Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression

Tortelli, Rosanna; Ruggieri, Maddalena; Cortese, Rosa; D’Errico, Eustachio; Capozzo, Rosa; Leo, Antonio; Mastrapasqua, Mariangela; Zoccolella, Stefano; Leante, Rosaria; Livrea, Paolo; Logroscino, Giancarlo; Simone, I. L.

doi:10.1111/j.1468-1331.2012.03777.x

Cited by 139 publications

(105 citation statements)

References 36 publications

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“…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].…”

Section: Neurofilament Proteinsmentioning

confidence: 64%

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Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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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.

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Section: Neurofilament Proteinsmentioning

confidence: 64%

“…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: 98%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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“…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

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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.

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“…To aid diagnostics, patient stratification and studies seeking to find further treatments for these diseases, there is a need to establish a way to reliably and objectively assess disease severity and the amount of ongoing neurodegeneration. Previous studies have suggested that cerebrospinal fluid (CSF) neurofilament light (NFL) may serve this purpose (Tortelli et al, 2012, Menke et al, 2015. NFL is part of a family of proteins with all members acting as important parts of the scaffolding of the neuronal and axonal cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival

Skillbäck

Mattsson

Blennow

et al. 2017

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression

Abstract: High CSF NFL levels were found in patients with ALS, reflecting the burden of neurodegeneration. The significant relation between CSF NFL levels and disease progression suggests that NFL may be a useful marker of disease activity and progression in ALS.

Cited by 139 publications

References 36 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?

Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival

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