Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

Abstract Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer’s disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) regarding clinical diagnosis and amyloid positivity in an outpatient memory clinic - based cohort. Methods: In this retrospective analysis, we included a total of 185 patients, 141 patients along clinical the AD continuum, i.e. subjective cognitive decline (SCD, n=18), mild cognitive impairment (MCI, n=63), AD (n=60) and 44 age-matched healthy controls (HC). CSF and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOAâ) technology using the Neurology 2-Plex B kit from Quanterix. Amyloid-PET was performed in 75 patients and graded as amyloid positive and negative by visual rating. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong’s test for correlated AUC curves.Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (age+sex+APOE4+GFAP+NfL panel). Using this panel, AUC was 91.6% for HC vs. AD, 81.7% for HC vs. MCI, 85% for SCD vs. AD, 81.3% for SCD vs. MCI, 77.7% for HC vs. SCD and 72.3% for MCI vs. AD. In terms of predicting amyloid PET status, we computed an AUC of 88.4%. Conclusion: The combination of plasma GFAP and NfL with well-established risk factors could contribute crucially to the identification of patients at risk, and thereby facilitate inclusion of patients in clinical trials for disease modifying therapies.

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Blood-based NfL

Neurology ◽

10.1212/wnl.0000000000003680 ◽

2017 ◽

Vol 88 (10) ◽

pp. 930-937 ◽

Cited By ~ 156

Author(s):

Oskar Hansson ◽

Shorena Janelidze ◽

Sara Hall ◽

Nadia Magdalinou ◽

Andrew J. Lees ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Single Molecule ◽

Area Under The Curve ◽

Diagnostic Workup ◽

Healthy Controls ◽

Class Iii ◽

Early Disease ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Parkinsonian Disorders

Objective:To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.Methods:The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.Results:We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).Conclusions:Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.Classification of evidence:This study provides Class III evidence that blood NfL levels discriminate between PD and APD.

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Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

Neurology ◽

10.1212/wnl.0000000000010111 ◽

2020 ◽

Vol 95 (12) ◽

pp. e1754-e1759 ◽

Cited By ~ 30

Author(s):

Nelly Kanberg ◽

Nicholas J. Ashton ◽

Lars-Magnus Andersson ◽

Aylin Yilmaz ◽

Magnus Lindh ◽

...

Keyword(s):

Single Molecule ◽

Severe Disease ◽

Plasma Concentrations ◽

Neuronal Injury ◽

Cns Injury ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Plasma Biomarkers

ObjectiveTo test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury.MethodsWe recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort.ResultsThe patients with severe COVID-19 had higher plasma concentrations of GFAp (p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.ConclusionWe show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19–related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.

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Serum neurofilament measurement improves clinical risk scores for outcome prediction after cardiac arrest: results of a prospective study

Critical Care ◽

10.1186/s13054-021-03459-y ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Sabina Hunziker ◽

Adrian Quinto ◽

Maja Ramin-Wright ◽

Christoph Becker ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Area Under The Curve ◽

Risk Scores ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Clinical Risk ◽

Poor Neurological Outcome

Abstract Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p < 0.001) and CAHP score (from AUC 0.89 to 0.92, p < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 (p < 0.001) for OHCA and 0.83 (p < 0.001) for CAHP. Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

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Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-326914 ◽

2021 ◽

pp. jnnp-2021-326914

Author(s):

Dario Saracino ◽

Karim Dorgham ◽

Agnès Camuzat ◽

Daisy Rinaldi ◽

Armelle Rametti-Lacroux ◽

...

Keyword(s):

Single Molecule ◽

Light Chain ◽

Rate Of Change ◽

Longitudinal Change ◽

Youden Index ◽

Clinical Genetic ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Link Type ◽

Therapeutic Trials

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.

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Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19

Journal of Neurology ◽

10.1007/s00415-021-10517-6 ◽

2021 ◽

Author(s):

Anne Hege Aamodt ◽

Einar August Høgestøl ◽

Trine Haug Popperud ◽

Jan Cato Holter ◽

Anne Ma Dyrhol-Riise ◽

...

Keyword(s):

Nervous System ◽

Single Molecule ◽

Linear Models ◽

Clinical Signs ◽

Repeated Measurements ◽

Cns Injury ◽

Serum Concentrations ◽

Blood Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Abstract Objective To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. Methods Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. Results In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10–7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). Conclusion Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

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CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event

Multiple Sclerosis Journal ◽

10.1177/13524585211010082 ◽

2021 ◽

pp. 135245852110100

Author(s):

Manuel Comabella ◽

Margareta A Clarke ◽

Sabine Schaedelin ◽

Mar Tintoré ◽

Deborah Pareto ◽

...

Keyword(s):

Single Molecule ◽

Multivariable Analysis ◽

Enzyme Linked Immunosorbent Assay ◽

Lesion Volume ◽

Univariable Analysis ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Multivariable Analyses ◽

Prognostic Implications ◽

The Relationship

Background: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis. Objective: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event. Methods: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (β = 1.41; 95% confidence interval (CI) = 1.10–1.79; p < 0.01) and serum NfL levels (β = 2.30; 95% CI = 1.47–3.60; p < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (β = 1.45; 95% CI = 1.11–1.90; p < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses. Conclusion: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.

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Texture-Based Analysis of 18F-Labeled Amyloid PET Brain Images

Applied Sciences ◽

10.3390/app11051991 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1991

Author(s):

Alexander P. Seiffert ◽

Adolfo Gómez-Grande ◽

Eva Milara ◽

Sara Llamas-Velasco ◽

Alberto Villarejo-Galende ◽

...

Keyword(s):

Area Under The Curve ◽

Standardized Uptake Value ◽

Texture Features ◽

Roc Curves ◽

Significant Feature ◽

Study Cohort ◽

Amyloid Pet ◽

Reference Region ◽

Brain Images ◽

Positron Emission

Amyloid positron emission tomography (PET) brain imaging with radiotracers like [18F]florbetapir (FBP) or [18F]flutemetamol (FMM) is frequently used for the diagnosis of Alzheimer’s disease. Quantitative analysis is usually performed with standardized uptake value ratios (SUVR), which are calculated by normalizing to a reference region. However, the reference region could present high variability in longitudinal studies. Texture features based on the grey-level co-occurrence matrix, also called Haralick features (HF), are evaluated in this study to discriminate between amyloid-positive and negative cases. A retrospective study cohort of 66 patients with amyloid PET images (30 [18F]FBP and 36 [18F]FMM) was selected and SUVRs and 6 HFs were extracted from 13 cortical volumes of interest. Mann–Whitney U-tests were performed to analyze differences of the features between amyloid positive and negative cases. Receiver operating characteristic (ROC) curves were computed and their area under the curve (AUC) was calculated to study the discriminatory capability of the features. SUVR proved to be the most significant feature among all tests with AUCs between 0.692 and 0.989. All HFs except correlation also showed good performance. AUCs of up to 0.949 were obtained with the HFs. These results suggest the potential use of texture features for the classification of amyloid PET images.

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Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing–remitting MS

Multiple Sclerosis Journal ◽

10.1177/13524585211032348 ◽

2021 ◽

pp. 135245852110323

Author(s):

Jens Kuhle ◽

Nadia Daizadeh ◽

Pascal Benkert ◽

Aleksandra Maceski ◽

Christian Barro ◽

...

Keyword(s):

Single Molecule ◽

Light Chain ◽

Interferon Beta ◽

Efficacy And Safety ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Highly Active ◽

Sustained Reduction ◽

Relapsing Remitting ◽

Healthy Control

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ). Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively. Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion. Results: Baseline median sNfL levels were similar in alemtuzumab ( n = 354) and SC IFNB-1a–treated ( n = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; p < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; p < 0.0001); 73% for alemtuzumab at Y7. HAD patients ( n = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7). Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7. ClinicalTrials.gov identifier: NCT00530348, NCT00930553, NCT02255656

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Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000679 ◽

2020 ◽

Vol 7 (3) ◽

pp. e679 ◽

Cited By ~ 2

Author(s):

Sinah Engel ◽

Falk Steffen ◽

Timo Uphaus ◽

Peter Scholz-Kreisel ◽

Frauke Zipp ◽

...

Keyword(s):

Single Molecule ◽

Leukocyte Count ◽

Cross Sectional Study ◽

Axonal Damage ◽

Oligoclonal Bands ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Igg Synthesis ◽

Healthy Donors

ObjectiveTo investigate the association of serum neurofilament light chain (sNfL) levels with CSF parameters in clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), taking into account radiologic and clinical parameters of disease activity.MethodsSimultaneously collected serum and CSF samples of 112 untreated patients newly diagnosed with CIS or RRMS were included in this cross-sectional study. CSF parameters were obtained as part of routine diagnostic tests. sNfL levels of patients and of 62 healthy donors were measured by highly sensitive single molecule array (SiMoA) immunoassay.ResultsPatients with RRMS (n = 91, median 10.13 pg/mL, interquartile range [IQR] 6.67–17.77 pg/mL) had higher sNfL levels than healthy donors (n = 62, median 5.25 pg/mL, IQR 4.05–6.81 pg/mL, p < 0.001) and patients with CIS (n = 21, median 5.69 pg/mL, IQR 4.73–9.07 pg/mL, p < 0.001). Patients positive for oligoclonal bands (OCBs) (n = 101, median 9.19 pg/mL, IQR 6.34–16.38 pg/mL) had higher sNfL levels than OCB-negative patients (n = 11, median 5.93 pg/mL, IQR 2.93–8.56 pg/mL, p = 0.001). sNfL levels correlated with CSF immunoglobulin G (IgG) levels (r = 0.317, p = 0.002), IgG ratio (QIgG) (r = 0.344, p < 0.001), and CSF leukocyte count (r = 0.288, p = 0.002). In linear regression modeling, the CSF leukocyte count combined with the number of contrast-enhancing lesions in MRI predicted sNfL levels best.ConclusionsIn active MS, sNfL levels correlate with intrathecal pleocytosis and IgG synthesis, indicating that axonal damage is associated with both acute and chronic CNS-intrinsic inflammation.

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Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD

Neurology ◽

10.1212/wnl.0000000000008160 ◽

2019 ◽

Vol 93 (13) ◽

pp. e1299-e1311 ◽

Cited By ~ 21

Author(s):

Mitsuru Watanabe ◽

Yuri Nakamura ◽

Zuzanna Michalak ◽

Noriko Isobe ◽

Christian Barro ◽

...

Keyword(s):

Disease Activity ◽

Single Molecule ◽

Multivariate Analyses ◽

Serum Levels ◽

Strongly Correlated ◽

Serum Samples ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Disability Status ◽

Spectrum Disorders

ObjectiveTo test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD).MethodsLevels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined.ResultsFor both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p = 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of 75.8%.ConclusionssGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.

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