scholarly journals Plasma tau is increased in frontotemporal dementia

2018 ◽  
Vol 89 (8) ◽  
pp. 804-807 ◽  
Author(s):  
Martha S Foiani ◽  
Ione OC Woollacott ◽  
Carolin Heller ◽  
Martina Bocchetta ◽  
Amanda Heslegrave ◽  
...  

BackgroundFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations in GRN, MAPT and C9orf72 being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life.MethodsThis study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in either MAPT (n=12), GRN (n=9) or C9orf72 (n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression.ResultsHigher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only the MAPT group had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration.ConclusionPlasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only in MAPT mutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.

2020 ◽  
Vol 7 (3) ◽  
pp. e679 ◽  
Author(s):  
Sinah Engel ◽  
Falk Steffen ◽  
Timo Uphaus ◽  
Peter Scholz-Kreisel ◽  
Frauke Zipp ◽  
...  

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.


2021 ◽  
Author(s):  
Beatriz Ruiz-Saez ◽  
Manuela Martín-Bejarano ◽  
Ana Martínez Aragon ◽  
Magnus Gisslen ◽  
Henrik Zetterberg ◽  
...  

Abstract Background: Higher plasma concentration of neurofilament light (pNfL) is associated with neurodegeneration. However, to our knowledge, up to now, there are no data in HIV patients with infection due to vertical transmission. This is the first study to report pNfL in a cohort of HIV perinatally infected (PHIV) young adults compared with non-HIV (HIV-) controls.Methods: Thirty-three PHIV patients and 25 age-matched HIV- were recruited to this cross-sectional study. Plasma NfL concentrations were compared between both groups. In a subgroup of 48 participants (25 PHIV patients and 23 HIV-), brain volumes through magnetic resonance imaging (MRI) and neuropsychological testing (NT), were also conducted and compared with pNfL values.Plasma NfL concentration was measured using Single Molecule Array (Simoa) immunoassay.NT included fluid intelligence and processing speed through the WAIS-IV Coding subtest, and the Stroop Test.ResultsFifty-eight participants were included, median age 20.7 years [IQR 17.8-23.4]. 100% of the patients were under antiretroviral treatment (cART) and 85% had viral load <50 copies/ml.Although no statistically significant differences were found between patients and controls regarding pNfL concentration, there was a trend towards higher levels in patients with viral load >50 copies/ml.With regard to brain volumes and NT, in the PHIV group, lower white matter volumes and lower score in the coding subtest were associated with higher pNfL values. ConclusionsMost PHIV adolescents under cART have similar levels of pNfL than HIV-. As reported in adults, those with HIV-RNA >50 copies/ml showed higher values and lower white matter volumes that may imply an ongoing CNS injury. Plasma NfL could be a feasible biomarker of CNS injury in PHIV patients with unsuppressed viral load.


2020 ◽  
Vol 49 (6) ◽  
pp. 533-538
Author(s):  
Anders Toft ◽  
Peter Roos ◽  
Olli Jääskeläinen ◽  
Christian Sandøe Musaeus ◽  
Emil Elbæk Henriksen ◽  
...  

<b><i>Introduction:</i></b> The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to <i>CHMP2B</i> mutation (FTD-3). <b><i>Methods:</i></b> This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected <i>CHMP2B</i> mutation carriers, 10 presymptomatic carriers, and 16 noncarriers. Serum-NfL levels measured by single-molecule array (Simoa) technology were tested for associations with the clinical groups and clinical parameters. Serum and CSF data were compared, and CSF/serum-albumin ratio was included as a measure of blood-brain barrier (BBB) function. <b><i>Results:</i></b> Serum-NfL concentrations were significantly increased in symptomatic <i>CHMP2B</i> mutation carriers compared to presymptomatic carriers and in both groups compared to healthy family controls. Serum-NfL levels appear to increase progressively with age in presymptomatic carriers, and this is perhaps followed by a change in trajectory when patients become symptomatic. Measurements of NfL in serum and CSF were highly correlated and fold-changes in serum and CSF between clinical groups were similar. Increase in serum-NFL levels was correlated with reduced ACE-score. Higher CSF/serum-albumin ratios were demonstrated in FTD-3 patients, but this did not affect the significant associations between serum-NfL and clinical groups. <b><i>Conclusion:</i></b> Serum-NfL could be utilized as an accurate surrogate marker of CSF levels to segregate symptomatic <i>CHMP2B</i> carriers, presymptomatic carriers, and non-carriers. The observed indication of BBB dysfunction in FTD-3 patients did not confound this use of serum-NfL. The results support the occurrence of mutation-related differences in NfL dynamics in familial FTD.


2022 ◽  
Vol 8 (1) ◽  
pp. 205521732110693
Author(s):  
Hrishikesh Lokhande ◽  
Mattia Rosso ◽  
Shahamat Tauhid ◽  
Renxin Chu ◽  
Brian C. Healy ◽  
...  

Background Serum neurofilament light chain (sNfL) levels are associated with relapses, MRI lesions, and brain volume in multiple sclerosis (MS). Objective To explore the value of early serum neurofilament light (sNfL) measures in prognosticating 10-year regional brain volumes in MS. Methods Patients with MS enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study within five years of disease onset who had annual blood samples from years 1–10 (n = 91) were studied. sNfL was measured with a single molecule array (SIMOA) assay. We quantified global cortical thickness and normalized deep gray matter (DGM) volumes (fractions of the thalamus, caudate, putamen, and globus pallidus) from high-resolution 3 T MRI at 10 years. Correlations between yearly sNfL levels and 10-year MRI outcomes were assessed using linear regression models. Results sNfL levels from years 1 and 2 were associated with 10-year thalamus fraction. Early sNfL levels were not associated with 10-year putamen, globus pallidus or caudate fractions. At 10 years, cortical thickness was not associated with early sNfL levels, but was weakly correlated with total DGM fraction. Conclusions Early sNfL levels correlate with 10-year thalamic volume, supporting its role as a prognostic biomarker in MS.


Neurology ◽  
2020 ◽  
Vol 95 (12) ◽  
pp. e1754-e1759 ◽  
Author(s):  
Nelly Kanberg ◽  
Nicholas J. Ashton ◽  
Lars-Magnus Andersson ◽  
Aylin Yilmaz ◽  
Magnus Lindh ◽  
...  

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.


2019 ◽  
Vol 26 (13) ◽  
pp. 1670-1681 ◽  
Author(s):  
Dejan Jakimovski ◽  
Robert Zivadinov ◽  
Murali Ramanthan ◽  
Jesper Hagemeier ◽  
Bianca Weinstock-Guttman ◽  
...  

Background: A limited number of studies investigated associations between serum neurofilament light chain (sNfL) and cognition in persons with multiple sclerosis (PwMS). Objective: To assess cross-sectional and longitudinal associations between sNfL levels, clinical, and cognitive performance in PwMS and age-matched healthy controls (HCs). Materials: One hundred twenty-seven PwMS (85 relapsing–remitting MS/42 progressive MS), 20 clinically isolated syndrome patients, and 52 HCs were followed for 5 years. sNfL levels were measured using the single-molecule array (Simoa) assay and quantified in picograms per milliliter. Expanded Disability Status Scale (EDSS), walking, and manual dexterity tests were obtained. At follow-up, Brief International Cognitive Assessment for MS (BICAMS) was utilized. Cognitively impaired (CI) status was derived using HC-based z-scores. Age-, sex-, and education-adjusted analysis of covariance (ANCOVA) and regression models were used. Multiple comparison–adjusted values of q < 0.05 were considered significant. Results: In PwMS, sNfL levels were cross-sectionally associated with walking speed ( r = 0.235, q = 0.036), manual dexterity ( r = 0.337, q = 0.002), and cognitive processing speed (CPS; r =−0.265, q = 0.012). Baseline sNfL levels predicted 5-year EDSS scores ( r = 0.25, q = 0.012), dexterity ( r = 0.224, q = 0.033), and CPS ( r =−0.205, q = 0.049). CI patients had higher sNfL levels (27.2 vs. 20.6, p = 0.016) and greater absolute longitudinal sNfL increase when compared with non-CI patients (4.8 vs. 0.7, p = 0.04). Conclusion: Higher sNfL levels are associated with poorer current and future clinical and cognitive performance.


Author(s):  
Tobias Geis ◽  
◽  
Susanne Brandstetter ◽  
Antoaneta A. Toncheva ◽  
Otto Laub ◽  
...  

Abstract Background Serum neurofilament light chain (sNfL) is an established biomarker of neuro-axonal damage in multiple neurological disorders. Raised sNfL levels have been reported in adults infected with pandemic coronavirus disease 2019 (COVID-19). Levels in children infected with COVID-19 have not as yet been reported. Objective To evaluate whether sNfL is elevated in children contracting COVID-19. Methods Between May 22 and July 22, 2020, a network of outpatient pediatricians in Bavaria, Germany, the Coronavirus antibody screening in children from Bavaria study network (CoKiBa), recruited healthy children into a cross-sectional study from two sources: an ongoing prevention program for 1–14 years, and referrals of 1–17 years consulting a pediatrician for possible infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined sNfL levels by single molecule array immunoassay and SARS-CoV-2 antibody status by two independent quantitative methods. Results Of the 2652 included children, 148 (5.6%) were SARS-CoV-2 antibody positive with asymptomatic to moderate COVID-19 infection. Neurological symptoms—headache, dizziness, muscle aches, or loss of smell and taste—were present in 47/148 cases (31.8%). Mean sNfL levels were 5.5 pg/ml (SD 2.9) in the total cohort, 5.1 (SD 2.1) pg/ml in the children with SARS-CoV-2 antibodies, and 5.5 (SD 3.0) pg/ml in those without. Multivariate regression analysis revealed age—but neither antibody status, antibody levels, nor clinical severity—as an independent predictor of sNfL. Follow-up of children with pediatric multisystem inflammatory syndrome (n = 14) showed no association with sNfL. Conclusions In this population study, children with asymptomatic to moderate COVID-19 showed no neurochemical evidence of neuronal damage.


Neurology ◽  
2018 ◽  
Vol 91 (14) ◽  
pp. e1338-e1347 ◽  
Author(s):  
Steffen Tiedt ◽  
Marco Duering ◽  
Christian Barro ◽  
Asli Gizem Kaya ◽  
Julia Boeck ◽  
...  

ObjectiveTo explore the utility of serum neurofilament light chain (NfL) as a biomarker for primary and secondary neuroaxonal injury after ischemic stroke (IS) and study its value for the prediction of clinical outcome.MethodsWe used an ultrasensitive single-molecule array assay to measure serum NfL levels in healthy controls (n = 30) and 2 independent cohorts of patients with IS: (1) with serial serum sampling at hospital arrival (n = 196), at days 2, 3, and 7 (n = 89), and up to 6 months post stroke; and (2) with standardized MRI at baseline and at 6 months post stroke, and with cross-sectional serum sampling at 6 months (n = 95). We determined the temporal profile of serum NfL levels, their association with imaging markers of neuroaxonal injury, and with clinical outcome.ResultsPatients with IS had higher serum NfL levels compared with healthy controls starting from admission until 6 months post stroke. Serum NfL levels peaked at day 7 (211.2 pg/mL [104.7–442.6], median [IQR]) and correlated with infarct volumes (day 7: partial r = 0.736, p = 1.5 × 10−15). Six months post stroke, patients with recurrent ischemic lesions on MRI (n = 19) had higher serum NfL levels compared to those without new lesions (n = 76, p = 0.002). Serum NfL levels 6 months post stroke further correlated with a quantitative measure of secondary neurodegeneration obtained from diffusion tensor imaging MRI (r = 0.361, p = 0.001). Serum NfL levels 7 days post stroke independently predicted modified Rankin Scale scores 3 months post stroke (cumulative odds ratio [95% confidence interval] = 2.35 [1.60–3.45]; p = 1.24 × 10−05).ConclusionSerum NfL holds promise as a biomarker for monitoring primary and secondary neuroaxonal injury after IS and for predicting functional outcome.


2021 ◽  
pp. jnnp-2021-326914
Author(s):  
Dario Saracino ◽  
Karim Dorgham ◽  
Agnès Camuzat ◽  
Daisy Rinaldi ◽  
Armelle Rametti-Lacroux ◽  
...  

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.


Author(s):  
Anne Hege Aamodt ◽  
Einar August Høgestøl ◽  
Trine Haug Popperud ◽  
Jan Cato Holter ◽  
Anne Ma Dyrhol-Riise ◽  
...  

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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