Publications by authors named "Jens Kuhle"

230 Publications

Antibodies to neurofilament light as potential biomarkers in multiple sclerosis.

BMJ Neurol Open 2021 11;3(2):e000192. Epub 2021 Nov 11.

Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background And Objective: The concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and blood is widely considered as a quantitative measure of neuro-axonal injury. Immune reactivity to NfL released into extracellular fluids induces specific autoantibody response. We investigated the levels and avidity of antibodies to NfL in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs) and their correlation with disease worsening and NfL protein concentration.

Methods: We conducted a prospective longitudinal study in 246 patients with MS (125 DMT-treated and 121 untreated at baseline). Serum levels of NfL antibodies, antibody avidity and immune complexes were determined by ELISA. NfL protein was measured using the Simoa platform. Clinical variables were tested for their association with the measured parameters in multivariate generalised estimating equation models.

Results: Multivariate analysis showed that levels of NfL antibodies were higher in progressive MS compared with clinically isolated syndrome (CIS)/relapsing remitting multiple sclerosis (RRMS) (p=0.010). Anti-NfL levels drop with increasing disability score (Expanded Disability Status Scale (EDSS)) (p=0.002), although conversely, were significantly elevated in CIS/RRMS after a recent EDSS increase (p=0.012). Patients receiving DMTs showed decreased levels of anti-NfL (p=0.008), high-avidity antibodies (p=0.017) and immune-complexes compared with untreated CIS/RRMS. Patients with MS switching to natalizumab showed lower levels of anti-NfL but higher immune complexes compared with healthy controls (p=0.0071). A weak association was observed between the levels of NfL protein and NfL antibodies.

Conclusions: These results support the potential usefulness of quantifying antibody response to NfL as potential markers of progression and treatment response in MS and need to be considered when interpreting peripheral blood NfL levels.
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http://dx.doi.org/10.1136/bmjno-2021-000192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587694PMC
November 2021

Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach.

Brain Commun 2021 12;3(4):fcab240. Epub 2021 Oct 12.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise. In this study, we sought to determine if metabolic perturbations are present during multiple sclerosis relapses, and, if so, identify candidate metabolite biomarkers and evaluate their discriminatory abilities at both group and individual levels, in comparison with neurofilament-light chain. High-resolution global and targeted H nuclear magnetic resonance metabolomics as well as neurofilament-light chain measurements were performed on the serum in four groups of relapsing-remitting multiple sclerosis patients, stratified by time since relapse onset: (i) in relapse (R); (ii) last relapse (LR) ≥ 1 month (M) to < 6 M ago; (iii) LR ≥ 6 M to < 24 M ago; and (iv) LR ≥ 24 M ago. Two hundred and one relapsing-remitting multiple sclerosis patients were recruited: R ( = 38), LR 1-6 M ( = 28), LR 6-24 M ( = 34), LR ≥ 24 M ( = 101). Using supervised multivariate analysis, we found that the global metabolomics profile of R patients was significantly perturbed compared to LR ≥ 24 M patients. Identified discriminatory metabolites were then quantified using targeted metabolomics. Lysine and asparagine (higher in R), as well as, isoleucine and leucine (lower in R), were shortlisted as potential metabolite biomarkers. ANOVA of these metabolites revealed significant differences across the four patient groups, with a clear trend with time since relapse onset. Multivariable receiver operating characteristics analysis of these four metabolites in discriminating R versus LR ≥ 24 M showed an area under the curve of 0.758, while the area under the curve for serum neurofilament-light chain was 0.575. Within individual patients with paired relapse-remission samples, all four metabolites were significantly different in relapse versus remission, with the direction of change consistent with that observed at group level, while neurofilament-light chain was not discriminatory. The perturbations in the identified metabolites point towards energy deficiency and immune activation in multiple sclerosis relapses, and the measurement of these metabolites, either singly or in combination, are useful as biomarkers to differentiate relapse from remission at both group and individual levels.
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http://dx.doi.org/10.1093/braincomms/fcab240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568847PMC
October 2021

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study.

Ann Neurol 2021 Nov 7. Epub 2021 Nov 7.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.

Objective: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage.

Methods: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls.

Results: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates.

Interpretation: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26265DOI Listing
November 2021

Development, validation and clinical usefulness of a prognostic model for relapse in relapsing-remitting multiple sclerosis.

Diagn Progn Res 2021 Oct 27;5(1):17. Epub 2021 Oct 27.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Background: Prognosis for the occurrence of relapses in individuals with relapsing-remitting multiple sclerosis (RRMS), the most common subtype of multiple sclerosis (MS), could support individualized decisions and disease management and could be helpful for efficiently selecting patients for future randomized clinical trials. There are only three previously published prognostic models on this, all of them with important methodological shortcomings.

Objectives: We aim to present the development, internal validation, and evaluation of the potential clinical benefit of a prognostic model for relapses for individuals with RRMS using real-world data.

Methods: We followed seven steps to develop and validate the prognostic model: (1) selection of prognostic factors via a review of the literature, (2) development of a generalized linear mixed-effects model in a Bayesian framework, (3) examination of sample size efficiency, (4) shrinkage of the coefficients, (5) dealing with missing data using multiple imputations, (6) internal validation of the model. Finally, we evaluated the potential clinical benefit of the developed prognostic model using decision curve analysis. For the development and the validation of our prognostic model, we followed the TRIPOD statement.

Results: We selected eight baseline prognostic factors: age, sex, prior MS treatment, months since last relapse, disease duration, number of prior relapses, expanded disability status scale (EDSS) score, and number of gadolinium-enhanced lesions. We also developed a web application that calculates an individual's probability of relapsing within the next 2 years. The optimism-corrected c-statistic is 0.65 and the optimism-corrected calibration slope is 0.92. For threshold probabilities between 15 and 30%, the "treat based on the prognostic model" strategy leads to the highest net benefit and hence is considered the most clinically useful strategy.

Conclusions: The prognostic model we developed offers several advantages in comparison to previously published prognostic models on RRMS. Importantly, we assessed the potential clinical benefit to better quantify the clinical impact of the model. Our web application, once externally validated in the future, could be used by patients and doctors to calculate the individualized probability of relapsing within 2 years and to inform the management of their disease.
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http://dx.doi.org/10.1186/s41512-021-00106-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549310PMC
October 2021

Prediction of multiple sclerosis outcomes when switching to ocrelizumab.

Mult Scler 2021 Oct 8:13524585211049986. Epub 2021 Oct 8.

Central Clinical School, Monash University, Melbourne, VIC, Australia.

Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab.

Objective: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab.

Methods: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP).

Results: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11,  = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64,  = 0.006).

Conclusion: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
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http://dx.doi.org/10.1177/13524585211049986DOI Listing
October 2021

Measurement of neurofilaments improves stratification of future disease activity in early multiple sclerosis.

Mult Scler 2021 Nov 6;27(13):2001-2013. Epub 2021 Oct 6.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.

Background: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail.

Objective: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year.

Methods: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile).

Results: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95];  = 0.0001) and greater whole brain volume loss during the following year (β = -0.36%; 95% CI = [-0.60, -0.13];  = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%).

Conclusion: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.
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http://dx.doi.org/10.1177/13524585211047977DOI Listing
November 2021

Central nervous system atrophy predicts future dynamics of disability progression in a real-world multiple sclerosis cohort.

Eur J Neurol 2021 Dec 17;28(12):4153-4166. Epub 2021 Sep 17.

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Background And Purpose: In an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short-term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse-onset MS.

Methods: Brain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing-remitting [RRMS] and 43 secondary-progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine-hole peg test and the timed 25-foot walk test.

Results: Higher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy.

Conclusion: This study demonstrates the capability of short-term MRI metrics to accurately predict future dynamics of disability progression in a real-world relapse-onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care.
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http://dx.doi.org/10.1111/ene.15098DOI Listing
December 2021

Death Anxiety and Attitudes towards Death in Patients with Multiple Sclerosis: An Exploratory Study.

Brain Sci 2021 Jul 22;11(8). Epub 2021 Jul 22.

Neuropsychology and Behavioral Neurology Unit, Division of Molecular and Cognitive Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland.

Background: Death and the anxiety of it becomes more apparent when confronted with a chronic disease. Even though multiple sclerosis (MS) is a treatable condition today, it is still accompanied by a multitude of impairments, which in turn may intensify of death anxiety.

Objective: The aim of this study is to explore the relationship between depression, anxiety and death anxiety in individuals with MS.

Methods: Fifty-six MS patients were recruited at the Department of Neurology of the University Clinic in Basel. Death anxiety was assessed using the Bochumer Questionnaire on attitude to death and death anxiety 2.0 (BOFRETTA 2.0).

Results: Scores of death anxiety towards it in MS patients were low. Only disability (EDSS) was moderately correlated with death anxiety. Depression in MS was significantly correlated with fatigue and disability, but not with the BOFRETTA 2.0.

Conclusion: Scores of death anxiety and the attitude towards death are low in this MS cohort. It was shown that both psychopathological and neurological deficits impact the subject of death with respect to multiple sclerosis.
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http://dx.doi.org/10.3390/brainsci11080964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391402PMC
July 2021

Prediagnostic Neurofilament Light Chain Levels in Amyotrophic Lateral Sclerosis.

Neurology 2021 Aug 11. Epub 2021 Aug 11.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Objective: To assess whether plasma neurofilament light chain (NfL) levels are elevated before ALS diagnosis and to evaluate whether pre-diagnostic NfL levels are associated with metabolic alterations.

Methods: We conducted a matched case-control study nested in three large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study), and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels.

Results: Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 standard deviation [SD] increase: 2.68, 95% CI: 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI: 0.78-1.73). A total of 21 metabolites were correlated with pre-diagnostic NfL levels in ALS cases (p < 0.05), but none of these remained significant after multiple comparison adjustments.

Conclusions: Plasma NfL levels were elevated in pre-diagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease.

Classification Of Evidence: This study provides Class II evidence that plasma NfL levels are elevated in pre-diagnostic ALS patients.
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http://dx.doi.org/10.1212/WNL.0000000000012632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575132PMC
August 2021

Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing-remitting MS.

Mult Scler 2021 Aug 11:13524585211032348. Epub 2021 Aug 11.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ).

Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively.

Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion.

Results: Baseline median sNfL levels were similar in alemtuzumab ( = 354) and SC IFNB-1a-treated ( = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; < 0.0001); 73% for alemtuzumab at Y7. HAD patients ( = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7).

Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7.

Clinicaltrials.gov Identifier: NCT00530348, NCT00930553, NCT02255656.
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http://dx.doi.org/10.1177/13524585211032348DOI Listing
August 2021

Serum neurofilament is associated with motor function, cognitive decline and subclinical cardiac damage in advanced Parkinson's disease (MARK-PD).

Parkinsonism Relat Disord 2021 Sep 29;90:44-48. Epub 2021 Jul 29.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Introduction: Serum neurofilament light chain (NfL) levels are associated with disease severity in early Parkinson's disease (PD). We assessed the association of serum NfL with motor and cognitive function and decline in advanced PD patients.

Methods: NfL concentrations were analyzed with single molecule array (Simoa) assay in serum of 289 PD patients with advanced disease from the single-center prospective observational biobank study Biomarkers in Parkinson's disease (MARK-PD). Motor and cognitive symptoms were assessed with MDS-UPDRS III, Hoehn&Yahr stages and Montreal Cognitive Assessment (MoCA) at baseline and during 520 [364, 674] days of follow-up.

Results: Serum NfL concentrations were associated with Hoehn&Yahr stages. During follow-up, baseline NfL levels were associated with time to cognitive decline in adjusted Cox regression models (hazard ratio: 3.23; 95% CI [1.16, 9.00], P < 0.025). Serum NfL was associated with NT-proBNP in adjusted models linking neuronal and cardiac damage in advanced PD patients.

Conclusion: In advanced PD patients, serum NfL concentrations are associated with motor function, cognitive decline and subclinical cardiac damage.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.028DOI Listing
September 2021

Increased Serum Neurofilament Light and Thin Ganglion Cell-Inner Plexiform Layer Are Additive Risk Factors for Disease Activity in Early Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 09 4;8(5). Epub 2021 Aug 4.

From the Experimental and Clinical Research Center (T.-Y.L., V.V., S.A., I.M.S., S.M., C.C., A.P., J.B.-S., F.P., A.U.B., H.G.Z.), Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; NeuroCure Clinical Research Center (T.-Y.L., V.V., S.A., I.M.S., S.M., C.C., A.P., J.B.-S., F.P., A.U.B., H.G.Z.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Department of Psychiatry and Psychotherapy (C.C.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Department of Statistics (M.D.), TU Dortmund University, Germany; Neurology Clinic and Policlinic (A.P., J.K.), MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel; Clinical Trial Unit (P.B.), Department of Clinical Research, University Hospital Basel, University of Basel, Switzerland; Department of Neurology (K.R., F.P.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; and Department of Neurology (A.U.B.), University of California, Irvine.

Objective: To investigate the association of combined serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements with future disease activity in patients with early multiple sclerosis (MS).

Methods: We analyzed sNfL by single molecule array technology and performed OCT measurements in a prospective cohort of 78 patients with clinically isolated syndrome and early relapsing-remitting MS with a median (interquartile range) follow-up of 23.9 (23.3-24.7) months. Patients were grouped into those with abnormal or normal sNfL levels, defined as sNfL ≥/<80th percentile of age-corrected reference values. Likewise, patients were grouped by a median split into those with thin or thick ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer, and inner nuclear layer in nonoptic neuritis eyes. Outcome parameters were violation of no evidence of disease activity (NEDA-3) criteria or its components.

Results: Patients with abnormal baseline sNfL had a higher risk of violating NEDA-3 (hazard ratio [HR] 2.28, 95% CI 1.27-4.09, = 0.006) and developing a new brain lesion (HR 2.47, 95% CI 1.30-4.69, = 0.006), but not for a new relapse (HR 2.21, 95% CI 0.97-5.03, p = 0.058). Patients with both abnormal sNfL and thin GCIP had an even higher risk for NEDA-3 violation (HR 3.61, 95% CI 1.77-7.36, = 4.2e), new brain lesion (HR 3.19, 95% CI 1.51-6.76, = 0.002), and new relapse (HR 5.38, 95% CI 1.61-17.98, = 0.006) than patients with abnormal sNfL alone.

Conclusions: In patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone.
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http://dx.doi.org/10.1212/NXI.0000000000001051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362351PMC
September 2021

Microstructure-Weighted Connectomics in Multiple Sclerosis.

Brain Connect 2021 Sep 8. Epub 2021 Sep 8.

Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Graph theory has been applied to study the pathophysiology of multiple sclerosis (MS) since it provides global and focal measures of brain network properties that are affected by MS. Typically, the connection strength and, consequently, the network properties are computed by counting the number of streamlines (NOS) connecting couples of gray matter regions. However, recent studies have shown that this method is not quantitative. We evaluated diffusion-based microstructural measures extracted from three different models to assess the network properties in a group of 66 MS patients and 64 healthy subjects. Besides, we assessed their correlation with patients' disability and with a biological measure of neuroaxonal damage. Graph metrics extracted from connectomes weighted by intra-axonal microstructural components were the most sensitive to MS pathology and the most related to clinical disability. In contrast, measures of network segregation extracted from the connectomes weighted by maps describing extracellular diffusivity were the most related to serum concentration of neurofilament light chain. Network properties assessed with NOS were neither sensitive to MS pathology nor correlated with clinical and pathological measures of disease impact in MS patients. Using tractometry-derived graph measures in MS patients, we identified a set of metrics based on microstructural components that are highly sensitive to the disease and that provide sensitive correlates of clinical and biological deterioration in MS patients. Impact statement Graph theory has been widely used to study the alterations in the structural connectivity of multiple sclerosis (MS) patients. Usually, brain graphs used for the extraction of network metrics are created by counting the number of streamlines connecting gray matter regions, however, this method is not quantitative. In this study, we used tractometry to average the values of diffusion-based microstructural maps along the reconstructed streamlines. Our results show that network metrics extracted from the connectomes weighted on microstructural maps provide sensitive information to MS pathology, which correlate with clinical and biological measures of disease impact.
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http://dx.doi.org/10.1089/brain.2021.0047DOI Listing
September 2021

The Effect of Depression on Health-Related Quality of Life Is Mediated by Fatigue in Persons with Multiple Sclerosis.

Brain Sci 2021 Jun 5;11(6). Epub 2021 Jun 5.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich (UZH), 8001 Zurich, Switzerland.

The interrelations between fatigue, depression and health-related quality of life (HRQoL) in persons with multiple sclerosis (PwMS) are complex, and the directionality of the effects is unclear. To address this gap, the current study used a longitudinal design to assess direct and indirect effects of fatigue and depression on HRQoL in a one-year follow-up survey. A sample of 210 PwMS from the nationwide Swiss MS Registry was used. HRQoL was assessed using the European Quality of Life 5-Dimension 5-Level questionnaire. Path analysis on HRQoL, with fatigue and depression as predictors, was applied. Fatigue was measured by the Modified Fatigue Impact Scale (MFIS), including physical, cognitive and psychosocial subscales, and non-somatic depressive symptomatology was examined with the Beck Depression Inventory-Fast Screen (BDI-FS). Fatigue acted as a fully mediating variable (B = -0.718, SE = 0.253) between non-somatic depressive symptomatology and HRQoL. This indirect effect became apparent in the physical (B = -0.624, SE = 0.250), psychosocial (B = -0.538, SE = 0.256) and cognitive subscales (B = -0.485, SE = 0.192) of fatigue. In contrast, non-somatic depressive symptomatology did not act as a mediator. Our findings provide novel and clinically relevant longitudinal evidence showing that the debilitating effect of non-somatic aspects of depression on HRQoL was fully mediated and therefore explainable via fatigue.
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http://dx.doi.org/10.3390/brainsci11060751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227168PMC
June 2021

Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression.

Comput Methods Programs Biomed 2021 Sep 18;208:106180. Epub 2021 May 18.

19 Mayis University, Samsun, Turkey.

Background And Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem.

Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used.

Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features.

Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS.
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http://dx.doi.org/10.1016/j.cmpb.2021.106180DOI Listing
September 2021

Altered neuroaxonal integrity in schizophrenia and major depressive disorder assessed with neurofilament light chain in serum.

J Psychiatr Res 2021 08 2;140:141-148. Epub 2021 Jun 2.

Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zürich, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.

Background: Schizophrenia (SZ) and major depressive disorders (MDD) have been frequently linked to anatomical brain alterations. However, the relationship between brain pathology, inflammation and clinical symptoms in these disorders is still unclear. Thus, by applying novel blood markers of neuroaxonal integrity such as neurofilament light chain (NfL), we can now address main issues in psychiatric research and potentially offer innovative diagnostic tools toward better clinical characterizations and monitoring in both SZ and MDD.

Methods: NfL levels were measured in serum of 44 patients with SZ and in 41 patients with MDD applying single molecule array technology and compared to a healthy norm population. Main inflammatory markers (C- reactive protein, interleukins IL-6 and IL-10) were measured to define patients with inflammatory phenotype. The Digit Symbol Substitution Task (DSST) and the Letter-Number-Sequencing Task were performed to estimate cognitive function in both groups.

Results: NfL levels in MDD group (but not in SZ group) were significantly higher than reference values of healthy norm population. A higher than expected proportion of patients with NfL levels above age-specific cut-off values was observed in both SZ and MDD groups. No correlation was observed between NfL and inflammatory markers. A negative correlation between DSST and NfL-values was observed in patients with MDD.

Conclusions: Both SZ and MDD showed elevated serum levels of NfL, which were independent from inflammatory markers but associated with cognitive performance.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.072DOI Listing
August 2021

Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis.

Neurology 2021 08 4;97(6):e543-e553. Epub 2021 Jun 4.

From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.

Objective: To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.

Methods: In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.

Results: In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (β, 16.3; 95% confidence interval [CI], 4.6-28.0; < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; β, 30.4; 95% CI, 15.6-45.2; < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (β, 1.1; 95% CI, 0.3-1.9; < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: = 0.004 and = 0.0002, respectively).

Conclusion: Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.
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http://dx.doi.org/10.1212/WNL.0000000000012326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424501PMC
August 2021

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

Ann Neurol 2021 09 22;90(3):477-489. Epub 2021 Jun 22.

Neurology Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening.

Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG and IgM ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models.

Results: By categorical analysis, in patients with IgM the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG . Furthermore, quantitative analyses revealed that in patients with IgM  ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM  < median. Dose-dependent associations were also found for IgM but not for IgG with magnetic resonance imaging-defined disease activity and sNfL.

Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.
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http://dx.doi.org/10.1002/ana.26137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518907PMC
September 2021

Reply to: Neurofilament Light Chain in Patients with COVID-19 and Bacterial Pneumonia.

Ann Neurol 2021 07 4;90(1):175-176. Epub 2021 Jun 4.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, Basel, Switzerland.

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http://dx.doi.org/10.1002/ana.26132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222927PMC
July 2021

Integrative biochemical, proteomics and metabolomics cerebrospinal fluid biomarkers predict clinical conversion to multiple sclerosis.

Brain Commun 2021 19;3(2):fcab084. Epub 2021 Apr 19.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalized medicine approach. We sought to identify biomarkers from biochemical, metabolic and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2-10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict the occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcab084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111065PMC
April 2021

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

J Neuroinflammation 2021 May 1;18(1):105. Epub 2021 May 1.

Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG) NMOSD.

Methods: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG patients over a median observation period of 4.25 years.

Results: In patients with AQP4-IgG NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG, but not MOG-IgG patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG, but not MOG-IgG patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG NMOSD. Patients with AQP4-IgG NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75 age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG NMOSD.

Conclusion: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG NMOSD in phases of clinical remission.
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http://dx.doi.org/10.1186/s12974-021-02138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088712PMC
May 2021

Serum neurofilament light chain (sNfL) values in a large cross-sectional population of children with asymptomatic to moderate COVID-19.

J Neurol 2021 Nov 23;268(11):3969-3974. Epub 2021 Apr 23.

University Children's Hospital Regensburg (KUNO), Hospital St. Hedwig of the Order of St. John, University of Regensburg, Steinmetzstr. 1-3, 93049, Regensburg, Germany.

Background: Serum neurofilament light chain (sNfL) is an established biomarker of neuro-axonal damage in multiple neurological disorders. Raised sNfL levels have been reported in adults infected with pandemic coronavirus disease 2019 (COVID-19). Levels in children infected with COVID-19 have not as yet been reported.

Objective: To evaluate whether sNfL is elevated in children contracting COVID-19.

Methods: Between May 22 and July 22, 2020, a network of outpatient pediatricians in Bavaria, Germany, the Coronavirus antibody screening in children from Bavaria study network (CoKiBa), recruited healthy children into a cross-sectional study from two sources: an ongoing prevention program for 1-14 years, and referrals of 1-17 years consulting a pediatrician for possible infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined sNfL levels by single molecule array immunoassay and SARS-CoV-2 antibody status by two independent quantitative methods.

Results: Of the 2652 included children, 148 (5.6%) were SARS-CoV-2 antibody positive with asymptomatic to moderate COVID-19 infection. Neurological symptoms-headache, dizziness, muscle aches, or loss of smell and taste-were present in 47/148 cases (31.8%). Mean sNfL levels were 5.5 pg/ml (SD 2.9) in the total cohort, 5.1 (SD 2.1) pg/ml in the children with SARS-CoV-2 antibodies, and 5.5 (SD 3.0) pg/ml in those without. Multivariate regression analysis revealed age-but neither antibody status, antibody levels, nor clinical severity-as an independent predictor of sNfL. Follow-up of children with pediatric multisystem inflammatory syndrome (n = 14) showed no association with sNfL.

Conclusions: In this population study, children with asymptomatic to moderate COVID-19 showed no neurochemical evidence of neuronal damage.
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http://dx.doi.org/10.1007/s00415-021-10554-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064423PMC
November 2021

GAMER-MRI in Multiple Sclerosis Identifies the Diffusion-Based Microstructural Measures That Are Most Sensitive to Focal Damage: A Deep-Learning-Based Analysis and Clinico-Biological Validation.

Front Neurosci 2021 6;15:647535. Epub 2021 Apr 6.

Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Conventional magnetic resonance imaging (cMRI) in multiple sclerosis (MS) patients provides measures of focal brain damage and activity, which are fundamental for disease diagnosis, prognosis, and the evaluation of response to therapy. However, cMRI is insensitive to the damage to the microenvironment of the brain tissue and the heterogeneity of MS lesions. In contrast, the damaged tissue can be characterized by mathematical models on multishell diffusion imaging data, which measure different compartmental water diffusion. In this work, we obtained 12 diffusion measures from eight diffusion models, and we applied a deep-learning attention-based convolutional neural network (CNN) (GAMER-MRI) to select the most discriminating measures in the classification of MS lesions and the perilesional tissue by attention weights. Furthermore, we provided clinical and biological validation of the chosen metrics-and of their most discriminative combinations-by correlating their respective mean values in MS patients with the corresponding Expanded Disability Status Scale (EDSS) and the serum level of neurofilament light chain (sNfL), which are measures of disability and neuroaxonal damage. Our results show that the neurite density index from neurite orientation and dispersion density imaging (NODDI), the measures of the intra-axonal and isotropic compartments from microstructural Bayesian approach, and the measure of the intra-axonal compartment from the spherical mean technique NODDI were the most discriminating (respective attention weights were 0.12, 0.12, 0.15, and 0.13). In addition, the combination of the neurite density index from NODDI and the measures for the intra-axonal and isotropic compartments from the microstructural Bayesian approach exhibited a stronger correlation with EDSS and sNfL than the individual measures. This work demonstrates that the proposed method might be useful to select the microstructural measures that are most discriminative of focal tissue damage and that may also be combined to a unique contrast to achieve stronger correlations to clinical disability and neuroaxonal damage.
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http://dx.doi.org/10.3389/fnins.2021.647535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055933PMC
April 2021

CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event.

Mult Scler 2021 Apr 19:13524585211010082. Epub 2021 Apr 19.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis.

Objective: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event.

Methods: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (β = 1.41; 95% confidence interval (CI) = 1.10-1.79; < 0.01) and serum NfL levels (β = 2.30; 95% CI = 1.47-3.60; < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (β = 1.45; 95% CI = 1.11-1.90; < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses.

Conclusion: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.
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http://dx.doi.org/10.1177/13524585211010082DOI Listing
April 2021

Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging.

Brain 2021 07;144(6):1684-1696

Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel and University of Basel, Basel, Switzerland.

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.
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http://dx.doi.org/10.1093/brain/awab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374972PMC
July 2021

The cholesterol autoxidation products, 7-ketocholesterol and 7β-hydroxycholesterol are associated with serum neurofilaments in multiple sclerosis.

Mult Scler Relat Disord 2021 May 26;50:102864. Epub 2021 Feb 26.

Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, United States; Jacobs Comprehensive MS Treatment and Research Center, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, United States. Electronic address:

Background: Serum neurofilament light chain (sNfL) is an established marker of neuroaxonal injury in multiple sclerosis (MS).

Objectives: To investigate if oxysterols produced from non-enzymatic and enzymatic cholesterol oxidation are differentially associated with sNfL measurements in MS.

Methods: This longitudinal study included 62 relapsing-remitting (RR-MS) and 36 progressive MS (PMS) patients with baseline and 5-year follow-up measures of serum levels of 6 oxysterols, sNfL and lipids. The oxysterols, 24-hydroxycholesterol (24HC), 25HC, 27HC, 7αHC, 7βHC and 7-ketocholesterol (7KC), were measured using liquid chromatography-mass spectrometry. sNfL was measured using single molecular array assay. Serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were obtained from a lipid profile.

Results: The enzymatically produced oxysterols 24HC, 25HC, 27HC and 7αHC were not associated with sNfL. However, baseline levels of reactive oxygen species (ROS) produced oxysterols, 7KC (p = 0.032) and 7βHC (p = 0.0025), were positively associated with sNfL levels at follow-up. Follow-up 7KC (p = 0.038) levels were also associated with follow-up sNfL levels. The associations of 7KC or 7βHC with sNfL remained significant after adjusting for LDL-C or HDL-C.

Conclusions: 7KC and 7βHC, produced by ROS-mediated cholesterol oxidation are associated with neuroaxonal injury as assessed by sNfL in MS.
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http://dx.doi.org/10.1016/j.msard.2021.102864DOI Listing
May 2021

Impact of complement activation on clinical outcomes in multiple sclerosis.

Ann Clin Transl Neurol 2021 04 1;8(4):944-950. Epub 2021 Mar 1.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, 48149, Germany.

We determined activation profiles of the classical and alternative complement pathway in 39 treatment-naïve patients with early relapse-onset MS. Plasma concentrations of complement fragments were unchanged in MS compared to 32 patients with non-inflammatory neurological diseases. Profiles in patients experiencing clinical exacerbations did not differ from patients with stable disease and did not correlate with baseline EDSS, numbers of T2 lesions and time to second relapse. Long-term EDSS outcomes 4 years after diagnosis did not significantly correlate with baseline complement levels. These data do not support the use of complement activation products as biomarkers for disease activity in early MS.
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http://dx.doi.org/10.1002/acn3.51334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045986PMC
April 2021

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis.

Mult Scler 2021 Nov 26;27(13):2014-2022. Epub 2021 Feb 26.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS.

Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS.

Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable.

Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were  = 0.52 and  = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum ( = 0.76) or CSF ( = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed.

Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.
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http://dx.doi.org/10.1177/1352458520986956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387506PMC
November 2021

Major depressive disorder subtypes and depression symptoms in multiple sclerosis: What is different compared to the general population?

J Psychosom Res 2021 05 16;144:110402. Epub 2021 Feb 16.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich (UZH), Zurich, Switzerland.

Objective: To compare and characterize major depressive disorder (MDD) subtypes (i.e., pure atypical, pure melancholic and mixed atypical-melancholic) and depression symptoms in persons with multiple sclerosis (PwMS) with persons without MS (Pw/oMS) fulfilling the DSM-5 criteria for a past 12-month MDD.

Methods: MDD in PwMS (n = 92) from the Swiss Multiple Sclerosis Registry was compared with Pw/oMS (n = 277) from a Swiss community-based study. Epidemiological MDD diagnoses were based on the Mini-SPIKE (shortened form of the Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology). Logistic and multinomial regression analyses (adjusted for sex, age, civil status, depression and severity) were computed for comparisons and characterization. Latent class analysis (LCA) was conducted to empirically identify depression subtypes in PwMS.

Results: PwMS had a higher risk for the mixed atypical-melancholic MDD subtype (OR = 2.22, 95% CI = 1.03-4.80) compared to Pw/oMS. MDD in PwMS was specifically characterized by a higher risk of the two somatic atypical depression symptoms 'weight gain' (OR = 6.91, 95% CI = 2.20-21.70) and 'leaden paralysis' (OR = 3.03, 95% CI = 1.35-6.82) and the symptom 'irritable/angry' (OR = 3.18, 95% CI = 1.08-9.39).

Conclusions: MDD in PwMS was characterized by a higher risk for specific somatic atypical depression symptoms and the mixed atypical-melancholic MDD subtype. The pure atypical MDD subtype, however, did not differentiate between PwMS and Pw/oMS. Given the high phenomenological overlap with MS symptoms, the mixed atypical-melancholic MDD subtype represents a particular diagnostic challenge.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110402DOI Listing
May 2021
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