Publications by authors named "Christian Barro"

57 Publications

Neurological symptoms and blood neurofilament light levels.

Acta Neurol Scand 2021 Mar 18. Epub 2021 Mar 18.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Neurofilament light chain (NfL) is an incredibly specific marker of neuronal injury that is not specific for cause or location of the neuronal damage. NfL is increasingly considered as possible biomarker of disease activity in neurological conditions. Several works reviewed the utility of NfL in the different diseases. Nonetheless, NfL is a universal marker of neuronal damage, which interpretation spaces beyond the single disease. Because of this, the interpretation of NfL may benefit by also considering how neurological symptoms relate to its blood concentration. Here, we review how different neurological symptoms can be associated with blood NfL levels with a practical interpretation of it.
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http://dx.doi.org/10.1111/ane.13415DOI Listing
March 2021

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

Mult Scler 2021 Feb 26:1352458520986956. 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
February 2021

Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance.

Hum Brain Mapp 2021 Feb 24. Epub 2021 Feb 24.

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

There is evidence that multiple sclerosis (MS) pathology leads to distinct patterns of volume loss over time (VLOT) in different central nervous system (CNS) structures. We aimed to use such patterns to identify patient subgroups. MS patients of all classical disease phenotypes underwent annual clinical, blood, and MRI examinations over 6 years. Spinal, striatal, pallidal, thalamic, cortical, white matter, and T2-weighted lesion volumes as well as serum neurofilament light chain (sNfL) were quantified. CNS VLOT patterns were identified using principal component analysis and patients were classified using hierarchical cluster analysis. 225 MS patients were classified into four distinct Groups A, B, C, and D including 14, 59, 141, and 11 patients, respectively). These groups did not differ in baseline demographics, disease duration, disease phenotype distribution, and lesion-load expansion. Interestingly, Group A showed pronounced spinothalamic VLOT, Group B marked pallidal VLOT, Group C small between-structure VLOT differences, and Group D myelocortical volume increase and pronounced white matter VLOT. Neurologic deficits were more severe and progressed faster in Group A that also had higher mean sNfL levels than all other groups. Group B experienced more frequent relapses than Group C. In conclusion, there are distinct patterns of VLOT across the CNS in MS patients, which do not overlap with clinical MS subtypes and are independent of disease duration and lesion-load but are partially associated to sNfL levels, relapse rates, and clinical worsening. Our findings support the need for a more biologic classification of MS subtypes including volumetric and body-fluid markers.
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http://dx.doi.org/10.1002/hbm.25375DOI Listing
February 2021

Fingolimod in children with Rett syndrome: the FINGORETT study.

Orphanet J Rare Dis 2021 Jan 6;16(1):19. Epub 2021 Jan 6.

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel and University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

Background: Rett syndrome (RS) is a severe neurodevelopmental disorder for which there is no approved therapy. This study aimed to assess safety and efficacy of oral fingolimod in children with RS using a pre-post and case-control design.

Methods: At the University of Basel Children's Hospital, Basel, Switzerland, children with RS were included if they were older than 6 years and met the established diagnostic criteria of RS, including a positive MeCP2 mutation. Participants were observed 6 months before and after treatment and received 12 months of fingolimod treatment. Serum samples of 50 children without RS served as reference for brain-derived neurotrophic factor (BDNF) measurements. Primary outcome measures were safety and efficacy, the latter measured by change in levels of BDNF in serum/CSF (cerebrospinal fluid) and change in deep gray matter volumes measured by magnetic resonance imaging (MRI). Secondary outcome measure was efficacy measured by change in clinical scores [Vineland Adaptive Behaviour Scale (VABS), Rett Severity Scale (RSSS) and Hand Apraxia Scale (HAS)].

Results: Six children with RS (all girls, mean and SD age 11.3 ± 3.1 years) were included. Serum samples of 50 children without RS (25 females, mean and SD age 13.5 ± 3.9 years) served as reference for BDNF measurements. No serious adverse events occurred. Primary and secondary outcome measures were not met. CSF BDNF levels were associated with all clinical scores: RSSS (estimate - 0.04, mult.effect 0.96, CI [0.94; 0.98], p = 0.03), HAS (estimate - 0.09, mult.effect 0.91, CI [0.89; 0.94], p <  0.01) and VABS (communication: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/daily living: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/social skills: estimate 0.07, mult.effect 1.08, CI [1.05; 1.11], p < 0.01/motoric skills: estimate 0.04, mult.effect 1.04, CI [1.03; 1.06], p = 0.02).

Conclusions: In children with RS, treatment with fingolimod was safe. The study did not provide supportive evidence for an effect of fingolimod on clinical, laboratory, and imaging measures. CSF BDNF levels were associated with clinical scores, indicating a need to further evaluate its potential as a biomarker for RS. This finding should be further validated in independent patient groups.

Trial Registration: Clinical Trials.gov NCT02061137, registered on August 27th 2013, https://clinicaltrials.gov/ct2/show/study/NCT02061137 .
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http://dx.doi.org/10.1186/s13023-020-01655-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789265PMC
January 2021

Biomarkers of treatment response in patients with progressive multiple sclerosis treated with high-dose pharmaceutical-grade biotin (MD1003).

Brain Behav 2021 Feb 13;11(2):e01998. Epub 2020 Dec 13.

Department of Neurology, University Hospital of Strasbourg, Strasbourg, France.

Background: High-dose pharmaceutical-grade biotin (MD1003) has positive effects on disability in progressive multiple sclerosis (PMS), but its mechanism of action remains unclear. The objective of our study was to quantify the effect of MD1003 in patients with PMS, using clinical response, plasma neurofilament light chain (pNfL) levels, and brain (BV) or cervical spinal cord volume (CSCV).

Materials And Methods: Forty-eight patients with PMS newly treated with MD1003 were followed during one year. Patients were assessed clinically using the Expanded Disability Status Scale (EDSS), the nine-hole peg test (9HPT), and the 25-foot walk time (25FWT). CSCV was quantified using CORDIAL software and BV using SIENA or SIENAX. We measured pNfL level using SIMOA at several time points. Bayesian linear and logistic regressions were used to evaluate potential prognostic factors.

Results: Treatment response, defined as a significant decrease of EDSS, 25FWT, or 9HPT at 1 year, was observed in 13 patients (27%). A gain of volume was noted in 7/24 patients for brain and in 10/19 patients for cervical spinal cord. The strongest predictors of poor treatment response were a high pNfL level at MD1003 onset (OR 0.96; 95% CI [0.91; 1]), high age at MS onset (OR 0.95; 95% CI [0.89; 1.01]), and an increase in brain lesion load during MD1003 treatment (OR 0.81; 95% CI [0.55; 1.05]).

Conclusions: MD1003 treatment was associated with clinical, BV, and CSCV improvement at 1 year. The correlation between the levels of pNfL at baseline, the age at multiple sclerosis onset, and a treatment response at M12 is consistent with a better effect in less disabled patients.
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http://dx.doi.org/10.1002/brb3.1998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882156PMC
February 2021

Blood neurofilament light: a critical review of its application to neurologic disease.

Ann Clin Transl Neurol 2020 12 4;7(12):2508-2523. Epub 2020 Nov 4.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Neuronal injury is a universal event that occurs in disease processes that affect both the central and peripheral nervous systems. A blood biomarker linked to neuronal injury would provide a critical measure to understand and treat neurologic diseases. Neurofilament light chain (NfL), a cytoskeletal protein expressed only in neurons, has emerged as such a biomarker. With the ability to quantify neuronal damage in blood, NfL is being applied to a wide range of neurologic conditions to investigate and monitor disease including assessment of treatment efficacy. Blood NfL is not specific for one disease and its release can also be induced by physiological processes. Longitudinal studies in multiple sclerosis, traumatic brain injury, and stroke show accumulation of NfL over days followed by elevated levels over months. Therefore, it may be hard to determine with a single measurement when the peak of NfL is reached and when the levels are normalized. Nonetheless, measurement of blood NfL provides a new blood biomarker for neurologic diseases overcoming the invasiveness of CSF sampling that restricted NfL clinical application. In this review, we examine the use of blood NfL as a biologic test for neurologic disease.
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http://dx.doi.org/10.1002/acn3.51234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732243PMC
December 2020

Serum Neurofilament Light Chain Is Associated with Incident Lacunes in Progressive Cerebral Small Vessel Disease.

J Stroke 2020 Sep 29;22(3):369-376. Epub 2020 Sep 29.

Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background And Purpose: Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally.

Methods: From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA).

Results: Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=-0.159; 95% confidence interval [CI], -0.242 to -0.068; P=0.001; executive function β=-0.095; 95% CI, -0.170 to -0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age.

Conclusions: Longitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly.
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http://dx.doi.org/10.5853/jos.2019.02845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568975PMC
September 2020

The weak association between neurofilament levels at multiple sclerosis onset and cognitive performance after 9 years.

Mult Scler Relat Disord 2020 Nov 28;46:102534. Epub 2020 Sep 28.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Katerinska 30, 120 00 Prague, Czech Republic. Electronic address:

Background: Neurofilament light chain level in serum (sNfL) and cerebrospinal fluid (CSF-NfL) is a promising biomarker of disease activity in multiple sclerosis (MS). However, predictive value of neurofilaments for development of cognitive decline over long-term follow-up has not been extensively studied.

Objective: To investigate the relationship between early neurofilament levels and cognitive performance after 9-years.

Methods: We included 58 MS patients from the SET study. sNfL levels were measured at screening, at 1 and 2 years. CSF-NfL were measured in 36 patients at screening. Cognitive performance was assessed by the Brief International Cognitive Assessment for Multiple Sclerosis and the Paced Auditory Serial Addition Test-3 s at baseline, at 1, 2 and 9 years. Association between neurofilament levels and cognition was analyzed using Spearman´s correlation, logistic regression and mixed models.

Results: We did not observe associations among early sNfL levels and cross-sectional or longitudinal cognitive measures, except of a trend for association between higher sNfL levels at screening and lower California Verbal Learning Test-II (CVLT-II) scores at year 1 (rho=-0.31, unadjusted p = 0.028). Higher sNfL level was not associated with increased risk of cognitive decline, except of a trend for greater risk of CVLT-II decrease in patients with higher sNfL levels at 1 year (OR=15.8; 95% CI=1.7-147.0; unadjusted p = 0.015). Similar trends were observed for CSF-NfL.

Conclusion: We found only weak association between sNfL levels at disease onset and evolution of cognitive performance over long-term follow-up.
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http://dx.doi.org/10.1016/j.msard.2020.102534DOI Listing
November 2020

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice.

EMBO Mol Med 2020 07 8;12(7):e11803. Epub 2020 Jun 8.

Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.
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http://dx.doi.org/10.15252/emmm.201911803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338806PMC
July 2020

Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis.

Neurology 2020 06 20;94(23):e2457-e2467. Epub 2020 May 20.

From the Department of Clinical Neuroscience (A.M., P.S., M.K., F.P., T.O., I.K.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Karolinska Institutet; Centre for Molecular Medicine (A.M., P.S., M.K., F.P., T.O., I.K.), Karolinska University Hospital, Stockholm, Sweden; Departments of Medicine, Biomedicine, and Clinical Research (D.L., C.B., Z.M., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel; Clinical Trial Unit (P.B.), Department of Clinical Research, University Hospital Basel, University of Switzerland; Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Gothenburg; Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.

Objective: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.

Methods: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).

Results: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS ( < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.

Conclusions: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.
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http://dx.doi.org/10.1212/WNL.0000000000009571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455371PMC
June 2020

Serum neurofilament light chain and optical coherence tomography measures in MS: A longitudinal study.

Neurol Neuroimmunol Neuroinflamm 2020 07 18;7(4). Epub 2020 May 18.

From the Buffalo Neuroimaging Analysis Center (E.T., D.J., J.H., O.O., N.B., M.G.D., R.Z.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; IRCCS (N.B.), Fondazione Don Carlo Gnocchi, Milan, Italy; Neurologic Clinic and Policlinic (J.K., C.B., Z.M., N.L.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; Department of Pharmaceutical Sciences (M.R.), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; Novartis Pharma AG (D.T., H.K., D.L.), Basel, Switzerland; Jacobs MS Center (R.H.B.B., B.W.-G.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z.), University at Buffalo, State University of New York.

Objective: To study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs).

Methods: In this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and values were adjusted for the false discovery rate.

Results: At baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) ( = 0.007, = 0.001) and nonaffected MSON (n-MSON) eyes ( = 0.003, = 0.018), along with total macular volume (TMV) in n-MSON eyes ( = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes ( < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP ( = 0.019). No significant associations were found in MSON eyes.

Conclusions: This study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials.

Classification Of Evidence: This study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT.
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http://dx.doi.org/10.1212/NXI.0000000000000737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251512PMC
July 2020

Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2020 07 13;7(4). Epub 2020 May 13.

From the Department of Pediatrics and Adolescent Medicine (M.-C.R., P.H., W.S., J.G.), Division of Pediatric Neurology, University Medical Centre Göttingen, Georg August University Göttingen, Germany; Clinical Trial Unit (P.B.), Department of Clinical Research, University Hospital Basel, University of Basel; Medical Image Analysis Centre Basel (MIAC AG) (J.W., E.R.); Department of Biomedical Engineering (J.W.), University Basel; Neurologic Clinic and Policlinic (Z.M., C.B., D.L., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel; Novartis Pharma AG (H.K., D.T.), Basel, Switzerland; and Institute of Neuropathology (W.B.), University Medical Centre Göttingen, Georg August University Göttingen, Germany.

Objective: To investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).

Methods: In this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12-105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.

Results: Untreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], < 0.001).

Conclusions: sNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.
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http://dx.doi.org/10.1212/NXI.0000000000000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238898PMC
July 2020

Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT.

Neurology 2020 05 16;94(18):e1950-e1960. Epub 2020 Apr 16.

From the Department of Nutrition (M.C., K.L.M, A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Global Public Health and Primary Care (M.C.), University of Bergen, Bergen, Norway; Department of Neurology (E.H.M.-L.), Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Departments of Medicine, Biomedicine and Clinical Research (C.B., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel, Basel, Switzerland; CHU Hôpital Pontchaillou (G.E.), Rennes, France; University of Ottawa and Ottawa Hospital Research Institute (M.S.F.), Ottawa, Canada; Department of Neurology (H.-P.H.), Medical Faculty, Heinrich-Heine Universität, Düsseldorf, Germany; St. Michael's Hospital (X.M.), University of Toronto, Canada and Multiple Sclerosis Center of Catalonia (Cemcat) (X.M.), Vall d'Hebron University Hospital, Barcelona, Spain; Ferkauf Graduate School of Psychology (F.W.F.), Yeshiva University, New York, NY; Department of Neurology (I.K.P.), Medical Faculty, Heinrich-Heine Universität, Düsseldorf and COGITO Center for Applied Neurocognition and Neuropsychological Research (I.K.P.), Düsseldorf, Germany; Technical University of Munich (B.H.), School of Medicine and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Central Texas Neurology Consultants (E.J.F.), Round Rock, TX; Neuroimmunology and Multiple Sclerosis Research (S.S.), Department of Neurology, University Hospital Zurich, University of Zurich and Center for Neuroscience Zurich (S.S.), Federal Institute of Technology (ETH), Zurich, Switzerland; Bayer AG (E.-M.W.), Berlin, Germany; Department of Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA and Channing Division of Network Medicine (A.A.); and Department of Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: To investigate whether vitamin D, smoking, and anti-Epstein-Barr virus (EBV) antibody concentrations predict long-term cognitive status and neuroaxonal injury in multiple sclerosis (MS).

Methods: This study was conducted among 278 patients with clinically isolated syndrome who participated in the clinical trial BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) and completed the 11-year assessment (BENEFIT-11). We measured serum 25-hydroxyvitamin-D (25(OH)D), cotinine (smoking biomarker), and anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) at baseline and at months 6, 12, and 24 and examined whether these biomarkers contributed to predict Paced Auditory Serial Addition Test (PASAT)-3 scores and serum neurofilament light chain (NfL) concentrations at 11 years. Linear and logistic regression models were adjusted for sex, baseline age, treatment allocation, steroid treatment, multifocal symptoms, T2 lesions, and body mass index.

Results: Higher vitamin D predicted better, whereas smoking predicted worse cognitive performance. A 50-nmol/L higher mean 25(OH)D in the first 2 years was related to 65% lower odds of poorer PASAT performance at year 11 (95% confidence intervals [95% CIs]: 0.14-0.89). Standardized PASAT scores were lower in smokers and heavy smokers than nonsmokers ( = 0.026). Baseline anti-EBNA-1 IgG levels did not predict cognitive performance ( = 0.88). Associations with NfL concentrations at year 11 corroborated these findings-a 50-nmol/L higher mean 25(OH)D in the first 2 years was associated with 20% lower NfL (95% CI: -36% to 0%), whereas smokers had 20% higher NfL levels than nonsmokers (95% CI: 2%-40%). Anti-EBNA-1 antibodies were not associated with NfL.

Conclusions: Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS.
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http://dx.doi.org/10.1212/WNL.0000000000009371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274920PMC
May 2020

Monitoring of radiologic disease activity by serum neurofilaments in MS.

Neurol Neuroimmunol Neuroinflamm 2020 07 9;7(4). Epub 2020 Apr 9.

From the Department of Medicine (T.U., T.K.), CORe, The University of Melbourne, Victoria, Australia; Department of Neurology and Center of Clinical Neuroscience (T.U., B.S., M.T., K.V., E.K.H., D.H.), Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic; Clinical Trial Unit (S.S., P.B.), Department of Clinical Research, University Hospital Basel, University of Basel; Departments of Medicine, Biomedicine and Clinical Research (C.B., J.O., D.L., Y.N., L.K., J. Kuhle), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel, Switzerland; Department of Neurology, Jacobs School of Medicine and Biomedical Sciences (N.B., M.D., R.Z.), Buffalo Neuroimaging Analysis Center, University at Buffalo, State University of New York, Buffalo; IRCCS "S. Maria Nascente" (N.B.), Don Carlo Gnocchi Foundation, Milan, Italy; Department of Radiology (J. Krasensky, M.V.), Charles University in Prague, First Faculty of Medicine and General University Hospital in Prague, Czech Republic; Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z.), University at Buffalo, State University of New York, NY; and Department of Neurology (T.K.), The Royal Melbourne Hospital, Victoria, Australia.

Objective: To determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS).

Methods: This observational study included 163 patients (405 samples) with early RRMS from the Study of Early interferon-beta1a (IFN-β1a) Treatment (SET) cohort and 179 patients (664 samples) with more advanced RRMS from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA) cohort. Based on annual brain MRI, we assessed the ability of sNfL cutoffs to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI in the preceding year or contrast-enhancing lesion. The probability of active MRI lesions among patients with different sNfL levels was estimated with generalized estimating equations models.

Results: From the sNfL samples ≥90th percentile, 81.6% of the SET (OR = 3.4, 95% CI = 1.8-6.4) and 48.9% of the GeneMSA cohort samples (OR = 2.6, 95% CI = 1.7-3.9) was associated with radiological disease activity on MRI. The sNfL level between the 10th and 30th percentile was reflective of negligible MRI activity: 1.4% (SET) and 6.5% (GeneMSA) of patients developed ≥3 active lesions, 5.8% (SET) and 6.5% (GeneMSA) developed ≥2 active lesions, and 34.8% (SET) and 11.8% (GeneMSA) showed ≥1 active lesion on brain MRI. The sNfL level <10th percentile was associated with even lower MRI activity. Similar results were found in a subgroup of clinically stable patients.

Conclusions: Low sNfL levels (≤30th percentile) help identify patients with MS with very low probability of recent radiologic disease activity during the preceding year. This result suggests that in future, sNfL assessment may substitute the need for annual brain MRI monitoring in considerable number (23.1%-36.4%) of visits in clinically stable patients.
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http://dx.doi.org/10.1212/NXI.0000000000000714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176248PMC
July 2020

Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis.

Mult Scler 2021 02 7;27(2):220-231. Epub 2020 Apr 7.

Department of Pharmaceutical Sciences, The State University of New York, Buffalo, NY, USA/Department of Neurology, The State University of New York, Buffalo, NY, USA.

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS).

Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event.

Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen locus gene ()*1501, anti-Epstein-Barr virus (EBV) antibodies, and 25-hydroxy vitamin D, were also measured.

Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient ( < 0.001), CSF CD80+ ( = 0.012), and CD80+ CD19+ ( = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all  ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels ( = 0.0026).

Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.
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http://dx.doi.org/10.1177/1352458520912379DOI Listing
February 2021

Blood neurofilament light levels segregate treatment effects in multiple sclerosis.

Neurology 2020 03 11;94(11):e1201-e1212. Epub 2020 Feb 11.

From the Department of Medicine Solna, Clinical Epidemiology Division (B.D.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience (A.M., I.K., T.O., F.P.), and Institute of Environmental Medicine (L.A.), Karolinska Institutet; Centre for Molecular Medicine (A.M., I.K., T.O., F.P.), Karolinska University Hospital, Stockholm, Sweden; Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research (C.B., Z.M., L.K., D.L., J.K.), and Clinical Trial Unit, Department of Clinical Research (P.B.), University Hospital Basel, University of Basel, Switzerland; Sanofi Genzyme (J.A.T.), Stockholm, Sweden; Biogen (T.P., B.C.K.), Cambridge, MA; Department of Neurology, Medical Faculty (B.C.K.), Heinrich-Heine University, Duesseldorf, Germany; and Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Sweden.

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).

Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).

Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.

Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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http://dx.doi.org/10.1212/WNL.0000000000009097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387108PMC
March 2020

Serum neurofilament light levels in normal aging and their association with morphologic brain changes.

Nat Commun 2020 02 10;11(1):812. Epub 2020 Feb 10.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also in serum, which allows for repeated assessments. There is still limited knowledge regarding the association of serum NfL (sNfL) with age and subclinical morphologic brain changes and their dynamics in the normal population. We measured sNfL by a single molecule array (Simoa) assay in 335 individuals participating in a population-based cohort study and after a mean follow-up time of 5.9 years (n = 103). Detailed clinical examination, cognitive testing and 3T brain MRI were performed to assess subclinical brain damage. We show that rising and more variable sNfL in individuals >60 years indicate an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This is supported by a close association of sNfL with brain volume changes in a cross-sectional and especially longitudinal manner.
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http://dx.doi.org/10.1038/s41467-020-14612-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010701PMC
February 2020

Growth differentiation factor 15 is increased in stable MS.

Neurol Neuroimmunol Neuroinflamm 2020 03 5;7(2). Epub 2020 Feb 5.

From the Department of Biomedicine (A.A., M.C., C.F.), University of Basel; Neurologic Clinic and Policlinic (C.B., J.O., L.K., Y.N., J.K., M.M.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel; Medical Image Analysis Center Basel AG (M.A.); Division of Neuroradiology (M.A.), University Hospital Basel; Department of Biomedical Engineering (M.A.), University Basel, Switzerland; and Department of Gynaecology (J.W.), University Hospital Würzburg, Germany.

Objective: To assess whether serum concentrations of the anti-inflammatory cytokine growth differentiation factor 15 (GDF-15) differ in patients with highly active multiple sclerosis (MS) vs patients with stable MS and healthy controls (HCs).

Methods: GDF-15 concentrations were measured by ELISA in serum and CSF in a cross-sectional cohort of patients with MS, patients with other inflammatory neurologic diseases (OIND), patients with noninflammatory neurologic diseases (NIND), and healthy controls (HC). Serum GDF-15 concentrations were measured in a longitudinally sampled cohort of clinically and radiologically well-characterized patients with MS and corresponding controls.

Results: Cross-sectionally measured median serum GDF-15 concentrations were significantly higher in patients with OIND (n = 42) (600 pg/mL, interquartile range [IQR] = 320-907 pg/mL) compared with HCs (n = 29) (325 pg/mL, IQR = 275-419 pg/mL; = 0.0007), patients with NIND (n = 46) (304 pg/mL, IQR = 245-493 pg/mL; = 0.0002), or relapsing MS (n = 42) (356 pg/mL, IQR = 246-460 pg/mL; = 0.0002). CSF and serum concentrations of GDF-15 were correlated (r = 0.41, 95% CI = 0.25-0.56, < 0.0001). In a longitudinally sampled cohort of patients with MS (n = 48), deeply phenotyped with quantitative clinical and MRI assessments, mean GDF-15 concentrations were significantly higher in patients with a stable disease course (405 pg/mL, SD = 202) than in patients with intermittent MRI activity (333 pg/mL, SD = 116; = 0.02).

Conclusions: Serum GDF-15 concentrations are increased in patients with MS with a stable disease course. These data suggest that GDF-15 may serve as a biomarker for disease stability in MS.
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http://dx.doi.org/10.1212/NXI.0000000000000675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051204PMC
March 2020

NfL and pNfH are increased in Friedreich's ataxia.

J Neurol 2020 May 30;267(5):1420-1430. Epub 2020 Jan 30.

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.

Objective: To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia.

Methods: Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length.

Results: Median serum levels of NfL were 21.2 pg/ml (range 3.6-49.3) in controls and 26.1 pg/ml (0-78.1) in Friedreich's ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3-43.3) in controls and 92 pg/ml (3.1-303) in Friedreich's ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16-31 years, p < 0.001) and patients aged 32-47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = - 0.24, p = 0.02) but not with disease severity (r = - 0.13, p = 0.22), disease duration (r = - 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62).

Conclusion: Serum levels of NfL and pNfH are elevated in Friedreich's ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up-a period relevant for biomarkers indicating treatment effects-we found NfL levels to be stable.
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http://dx.doi.org/10.1007/s00415-020-09722-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184046PMC
May 2020

Serum neurofilament light chain reflects inflammation-driven neurodegeneration and predicts delayed brain volume loss in early stage of multiple sclerosis.

Mult Scler 2021 01 21;27(1):52-60. Epub 2020 Jan 21.

Department of Neurology and Center of Clinical Neuroscience, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury. There is a lack of studies investigating the dynamics of relationships between sNfL levels and radiological disease activity over long-term follow-up in multiple sclerosis (MS).

Objectives: To investigate the relationship among repeated measures of sNfL, lesion burden accumulation, brain volume loss and clinical measures.

Methods: We investigated 172 patients in the early stages of MS (McDonald 2017 criteria). Clinical exams were performed every 3 months and brain magnetic resonance imaging (MRI) scans were collected annually over 48 months. sNfL levels were measured in serum by Simoa assay at the time of treatment initiation and then annually over 36 months.

Results: In repeated-measures analysis, considering all time points, we found a strong relationship between percentage changes of sNfL and lesion burden accumulation assessed by T1 lesion volume ( < 0.001) and T2 lesion number ( < 0.001). There was no relationship between percentage changes of sNfL and brain volume loss over 36 months ( > 0.1). Early sNfL levels were associated with delayed brain volume loss after 48 months ( < 0.001). Patients with No Evidence of Disease Activity (NEDA-3) status showed lower sNfL levels compared with active MS patients.

Conclusions: sNfL is associated with ongoing neuroinflammation and predictive of future neurodegeneration in early MS.
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http://dx.doi.org/10.1177/1352458519901272DOI Listing
January 2021

Impact of parturition on maternal cardiovascular and neuronal integrity in a high risk cohort - a prospective cohort study.

BMC Pregnancy Childbirth 2019 Nov 5;19(1):403. Epub 2019 Nov 5.

Division of Neonatology, University Children's Hospital Basel (UKBB), Spitalstrasse 33, 4056, Basel, Switzerland.

Background: To better understand the profound multisystem changes in maternal physiology triggered by parturition, in particular in the underexplored neuronal system, by deploying a panel of pre- vs post-delivery maternal serum biomarkers, most notably the neuronal cytoskeleton constituent neurofilament light chain (NfL). This promising fluid biomarker is not only increasingly applied to investigate disease progression in numerous brain diseases, particularly in proteopathies, but also in detection of traumatic brain injury or monitoring neuroaxonal injury after ischemic stroke.

Methods: The study was nested within a prospective cohort study of pregnant women at risk of developing preeclampsia at the University Hospital of Basel. Paired ante- and postpartum levels of progesterone, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin (CT-proAVP), and NfL were measured in 56 women with complete clinical data.

Results: Placental delivery significantly decreased all placental markers: progesterone 4.5-fold, PlGF 2.2-fold, and sFlt-1 1.7-fold. Copeptin and MR-proANP increased slightly (1.4- and 1.2-fold, respectively). Unexpectedly, NfL levels (median [interquartile range]) increased significantly post-partum: 49.4 (34.7-77.8) vs 27.7 (16.7-31.4) pg/ml (p < 0.0001). Antepartum NfL was the sole independent predictor of NfL peri-partum change; mode of delivery, duration of labor, clinical characteristics and other biomarkers were all unrelated. Antepartum NfL levels were themselves independently predicted only by maternal age.

Conclusions: Parturition per se increases maternal serum NfL levels, suggesting a possible impact of parturition on maternal neuronal integrity.
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http://dx.doi.org/10.1186/s12884-019-2570-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833198PMC
November 2019

Neurofilament light levels are associated with long-term outcomes in multiple sclerosis.

Mult Scler 2020 11 4;26(13):1691-1699. Epub 2019 Nov 4.

Biogen, Cambridge, MA, USA.

Background: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear.

Objective: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years.

Methods: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients ( = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon β-1a, and in serum ( = 164) from the extension study.

Results: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years ( < 0.0001,  = -0.46;  < 0.05.  = -0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2-9.9,  < 0.05; OR = 11.0, 95% CI = 2.0-114.6;  < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4-20.4;  < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes.

Conclusion: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.
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http://dx.doi.org/10.1177/1352458519885613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604552PMC
November 2020

Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study.

Mult Scler 2020 11 15;26(13):1670-1681. Epub 2019 Oct 15.

Jacobs MS Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.

Background: A limited number of studies investigated associations between serum neurofilament light chain (sNfL) and cognition in persons with multiple sclerosis (PwMS).

Objective: To assess cross-sectional and longitudinal associations between sNfL levels, clinical, and cognitive performance in PwMS and age-matched healthy controls (HCs).

Materials: One hundred twenty-seven PwMS (85 relapsing-remitting MS/42 progressive MS), 20 clinically isolated syndrome patients, and 52 HCs were followed for 5 years. sNfL levels were measured using the single-molecule array (Simoa) assay and quantified in picograms per milliliter. Expanded Disability Status Scale (EDSS), walking, and manual dexterity tests were obtained. At follow-up, Brief International Cognitive Assessment for MS (BICAMS) was utilized. Cognitively impaired (CI) status was derived using HC-based -scores. Age-, sex-, and education-adjusted analysis of covariance (ANCOVA) and regression models were used. Multiple comparison-adjusted values of  < 0.05 were considered significant.

Results: In PwMS, sNfL levels were cross-sectionally associated with walking speed ( = 0.235,  = 0.036), manual dexterity ( = 0.337,  = 0.002), and cognitive processing speed (CPS;  =-0.265,  = 0.012). Baseline sNfL levels predicted 5-year EDSS scores ( = 0.25,  = 0.012), dexterity ( = 0.224,  = 0.033), and CPS ( =-0.205,  = 0.049). CI patients had higher sNfL levels (27.2 vs. 20.6,  = 0.016) and greater absolute longitudinal sNfL increase when compared with non-CI patients (4.8 vs. 0.7,  = 0.04).

Conclusion: Higher sNfL levels are associated with poorer current and future clinical and cognitive performance.
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http://dx.doi.org/10.1177/1352458519881428DOI Listing
November 2020

Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis.

JAMA Neurol 2020 01;77(1):58-64

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

Importance: Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease.

Objective: To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset.

Design, Setting, And Participants: Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding.

Exposures: Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa).

Main Outcomes And Measurements: Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models.

Results: Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009).

Conclusions And Relevance: The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
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http://dx.doi.org/10.1001/jamaneurol.2019.3238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745051PMC
January 2020

Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD.

Neurology 2019 09 30;93(13):e1299-e1311. Epub 2019 Aug 30.

From the Departments of Neurology (M.W., Y.N., T.M., F.H., R.Y., J.-i.K.) and Neurological Therapeutics (N.I.), Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Neurology (Z.M., C.B., D.L., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland.

Objective: To test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD).

Methods: Levels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined.

Results: For both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD ( = 0.026 and < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of 75.8%.

Conclusions: sGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.
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http://dx.doi.org/10.1212/WNL.0000000000008160DOI Listing
September 2019

Serum neurofilament light chain levels associations with gray matter pathology: a 5-year longitudinal study.

Ann Clin Transl Neurol 2019 09 22;6(9):1757-1770. Epub 2019 Aug 22.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York.

Background: Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression.

Objectives: To assess the cross-sectional and longitudinal associations between sNfL and MRI-derived lesion and brain volume outcomes in PwMS and age-matched healthy controls (HCs).

Materials And Methods: Forty-seven HCs and 120 PwMS were followed over 5 years. All subjects underwent baseline and follow-up 3T MRI and sNfL examinations. Lesion volumes (LV) and global, tissue-specific and regional brain volumes were assessed. sNfL levels were analyzed using single molecule array (Simoa) assay and quantified in pg/mL. The associations between sNfL levels and MRI outcomes were investigated using regression analyses adjusted for age, sex, baseline disease modifying treatment (DMT) use and change in DMT over the follow-up. False discovery rate (FDR)-adjusted q-values <0.05 were considered significant.

Results: In PwMS, baseline sNfL was associated with baseline T -, T - and gadolinium-LV (q = 0.002, q = 0.001 and q < 0.001, respectively), but not with their longitudinal changes. Higher baseline sNfL levels were associated with lower baseline deep GM (β = -0.257, q = 0.017), thalamus (β = -0.216, q = 0.0017), caudate (β = -0.263, q = 0.014) and hippocampus (β = -0.267, q = 0.015) volumes. Baseline sNfL was associated with longitudinal decline of deep GM (β = -0.386, q < 0.001), putamen (β = -0.395, q < 0.001), whole brain (β = -0.356, q = 0.002), thalamus (β = -0.272, q = 0.049), globus pallidus (β = -0.284, q = 0.017), and GM (β = -0.264, q = 0.042) volumes. No associations between sNfL and MRI-derived measures were seen in the HCs.

Conclusion: Higher sNfL levels were associated with baseline LVs and greater development of GM atrophy in PwMS.
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http://dx.doi.org/10.1002/acn3.50872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764487PMC
September 2019

Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years.

JAMA Neurol 2019 Aug 12. Epub 2019 Aug 12.

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

Importance: Blood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed.

Objective: To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set.

Design, Setting, And Participants: Single-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses.

Main Outcomes And Measures: The main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy.

Results: Mean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (β, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (β, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (β, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (β, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years' follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: β, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: β, 0.972; 95% CI, 0.948-0.998; P = .04).

Conclusions And Relevance: This study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay's utility for decision-making in individual patients.
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http://dx.doi.org/10.1001/jamaneurol.2019.2137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692664PMC
August 2019

Serum neurofilament light chain in pediatric MS and other acquired demyelinating syndromes.

Neurology 2019 09 5;93(10):e968-e974. Epub 2019 Aug 5.

From the Department of Neurology, MS Centre ErasMS (Y.Y.M.W., A.L.B., D.v.P., R.Q.H.), Department of Immunology (M.-J.M., A.F.W., R.Q.H.), and Department of Pediatric Neurology (R.F.N.), Erasmus MC, Rotterdam, the Netherlands; and Neurologic Clinic and Policlinic (C.B., Z.M., J.K.), University Hospital Basel, Switzerland.

Objective: To explore the correlation between serum and CSF neurofilament light chain (NfL) and the association of NfL levels and future disease activity in pediatric patients with a first attack of acquired demyelinating syndromes (ADS).

Methods: In total, 102 children <18 years with a first attack of CNS demyelination and 23 age-matched controls were included. Clinically definite multiple sclerosis (CDMS) was set as an endpoint for analysis. CSF NfL was tested by the commercially available ELISA (UmanDiagnostics); serum NfL (sNfL) was tested with a Simoa assay. Hazard ratios (HR) were calculated with Cox regression analysis.

Results: Of the 102 patients, 47 (46%) were tested for CSF NfL. CSF and serum NfL correlated significantly in the total group (ρ 0.532, < 0.001) and even more significantly in the subgroup of patients with future CDMS diagnosis (ρ 0.773, < 0.001). sNfL was higher in patients than in controls (geometric mean 6.1 pg/mL, < 0.001), and was highest in ADS presenting with encephalopathy (acute disseminated encephalomyelitis, n = 28, 100.4 pg/mL), followed by patients without encephalopathy (ADS-) with future CDMS diagnosis (n = 40, 32.5 pg/mL), and ADS- who remained monophasic (n = 34, 17.6 pg/mL). sNfL levels higher than a median of 26.7 pg/mL at baseline are associated with a shorter time to CDMS diagnosis in ADS- ( = 0.045). HR for CDMS diagnosis was 1.09 for each 10 pg/mL increase of sNfL, after correction for age, oligoclonal bands, and MRI measures ( = 0.012).

Conclusion: The significant correlation between CSF and serum NfL strengthens its reliability as a peripheral marker of neuroaxonal damage. Higher sNfL levels at baseline were associated with higher probability of future CDMS diagnosis in ADS-.
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http://dx.doi.org/10.1212/WNL.0000000000008057DOI Listing
September 2019

Serum neurofilament light chain as a prognostic marker in postanoxic encephalopathy.

Epilepsy Behav 2019 12 30;101(Pt B):106432. Epub 2019 Jul 30.

Neurocenter of Southern Switzerland, Civic Hospital, Lugano, Switzerland. Electronic address:

Functional outcome in patients with postanoxic encephalopathy after cardiac arrest (CA) often remains unclear, and there is a strong need of new prognostication measures. We aimed at investigating serum neurofilament light (NfL) chain concentration in patients with a postanoxic encephalopathy after CA and its prognostic potential. Serum samples were prospectively collected at different time points after CA in consecutive patients admitted to the intensive care unit (ICU) of Ticino Cardiocentre (Lugano, Switzerland) between June 2017 and March 2018. Serum NfL concentration was measured using a single molecule array (SIMOA) assay. The association of NfL levels with time to return of spontaneous circulation (ROSC), serum neuronal specific enolase (NSE) concentration, time between CA and sample collection, electroencephalogram (EEG) pattern and clinical outcome (death status at one month) were explored. Fourteen patients experiencing 15 CAs were included in the study (median age = 58 (57-68) years, 8 males). Median serum NfL concentration was 1027.0 (25.5-6033.7) pg/ml. There were positive associations between serum NfL and time to ROSC (rho = 0.60, p < 0.0001), NSE concentration (rho = 0.76, p < 0.0001), and severity of brain damage as estimated by EEG, with the highest concentrations measured in patients with suppressed electrical activity (14,954.0 [9006.0-25,364.0] pg/ml). Neurofilament light concentration remained high in samples collected up to 17 days after CA. Median NfL levels were higher among dead than alive patients at one month (6401.7 [3768.5-15,573.3] vs 25.5 [25.2-75.4] pg/ml). High NfL levels performed better than NSE in predicting death status at one month (NfL area under the curve (AUC) = 0.98, 95% confidence interval (CI) = 0.94-1.00; NSE AUC = 0.80, 95% CI = 0.67-0.94). These results support the potential inclusion of serum NfL in the battery of prognostication measures to be used in patients with postanoxic encephalopathy in ICU settings. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
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http://dx.doi.org/10.1016/j.yebeh.2019.07.033DOI Listing
December 2019

Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approaches.

Clin Chem Lab Med 2019 Sep;57(10):1556-1564

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.

Background Phosphorylated neurofilament heavy (pNfH), a neuronal cytoskeleton protein, might provide a promising blood biomarker of neuronal damage in neurodegenerative diseases (NDDs). The best analytical approaches to measure pNfH levels and whether serum levels correlate with cerebrospinal fluid (CSF) levels in NDDs remain to be determined. Methods We here compared analytical sensitivity and reliability of three novel analytical approaches (homebrew Simoa, commercial Simoa and ELISA) for quantifying pNfH in both CSF and serum in samples of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and control subjects. Results While all three assays showed highly correlated CSF measurements, Simoa assays also yielded high between-assay correlations for serum measurements (ϱ = 0.95). Serum levels also correlated strongly with CSF levels for Simoa-based measurements (both ϱ = 0.62). All three assays allowed distinguishing ALS from controls by increased CSF pNfH levels, and Simoa assays also by increased serum pNfH levels. pNfH levels were also increased in FTD. Conclusions pNfH concentrations in CSF and, if measured by Simoa assays, in blood might provide a sensitive and reliable biomarker of neuronal damage, with good between-assay correlations. Serum pNfH levels measured by Simoa assays closely reflect CSF levels, rendering serum pNfH an easily accessible blood biomarker of neuronal damage in NDDs.
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http://dx.doi.org/10.1515/cclm-2019-0015DOI Listing
September 2019