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

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.

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

Multiple Sclerosis Journal ◽

10.1177/13524585211032348 ◽

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

Journal of Neuroinflammation ◽

10.1186/s12974-020-01966-3 ◽

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.

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Thirty years after anorexia nervosa onset, serum neurofilament light chain protein concentration indicates neuronal injury

European Child & Adolescent Psychiatry ◽

10.1007/s00787-020-01657-7 ◽

2020 ◽

Author(s):

Elisabet Wentz ◽

Sandra Rydberg Dobrescu ◽

Lisa Dinkler ◽

Carina Gillberg ◽

Christopher Gillberg ◽

...

Keyword(s):

Anorexia Nervosa ◽

Single Molecule ◽

Light Chain ◽

Axonal Degeneration ◽

Neuronal Injury ◽

Serum Levels ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

National Patient ◽

History Of

Abstract Little is known about the long-term consequences of anorexia nervosa (AN) in terms of possible brain neuronal injury. We aimed at investigating whether women with adolescent-onset AN exhibit increased serum levels of neurofilament light chain protein (NfL), a biomarker for neuronal injury, compared with matched controls at 30-year follow-up. Blood samples were collected from 34 women with adolescent-onset AN and 38 matched healthy comparison women (COMP), at a mean age of 44 years (range 38–48 years). NfL was measured in serum using the in-house single molecule array (Simoa) method. The individuals were asked whether they or their parents had been diagnosed with dementia. The Swedish National Patient Register was searched for diagnoses related to dementia. Serum NfL concentrations were significantly higher in the AN group (AN 27.7 pg/ml; COMP 19.0 pg/ml; p = 0.041). When individuals with medical/neurological disorders in the AN and COMP groups were excluded, there was a statistically non-significant trend towards higher concentrations in the AN group (AN 27.4 pg/ml; COMP 18.8 pg/ml; p = 0.060). None of the participants had been diagnosed with dementia. There was no significant correlation between serum NfL and AN duration (r = 0.15). There was a moderate negative correlation between the serum NfL concentration and the current BMI in the AN group (r = 0.44). This is the first time that serum NfL has been assessed in middle-aged women with a history of adolescent-onset AN. The results suggest that there might be increased axonal degeneration as a sequel of AN. Individuals remaining underweight had higher serum NfL concentrations than those with a normal/high BMI. Additional studies are needed to confirm increased serum NfL concentrations in individuals recovered from AN. There is a need for further study of axonal degeneration as a consequence of AN.

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Neurofilament Light Chain as A Biomarker for Brain Metastases

Cancers ◽

10.3390/cancers12102852 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2852 ◽

Cited By ~ 1

Author(s):

Anne Winther-Larsen ◽

Claus Vinter Bødker Hviid ◽

Peter Meldgaard ◽

Boe Sandahl Sorensen ◽

Birgitte Sandfeld-Paulsen

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Brain Metastases ◽

Cancer Patients ◽

Single Molecule ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Lung Cancer Patients ◽

Potential Biomarker

Background: Brain metastases are feared complications in cancer. Treatment by neurosurgical resection and stereotactic radiosurgery are only available when metastatic lesions are limited and early detection is warranted. The neurofilament light chain (NfL) is a sensitive neuron-specific biomarker released following neuronal decay. We explored serum NfL as a biomarker of brain metastases. Methods: Serum was collected from 43 stage IV lung cancer patients with brain metastases and 25 stage I lung cancer patients. Serum was collected at time of cancer diagnosis and at time of brain metastasis diagnosis. In nine patients with brain metastases, additional samples were available between the two time points. NfL was quantified by Single Molecule Array (Simoa)™. Results: The median NfL level was significantly higher in patients with brain metastases than in patients without (35 versus 16 pg/mL, p = 0.001) and separated patients with an area under the curve of 0.77 (0.66–0.89). An increase in NfL could be measured median 3 months (range: 1–5) before the brain metastasis diagnosis. Further, a high level of NfL at time of brain metastasis diagnosis correlated with an inferior survival (hazard ratio: 2.10 (95% confidence interval: 1.11–3.98)). Conclusions: This study implies that NfL could be a potential biomarker of brain metastases.

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

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000749 ◽

2020 ◽

Vol 7 (4) ◽

pp. e749 ◽

Cited By ~ 4

Author(s):

Marie-Christine Reinert ◽

Pascal Benkert ◽

Jens Wuerfel ◽

Zuzanna Michalak ◽

Esther Ruberte ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Treatment Response ◽

Single Molecule ◽

Light Chain ◽

Interferon Beta ◽

Class Iii ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Potential Biomarker

ObjectiveTo investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).MethodsIn 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.ResultsUntreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 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], p < 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], p < 0.001).ConclusionssNfL 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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Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod

Multiple Sclerosis Journal ◽

10.1177/1352458517715132 ◽

2017 ◽

Vol 24 (8) ◽

pp. 1046-1054 ◽

Cited By ~ 73

Author(s):

Fredrik Piehl ◽

Ingrid Kockum ◽

Mohsen Khademi ◽

Kaj Blennow ◽

Jan Lycke ◽

...

Keyword(s):

Single Molecule ◽

Light Chain ◽

Detection Threshold ◽

Therapy Response ◽

Serum Levels ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Post Marketing ◽

Highly Correlated ◽

Ms Therapy

Background: Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS). Objective: To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod. Methods: A first cohort consisted of MS patients ( n = 39) and neurological disease controls ( n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort ( n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL). Results: Mean NFL pg/mL (standard deviation ( SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated ( n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod ( n = 243), mean NFL pg/mL ( SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10−6), and levels remained stable at 24 months (13.2 (6.2)). Conclusion: NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.

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

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.717930 ◽

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.

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Peran Neurofilament Light Chain sebagai Biomarker Prediktor Risiko Cognitive Impairment pada Penderita Chronic Kidney Disease

Callosum Neurology ◽

10.29342/cnj.v2i3.81 ◽

2019 ◽

Vol 2 (3) ◽

pp. 7-8

Author(s):

Nella Rosyalina Damayanti ◽

Divayari Gardiani

Keyword(s):

Chronic Kidney Disease ◽

Cognitive Impairment ◽

Kidney Disease ◽

Single Molecule ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light

Latar Belakang: Chronic Kidney Disease (CKD) dapat menyebabkan cognitive impairment yang dapat menurunkan kualitas hidup dan kesejahteraan emosional pasien. Neurofilament Light Chain (NF-L) merupakan protein yang terletak di aksoplasma yang berperan menjaga struktur neuron. Diskusi: Defisit kognitif yang terjadi pada pasien dengan CKD diakibatkan toksin uremik yang menyebabkan cedera saraf. Prevalensi defisit kognitif berkisar 20-50% pada pasien CKD moderat dan 70% pada pasien CKD berat/ menjalani dialisis. Penurunan fungsi kognitif memiliki korelasi positif dengan penurunan eGFR pada pasien CKD. Kadar NF-L serum ditemukan mengalami peningkatan pada pasien setelah cedera akut pada otak seperti iskemia, perdarahan, dan pada pasien dengan penyakit neurodegeneratif seperti Alzheimer, dibandingkan pada individu sehat. Kadar NF-L serum dapat dideteksi dengan menggunakan pengujian single molecule array (Simoa). Simpulan: Pemeriksaan NF-L dapat dijadikan biomarker terjadinya defisit kognitif pada pasien CKD. Kata Kunci: Chronic Kidney Disease, Neurofilament Light Chain, Fungsi Kognitif, Biomarker

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Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458518765666 ◽

2018 ◽

Vol 25 (5) ◽

pp. 678-686 ◽

Cited By ~ 62

Author(s):

Nelly Siller ◽

Jens Kuhle ◽

Muthuraman Muthuraman ◽

Christian Barro ◽

Timo Uphaus ◽

...

Keyword(s):

Multiple Sclerosis ◽

Single Molecule ◽

Light Chain ◽

Neuronal Damage ◽

Axonal Damage ◽

Lesion Volume ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Magnetic Resonance Imaging Mri ◽

Brain Parenchymal

Background: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament – a major component of the neuro-axonal cytoskeleton – is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. Objective: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. Methods: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1–3 consecutive follow-ups (42 patients; range: 6–37 months). Results: Baseline sNfL correlated significantly with T2 lesion volume ( r = 0.555, p < 0.0001). There was no correlation between baseline sNfL and age, Expanded Disability Status Scale (EDSS) score or other calculated MRI measures. However, T2 lesion volume increased ( r = 0.67, p < 0.0001) and brain parenchymal volume decreased more rapidly in patients with higher baseline sNfL ( r = −0.623, p = 0.0004). Gd-enhancing lesions correlated positively with sNfL levels. Initiation of disease-modifying treatment led to a significant decrease in sNfL levels. Conclusion: sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.

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