L. Kappos
University of BaselAuthor Of 7 Presentations
FC03.03 - Depicting multiple sclerosis pathology at 160μm isotropic resolution by human whole-brain postmortem 3T magnetic resonance imaging
Abstract
Background
Postmortem magnetic resonance imaging (MRI) of formalin-fixed healthy and diseased human brains with ultra-high spatial resolution has the great potential to depict tissue architecture in fine detail, allowing a deeper understanding of pathological processes. Whole-brain imaging is important since it provides neuroanatomic relationships, reference points across distant brain regions, and a comprehensive view of pathologies affecting the brain. However, ultra-high-resolution whole-brain postmortem MRI is challenging and has been so far almost exclusively performed at 7T with specialized hardware.
Objectives
To develop a 3D isotropic 160µm ultra-high-resolution imaging (URI) approach for human whole-brain ex vivo acquisitions on a standard clinical 3T MRI system. To explore the sensitivity and specificity of the approach to specific pathological features of multiple sclerosis (MS).
Methods
A fixed whole human brain from a patient with secondary progressive MS was investigated. Acquisitions were performed on a clinical 3T Siemens Prismafit MRI system with standard hardware components. URI is based on a gradient echo sequence similar to the 7T approach by Edlow et al. 2019. However, it allows to acquire an isotropic 160µm resolution with low hardware demands and to directly reconstruct the image data on the standard 3T MRI system. URI images display a strong, susceptibility-enhanced tissue contrast.
Results
The reconstructed URI images depicted with remarkable quality the diseased human MS brain at 3T field strength. URI allowed to distinguish fine anatomical details such as the subpial molecular layer, the stria of Gennari as well as some intrathalamic nuclei. Additionally, because of the unprecedented spatial resolution and contrast at 3T, URI permitted to easily identify the presence of subpial lesions, detailed features of intracortical lesions such the presence of incomplete/complete iron rims or patterns of iron accumulation in the entire lesion core in both cortical and white matter lesions (CLs/WMLs), lesions affecting the convoluted layers of the cerebellar cortex and nascent submillimetric CLs/WMLs.
Conclusions
URI provides a comprehensive microscopic insight into the whole-human brain at 3T through the micrometric resolution and a tissue-specific, susceptibility-enhanced contrast. We propose URI as an excellent approach to investigate microscopic brain changes of complex pathologies like MS.
FC03.05 - Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO
Abstract
Background
In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.
Objectives
To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.
Methods
At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.
Results
In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.
Conclusions
In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.
FC04.03 - High plasma glial fibrillary acidic protein levels predict disability milestone EDSS 7 in non-active secondary progressive multiple sclerosis
Abstract
Background
Glial fibrillary acidic protein (GFAP) is released into the cerebrospinal fluid and blood upon astroglial injury and activation, one of the hallmarks of progressive multiple sclerosis (PMS). It is unclear whether blood GFAP levels are associated with disability accumulation in secondary progressive MS (SPMS).
Objectives
To explore GFAP as a prognostic biomarker of disability worsening in patients with active and/or non-active SPMS (aSPMS and/or naSPMS) in the Phase 3 EXPAND study.
Methods
In this post-hoc analysis from the EXPAND study, baseline (BL) GFAP was quantified in EDTA plasma samples using Single Molecule Array technology. GFAP was categorized as high/low based on the gender stratified 80 percentile. The effect of GFAP on time to Expanded Disability Status Scale [EDSS] 7 (wheelchair restricted) was assessed using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and BL EDSS. Subgroup analyses were conducted in patients with aSPMS/naSPMS (with/without relapses ≤24 months prior to study entry, and/or gadolinium-enhancing T1 lesions at BL) and were also stratified by gender.
Results
Samples were available for 1405 of the 1651 patients randomized in the EXPAND study; median GFAP levels (pg/mL) were 119.6 (male) and 141.4 (female). Overall, the risk of reaching EDSS 7 was higher in patients with high BL GFAP (96%: high vs low GFAP, [34/281, 12.1%] vs [54/1117, 4.8%]; HR 1.96 [1.27; 3.03]; p=0.0024). Interestingly, the increased risk of reaching EDSS 7 was mainly seen in females (23/169; 13.6%] vs [34/673; 5.1%]; HR 2.22 [1.30; 3.80]; p=0.0035), and not significant in males ([11/112, 9.8%] vs [20/444, 4.5%]; HR 1.45 [0.67; 3.12]; p=0.3457). Increase in risk of reaching EDSS 7 was mainly observed in naSPMS patients (high GFAP [14/133; 10.5%] vs low GFAP [22/570; 3.9%]; HR 3.40 [1.71; 6.75]; p=0.0005) and was not significant in aSPMS patients (high GFAP [20/144; 13.9%] vs low GFAP [30/521; 5.8%]; HR 1.58 [0.88; 2.82]; p=0.1250). However, associations between BL GFAP levels and time to 6-months confirmed disability progression showed similar trends, but were less pronounced.
Conclusions
Blood GFAP appears to be a prognostic biomarker of disability worsening. The relevance of the gender difference and the stronger correlations found in SPMS patients with non-active versus active disease needs further investigation.
LB01.03 - Neutrophil granulocyte markers in cerebrospinal fluid differentiate NMOSD and anti-MOG antibody associated disease from MS in acute disease phase
Abstract
Background
Background
Neuromyelitis optica spectrum disorders (NMOSD), anti-MOG-antibody associated disease (MOGAD) and multiple sclerosis (MS) may be difficult to differentiate. Detection of antibodies (Ab) targeting AQP4 and MOG is the diagnostic gold standard for the former two diseases, but has limited sensitivity and long laboratory turnaround time. Neutrophil granulocyte (NG) invasion of brain tissue is a key differentiator of NMOSD from MS, and has also been described in MOGAD.
Objectives
Objectives
To examine the capability to differentiate NMOSD/MOGAD from MS by the profile of secreted primary (elastase (Ela); myeloperoxidase (MPO)) and secondary (matrix metalloproteinase-8 (MMP-8); neutrophil gelatinase-associated lipocalin (NGAL)) neutrophil granule products in CSF.
Methods
Methods
CSF from patients with NMOSD (n=42), MOGAD (n=6) and RRMS (n=41) were evaluated for Ela, MPO, MMP-8, NGAL, and compared with markers of neuronal (NfL) and astrocyte (GFAP, S100B) damage by conventional ELISA or single molecule array assay. CSFs from healthy controls (HC) (n=25) served as reference. The association between biomarkers and disease groups was assessed in linear models. The kinetic change of biomarkers in function of time since last relapse was modelled across disease groups. ROC curves and area under the curve (AUC) were calculated to estimate the potential to differentiate NMOSD/MOGAD from RRMS in acute disease phase (≤20 days after relapse), as well as between acute NMOSD and MOGAD. The association of biomarkers with EDSS in acute NMOSD and RRMS was assessed by linear models and Spearman correlation.
Results
Results
All disease groups had elevated NfL vs HC (p<0.01), while GFAP levels were increased only in NMOSD (p<0.01). In acute NMOSD, all 4 NG markers were increased vs HC and acute RRMS (all p<0.01). In MOGAD, Ela, MPO and MMP-8 were increased vs HC (p<0.025) and acute RRMS (p<0.04). AUC in ROC analyses comparing acute NMOSD/MOGAD vs acute RRMS was high (Ela and NGAL: 0.91; MPO: 0.82; MMP-8: 0.81). In acute NMOSD, S100B and GFAP levels were increased in 89% (AUC=0.82) and 83% (AUC=0.80) of patients, respectively, vs median values of MOGAD. In acute NMOSD, EDSS scores correlated with all 4 NG markers (all p<0.01), and GFAP (p<0.031), but not with NfL and S100B (both p=0.21).
Conclusions
Conclusion
NG-specific biomarkers correlate with current EDSS scores in NMOSD. They show high sensitivity and specificity for rapid differentiation of acute NMOSD and MOGAD vs RRMS, similar to those reported for Ab against AQP4 and MOG. As the 4 NG biomarkers can be measured within few hours, as compared to an up to 2-week turnaround time for gold-standard cell-based assays for AQP4 and MOG, they could support individual decision making for acute therapeutic intervention. Further, increased S100B and GFAP levels differentiate acute NMOSD from MOGAD. NG markers may have a role in the diagnosis of Ab-negative NMOSD.
LB01.06 - Interrupting disease modifying treatment for pregnancy in multiple sclerosis – effect on disease activity and serum neurofilament light chain
Abstract
Background
Pregnancy in MS typically goes along with reduced disease activity in the third trimester, followed by an increase in relapse frequency postpartum. Neurofilament light chain levels in serum (NfL) is a specific biomarker of neuroaxonal injury. Increased NfL levels are associated with relapses and MRI activity, while disease modifying treatment (DMT) response is reflected by a decrease of NfL.
Objectives
The objective of this study was to evaluate whether interrupting DMT due to pregnancy leads to increased NfL levels in MS.
Methods
We investigated prospectively documented pregnancies in the Swiss MS Cohort Study. Serum samples were collected 6- or 12-monthly and were analyzed by Simoa NF-light® assay. Uni- and multivariable mixed effect models were used to investigate associations between clinical characteristics and longitudinal NfL levels.
Results
We investigated 72 pregnancies in 63 relapsing MS patients (median age 31.4; disease duration 7.1 years; EDSS 1.5 at last visit before birth). In total, 433 samples were included: 92 during pregnancy or up to initiation of DMT but max. 9 months postpartum (pregnancy/post-partum period, pp), 167 prior to pp and 174 after the pp. Four patients had no DMT before, during and after pregnancy. DMT was continued in 13/72 pregnancies (>6 months during pregnancy: 6 rituximab/ocrelizumab, 4 natalizumab, 1 interferon-beta 1a i.m., 1 fingolimod and 1 glatiramer acetate). In univariable analysis, NfL levels were on average 22% higher during vs. outside the pp (β: 1.22, 95%CI: 1.10-1.35; p<0.001). We observed 29 relapses during the pp. In a multivariable analysis, relapses (within 120 days before serum sampling) were associated with 98% higher NfL (β: 1.98, 95%CI: 1.75-2.25; p<0.001); NfL was 7% higher per EDSS step increase (β: 1.07, 95%CI: 1.01-1.12; p=0.013) and on average 13% higher during vs. outside the pp (β: 1.13, 95%CI: 1.03-1.24; p=0.009). The effect of the pp on NfL disappeared after including DMT exposure (yes/no) at the sampling timepoint to the model (β:1.07, 95%CI: 0.97-1.18; p=0.178). Patients sampled during DMT had on average 12% lower NfL levels compared to patients without (β:0.88, 95%CI: 0.79-0.98; p=0.019).
Conclusions
Higher NfL levels were found during pp. This increase was independent of relapses suggesting increased subclinical disease activity during this time span. After including DMT into the model the effect of pregnancy on NfL disappeared: strategies allowing to continue DMT during pregnancy may be warranted.
PS09.05 - Value of serum neurofilament light chain levels as a biomarker of suboptimal treatment response in MS clinical practice
- Ö. Yaldizli
- P. Benkert
- A. Maceski
- M. Barakovic
- R. Todea
- A. Cagol
- S. Schaedelin
- G. Disanto
- J. Oechtering
- A. Orleth
- D. Rey
- T. Sinnecker
- R. Rahmanzadeh
- S. Zadic
- R. Galbusera
- L. Achtnichts
- S. Aeschbacher
- A. Chan
- D. Conen
- T. Derfuss
- O. Findling
- B. Fischer-Barnicol
- K. Hrusovsky
- H. Kropshofer
- P. Lalive
- J. Lieb
- J. Lorscheider
- P. Maggi
- C. Müller
- S. Müller
- Y. Naegelin
- J. Müller
- J. Oksenberg
- C. Pot
- R. Du Pasquier
- E. Radue
- A. Salmen
- J. Vehoff
- E. Waubant
- S. Wellmann
- H. Wiendl
- J. Wuerfel
- C. Zecca
- K. Berger
- C. Gobbi
- L. Kappos
- D. Leppert
- C. Granziera
- J. Kuhle
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.
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.