Author Of 5 Presentations
P0119 - Neurofilament light chain levels correlate with lesion activity and axonal damage in MS (ID 902)
Abstract
Background
The level of neurofilament light chain (NfL), a major component of the neuronal cytoskeleton, in plasma or cerebrospinal fluid (CSF) is considered a promising biomarker in multiple sclerosis (MS) for inflammation-mediated axonal damage.
Objectives
The relation between NfL levels and MS specific neuropathological measures is not yet known, and is the subject of this study.
Methods
In this autopsy study (n=105), CSF NfL levels were measured using a Simoa assay and were correlated with hallmarks for acute and chronic damage axonal damage, clinical and pathological donor characteristics, and to proportions and activity of MS white matter lesions determined with myelin and HLA stainings.
Results
CSF NfL levels correlated with presence of acute axonal damage features (APP+ bulbs: p=0.04, APP+ axons: p=0.03) and correlated negatively with axonal density (Bielschowsky+ axons: p=8.3e-3) in the normal appearing pyramid tract. As CSF NfL levels were confounded by stroke (<1 year before death, p=2.0e-3), these donors were excluded from further MS specific clinical and neuropathological analysis. NfL correlated negatively with disease duration (p=6.9e-3), thus with more severe MS. NfL levels positively correlated with the proportion of active MS lesions containing foamy microglia (p=9.85e-10) and not those containing ramified microglia. NfL levels of donors without atrophy at neuropathological examination were positively correlated with the proportion of mixed lesions with foamy microglia (p=1.75e-3), and negatively correlated with the proportion of inactive lesions (p=5.66e-3) and remyelinated lesion presence (p=0.04).
Conclusions
We validated that CSF NfL levels reflect pathological hallmarks of acute disease activity and concomitant axonal degeneration. These observations support the clinical use of NfL to monitor these neuropathological processes in people with MS.
P0151 - Serum contactin-1 levels as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis. (ID 1674)
Abstract
Background
Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.
Objectives
To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).
Methods
Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.
Results
Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).
Conclusions
Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.
P0398 - Switching from natalizumab to ocrelizumab in patients with relapsing-remitting multiple sclerosis. (ID 1725)
Abstract
Background
Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.
Objectives
To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.
Methods
All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.
Results
Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.
Conclusions
A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.
P0792 - Cerebrospinal fluid amyloid-β as potential biomarker for cognitive functioning in multiple sclerosis. (ID 1698)
Abstract
Background
Cognitive dysfunction occurs in 40-65% of the people with MS (PwMS), which has been related to grey matter (GM) and thalamic atrophy. Whether biomarkers specific to Alzheimer’s disease (AD, i.e. amyloid beta (Aβ42), total Tau, phosphorylated Tau (ptau-181)) are also involved in cognitive dysfunction in MS is not fully elucidated yet.
Objectives
To identify biomarkers in the cerebrospinal fluid (CSF) that are associated with cognition in MS and determine its relation with brain volume.
Methods
In total 62 PwMS visiting the Second Opinion MS and Cognition Outpatient Clinic (41 females; mean age: 47.10±9.30; mean disease duration: 12.65±9.07) underwent lumbar puncture, brain MRI, neurological (EDSS) and neuropsychological examination (MACFIMS). PwMS were classified as cognitively impaired (CI) with 20% of the cognitive test scores of ≤-1.5 SD compared to normative scores. Aβ42 (pg/ml), total tau (pg/ml), ptau-181 (pg/ml), the ratio of ptau-181:Aβ42 and total proteins (mg/l) were measured using Elecsys immunoassays on the Cobas System. FSL’s SIENAX and FIRST were used to calculate brain volumes (white matter volume, GM volume (GMV), thalamus volume and lesion load). Differences between cognitively preserved (CP) and CI patients were calculated as were correlations between CSF biomarkers and brain volumes.
Results
Demographic and MS-specific characteristics were not different between CP and CI patients. Aβ42 was below the clinical cut-off (<1000pg/ml) in 13/35 CI patients compared to 2/25 CP patients (37% and 8% respectively, P=.013). The chance of being CI was 6.5 times higher if Aβ42 was below this cut-off (odds-ratio; 95% CI [1.3 – 32.3]). On a group level, a trend towards lowered Aβ42 was found in CI compared to CP patients (1264.20±478.63 versus 1490.79±384.37 pg/ml; P=.059), albeit within the normal range. No differences were found for the other CSF markers. CI patients had lower GMV (P=.002) and thalamic volume (P=.011), compared to CP patients. Only in CP patients, thalamus volume correlated with Aβ42 (r=.475, P=.019). No other correlations were found between Aβ42 and brain volumes.
Conclusions
Aβ42 levels below the clinical cut-off was seen more often in CI patients, as were a lower GMV and lower thalamic volume compared to CP patients. Only in CP patients Aβ42 and thalamic volume were correlated, which disappeared in the more advanced disease stage (CI), comparable to findings in mild cognitive impairment and AD. The specificity of Aβ42 pathology in relation to cognition in MS needs further investigation.
P0881 - “Mild disease course of carry-over progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab” (ID 1406)
Abstract
Background
Natalizumab is an effective disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Nine confirmed cases of PML have been reported in patients using ocrelizumab, another effective DMT for MS. In 8 cases, patients previously used natalizumab or fingolimod, likely causing PML. This phenomenon has been described as carry-over PML.
Objectives
To describe the disease course of carry-over PML after switching from natalizumab to ocrelizumab in two patients with RRMS.
Methods
Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (sNfL) levels and B-cell count. Both patients provided informed consent.
Results
Regular follow-up showed no disease activity under natalizumab treatment and both patients switched to ocrelizumab following a stringent safety protocol including two additional MRI brain scans and cerebrospinal fluid (CSF) analysis. Both patients received a single infusion of 300 mg ocrelizumab before PML diagnosis. PML was diagnosed ±11 weeks (case 1) and ±13 weeks (case 2) after the last natalizumab infusion. At that time, both patients were asymptomatic. In retrospect, subtle signs suggestive of PML were already present on MRI under natalizumab treatment. One patient developed PML despite extended interval dosing of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite complete B-cell depletion. SNfL levels were 9.9 pg/ml (reference range 1-15 pg/ml) for case 1 and 16.7 pg/ml (reference range 2-18 pg/ml) for case 2 at the time of PML diagnosis and increased to 15.0 pg/ml and 36.5 pg/mL during PML-IRIS. SNfL was not elevated before radiological diagnosis of PML. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine followed by methylprednisolone with sNfL levels of 9.0 pg/mL and 12.3 pg/mL, respectively. One patient reported no clinical symptoms and one patient only mild clinical symptoms with full recovery during the disease course of PML-IRIS. Both patients continued with ocrelizumab when B-cells started to repopulate ±10 months after the first ocrelizumab infusion.
Conclusions
The clinical course of carry-over PML was mild in both patients, suggesting that B-cell depletion did not aggravate PML-IRIS in these two patients.