast enhancement did not. In NEDA-3 patients, change of sNfLz (per standard deviation) was associated with a 37% increased risk of clinical events in the subsequent year (OR 1.37 [95%CI 1.04-1.78], p=0.025, n=587).

Conclusions

Our data support the value of sNfL levels, beyond the NEDA3 concept, for treatment monitoring in MS clinical practice.

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Imaging Oral Presentation

PS11.04 - Quantitative susceptibility mapping classifies white matter lesions with different myelin and axonal content and quantifies diffuse pathology in MS

Abstract

Background

Quantitative susceptibility mapping (QSM) identifies iron accumulation and myelin loss in smoldering white matter lesions (WMLs). Yet, QSM may be also used to provide a broader understanding of focal and diffuse MS pathology.

Objectives

To study QSM features across WMLs, to assess myelin and axonal loss in WMLs with different QSM features and to quantify QSM pathology in normal-appearing white and cortical grey matter (NAWM, NAGM).

Methods

Ninety-one MS patients (62 RRMS, 29 PMS) and 72 healthy controls (HC) underwent QSM, myelin water imaging (MWI) and multishell diffusion at 3T MRI. In WMLs, cortical lesions (CLs), NAWM and NAGM, we extracted mean QSM, myelin water fraction (MWF) and neurite density index (NDI). WMLs were classified into 5 groups according to their appearance on 3D-EPI QSM: (i) isointense; (ii) with hyperintense rim, Rim+ (iii); with hypointense rim relative to the lesion core, hypo Rim; (iv) hyperintense; (v) hypointense. Mann-Whitney and Kruskal-Wallis test with Dunn’s correction for multiple comparison were used to compare (a) lesion types and (b) specific lesions vs all other WMLs. Voxel-wise comparisons of NAWM QSM were performed using Threshold-Free Cluster Enhancement (TFCE) clustering. Cortical analysis of QSM NAGM and GM-HC was performed using FreeSurfer and compared using a General Linear model (GLM).

Results

Of 1136 WMLs in QSM maps, we detected: (i) 314 (27.6%), (ii) 183 (16.1%), (iii) 16 (1.41%), (iv) 577 (50.8%) and (v) 46 (4.05%) WML. All WML exhibited lower NDI than NAWM and WM-HC (P<0.0001). Isointense lesions exhibited higher NDI (P=0.0115) and MWF (P<0.0001) than other WMLs. Rim + and hyperintense lesions exhibited lower MWF than NAWM and WM-HC (P<0.0001). Rim + lesions showed lower MWF and NDI than other WML types (P<0.001). Hypo Rim+ lesions and hypointense lesions exhibited higher MWF than other WMLs (P=0.0006, P<0.05). Hyperintense lesions exhibited lower MWF than other WMLs types (P<0.01) except Rim+ lesions. TFCE and vertex-wise cortical surface analysis showed areas throughout the NA tissue, where QSM is either lower or higher compared to healthy tissue in HC and in PMS compared to RMS (P<0.01).

Conclusions

QSM is sensitive to diffuse and focal pathology with various myelin and axonal characteristics. We hypothesize that isointense WMLs show high repair activity, hypointense WMLs are remyelinated lesions and hyperintense WMLs are chronic inactive lesions. MRI-histopathology work is ongoing to confirm these findings.

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Author Of 6 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0097 - Intrathecal immunoglobulin M synthesis is associated with higher serum neurofilament light chain levels and increased MRI disease activity in MS (ID 1089)

Abstract

Background

Intrathecal IgM synthesis was reported to be associated with higher clinical disease activity and severity. We found an association also with earlier use of high efficacy treatments in relapsing MS (RMS).

Objectives

To explore whether patients with intrathecal IgM synthesis show a) higher serum neurofilament light chain levels (sNfL) as a reflection of neuronal damage, or b) signs of increased disease severity in cerebral MRI, in patients with RMS followed in the Swiss MS Cohort Study.

Methods

487 patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecally produced IgG/M:

1) OCGB-/IgG-/IgM- (reference [ref]);

2) OCGB+/IgG-/IgM-;

3) OCGB+/IgG+/IgM- and

4) OCGB+/IgG+/IgM+.

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modelled in 8865 healthy control samples to reflect the deviation of a patient sNfL value compared to mean values observed in same age healthy controls. Yearly T2 lesion number and occurrence of new/enlarging T2 lesions were automatically assessed in cerebral MRIs and checked manually. Contrast enhancing lesions (CEL) were manually quantified. Linear or negative binomial mixed models were used to investigate the associations between the four CSF Ig patterns and longitudinal sNfLz and MRI measures, adjusted for DMT and other covariates.

Results

IgM+ patients had higher sNfLz vs reference (estimate 0.50 [CI 0.12, 0.89], p=0.011), whereas those with only OCGB+ (0.11 [-0.28, 0.50], p=0.582) or with OCGB+/IgG+ (0.20 [-0.16, 0.56], p=0.270) did not (n=2970 observations). This was confirmed when analyzing only untreated patients adjusting for T2 and CEL numbers (1.16 [0.47, 1.86], p<0.01 vs 0.58 [-0.11, 1.27], p=0.1022 vs 0.51 [-0.11, 1.13], p=0.108 vs ref, respectively) (n=234).

IgM+ patients had 2.28-fold more T2 lesions ([1.51, 3.44], p<0.01) vs ref; for patients with only OCGB+ (1.61 [1.07, 2.43], p=0.0237) or OCGB+/IgG+ (1.58 [CI 1.08, 2.32], p=0.0179) (n=1580) this association was weaker.

IgM+ was associated with a 2.47-fold risk for new/enlarging T2 lesions on yearly follow-up MRIs vs ref (2.47 [1.28, 4.78], p<0.01) but not the two other patient groups (1.84 [CI 0.93; 3.65], p=0.0799 and 1.61 [CI 0.87; 2.95], p=0.1280) (n=861).

Conclusions

Intrathecal IgM synthesis was consistently associated with quantitative measures of neuro-axonal injury and disease severity in RMS. Our findings strongly support the clinical utiliy of this biomarker.

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Biomarkers and Bioinformatics Poster Presentation

P0160 - Serum NfL z-scores derived from a large healthy control group reflect different levels of treatment effect in a real-world setting (ID 916)

Abstract

Background

Serum neurofilament light chain (sNfL) levels reflect neuroaxonal damage and relate to disease activity in MS. sNfL may qualify as well as a biomarker of suboptimal treatment response to disease modifying therapies (DMT). Establishment of age-dependent reference ranges in healthy controls is a prerequisite for developing this biomarker for clinical use.

Objectives

To compare on-treatment sNfL levels with values from a healthy control cohort and to investigate the effect of DMTs on sNfL levels in patients from the Swiss MS Cohort Study.

Methods

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modeled in healthy controls using a generalized additive model for location scale and shape to reflect the deviation of a patient sNfL value from the mean value of same age healthy controls. Linear mixed models were used to investigate the associations between clinical characteristics, DMT and longitudinal sNfLz. Interaction terms and splines were used to model sNfLz and for comparison log(NfL), and their dynamics under treatment.

Results

sNfL was measured in 1368 patients with 7550 longitudinal samples (baseline: median age: 41.9 yrs; 5.4% CIS, 83.2% RRMS, 5.6% SPMS, 5.8% PPMS; median EDSS: 2.0; median follow-up: 4.6 yrs) and 4133 healthy controls with 8865 samples (median age: 44.8 yrs). In the multivariable model, sNfLz increased with EDSS (0.131/step, [95% CI 0.101;0.161]), recent (<120 days) relapse (0.739 [0.643;0.835]) decreased with age (-0.014/year [-0.02;-0.009]), and time on DMT (-0.040/year [-0.054;-0.027]); sNfLz were lower when sampled while on more effective DMT (oral versus platform injectables: -0.229 [-0.344;-0.144]; monoclonal antibodies (mAB) versus platform injectables: -0.349 [-0.475;-0.224]), (p<0.001 for all associations). sNfLz were inversely associated with the hierarchy in efficacy of mAB over orals and orals over platform therapies with regard to slope and extent of decrease (interaction between time under DMT and DMT class: p<0.001). sNfLz, but not log(NfL) showed normalization of sNfL levels by mAB to healthy control levels.

Conclusions

The dynamic change of sNfLz on DMT reflects closely their relative clinical efficacy and is more meaningful than log(sNfL) by excluding age as a confounding factor. Use of sNfLz based on a large normative database as an age-independent sNfL measure improves the accuracy of the sNfL signal and hence their clinical utility.

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Imaging Poster Presentation

P0534 - Advanced magnetic resonance imaging for myelin and axonal density in MS: correlation with clinical disability and serum neurofilament levels (ID 1781)

Abstract

Background

Myelin water imaging (MWI) and neurite orientation dispersion and density imaging (NODDI) provide sensitive surrogate markers of myelin and axonal content in lesions and normal-appearing tissue. However, to date, there is scarce information about the relationship of these measures with (i) disability; and (ii) the axonal damage specific biomarker serum neurofilament light chain (sNfL).

Objectives

To explore the correlation of MWI and NODDI measures in MS lesions and in normal-appearing (NA) brain tissue with disability and sNfL.

Methods

Ninety-one MS patients (62 relapsing-remitting MS-RRMS and 29 progressive MS-PMS) underwent MWI and NODDI. Mean myelin water fraction (MWF) and neurite density index (NDI) were extracted in white matter lesions (WMLs), cortical lesions (CLs), NA white matter (NAWM) and cortical NA gray matter (CNAGM). For sNfL, a logarithmic transformation was applied to comply with normality assumption. Correlation studies between MRI measures, sNfL and EDSS were performed using linear models, with age and gender as covariates. The models were performed for the whole sample and for patients with clinical deficits only (EDSS >1).

Results

MWF and NDI did not correlate with EDSS when the entire cohort was considered (P>0.05). However, for those patients with clinical deficits (EDSS> 1), NDI in WMLs was associated with EDSS (NDI: P<0.01, beta=-10.00; N=74). We also found that MWF and NDI in WMLs were related to sNfL (MWF: P<0.01, beta=0.13; NDI: P<0.01, beta=-3.60). Again, this correlation was stronger in patients with EDSS>1 (MWF: P<0.01, beta=0.13; NDI: P <0.01, beta=-3.60).

Conclusions

Imaging surrogate markers of myelin and axon pathology in WML – and not in CLs and NA tissues - are correlated with disability and sNfL. Interestingly, associations between those imaging markers and disability/sNFL were more evident in patients with clinical deficits as compared to those without neurological deficits.

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Imaging Poster Presentation

P0580 - Focal inflammatory activity and lesion repair are associated with brain atrophy rates in MS patients (ID 1092)

Abstract

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.

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Imaging Poster Presentation

P0595 - Investigating the relation between global structural network measures and serum neurofilament light in multiple sclerosis (ID 1325)

Speakers
Presentation Number
P0595
Presentation Topic
Imaging

Abstract

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.

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Imaging Poster Presentation

P0638 - Role of Gadolinium-based contrast agents to detect subclinical disease activity in clinically stable patients in the Swiss MS Cohort Study (ID 821)

Abstract

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.

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