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Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker.In a longitudinal cohort of familial Alzheimer’s disease patients, the rate of change of blood biomarker levels identifies disease carriers much earlier than absolute levels and predicts both neurodegeneration and cognitive decline.

Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.

INTRODUCTION Neurofilament light chain (NfL) quantification aids in diagnosing and predicting neurological disorders, but clinical and laboratory practices vary across centers. Differences in result interpretation and reporting further challenge test commutability. This study aimed to review the global analytical and post‐analytical methods used for NfL measurement in routine clinical practice across different contexts. METHODS We established an international working group (WG) and distributed a survey to its members to gather information on context of use (COU), (pre) analytical methods, cutoff usage, as well as the interpretation and reporting of NfL measurements. RESULTS Among the centers, 63% measured NfL in cerebrospinal fluid (CSF), 87% in blood, and 53% in both. COU was widespread, with 50% defining pathological cutoffs based on publications and 42% considering age. Reporting was primarily done through numeric results (95%). DISCUSSION Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice. Highlights Unique international overview of current analytical and post‐analytical methods for neurofilament light chain (NfL) measurement in routine clinical practice. Tailored sheets for each neurological application. Strategies to harmonize cutoffs, reporting, and interpretation of NfL's measurement.

Background After cardiac arrest, many patients remain comatose, and a substantial proportion do not survive. Neuroprognostication is essential for identifying patients with potential for recovery, and those with severe, irreversible hypoxic-ischemic brain injury. Neurofilament light chain (NfL) is a blood-based marker of neuronal injury that is under evaluation for neuroprognostication. NfL have potential advantages over the currently only guideline recommended blood biomarker for neuroprognostication, neuron-specific enolase, including earlier applicability. However, there is no consensus on optimal NfL cut-off levels. A previous large investigation in OHCA patients, identified NfL thresholds with high specificity for poor outcome, and the purpose of the present investigation is to validate these cutoffs. Methods The Blood Pressure and Oxygenation Targets in Post Resuscitation Care (BOX) trial included OHCA patients who were comatose at admission. Patients with at least one plasma biobank sample available at 24–48 h were included in this investigation. NfL was quantified by ELISA. Cerebral performance category score was estimated at 1 year. Diagnostic precision of NfL for prediction of poor neurologic outcome (CPC > 2) was determined by area under the receiver operator curve (AUROC), and the performance of previously identified cut-offs for a specificity of 100% were investigated. Results A total of 638 patients had a NfL measurement at either 24 or 48 h. The AUROC for prediction of poor neurologic outcome was 0.95 and 0.95 at 24 and 48 h, respectively. At 24 h, a cut-off of 1232 pg/mL had a specificity of 98%, for prediction of poor neurologic outcome, and false-positive results for 7 patients (1.4%). At 48 h, a cut-off of 1539 pg/ml similarly had a specificity of 98%, and false-positive results for 7 patients (1.3%). Conclusions The results of this investigation confirm the prognostic value of NfL for identification of risk of poor neurologic outcome after cardiac arrest. Previously identified cut-offs of 1232 pg/mL at 24 h, and 1539 pg/mL at 48 h, performed excellent with a very high specificity. This indicates that application of NfL will allow for reliable neuroprognostication as early as 24 h after cardiac arrest. Trial registration: ClinicalTrials.gov NCT03141099, registered April 30 2017

BackgroundNeurofilament proteins have been extensively studied in relapsing–remitting multiple sclerosis, where they are promising biomarkers of disease activity and treatment response. Their role in progressive multiple sclerosis, where there is a particularly urgent need for improved biomarkers, is less clear. The objectives of this systematic review are to summarise the literature on neurofilament light and heavy in progressive multiple sclerosis, addressing key questions.MethodsA systematic search of PubMed, Embase, Web of Science and Scopus identified 355 potential sources. 76 relevant sources were qualitatively reviewed using QUADAS-2 criteria, and 17 were identified as at low risk of bias. We summarise the findings from all relevant sources, and separately from the 17 high-quality studies.ResultsDifferences in neurofilament light between relapsing–remitting and progressive multiple sclerosis appear to be explained by differences in covariates. Neurofilament light is consistently associated with current inflammatory activity and future brain atrophy in progressive multiple sclerosis, and is consistently shown to be a marker of treatment response with immunosuppressive disease-modifying therapies. Associations with current or future disability are inconsistent, and there is no evidence of NFL being a responsive marker of purportedly neuroprotective treatments. Evidence on neurofilament heavy is more limited and inconsistent.ConclusionsNeurofilament light has shown consistent utility as a biomarker of neuroinflammation, future brain atrophy and immunosuppressive treatment response at a group level. Neither neurofilament light or heavy has shown a consistent treatment response to neuroprotective disease-modifying therapies, which will require further data from successful randomised controlled trials.

Background: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS. Methods: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939. Results: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival. Discussion: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.

Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.Neurofilaments have been validated as specific body fluid biomarkers of neuro-axonal injury. In this Review, Khalil and colleagues provide an update on the structure and function of neurofilaments, analytical approaches and challenges in different clinical contexts, and progress towards clinical application of neurofilaments as a biomarker in various neurological disorders.

In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases’ courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.

ObjectivesIn a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity.MethodsWe examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF.ResultsNFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001).ConclusionsThis study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p  < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL ( r = − 0.813, p  < 0.001), Serum-NFL ( r = − 0.493, p  = 0.001), CSF-pNFH ( r = − 0.637, p  < 0.001), and Serum-pNFH ( r = − 0.672, p  < 0.001); Peduncle-FA negatively with CSF-NFL ( r = − 0.562, p  < 0.001), CSF-pNFH ( r = − 0.506, p  = 0.001), and Serum-pNFH ( r = − 0.488, p  = 0.001); Peduncle-MD positively with CSF-NFL ( r  = 0.516, p  < 0.001), CSF-pNFH ( r  = 0.494, p  = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.