Author Of 4 Presentations
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.
P0163 - Smartphone keystroke dynamics are sensitive to changes in disease activity and clinical disability measures in multiple sclerosis (ID 748)
Abstract
Background
Typing behavior on a smartphone may be used as a biomarker in patients with multiple sclerosis (MS) by analyzing their keystroke dynamics (KD). The continuous acquisition of high sample rate data may provide unprecedented insights in short-term changes in important health outcomes in MS.
Objectives
To investigate the sensitivity of KD to clinically relevant change (i.e. responsiveness) in disease activity, fatigue, and clinical disability outcomes in patients with MS.
Methods
Patients with MS were recruited in this cohort study. Clinical outcomes were assessed at baseline and 3 months follow-up, including: MRI gadolinium-enhancing lesions (Gd-EL), patient-perceived fatigue, and clinical disability measures (Expanded Disability Status Scale, EDSS; Timed 25-foot Walk Test, TWT; Nine-Hole Peg Test, NHPT; Arm function in MS Questionnaire, AMSQ). Throughout the study, patients used the Neurokeys App which replaces the native keyboard with a smart-keyboard and unobtrusively collects time-stamped key press and release events in the real-world setting. Keystroke data of 14 days surrounding the clinical visits were aggregated for the analyses. The area under the receiver operating characteristics curve (AUROC) was calculated to assess responsiveness of KD in classifying anchor-based change within clinical outcomes. The minimally important change (MIC) was calculated as the mean change in KD in the lower +2 SD portion (to approximate minimal change) of patients with clinically relevant change for each clinical outcome. The MIC was compared to the smallest detectable change (SDC) to assess the capability of KD to distinguish important change from measurement error.
Results
102 patients with MS were included, of whom 94 completed follow-up. Responsiveness of KD were acceptable for change in number of MRI Gd-EL (highest AUROC = 0.73) and arm function based on the AMSQ score (highest AUROCs = 0.75). KD had excellent responsiveness to change in ambulatory function measured with TWT (highest AUROC = 0.84). EDSS and NHPT had lower AUC values than KD in classifying change in Gd-EL and AMSQ, respectively. For all keystroke features the MIC exceeded the SDC with differences ranging from 3.6 to 92.4%.
Conclusions
KD collected in patients with MS using the Neurokeys App demonstrated responsiveness to clinically relevant changes in gadolinium-enhancing lesions on MRI and clinical disability measures for arm and ambulatory function. Responsiveness of KD was higher than commonly used clinical measures in MS and sensitive enough to discriminate important change from measurement error.
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.