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1.
Nat Med ; 26(3): 387-397, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123386

RESUMO

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid ß positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid ß-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/diagnóstico , Proteínas tau/sangue , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cognição , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Neurofilamentos/sangue , Fosforilação , Tomografia por Emissão de Pósitrons , Índice de Gravidade de Doença , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
2.
Nat Commun ; 11(1): 812, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041951

RESUMO

Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also in serum, which allows for repeated assessments. There is still limited knowledge regarding the association of serum NfL (sNfL) with age and subclinical morphologic brain changes and their dynamics in the normal population. We measured sNfL by a single molecule array (Simoa) assay in 335 individuals participating in a population-based cohort study and after a mean follow-up time of 5.9 years (n = 103). Detailed clinical examination, cognitive testing and 3T brain MRI were performed to assess subclinical brain damage. We show that rising and more variable sNfL in individuals >60 years indicate an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This is supported by a close association of sNfL with brain volume changes in a cross-sectional and especially longitudinal manner.


Assuntos
Envelhecimento , Encéfalo/patologia , Proteínas de Neurofilamentos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Envelhecimento/patologia , Atrofia , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Cognição/fisiologia , Estudos Transversais , Feminino , Humanos , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
3.
Acta Neurol Scand ; 141(1): 77-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657006

RESUMO

OBJECTIVES: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D3 supplements were associated with lower circulating NfL levels. MATERIALS & METHODS: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D3 and N = 16 with placebo. Twenty-five hydroxyvitamin D3 (25(OH)D3 ) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. RESULTS: Serum 25(OH)D3 levels at 48 weeks were increased in the vitamin D3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P < .01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). CONCLUSIONS: Supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D3 on this biomarker of neuro-axonal injury.


Assuntos
Colecalciferol/uso terapêutico , Suplementos Nutricionais , Esclerose Múltipla Recidivante-Remitente/sangue , Proteínas de Neurofilamentos/sangue , Vitamina D/sangue , Adjuvantes Imunológicos/uso terapêutico , Adulto , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
4.
PLoS One ; 14(12): e0226697, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856243

RESUMO

Scrapie is a fatal neurodegenerative disease of sheep and goats belonging to the group of Transmissible Spongiform Encephalopathy or prion diseases. The EU has adopted mandatory measures for scrapie surveillance to safeguard public and animal health because it is highly contagious and might decimate all genetic susceptible animals in affected flocks. Definite diagnosis of scrapie relies on the detection of the pathological prion protein in brain tissues and there are still no blood biomarkers available for making diagnosis in living animals that can be used for the screening of sheep in scrapie-affected flocks. Neurofilament light (NfL) protein, a valid biomarker for neuronal and axonal damages, can now be easily measured in blood by the ultra-sensitive single molecule array (Simoa) technology. Recent work reported that serum NfL is increased in neurodegenerative diseases, including human prion diseases, but no data are available for scrapie or other animal prion diseases. Here, we found that the median serum NfL concentration in scrapie animals (56.2, IQR 42.2-84.8, n = 9) was more than 15 times higher (p = 0.00084) than that found in control samples (3.4, IQR 3.0-26.3, n = 11). Moreover, serum NfL concentration in scrapie sheep with clinical signs (n = 2; 75.3, 15.7 pg/ml) did not significantly (p = 0.541; t-test) differ from scrapie animals without clinical signs (n = 7; 61.0, 10.7 pg/ml). The receiver operating characteristic (ROC) curve analysis estimated the cut-off value of 31 pg/ml serum NfL for distinguishing scrapie-infected sheep from controls. The application of this cut-off value gives an accuracy of the test of 95% (percent error of 5.23%). These data indicate that the Simoa test for serum NfL might be a useful screening method for detecting preclinical scrapie in living sheep. Finally, the preliminary data reported here need confirmation in large and more structured studies.


Assuntos
Técnicas de Diagnóstico Molecular/veterinária , Proteínas de Neurofilamentos/sangue , Scrapie/diagnóstico , Animais , Biomarcadores/sangue , Técnicas de Diagnóstico Molecular/normas , Scrapie/sangue , Sensibilidade e Especificidade , Ovinos
6.
Neurology ; 93(13): e1299-e1311, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31471502

RESUMO

OBJECTIVE: To 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). METHODS: Levels 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. RESULTS: For 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%. CONCLUSIONS: sGFAP 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.


Assuntos
Biomarcadores/sangue , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Neuromielite Óptica/sangue , Adulto , Bioensaio/métodos , Pessoas com Deficiência , Feminino , Humanos , Filamentos Intermediários/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico
7.
Neurology ; 93(11): e1104-e1111, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31420461

RESUMO

OBJECTIVE: To examine whether plasma neurofilament light chain (NfL) levels were associated with motor and cognitive progression in Parkinson disease (PD). METHODS: This prospective follow-up study enrolled 178 participants, including 116 with PD, 22 with multiple system atrophy (MSA), and 40 healthy controls. We measured plasma NfL levels with electrochemiluminescence immunoassay. Patients with PD received evaluations of motor and cognition at baseline and at a mean follow-up interval of 3 years. Changes in the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score and Mini-Mental State Examination score were used to assess motor and cognition progression. RESULTS: Plasma NfL levels were significantly higher in the MSA group than in the PD and healthy groups (35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/mL, respectively, p < 0.001). In the PD group, NfL levels were significantly elevated in patients with advanced Hoehn-Yahr stage and patients with dementia (p < 0.001). NfL levels were modestly correlated with UPDRS part III scores (r = 0.42, 95% confidence interval 0.46-0.56, p < 0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox regression analysis adjusted for age, sex, disease duration, and baseline motor or cognitive status showed that higher baseline NfL levels were associated with higher risks for either motor or cognition progression (p = 0.029 and p = 0.015, respectively). CONCLUSIONS: Plasma NfL levels correlated with disease severity and progression in terms of both motor and cognitive functions in PD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that plasma NfL level distinguishes PD from MSA and is a surrogate biomarker for PD progression.


Assuntos
Progressão da Doença , Proteínas de Neurofilamentos/sangue , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Índice de Gravidade de Doença , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Estudos Prospectivos
8.
Neurology ; 93(10): e968-e974, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31383792

RESUMO

OBJECTIVE: To explore the correlation between serum and CSF neurofilament light chain (NfL) and the association of NfL levels and future disease activity in pediatric patients with a first attack of acquired demyelinating syndromes (ADS). METHODS: In total, 102 children <18 years with a first attack of CNS demyelination and 23 age-matched controls were included. Clinically definite multiple sclerosis (CDMS) was set as an endpoint for analysis. CSF NfL was tested by the commercially available ELISA (UmanDiagnostics); serum NfL (sNfL) was tested with a Simoa assay. Hazard ratios (HR) were calculated with Cox regression analysis. RESULTS: Of the 102 patients, 47 (46%) were tested for CSF NfL. CSF and serum NfL correlated significantly in the total group (ρ 0.532, p < 0.001) and even more significantly in the subgroup of patients with future CDMS diagnosis (ρ 0.773, p < 0.001). sNfL was higher in patients than in controls (geometric mean 6.1 pg/mL, p < 0.001), and was highest in ADS presenting with encephalopathy (acute disseminated encephalomyelitis, n = 28, 100.4 pg/mL), followed by patients without encephalopathy (ADS-) with future CDMS diagnosis (n = 40, 32.5 pg/mL), and ADS- who remained monophasic (n = 34, 17.6 pg/mL). sNfL levels higher than a median of 26.7 pg/mL at baseline are associated with a shorter time to CDMS diagnosis in ADS- (p = 0.045). HR for CDMS diagnosis was 1.09 for each 10 pg/mL increase of sNfL, after correction for age, oligoclonal bands, and MRI measures (p = 0.012). CONCLUSION: The significant correlation between CSF and serum NfL strengthens its reliability as a peripheral marker of neuroaxonal damage. Higher sNfL levels at baseline were associated with higher probability of future CDMS diagnosis in ADS-.


Assuntos
Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Proteínas de Neurofilamentos/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Feminino , Humanos , Masculino , Estudos Prospectivos , Síndrome
9.
Bioanalysis ; 11(15): 1405-1418, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31401845

RESUMO

Background: Neurofilament light (NfL) chain is an established cerebrospinal fluid (CSF) biomarker for neuroaxonal injury. The highly sensitive Quanterix Simoa™ platform is evaluated for NfL measurement in both CSF and blood. There is a need to link historical ELISA data that use bovine NfL to that of Simoa using a recombinant human (rhuman) NfL standard. Results/Methodology: The Simoa NF-light® Advantage Kit was validated for CSF and qualified for serum and plasma, using both rhuman and bovine NfL calibrators. Matched CSF, serum and plasma samples from 112 multiple sclerosis patients were analyzed using both calibrators. Conclusion: In multiple sclerosis, there is a good correlation between blood and CSF NfL levels. A conversion factor of approximately 5:1 was established between bovine and rhuman NfL calibrators.


Assuntos
Análise Química do Sangue/métodos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Animais , Análise Química do Sangue/normas , Calibragem , Bovinos , Humanos , Limite de Detecção , Proteínas de Neurofilamentos/química , Recidiva , Padrões de Referência
10.
Int J Mol Sci ; 20(17)2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31450699

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Filamentos Intermediários/metabolismo , Humanos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fosforilação , Prognóstico
11.
Transl Psychiatry ; 9(1): 180, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371701

RESUMO

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and, to a large extent, unknown pathophysiology. Structural brain differences, such as global or focal reductions in grey or white matter volumes, as well as enlargement of the sulci and the ventricles, have repeatedly been observed in individuals with AN. However, many of the documented aberrances normalize with weight recovery, even though some studies show enduring changes. To further explore whether AN is associated with neuronal damage, we analysed the levels of neurofilament light chain (NfL), a marker reflecting ongoing neuronal injury, in plasma samples from females with AN, females recovered from AN (AN-REC) and normal-weight age-matched female controls (CTRLS). We detected significantly increased plasma levels of NfL in AN vs CTRLS (medianAN = 15.6 pg/ml, IQRAN = 12.1-21.3, medianCTRL = 9.3 pg/ml, IQRCTRL = 6.4-12.9, and p < 0.0001), AN vs AN-REC (medianAN-REC = 11.1 pg/ml, IQRAN-REC = 8.6-15.5, and p < 0.0001), and AN-REC vs CTRLS (p = 0.004). The plasma levels of NfL are negatively associated with BMI overall samples (ß (±se) = -0.62 ± 0.087 and p = 6.9‧10-12). This indicates that AN is associated with neuronal damage that partially normalizes with weight recovery. Further studies are needed to determine which brain areas are affected, and potential long-term sequelae.


Assuntos
Anorexia Nervosa/sangue , Proteínas de Neurofilamentos/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
12.
Egypt J Immunol ; 26(1): 1-13, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332992

RESUMO

Multiple sclerosis (MS) is a disease of clinical diagnosis. There is no single specific diagnostic test available, no single clinical feature is sufficient to diagnose MS. Hence the necessity to research the presence of new diagnostic, prognostic markers and markers of activity of the disease. As principal components of the axonal cytoskeleton, Neurofilaments (NFs) are released in the interstitial fluid after axonal injury or degeneration. NFs was detected in the serum or cerebrospinal fluid (CSF) allowing their potential use as biomarkers of neurodegeneration as well as disease activity, progression and to directly assess the efficacy of current and emerging therapies for reducing axonal injury and the likely pathological substrate of progressive neurological decline. Serum biomarker of axonal injury could prove useful as a prognostic or monitoring tool. We aimed to study the relationship between serum Phosphorylated Neurofilament Heavy Chain (pNF-H) level and clinical activity of relapsing-remitting MS (RRMS) and disability measured by EDSS score. The study included 60 patients suffering from RRMS diagnosed according to McDonald's criteria 2010 and 30 healthy controls. After verbal consent, all were subjected to detailed medical history, clinical examination using EDSS score and measurement of serum pNF-H by quantitative ELISA. Results demonstrated a significantly higher serum levels of pNF-H in MS patients than healthy controls; pNF-H was 5.02±3.25 in cases and 0.65±0.2 in controls (P < 0.05), with a calculated sensitivity and specificity of 95% and 100%, respectively, and a positive and negative predictive values of 100% and 90.9%, respectively, at a cut-off level of 1.1ng/dl. Additionally, levels of pNF-H were significantly higher among relapsing than remission groups, with 93.33% and 83.33% calculated sensitivity and specificity, respectively, and a positive and negative predictive values of 84.8 % and 92.6 %, respectively, (at that cut-off level 4 ng/dl). In conclusion, pNF-H is a promising marker of MS disease activity and disability assessment.


Assuntos
Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Proteínas de Neurofilamentos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Humanos , Esclerose Múltipla Recidivante-Remitente/sangue , Fosforilação , Sensibilidade e Especificidade
13.
J Stroke Cerebrovasc Dis ; 28(8): 2242-2249, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151840

RESUMO

BACKGROUND AND PURPOSE: We studied serum neurofilaments diagnostic value in patients with acute ischemic stroke (AIS) or TIA and evaluated any correlation with symptom severity, cerebral infarction volume, aetiology, and clinical outcome. METHODS: One hundred and thirty-six patients (101 with AIS, and 35 with TIA) were included. Acute-phase serum neurofilament light chain (sNfL) was analyzed with a novel ultrasensitive single molecule array (Simoa). Cerebral infarction volume was measured from brain computed tomography in the subacute phase (>2 days). Stroke aetiology was defined by trial of ORG 10172 in acute stroke treatment classification, severity by National Institute of Health stroke scale (NIHSS) and the degree of disability by the Modified Rankin Scale (mRS) after 90 days. RESULTS: sNfL was markedly higher in patients with AIS (89.5 pg/mL [IQR: 44.7-195.3]) than with TIA (25.2 pg/mL [IQR: 14.6-48.0]), P= <.001), also after adjusting for age, NIHSS, and stroke volume (P= .003). In receiver operating characteristic analysis, sNfL concentration greater than or equal to 49 pg/mL proved to be the best cut-off value to differentiate between patients with stroke and those with TIA (sensitivity of 73% and specificity of 80%). sNfL concentration significantly correlated with cerebral infarction volume (r = .413, P= <.001), this association remained significant after adjusting for established predictors (P= .019). Patients with AIS due to cardioembolism or large artery atherosclerosis had the highest sNfL concentrations. NIHSS on admission (r = .343, P = <.001) and mRS scores after 3 months (r = .306, P = .004) correlated with sNfL concentration, however functional outcome 3 months after stroke was not associated with sNfL after adjusting for potential confounders. CONCLUSIONS: Cases with stroke were distinguishable from those with TIA following the determination of sNfL in the blood samples. The presence and amount of axonal damage estimated by sNfL correlated with the final cerebral infarction volume but was not predictive of degree of disability.


Assuntos
Infarto Encefálico/sangue , Proteínas de Neurofilamentos/sangue , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/terapia , Avaliação da Deficiência , Feminino , Finlândia , Humanos , Imagem por Ressonância Magnética , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Tomografia Computadorizada por Raios X , Regulação para Cima
14.
J Clin Lab Anal ; 33(7): e22948, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199010

RESUMO

BACKGROUND: Neurofilaments are the major cytoskeletal components of neurons, and cell injury leads to their release into the surrounding area. The aim of this study was to compare the cerebrospinal fluid (CSF) and serum (S) concentrations of neurofilament light chains (NFLs) and phosphorylated neurofilament heavy chains (pNFHs). METHODS: Neurofilament concentrations were measured in CSF and S samples from 172 patients using three enzyme-linked immunosorbent assays. Excel, Stata version 13, MedCal version 17.9.7., and NCSS 2007 software were used for the statistical analysis. RESULTS: There was a statistically significant correlation between the concentrations of CSF NFL and CSF pNFH (rs  = 0.748; n = 89; P < 0.001), but Passing-Bablok regression showed systematic deviation between the values obtained using the two assays. This indicates that the assays were not interchangeable. CSF pNFH and S pNFH concentrations showed low correlation. The kappa statistic showed moderate conformity between CSF pNFH and CSF NFL concentrations (κ = 0.556). CONCLUSIONS: The CSF NFL and CSF pNFH assays gave clinically consistent results that reflected the degree of axonal damage, independent of any particular neurological diagnosis. The S pNFH assays had a lower predictive value due to the low correlation coefficient and the kappa index of the CSF pNFH method.


Assuntos
Filamentos Intermediários/metabolismo , Doenças do Sistema Nervoso/metabolismo , Proteínas de Neurofilamentos/metabolismo , Análise de Variância , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/diagnóstico , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Análise de Regressão
15.
Neurology ; 93(3): e252-e260, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31182505

RESUMO

OBJECTIVE: We aimed to (1) assess and compare baseline plasma and CSF neurofilament light (NfL) for cross-sectional and longitudinal associations with neuroimaging or cognition and (2) determine whether change in plasma NfL corresponded with change in these outcomes. METHODS: Seventy-nine participants without dementia, median age 76 years, had plasma and CSF NfL, neuropsychological testing, and neuroimaging (MRI, amyloid PET, FDG-PET) at the same study visit, and a repeat visit (15 or 30 months later) with both plasma NfL and neuroimaging. Plasma NfL was measured on the Simoa-HD1 Platform and CSF NfL with an in-house ELISA. Linear mixed effects models were used to examine the associations between baseline plasma or CSF NfL and cognitive and neuroimaging outcomes adjusting for age, sex, and education. The relationship between change in plasma NfL and change in the outcomes was assessed using linear regression. RESULTS: There were no cross-sectional associations between CSF or plasma NfL and any neuroimaging or cognitive measure. Longitudinally, higher baseline plasma NfL was associated with worsening in all neuroimaging measures, except amyloid PET, and global cognition. Higher baseline CSF NfL was associated with worsening in cortical thickness and diffusion MRI. The beta estimates for CSF NfL were similar to those for plasma NfL. Change in plasma NfL was associated with change in global cognition, attention, and amyloid PET. CONCLUSION: Elevated baseline plasma NfL is a prognostic marker of cognitive decline and neuroimaging measures of neurodegeneration, and has similar effect sizes to baseline CSF NfL. Change in plasma NfL also tracked with short-term cognitive change.


Assuntos
Encéfalo/diagnóstico por imagem , Cognição , Disfunção Cognitiva/metabolismo , Proteínas de Neurofilamentos/metabolismo , Idoso , Compostos de Anilina , Atenção , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Feminino , Fluordesoxiglucose F18 , Humanos , Modelos Lineares , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tiazóis
16.
Stroke ; 50(7): 1669-1675, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31138085

RESUMO

Background and Purpose- Effective stroke prevention depends on accurate stroke risk prediction. We determined the discriminative ability of NfL (neurofilament light chain) levels for distinguishing between adults with diabetes mellitus who develop incident stroke and those who remain stroke free during a 7-year follow-up period. Methods- We performed a case-control study of participants selected from the previously completed ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Cases were all ACCORD subjects who were stroke free at enrollment and developed incident stroke during follow-up (n=113). Control subjects (n=250) were randomly selected ACCORD subjects who had no stroke events either before or after randomization. NfL was measured in baseline samples using Single Molecule Array technology (Quanterix). Results- Baseline NfL levels were higher in stroke subjects, compared to controls, after adjusting for age, race, blood pressure, weight, and the Framingham Stroke Risk Score. Relative to the subjects in the lowest quintile of NfL levels, the hazard ratios of incident stroke for subjects in the second to fifth quintiles were 3.91 (1.45-10.53), 4.05 (1.52-10.79), 5.63 (2.16-14.66), and 9.75 (3.84-27.71), respectively, after adjusting for race and Framingham Stroke Risk Score. Incorporating NfL levels into a predictive score that already included race and Framingham Stroke Risk Score increased the score's C statistic from 0.71 (95% CI, 0.66-0.77) to 0.78 (95% CI, 0.73-0.83), P<0.001. Older age, nonwhite race, higher systolic blood pressure, glomerular filtration rate <60, and higher hemoglobin A1C were independent predictors of serum NfL in this cohort but diastolic blood pressure, durations of hypertension or diabetes mellitus, and lipid levels were not. In total, cardiovascular disease risk factors explained 19.2% of the variability in baseline NfL levels. Conclusions- Serum NfL levels predict incident stroke and add considerably to the discriminatory power of the Framingham Stroke Risk Score in a cohort of middle-aged and older adults with diabetes mellitus.


Assuntos
Complicações do Diabetes/sangue , Complicações do Diabetes/epidemiologia , Proteínas de Neurofilamentos/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Grupos Étnicos , Feminino , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Humanos , Hipertensão/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores Socioeconômicos
17.
Med Hypotheses ; 127: 159-161, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31088642

RESUMO

Treatment resistant major depression is accompanied with a sizable impact on quality of life with severe consequences for social integrity, individual health and socioeconomic state. In- and outpatient care of patients with treatment resistant major depression remains very challenging for both patients and the health system. One reason is the limited knowledge on the etiology of treatment resistance in major depression resulting difficulties developing efficient treatment strategies for this group of severe depressed patients. Therefore, new focuses on research are needed. Biomarkers reliably reflecting neuropathological processes could help to understand the actual mechanisms in treatment resistance. Neurofilament light protein might be a reliable biomarker of axonal damage in the brain. Due to accumulating evidence that major depression is associated with axonal damage, it is our hypothesis that treatment resistant major depression is correlated with persistent axonal damage within circuits processing affective responses. Axonal damage is reflected by increased levels of neurofilament light protein in plasma. To evaluate our hypothesis, neurofilament light protein will be measured in a group of patients with homogeneous symptomatology of treatment resistant major depression.


Assuntos
Axônios/patologia , Encéfalo/patologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/terapia , Proteínas de Neurofilamentos/sangue , Biomarcadores/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Filamentos Intermediários/metabolismo , Luz , Doenças do Sistema Nervoso/patologia , Qualidade de Vida , Resultado do Tratamento
18.
Res Vet Sci ; 125: 1-6, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103855

RESUMO

Neurofilaments (NFs) are structural proteins of neurons that are released in significant quantities in the cerebrospinal fluid and blood as a result of neuronal degeneration or axonal damage. Therefore, NFs have potential as biomarkers for neurologic disorders. Neural degeneration increases with age and has the potential to confound the utility of NFs as biomarkers in the diagnosis of neurologic disorders. We investigated this relationship in horses with and without neurological diagnosis. While controlling for horse type (draft, pleasure, and racing), we evaluated the relationship between serum heavy-chain phosphorylated neurofilaments (pNF-H) and age, sex, and serum vitamin E concentrations. Serum pNF-H concentrations increased by 0.002 ng/ml for each year increase in age. There were significant differences in the serum pNF-H concentration among the type of activity performed by the horse. The highest serum pNF-H concentration was found in horses performing heavy work activity (racehorse) and with lower serum pNF-H concentration found among light (pleasure riding) and moderate (draft) activity. There was no significant association between the pNF-H concentration and sex or vitamin E concentration. Serum pNF-H concentration was elevated among horses afflicted with EMND and EPM when compared with control horses without evidence of neurologic disorders. Accordingly, serum pNF-H concentration can serve as a useful biomarker to complement the existing diagnostic work-up of horses suspected of having EPM or EMND.


Assuntos
Infecções Protozoárias do Sistema Nervoso Central/veterinária , Encefalomielite/veterinária , Doenças dos Cavalos/diagnóstico , Filamentos Intermediários/fisiologia , Doença dos Neurônios Motores/veterinária , Fatores Etários , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/epidemiologia , Encefalomielite/sangue , Encefalomielite/líquido cefalorraquidiano , Encefalomielite/diagnóstico , Feminino , Doenças dos Cavalos/sangue , Doenças dos Cavalos/líquido cefalorraquidiano , Doenças dos Cavalos/epidemiologia , Cavalos , Masculino , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/epidemiologia , Análise Multivariada , Proteínas de Neurofilamentos/sangue , Condicionamento Físico Animal/classificação , Análise de Regressão , Fatores Sexuais , Vitamina E/sangue
19.
PLoS One ; 14(4): e0211575, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30951523

RESUMO

People with Down syndrome (DS) are at high risk of developing Alzheimer disease (AD) with aging. The diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. Plasma neurofilament light chain (NfL) is one of the established biomarkers of AD, suggesting that it may be useful as an indicator of dementia in DS patients. The aims of this study were: 1) to examine whether plasma levels of NfL in DS patients are correlated with decreased adaptive behavior scores one year after sample collection, and 2) to compare plasma levels of NfL in adults with DS and an age-matched healthy control population. In this study, plasma levels of NfL in 24 patients with DS and 24 control participants were measured by the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma NfL levels in the DS compared with the control group. There was a significant correlation between age and levels of plasma NfL in both groups. This age-dependent elevation was steeper in the DS compared with the control group. Moreover, elevated plasma NfL was associated with decreased adaptive behavior scores one year later, after age-adjustment. Previously reported blood-based biomarkers available in Simoa for DS, plasma total tau and phosphorylated tau, were not significantly correlated with the annual decrement of adaptive behavior scores after age-adjustment. These results suggest that plasma NfL has the potential to serve as an objective biomarker to predict dementia in adult DS patients.


Assuntos
Demência/sangue , Demência/complicações , Síndrome de Down/complicações , Proteínas de Neurofilamentos/sangue , Adolescente , Adulto , Biomarcadores/sangue , Demência/diagnóstico , Síndrome de Down/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
20.
J Neurol ; 266(7): 1643-1648, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30944980

RESUMO

Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5-90) than in controls (median 6.9 pg/ml, range 2.7-12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.


Assuntos
Encefalite/sangue , Encefalite/líquido cefalorraquidiano , Doença de Hashimoto/sangue , Doença de Hashimoto/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Encefalite/diagnóstico por imagem , Feminino , Seguimentos , Doença de Hashimoto/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
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