Neurofilament light chain

Lu, Ching‐Hua; Macdonald‐Wallis, Corrie; Gray, Elizabeth; Pearce, Neil; Petzold, Axel; Norgren, Niklas; Giovannoni, Gavin; Fratta, Pietro; Sidle, Katie; Fish, Mark; Orrell, Richard W.; Howard, RS; Talbot, Kevin; Greensmith, Linda; Kühle, Jens; Turner, Martin R; Malaspina, Andrea

doi:10.1212/wnl.0000000000001642

Cited by 461 publications

(545 citation statements)

References 32 publications

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“…Previous studies on ALS patients reported stable NfL levels, but showed an increase over time for a subset of patients with a rapid disease progression 17, 42, 43. Serum NfL levels have also been shown to progressively increase in sporadic PPA patients 44.…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, the strong association between CSF NfL and survival supports the use of NfL as a prognostic marker. NfL can now be reliably measured in serum and plasma, which is collected less invasively than CSF, making it promising for clinical use, especially when frequent measures are needed 17, 18, 41…”

Section: Discussionmentioning

confidence: 99%

“…This protein is detectable in the cerebrospinal fluid (CSF) of presymptomatic and symptomatic C9orf72 expansion carriers,10, 11, 14 and poly(GP) levels in CSF from (G 4 C 2 ) 66 ‐expressing mice correlate with ASO‐induced decreases in G 4 C 2 RNA expression, RNA foci burden, and DPR protein levels within their brain 11. In addition, neurofilament light chain (NfL) is a potential marker of disease severity and progression for ALS, FTD, as well as other neurodegenerative diseases, including Alzheimer's disease 15, 16, 17. This marker for axonal injury is also increased in symptomatic but not presymptomatic C9orf72 expansion carriers, and correlates with prognosis and disease severity in genetic FTD 18, 19…”

Section: Introductionmentioning

confidence: 99%

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Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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“…There have been various ALS biomarker studies published with more ongoing, with special attention focused on identifying biomarkers in CSF or serum. Most of these studies have examined changes of individual biomarkers that might distinguish patients with ALS from healthy control subjects (Lu et al., 2015; Takahashi et al., 2015), but it is likely more appropriate to identify panels of biomarkers rather than focusing on a single factor to increase their specificity to ALS. Some studies were limited by the number of samples in the analysis (Turner et al., 2013), and some chose a different control population into the study (Tateishi et al., 2010).…”

Section: Introductionmentioning

confidence: 99%

Evaluating the levels of CSF and serum factors in ALS

et al. 2017

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ObjectivesThe aim of this study was to identify CSF and serum factors as biomarkers that may aid in distinguishing ALS patients from control subjects and predicting ALS progression as well as prognosis.MethodsSerum and CSF samples from 105 patients with ALS and 56 control subjects were analyzed for 13 factors using ELISA. The revised ALS functional rating scale (ALSFRS‐r) was used to evaluate the overall functional status of ALS patients, and we also followed up with ALS patients either by phone or with clinic visits for five years after enrollment in this study. Finally, we examined the correlations between factor levels and various clinical parameters and evaluated the predictive value for prognosis through a multivariate statistic model.ResultsA total of eight factors were obviously elevated in CSF, and twelve markers were increased in serum. In the correlation analyses, there were trends toward higher bFGF, VEGF, MIP‐1α levels in ALS with a longer disease duration and slower disease progression in both CSF and serum. Higher MCP‐1 levels were associated with worse disease severity and faster progression, and the IFN‐γ levels were positively associated with disease progression in either CSF or serum. Finally, a better prognosis was observed with higher levels bFGF in CSF and VEGF in CSF and serum; conversely, patients with higher levels of IFN‐γ in the CSF had shorter overall survival.ConclusionsWe demonstrated that a factor profile of ALS patients is distinct from control subjects and may be useful in clinical practice and therapeutic trials.

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“…NfL levels are increased in the cerebrospinal fluid (CSF) of MS patients as well as in degenerative and traumatic neurological diseases (eg, dementia, amyotrophic lateral sclerosis, and spinal cord injury) 4, 5, 6, 7, 8, 9. CSF NfL levels are further increased during relapses and are positively associated with magnetic resonance imaging (MRI) lesion load and disability scores in MS 10, 11, 12.…”

mentioning

confidence: 99%

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Disanto

Barro

Benkert

et al. 2017

Annals of Neurology

909

1,069

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ObjectiveNeurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).MethodssNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0–4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.ResultssNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2–65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7–71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9–41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21–3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07–5.42, p = 0.034).InterpretationThese results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857–870

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Neurofilament light chain

Cited by 461 publications

References 32 publications

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Evaluating the levels of CSF and serum factors in ALS

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

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