Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing–remitting multiple sclerosis

Håkansson, Irene; Tisell, Anders; Cassel, Petra; Blennow, Kaj; Zetterberg, Henrik; Lundberg, Peter; Dahle, Charlotte; Vrethem, Magnus; Ernerudh, Jan

doi:10.1111/ene.13274

Cited by 104 publications

(110 citation statements)

References 32 publications

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“…The evaluation of sNfL is a promising opportunity to evaluate MS disease activity. While measurement of NfL in CSF has already demonstrated a significant correlation with inflammatory disease activity, [12][13][14] fourth-generation immunoassays allow the implementation of sNfL measurement from patients`blood as "easy-to-measure" marker to reflect acute neuroaxonal damage. Of particular interest is the proof that sNfL levels can be used to separate not only patients with MS from healthy controls but also to separate patients with MS with and without persistent clinical and subclinical MRI disease activity.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the reappearance of disease activity, ATZ retreatment was initiated in 8 patients (figures 3-5, patient [8][9][10][11][12][13][14][15]. At least, 10 ATZ retreatments (7 patients received 1 ATZ retreat and 1 patient received 3 ATZ retreats) had to be performed in our cohort.…”

Section: Snfl After Atz Retreatmentmentioning

confidence: 99%

“…[8][9][10] Different studies presented that neurofilament light chain (NfL) is increased in the CSF of patients with clinically isolated syndrome and MS and correlates with MRI activity, disability, and relapse activity. [11][12][13][14][15][16] Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array [SIMOA]) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. Previous studies suggest serum (s)NfL as a potential predictive marker for MS disease outcome.…”

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confidence: 99%

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Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS

Akgün

Kretschmann

Haase

et al. 2019

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo evaluate individual neurofilament light chain (NfL) variation over the time of disease course and the potential of NfL measurement to predict treatment response in patients with MS.MethodsWe investigated 15 patients with MS after immune reconstitution treatment with alemtuzumab (ATZ). Monthly serum NfL (sNFL) measurements were correlated with Expanded Disability Status Scale (EDSS), MRI, and relapse activity over an observational period of up to 102 months.ResultsBefore ATZ, sNfL was significantly increased in correlation with previous relapse/MRI activity. After ATZ, sNfL decreased quickly within the first 6 months. In patients classified as NEDA-3, sNfL declined and persisted at an individual low steady-state level of <8 pg/mL. During follow-up, 34 sNfL peaks with a >20 fold increase could be detected, which were associated with clinical or MRI disease activity. Even patient-reported relapse-suspicious symptoms, which have not been confirmed because relapses were accompanied by sNfL, increase, proposing sNfL assessment as a marker for relapse activity. sNfL started to increase earliest 5 months before, peaked at clinical onset, and recovered within 4–5 months. sNfL presented at higher levels in active patients requiring ATZ retreatment compared with responder patients. During 2 documented pregnancies, sNfL was at a low level, whereas a postpartum transient sNfL increase was seen without any signs of activity.ConclusionsThis study applied a long-term high-frequency sNfL assessment in an ATZ-treated cohort, allowing a holistic profiling on the individual level and highlighted that sNfL can eminently complement the individual clinical and MRI monitoring in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Section: Snfl After Atz Retreatmentmentioning

confidence: 99%

mentioning

confidence: 99%

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Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS

Akgün

Kretschmann

Haase

et al. 2019

Neurol Neuroimmunol Neuroinflamm

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“…2,3 NfL are released upon axonal or neuronal damage or degeneration, and can be found as a consequence, in the CSF and blood. Prior studies have shown that NfL concentrations in cerebrospinal fluid (CSF) are associated with the occurrence of MRI lesions, relapses, neurological disability, and treatment status in MS. [4][5][6][7] Additional studies have demonstrated predictive value of CSF neurofilament light or heavy chain levels with clinical outcomes, [8][9][10] and MRI measures. 11 More recently, single molecule array (SIMOA) based assays, which offer improved sensitivity for detection of molecules, have been used to measure NfL in serum samples.…”

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

124

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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“…These structural elements have been shown to accumulate secondary to aberrant phosphorylation and disruption of slow axonal transport (9,18,26,42). Interestingly, increased levels of neurofilaments have been found in the CSF of patients with multiple neurodegenerative diseases and are thought to correspond to axonal damage (15,30,43). Non-useful proteins are marked by ubiquitin for degradation by the ubiquitin protease system (UPS) (3).…”

Section: Discussionmentioning

confidence: 99%

Axonal swellings and spheroids: a new insight into the pathology of neurocysticercosis

et al. 2018

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Neurocysticercosis is a parasitic brain disease caused by the larval form (Cysticercus cellulosae) of Taenia solium and is the leading cause of preventable epilepsy worldwide. However, the pathophysiology and relation to the wide range of clinical features remains poorly understood. Axonal swelling is emerging as an important early pathological finding in multiple neurodegenerative diseases and as a cause of brain injury, but has not been well described in neurocysticercosis. Histological analysis was performed on human, rat and porcine NCC brain specimens to identify axonal pathology. Rat infection was successfully carried out via two routes of inoculation: direct intracranial injection and oral feeding. Extensive axonal swellings, in the form of spheroids, were observed in both humans and rats and to a lesser extent in pigs with NCC. Spheroids demonstrated increased immunoreactivity to amyloid precursor protein and neurofilament indicating probable impairment of axonal transport. These novel findings demonstrate that spheroids are present in NCC which is conserved across species. Not only is this an important contribution toward understanding the pathogenesis of NCC, but it also provides a model to analyze the association of spheroids with specific clinical features and to investigate the reversibility of spheroid formation with antihelminthic treatment.

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Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing–remitting multiple sclerosis

Abstract: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

Cited by 104 publications

References 32 publications

Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS

Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS

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

Axonal swellings and spheroids: a new insight into the pathology of neurocysticercosis

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