Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis

Tortelli, Rosanna; Copetti, Massimiliano; Ruggieri, Maddalena; Cortese, Rosa; Capozzo, Rosa; Leo, Antonio; D’Errico, Eustachio; Mastrapasqua, Mariangela; Zoccolella, Stefano; Pellegrini, Fabio; Simone, I. L.; Logroscino, Giancarlo

doi:10.1111/ene.12421

Cited by 64 publications

(48 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to pNFH, increased levels of NFL were correlated with rate of progression, as monitored by the rate of decline in ALSFRS-R scores, as well as upper MN involvement [36,39]. A rapid time to generation (time of symptom spreading from bulbar or spinal localization to both) has also been noted with increased CSF NFL [37]. Diffusion tensor imaging was recently used to evaluate the correlation between increased CSF NFL levels and white matter damage, where decreased fractional anisotropy and increased radial diffusivity were observed within the corticospinal tracts of patients with ALS but not in healthy controls, reflecting the degeneration of axons and subsequent release of NFL into the CSF [39].…”

Section: Neurofilament Proteinsmentioning

confidence: 70%

See 1 more Smart Citation

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

show abstract

Section: Neurofilament Proteinsmentioning

confidence: 70%

“…Many studies have also examined levels of NFL in ALS and control groups [35][36][37][38]. Similar to pNFH, increased levels of NFL were correlated with rate of progression, as monitored by the rate of decline in ALSFRS-R scores, as well as upper MN involvement [36,39].…”

Section: Neurofilament Proteinsmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…Phosphorylated neurofilament heavy chain appears elevated at stable levels throughout the disease [19][20][21][22][23][24][25][26]. Neurofilament light chain in cerebrospinal fluid (CSF) appears to increase as ALS progresses [19,[27][28][29][30][31]. Urate, which is lower in people with ALS than in controls, could serve a predictive or prognostic role [32][33][34][35][36].…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

View full text Add to dashboard Cite

The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

show abstract

“…6 Nf bioavailability and measurement depend on matrix-related biological phenomena such as protein aggregation, as recently reported. 7,8 In this study, we examined the prognostic value in ALS of neurofilament light chain (NfL), one of the main constituents of neurons and axons, building on previous small cross-sectional studies [9][10][11] to evaluate the temporal profile of NfL expression in plasma, serum, and CSF from patients with ALS.…”

mentioning

confidence: 99%

Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis

2015

Neurology

View full text Add to dashboard Cite

Objective: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS).Methods: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n 5 103/42) and Oxford (ALS/control, serum: n 5 64/36; paired CSF: n 5 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis.Results: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r 5 0.78, p , 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p , 0.001).Conclusion: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. Classification of evidence:This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls. Neurology ® 2015;84:2247-2257 GLOSSARY ALS 5 amyotrophic lateral sclerosis; CI 5 confidence interval; Nf 5 neurofilament; NfH 5 neurofilament heavy chain; NfL 5 neurofilament light chain; PRB 5 progression rate at baseline; PRL 5 progression rate at last visit.Various factors militate against the development of reliable biomarkers in amyotrophic lateral sclerosis (ALS), including clinical heterogeneity, variable rate of progression, and the lack of a recognizable preclinical state of this fatal neurodegenerative disorder. An easily accessible and reproducible prognostic biomarker would help patient stratification, improving assessment of individual prognosis and care-planning. It might also have potential as a pharmacodynamic measure of therapeutic response. The longitudinal assessment of a putative biomarker would allow a more reliable interpretation of the biomarker's behavior when monitoring treatment response. Blood-based biomarkers are preferable because they require minimally invasive collection compared to CSF sampling. Neurofilaments (Nfs), the main byproducts of neuroaxonal breakdown, are potential "universal" biomarkers of neurodegeneration.1 Nf levels in CSF from patients with ALS increase significantly compared to other neurodegenerative disorders 2-4 or to ALS-mim...

show abstract

Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis

Abstract: This study shows that in sporadic ALS NFL, a marker of neurodegeneration, is correlated with TTG, a clinical intermediate parameter of survivorship.

Cited by 64 publications

References 13 publications

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis

Contact Info

Product

Resources

About