scholarly journals Plasma proteome analysis of patients with hereditary transthyretin-mediated (hATTR) amyloidosis establishes neurofilament light chain (NfL) as a biomarker of disease and treatment response

2019 ◽  
Author(s):  
Simina Ticau ◽  
Gautham V Sridharan ◽  
Shira Tsour ◽  
William L Cantley ◽  
Amy Chan ◽  
...  
Keyword(s):  
Disease Progression ◽  
Light Chain ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Neuronal Damage ◽  
Disease Onset ◽  
Healthy Individuals ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
The Impact

SummaryBackgroundHereditary transthyretin-mediated (hATTR) amyloidosis is a rare, progressively debilitating, and fatal disease caused by deposition of aggregated transthyretin amyloid in multiple organs and tissues. Highly variable disease penetrance has made it difficult to predict disease onset and progression. Clinically validated, non-invasive plasma biomarkers may facilitate earlier diagnosis and aid monitoring of disease progression.MethodsPlasma levels of >1000 proteins were measured in patients with hATTR amyloidosis with polyneuropathy who received either placebo or patisiran in the phase 3 APOLLO study (NCT01960348) and in a cohort of healthy individuals. The impact of patisiran treatment on the time profile of each protein was determined by a linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) protein was further assessed using an orthogonal quantitative approach.FindingsA significant change in the levels of 66 proteins was observed with patisiran vs placebo, with change in NfL, a marker of neuronal damage, most significant (p<10−20). Analysis of the changes in protein levels demonstrated that the proteome of patients treated with patisiran trended towards healthy individuals at 18 months. Plasma NfL levels in healthy controls were four-fold lower than in patients with hATTR amyloidosis with polyneuropathy (16·3 [SD 12·0] pg/mL vs 69·4 [SD 42·1] pg/mL, p<10−16). Levels of NfL at 18 months increased with placebo (99·5 [SD 60·1] pg/mL) and decreased with patisiran treatment (48·8 [SD 29·9] pg/mL). At 18 months, improvement in modified Neuropathy Impairment Score+7 (mNIS+7) in patisiran-treated patients significantly correlated with a reduction in NfL levels (R=0·43, p<10−7).InterpretationThe observed correlation of NfL reduction with patisiran treatment and improvement in mNIS+7 suggests it may serve as a biomarker of nerve damage and polyneuropathy in hATTR amyloidosis. This biomarker may enable earlier diagnosis of polyneuropathy in patients with hATTR amyloidosis and facilitate monitoring of disease progression.

scholarly journals Neurofilament light chain (NfL) as a biomarker of hereditary transthyretin-mediated amyloidosis

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011090
Author(s):  
Simina Ticau ◽  
Gautham V. Sridharan ◽  
Shira Tsour ◽  
William L. Cantley ◽  
Amy Chan ◽  
...  
Keyword(s):  
Disease Progression ◽  
Light Chain ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Controlled Study ◽  
Healthy Controls ◽  
Class Iii ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
The Impact

ObjectiveTo identify changes in the proteome associated with onset and progression of ATTRv amyloidosis, we performed an observational, case-controlled study which compared proteomes of patients with ATTRv amyloidosis and healthy controls.MethodsPlasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in the APOLLO study and in healthy controls. The impact of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed using an orthogonal quantitative approach.ResultsLevels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10−20). Analysis of changes in protein levels demonstrated that the proteome of patisiran-treated patients trended toward healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 vs 69.4 pg/mL, effect: −53.1 pg/mL, 95% CI [–60.5 to −45.9]). NfL levels at 18 months increased with placebo (99.5 vs 63.2 pg/mL, 36.3 pg/mL, [16.5–56.1]) and decreased with patisiran treatment (48.8 vs 72.1 pg/mL, −23.3 pg/mL, [–33.4 to −13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 following patisiran significantly correlated with reduced NfL (R = 0.43, [0.29–0.55]).ConclusionsFindings suggest NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, may enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.Classification of evidenceThis study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.

scholarly journals No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach

2021 ◽  
pp. 100056
Author(s):  
Jasmini ALAGARATNAM ◽  
Wolfgang STÖHR ◽  
Jamie TOOMBS ◽  
Amanda HESLEGRAVE ◽  
Henrik ZETTERBERG ◽  
...  
Keyword(s):  
Light Chain ◽  
Neuronal Damage ◽  
Hiv Cure ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

scholarly journals Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Ngoc Dung Le ◽  
Lukas Muri ◽  
Denis Grandgirard ◽  
Jens Kuhle ◽  
David Leppert ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Light Chain ◽  
Pneumococcal Meningitis ◽  
Neuronal Damage ◽  
Neuronal Injury ◽  
Health Concern ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Inflammatory Phase

Abstract Background Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM). Methods Eleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively. Results In ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1β, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics. Conclusion Current results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

scholarly journals Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives

2021 ◽  
pp. 000486742110586
Author(s):  
Dhamidhu Eratne ◽  
Shorena Janelidze ◽  
Charles B Malpas ◽  
Samantha Loi ◽  
Mark Walterfang ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Light Chain ◽  
Neurodegenerative Disorders ◽  
Neuronal Damage ◽  
First Episode ◽  
Treatment Resistant ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
First Degree Relatives ◽  
Frontotemporal Dementias

Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. Methods: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine ( n = 13), and age- and sex-matched controls ( n = 59). Results: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman’s r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia ( r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight ( r = −0.305, 95% confidence interval: [−0.504, −0.076]). Conclusion: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

P3-251: SERUM NEUROFILAMENT LIGHT CHAIN LEVELS ARE ASSOCIATED WITH CSF NEUROFILAMENT LIGHT CHAIN, COGNITIVE STATUS, AND DISEASE PROGRESSION IN AUTOSOMAL DOMINANT AD

2006 ◽  
Vol 14 (7S_Part_22) ◽  
pp. P1170-P1170 ◽  
Author(s):  
Oliver Preische ◽  
Stephanie A. Schultz ◽  
Anja Apel ◽  
Jens Kuhle ◽  
Brian A. Gordon ◽  
...  
Keyword(s):  
Disease Progression ◽  
Light Chain ◽  
Autosomal Dominant ◽  
Cognitive Status ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

scholarly journals Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies

2021 ◽  
pp. 1-7
Author(s):  
Andrea Pilotto ◽  
Alberto Imarisio ◽  
Claudia Carrarini ◽  
Mirella Russo ◽  
Stefano Masciocchi ◽  
...  
Keyword(s):  
Light Chain ◽  
Neurological Disorders ◽  
Dementia With Lewy Bodies ◽  
Neuronal Damage ◽  
Lewy Bodies ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Predict Disease Progression

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

Biological variation of serum neurofilament light chain

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Claus Vinter Bødker Hviid ◽  
Anne Tranberg Madsen ◽  
Anne Winther-Larsen
Keyword(s):  
Light Chain ◽  
Reference Intervals ◽  
Biological Variation ◽  
Healthy Individuals ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Linear Mixed Effects ◽  
Serial Measurements ◽  
Analytical Variation ◽  
Apparently Healthy

Abstract Objectives The neurofilament light chain (NfL) has emerged as a versatile biomarker for CNS-diseases and is approaching clinical use. The observed changes in NfL levels are frequently of limited magnitude and in order to make clinical decisions based on NfL measurements, it is essential that biological variation is not confused with clinically relevant changes. The present study was designed to evaluate the biological variation of serum NfL. Methods Apparently healthy individuals (n=33) were submitted to blood draws for three days in a row. On the second day, blood draws were performed every third hour for 12 h. NfL was quantified in serum using the Simoa™ HD-1 platform. The within-subject variation (CVI) and between-subject variation (CVG) were calculated using linear mixed-effects models. Results The overall median value of NfL was 6.3 pg/mL (range 2.1–19.1). The CVI was 3.1% and the CVG was 35.6%. An increase in two serial measurements had to exceed 24.3% to be classified as significant at the 95% confidence level. Serum NfL levels remained stable during the day (p=0.40), whereas a minute variation (6.0–6.6 pg/mL) was observed from day-to-day (p=0.02). Conclusions Serum NfL is subject to tight homeostatic regulation with none or neglectable semidiurnal and day-to-day variation, but considerable between-subject variation exists. This emphasizes serum NfL as a well-suited biomarker for disease monitoring, but warrants caution when interpreting NfL levels in relation to reference intervals in a diagnosis setting. Furthermore, NfL’s tight regulation requires that the analytical variation is kept at a minimum.

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