scholarly journals Detection of Cerebrospinal Fluid Neurofilament Light Chain as a Marker for Alpha-Synucleinopathies

2021 ◽  
Vol 13 ◽  
Author(s):  
Sezgi Canaslan ◽  
Matthias Schmitz ◽  
Anna Villar-Piqué ◽  
Fabian Maass ◽  
Karin Gmitterová ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Light Chain ◽  
Clinical Symptoms ◽  
Alpha Synuclein ◽  
Test System ◽  
Marker Protein ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Different Types

Alpha-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are a class of neurodegenerative diseases. A diagnosis may be challenging because clinical symptoms partially overlap, and there is currently no reliable diagnostic test available. Therefore, we aimed to identify a suitable marker protein in cerebrospinal fluid (CSF) to distinguish either between different types of alpha-synucleinopathies or between alpha-synucleinopathies and controls. In this study, the regulation of different marker protein candidates, such as alpha-synuclein (a-Syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (tau) in different types of alpha-synucleinopathies, had been analyzed by using an ultrasensitive test system called single-molecule array (SIMOA). Interestingly, we observed that CSF-NfL was significantly elevated in patients with DLB and MSA compared to patients with PD or control donors. To differentiate between groups, receiver operating characteristic (ROC) curve analysis resulted in a very good diagnostic accuracy as indicated by the area under the curve (AUC) values of 0.87–0.92 for CSF-NfL. Furthermore, we observed that GFAP and tau were slightly increased either in DLB or MSA, while a-Syn levels remained unregulated. Our study suggests NfL as a promising marker to discriminate between different types of alpha-synucleinopathies or between DLB/MSA and controls.

scholarly journals Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Ngoc Dung Le ◽  
Lukas Muri ◽  
Denis Grandgirard ◽  
Jens Kuhle ◽  
David Leppert ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Light Chain ◽  
Pneumococcal Meningitis ◽  
Neuronal Damage ◽  
Neuronal Injury ◽  
Health Concern ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Inflammatory Phase

Abstract Background Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM). Methods Eleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively. Results In ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1β, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics. Conclusion Current results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

scholarly journals Implications of extreme serum neurofilament light chain levels for the management of patients with relapsing multiple sclerosis

2021 ◽  
Vol 14 ◽  
pp. 175628642110019
Author(s):  
Sinah Engel ◽  
Maria Protopapa ◽  
Falk Steffen ◽  
Vakis Papanastasiou ◽  
Christoforos Nicolaou ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Single Molecule ◽  
Light Chain ◽  
Clinical Symptoms ◽  
Threshold Value ◽  
Sample Collection ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
The Mean

Background: Serum neurofilament light chain (sNfL) is a promising biomarker to complement the decision-making process in multiple sclerosis (MS) patients. However, although sNfL levels are able to detect disease activity and to predict future disability, the growing evidence has not yet been translated into practicable recommendations for an implementation into clinical routine. Methods: The observation of a patient with extensive inflammatory activity in magnetic resonance imaging (MRI) along with an extremely high sNfL level in the absence of any clinical symptoms prompted us to investigate common characteristics of our MS patients with the highest sNfL levels in a retrospective cohort study. The 97.5th percentile was chosen as a cut-off value because the mean sNfL level of the resulting extreme neurofilament light chain (NfL) cohort corresponded well to the sNfL level of the presented case. Patient characterization included clinical and MRI assessment with a focus on disease activity markers. sNfL levels were determined by single molecule array. Results: The 97.5th percentile of our MS cohort (958 sNfL measurements in 455 patients) corresponded to a threshold value of 46.1 pg/ml. The mean sNfL level of the extreme sNfL cohort ( n = 24) was 95.6 pg/ml (standard deviation 68.4). Interestingly, only 15 patients suffered from a relapse at the time point of sample collection, whereas nine patients showed no signs of clinical disease activity. sNfL levels of patients with and without relapse did not differ [median 81.3 pg/ml (interquartile range [IQR] 48.0–128) versus 80.2 pg/ml (IQR 46.4–97.6), p = 0.815]. The proportion of patients with contrast-enhancing lesions was high and also did not differ between patients with and without relapse (92.9% versus 87.5%, p = 0.538); 78.9% of the patients not receiving a high-efficacious therapy had ongoing disease activity during a 2-year follow-up. Conclusion: Extremely high sNfL levels are indicative of subclinical disease activity and might complement treatment decisions in ambiguous cases.

scholarly journals Serum Neurofilament Light Chain Levels and Myelin Oligodendrocyte Glycoprotein Antibodies in Pediatric Acquired Demyelinating Syndromes

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Simone ◽  
Claudia Palazzo ◽  
Mariangela Mastrapasqua ◽  
Luca Bollo ◽  
Francesco Pompamea ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Light Chain ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Oligoclonal Bands ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Significant Difference ◽  
The Relationship

Introduction: The relationship between serum neurofilament light chain (sNfL) and myelin oligodendrocyte glycoprotein antibody (MOG-Ab) status has not been yet investigated in children with the acquired demyelinating syndrome (ADS).Objective and Methods: The sNfL levels and MOG-Abs were measured by ultrasensitive single-molecule array and cell-based assay in a cohort of 37 children with ADS and negativity for serum anti-aquaporin 4 (AQP4) antibodies. The sNfL levels were compared in MOG-Ab+/MOG-Ab– and in two subgroups MOG-Ab+ with/without encephalopathy.Results: About 40% ADS resulted in MOG-Ab+. MOG-Ab+ were younger at sampling (median = 9.8; range = 2.17–17.5 vs. 14.7/9–17; p = 0.002) with lower frequency of cerebrospinal fluid oligoclonal bands positivity (27% vs. 70%; p = 0.013) compared to MOG-Ab–. About 53% of MOG-Ab+ presented encephalopathy at onset, 1/22 of MOG-Ab– (p = 0.0006). Higher sNfL levels (p = 0.0001) were found in MOG-Ab+ (median/range = 11.11/6.8–1,129) and MOG-Ab– (median/range = 11.6/4.3–788) compared to age-matched controls (median/range = 2.98/1–4.53), without significant difference. MOG-Ab+ with encephalopathy resulted significantly younger at sampling (median/range: 4.5/2.17–11.17 vs. 14.16/9.8–17.5; p = 0.004), had higher sNfL levels (median/range:75.24/9.1–1,129 vs. 10.22/6.83–50.53; p = 0.04), and showed a trend for higher MOG-Ab titer (0.28/0.04–0.69 vs. 0.05/0.04–0.28; p = 0.1) in comparison to those without encephalopathy.Discussion: We confirmed high sNfL levels in pediatric ADS independently from the MOG-Ab status. Encephalopathy at onset is associated more frequently with MOG Ab+ children with higher sNfL levels and MOG titer. These findings suggest a role of acute demyelination in association with axonal damage in the pathogenesis of encephalopathy in pediatric ADS.

scholarly journals Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

2021 ◽  
pp. jnnp-2021-326914
Author(s):  
Dario Saracino ◽  
Karim Dorgham ◽  
Agnès Camuzat ◽  
Daisy Rinaldi ◽  
Armelle Rametti-Lacroux ◽  
...  
Keyword(s):  
Single Molecule ◽  
Light Chain ◽  
Rate Of Change ◽  
Longitudinal Change ◽  
Youden Index ◽  
Clinical Genetic ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Link Type ◽  
Therapeutic Trials

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.

scholarly journals Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: a meta-analysis of case–control studies

2019 ◽  
Vol 90 (9) ◽  
pp. 1059-1067 ◽  
Author(s):  
Sarah-Jane Martin ◽  
Sarah McGlasson ◽  
David Hunt ◽  
James Overell
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Light Chain ◽  
Meta Analysis ◽  
Grey Literature ◽  
Case Control ◽  
Disease Stage ◽  
Case Control Studies ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

ObjectiveNeurofilament is a biomarker of axonal injury proposed as a useful adjunct in the monitoring of patients with multiple sclerosis (MS). We conducted a systematic review and meta-analysis of case–control studies that have measured neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of people with MS (pwMS), in order to determine whether, and to what degree, CSF NfL levels differentiate MS from controls, or the subtypes or stages of MS from each other.MethodsGuidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Electronic databases were searched for published and ‘grey’ literature, with 151 hits. Of 51 full articles screened, 20 were included in qualitative analysis, and 14 in meta-analysis.ResultsCSF NfL was higher in 746 pwMS than 435 (healthy and disease) controls, with a moderate effect size of 0.61 (p < 0.00001). Mean CSF NfL levels were significantly higher in 176 pwMS with relapsing disease than 92 with progressive disease (2124.8 ng/L, SD 3348.9 vs 1121.4 ng/L, SD 947.7, p = 0.0108). CSF NfL in 138 pwMS in relapse (irrespective of MS subtype) was double that seen in 268 pwMS in remission (3080.6 ng/L, SD 4715.9 vs 1541.7 ng/L, SD 2406.5, p < 0.0001).ConclusionsCSF NfL correlates with MS activity throughout the course of MS, reflecting the axonal damage in pwMS. Relapse is more strongly associated with elevated CSF NfL levels than the development of progression, and NfL may be most useful as a marker of disease ‘activity’ rather than as a marker of disability or disease stage.

scholarly journals ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration

2020 ◽  
Author(s):  
Katheryn A.Q. Cousins ◽  
Jeffrey S. Phillips ◽  
David J. Irwin ◽  
Edward B. Lee ◽  
David A. Wolk ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Light Chain ◽  
Frontotemporal Lobar Degeneration ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

scholarly journals Elevated Neurofilament Light Chain in Cerebrospinal Fluid and Plasma Reflect Inflammatory MRI Activity in Neurosarcoidosis

2021 ◽  
Vol 11 (2) ◽  
pp. 238
Author(s):  
Keld-Erik Byg ◽  
Helle H. Nielsen ◽  
Tobias Sejbaek ◽  
Jonna Skov Madsen ◽  
Dorte Aalund Olsen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Light Chain ◽  
Plasma Levels ◽  
Healthy Controls ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Potential Biomarker ◽  
Fluid Levels

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites. Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients (n = 20) median 2304 pg/mL (interquartile range (IQR) 630–19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients (n = 20) and 336 pg/mL (IQR 194–402) in healthy controls (n = 11) (p = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5–49.3) compared to 6.2 pg/mL (IQR 4.3–8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2–9.0) in healthy controls (p = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI (p = 0.009 and p = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity. Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.

scholarly journals Evaluation of Cerebrospinal Fluid Neurofilament Light Chain as a Routine Biomarker in a Memory Clinic

2018 ◽  
Vol 74 (4) ◽  
pp. 442-445 ◽  
Author(s):  
Matías Niikado ◽  
Patricio Chrem-Méndez ◽  
Tatiana Itzcovich ◽  
Micaela Barbieri-Kennedy ◽  
Ismael Calandri ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Light Chain ◽  
Memory Clinic ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

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

2021 ◽  
pp. 135245852110323
Author(s):  
Jens Kuhle ◽  
Nadia Daizadeh ◽  
Pascal Benkert ◽  
Aleksandra Maceski ◽  
Christian Barro ◽  
...  
Keyword(s):  
Single Molecule ◽  
Light Chain ◽  
Interferon Beta ◽  
Efficacy And Safety ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Highly Active ◽  
Sustained Reduction ◽  
Relapsing Remitting ◽  
Healthy Control

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 ( n = 354) and SC IFNB-1a–treated ( n = 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; p < 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%; p < 0.0001); 73% for alemtuzumab at Y7. HAD patients ( n = 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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