Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases

Bacioglu, Mehtap; Maia, Lenize F.; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A.; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Padovani, Alessandro; Shimshek, Derya R.; Neumann, Ulf; Kahle, Philipp J.; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

doi:10.1016/j.neuron.2016.05.018

Cited by 328 publications

(241 citation statements)

References 52 publications

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“…Our data show that NfL is elevated during the symptomatic phase of C9orf72 ‐associated dementia and correlate with indicators of disease severity (i.e., MMSE, CDR, and CDR‐SB), survival, and grey matter atrophy, consistent with other studies of NfL in sporadic and genetic FTD 18, 38, 39. In mouse models, NfL also correlates with disease severity, specifically with the burden of α‐synuclein, tau, or β ‐amyloid inclusions, and NfL levels are attenuated with treatment 40. Thus, NfL could be utilized in clinical trials to stratify patients into more homogeneous groups with respect to disease severity and to assess the neuroprotective effect of therapeutic interventions.…”

Section: Discussionsupporting

confidence: 88%

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: Discussionsupporting

confidence: 88%

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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“…sNfL levels were also slightly higher in the Lugano than in the SMSC samples, likely because the former were collected as part of the diagnostic workup, which is frequently performed shortly after relapses. The close association of increased blood NfL levels with neuronal damage has been suggested in other neurological conditions, including ALS, neurodegenerative disorders, and acute brain and spinal cord injury 8, 22, 23, 24, 39, 40. In conjunction with findings in other neurological diseases, our results in MS strongly suggest that increased sNfL levels reflect ongoing neuronal damage irrespective of the underlying pathogenic mechanism.…”

Section: Discussionsupporting

confidence: 85%

“…We did not observe a difference in sNfL between genders. The tight positive association between CSF and sNfL levels highlights that serum levels closely reflect NfL release within the central nervous system, as already indicated by previous studies 19, 39, 40…”

Section: Discussionsupporting

confidence: 78%

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

Disanto

Barro

Benkert

et al. 2017

Annals of Neurology

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911

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 (NfL) is a major component of the neuronal cytoskeleton and is important for axonal growth, stability, and intracellular transport 2, 3. NfL are released upon axonal or neuronal damage or degeneration, and can be found as a consequence, in the CSF and blood.…”

Section: Introductionmentioning

confidence: 99%

Neurofilament light chain serum levels correlate with 10‐year MRI outcomes in multiple sclerosis

Chitnis

Gonzalez

Healy

et al. 2018

Ann Clin Transl Neurol

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141

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ObjectiveTo assess the value of annual serum neurofilament light (NfL) measures in predicting 10‐year clinical and MRI outcomes in multiple sclerosis (MS).MethodsWe identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high‐resolution 3T MRI scans. Correlations between averaged annual NfL and 10‐year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models.ResultsAveraged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1–5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1–5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15–20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort.InterpretationSerum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10‐year MRI brain lesion load and atrophy.

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Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases

Cited by 328 publications

References 52 publications

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

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

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

Neurofilament light chain serum levels correlate with 10‐year MRI outcomes in multiple sclerosis

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