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1.
Nat Commun ; 12(1): 1816, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753741

RESUMO

X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability. Intriguingly, NfL was a significant predictor to discriminate non-converting AMN from cohorts later developing CALD. In CALD, markedly amplified NfL levels reflected brain lesion severity. In rare cases, atypically low NfL revealed a previously unrecognized smoldering CALD disease course with slowly progressive myelin destruction. Upon halt of brain demyelination by hematopoietic stem cell transplantation, NfL gradually normalized. Together, our study reveals that blood NfL reflects inflammatory activity and progression in CALD patients, thus constituting a potential surrogate biomarker that may facilitate clinical decisions and therapeutic development.


Assuntos
Adrenoleucodistrofia/metabolismo , Biomarcadores/metabolismo , Degeneração Neural/metabolismo , Proteínas de Neurofilamentos/metabolismo , Adolescente , Adrenoleucodistrofia/diagnóstico , Adulto , Biomarcadores/sangue , Criança , Estudos de Coortes , Progressão da Doença , Humanos , Filamentos Intermediários/metabolismo , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico , Proteínas de Neurofilamentos/sangue
2.
JAMA Netw Open ; 4(2): e2037731, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33616662

RESUMO

Importance: Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective: To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants: This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main Outcomes and Measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results: Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and Relevance: This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions.


Assuntos
Concussão Encefálica/sangue , Proteína Glial Fibrilar Ácida/sangue , Militares , Proteínas de Neurofilamentos/sangue , Ubiquitina Tiolesterase/sangue , Proteínas tau/sangue , Adolescente , Traumatismos em Atletas/sangue , Traumatismos em Atletas/fisiopatologia , Concussão Encefálica/fisiopatologia , Estudos de Casos e Controles , Cognição , Feminino , Humanos , Masculino , Traumatismos Ocupacionais/sangue , Traumatismos Ocupacionais/fisiopatologia , Estudos Prospectivos , Estados Unidos , Universidades , Adulto Jovem
3.
J Clin Neurosci ; 83: 108-111, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33317883

RESUMO

BACKGROUND: Serum neurofilament light chain (sNfL) is a promising biomarker for neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS), but there is limited validation data in specific ethnic and disease groups. OBJECTIVE: To investigate the levels of sNfL in a cohort of Chinese patients with NMOSD and compare sNfL levels in patients with different disease courses and treatments. METHODS: We analysed sNfL levels in 153 Chinese patients with NMOSD (n = 51) and MS (n = 102) using single-molecule array (Simoa) technology. The sNfL levels were compared with those of 71 healthy controls from two centres in southern China. For each disease, we assessed correlations between sNfL and disease phases and treatments. RESULTS: Higher levels of sNfL were found in the patients with NMOSD [17.97 (10.55-27.94) pg/mL] and MS [15.83 (8.92-25.67) pg/mL] compared to healthy controls [10.09 (7.19-13.29) pg/mL, p < 0.001]. No significant differences were found between the AQP4-IgG-positive NMOSD group and OCB-positive MS group. CONCLUSIONS: sNfL measured by Simoa technology is a potential candidate blood biomarker for the diagnosis and disease monitoring of NMOSD in Chinese patients, warranting further prospective and multicentre studies.


Assuntos
Biomarcadores/sangue , Proteínas de Neurofilamentos/sangue , Neuromielite Óptica/sangue , Adulto , Aquaporina 4/imunologia , Grupo com Ancestrais do Continente Asiático , China , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Neuromielite Óptica/imunologia , Bandas Oligoclonais/imunologia
4.
Neurosci Lett ; 744: 135593, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33359734

RESUMO

Plasma neurofilament light chain (pNfL) concentration is a biomarker for neuroaxonal injury and degeneration and can be used to monitor response to treatment. Spontaneous canine neurodegenerative diseases are a valuable comparative resource for understanding similar human conditions and as large animal treatment models. The features of pNfL concentration in healthy dogs is not well established. We present data reporting basic pNfL concentration trends in the Labrador Retriever breed. Fifty-five Labrador Retrievers were enrolled. pNfL concentration was measured and correlated to age, sex, neuter status, height, weight, body mass index, and coat color. We found increased pNfL with age (P < 0.0001), shorter stature (P = 0.009) and decreased body weight (P < 0.001). These are similar to findings reported in humans. pNfL concentration did not correlate with sex, BMI or coat color. This data further supports findings that pNfL increase with age in a canine population but highlights a need to consider weight and height when determining normal pNfL concentration in canine populations.


Assuntos
Envelhecimento/sangue , Envelhecimento/fisiologia , Peso Corporal/fisiologia , Proteínas de Neurofilamentos/sangue , Animais , Biomarcadores/sangue , Cães , Feminino , Humanos , Masculino , Plasma
5.
Ann Neurol ; 89(3): 610-616, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33377539

RESUMO

There is emerging evidence for multifarious neurological manifestations of coronavirus disease 2019 (COVID-19), but little is known regarding whether they reflect structural damage to the nervous system. Serum neurofilament light chain (sNfL) is a specific biomarker of neuronal injury. We measured sNfL concentrations of 29 critically ill COVID-19 patients, 10 critically ill non-COVID-19 patients, and 259 healthy controls. After adjusting for neurological comorbidities and age, sNfL concentrations were higher in patients with COVID-19 versus both comparator groups. Higher sNfL levels were associated with unfavorable short-term outcome, indicating that neuronal injury is common and pronounced in critically ill patients. ANN NEUROL 2021;89:610-616.


Assuntos
/sangue , Proteínas de Neurofilamentos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , /terapia , Estudos de Casos e Controles , Estado Terminal , Feminino , Escala de Resultado de Glasgow , Mortalidade Hospitalar , Humanos , Hiponatremia/sangue , Hiponatremia/terapia , Unidades de Terapia Intensiva , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Edema Pulmonar/sangue , Edema Pulmonar/terapia , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/sangue , Insuficiência Respiratória/terapia , Infecções Respiratórias/sangue , Infecções Respiratórias/terapia , Choque Cardiogênico/sangue , Choque Cardiogênico/terapia
6.
Medicine (Baltimore) ; 99(40): e21871, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019386

RESUMO

BACKGROUND: Neurofilament light chain (NfL), an index of neuroaxonal injury, is a promising diagnostic and prognostic fluid biomarker with high translational value in many neurodegenerative disorders. Blood NfL measurement has been an exciting and active field of research in idiopathic Parkinson disease (PD) and atypical parkinsonisms. However, blood NfL levels in these parkinsonisms from existing literature were inconsistent. No comprehensive meta-analysis has ever been conducted. METHODS: Three major biomedical electronic databases PubMed, Embase, and Web of Science were comprehensively searched from inception to July 10, 2020. This protocol will be prepared based on the guidelines recommended by the statement of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Original observational studies that measured blood (serum/plasma) NfL concentrations in patients with parkinsonisms (multiple system atrophy [MSA], progressive supranuclear palsy [PSP], corticobasal syndrome [CBS], and dementia with Lewy bodies [DLB]), and healthy controls (HCs) will be included. Quality assessment of the included studies will be performed using the Newcastle Ottawa Scale (NOS). Meta-analyses will be conducted using the STATA software version 13.0. The standardized mean differences as the measure of effect size and 95% confidence intervals were calculated for each comparison of blood NfL levels. Heterogeneity analysis, sensitivity analysis, publication bias, subgroup analysis, and meta-regression analysis will be carried out to test the robustness of the results. RESULTS: The meta-analysis will obtain the effect sizes of blood NfL levels in the following comparisons: PD versus HC, MSA versus HC, PSP versus HC, CBS versus HC, DLB versus HC, MSA versus PD, PSP versus PD, CBS versus PD, and DLB versus PD. CONCLUSIONS: The present meta-analysis will provide the quantitative evidence of NfL levels in idiopathic PD and atypical parkinsonisms, hoping to facilitate differential diagnoses in clinical practice. REGISTRATION NUMBER: INPLASY202070091.


Assuntos
Proteínas de Neurofilamentos/sangue , Doença de Parkinson/sangue , Biomarcadores/sangue , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
7.
PLoS One ; 15(10): e0236384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33108404

RESUMO

Neurofilaments are structural components of neurons and are particularly abundant in highly myelinated axons. The levels of neurofilament light chain (NfL) in both cerebrospinal fluid (CSF) and plasma have been related to degeneration in several neurodegenerative conditions including frontotemporal dementia (FTD) and NfL is currently considered as the most promising diagnostic and prognostic fluid biomarker in FTD. Although the location and function of filaments in the healthy nervous system suggests a link between increased NfL and white matter degeneration, such a claim has not been fully elucidated in vivo, especially in the context of FTD. The present study provides evidence of an association between the plasma levels of NfL and white matter involvement in behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The results of both voxel-wise and tract specific analysis showed that increased plasma NfL concentration is associated with a reduction in fractional anisotropy (FA) in a widespread set of white matter tracts including the superior longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic radiation and the dorsal cingulum bundle. Plasma NfL concentration also correlated with cortical thinning in a portion of the right medial prefrontal cortex and of the right lateral orbitofrontal cortex. These results support the hypothesis that blood NfL levels reflect the global level of neurodegeneration in bvFTD and help to advance our understanding of the association between this blood biomarker for FTD and the disease process.


Assuntos
Benchmarking , Biomarcadores/sangue , Imagem de Tensor de Difusão/métodos , Demência Frontotemporal/patologia , Proteínas de Neurofilamentos/sangue , Idoso , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico por imagem , Humanos , Estudos Longitudinais , Masculino
8.
Medicine (Baltimore) ; 99(31): e21458, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756166

RESUMO

BACKGROUND: Parkinson disease (PD) is a common neurodegenerative disorder. Elevations of neurofilament light chain (NfL) concentrations in the cerebrospinal fluid (CSF) and blood are a marker of neuronal/axonal injury and degeneration. However, CSF and blood NfL alterations in patients with PD from existing studies remain inconclusive. To better understand these conflicting data, we will conduct a meta-analysis. METHODS: We will comprehensively search PubMed, Embase, and Web of Science databases from each database's inception to 7th June, 2020. This protocol will conform to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols. We will only include original studies published in English that evaluated differences of NfL concentrations in the CSF or blood between idiopathic PD patients and healthy controls. The Newcastle-Ottawa Scale will be used to evaluate the quality of the included studies. Meta-analyses will be carried out using the STATA software version 13.0. Between-group difference of NfL concentrations in the CSF and blood will be expressed as the weighted standardized mean difference. A random-effects model will be used. Supplementary analyses, such as heterogeneity analysis, sensitivity analysis, publication bias, subgroup analysis, and meta-regression analysis will be performed. RESULTS: The meta-analysis will provide the differences of NfL concentrations in the CSF and blood between patients with PD and healthy controls and will show the magnitudes of their effect sizes. CONCLUSIONS: This meta-analysis will provide the evidence of NfL concentrations in the CSF and blood in PD and we hope that our study has an important impact on clinical practice. REGISTRATION NUMBER: INPLASY202060025.


Assuntos
Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Doença de Parkinson/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Masculino , Doença de Parkinson/diagnóstico , Análise de Regressão , Sensibilidade e Especificidade
9.
Neurology ; 95(6): e623-e636, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32641529

RESUMO

OBJECTIVE: To determine whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI. METHODS: Patients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days, and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. RESULTS: At enrollment, patients with TBI had increased serum NfL compared to controls (p < 0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls (p < 0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI. CONCLUSIONS: Serum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.


Assuntos
Lesões Encefálicas Traumáticas/sangue , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Ubiquitina Tiolesterase/sangue , Proteínas tau/sangue , Adulto , Área Sob a Curva , Atrofia , Biomarcadores/sangue , Encéfalo/patologia , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/epidemiologia , Doença Crônica , Lesão Axonal Difusa/sangue , Lesão Axonal Difusa/líquido cefalorraquidiano , Lesão Axonal Difusa/diagnóstico por imagem , Lesão Axonal Difusa/epidemiologia , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Estudos Prospectivos , Curva ROC , Recuperação de Função Fisiológica , Estados Unidos/epidemiologia
10.
Neurology ; 95(6): e610-e622, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32641538

RESUMO

OBJECTIVE: To determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI). METHODS: Participants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. RESULTS: In athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve [AUROC] 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = -0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI. CONCLUSIONS: Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.


Assuntos
Lesões Encefálicas Traumáticas/sangue , Hóquei/lesões , Proteínas de Neurofilamentos/sangue , Doença Aguda , Adulto , Área Sob a Curva , Atrofia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Concussão Encefálica/sangue , Concussão Encefálica/líquido cefalorraquidiano , Concussão Encefálica/patologia , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/epidemiologia , Doença Crônica , Lesão Axonal Difusa/sangue , Lesão Axonal Difusa/líquido cefalorraquidiano , Lesão Axonal Difusa/diagnóstico por imagem , Lesão Axonal Difusa/epidemiologia , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tamanho do Órgão , Estudos Prospectivos , Curva ROC , Recuperação de Função Fisiológica , Suécia/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
12.
Neurology ; 95(10): 436-444, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32675076

RESUMO

There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.


Assuntos
Biomarcadores/sangue , Esclerose Múltipla Crônica Progressiva/sangue , Proteínas de Neurofilamentos/sangue , Humanos
13.
Br J Anaesth ; 125(3): 282-290, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32536445

RESUMO

BACKGROUND: Postoperative neurocognitive disorders may arise in part from adverse effects of general anaesthetics on the CNS, especially in older patients or individuals otherwise vulnerable to neurotoxicity because of systemic disease or the presence of pre-existing neuropathology. Previous studies have documented cytokine and injury biomarker responses to surgical procedures that included general anaesthesia, but it is not clear to what degree anaesthetics contribute to these responses. METHODS: We performed a prospective cohort study of 59 healthy volunteers aged 40-80 yr who did not undergo surgery. Plasma markers of neurological injury and inflammation were measured immediately before and 5 h after induction of general anaesthesia with 1 minimum alveolar concentration of sevoflurane. Biomarkers included interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP), and neural injury (tau, neurofilament light [NF-L], and glial fibrillary acidic protein [GFAP]). RESULTS: Baseline biomarkers were in the normal range, although NF-L and GFAP were elevated as a function of age. At 5 h after induction of anaesthesia, plasma tau, NF-L, and GFAP were significantly decreased relative to baseline. Plasma IL-6 was significantly increased after anaesthesia, but by a biologically insignificant degree (<1 pg ml-1); plasma TNF-α and CRP were unchanged. CONCLUSIONS: Sevoflurane general anaesthesia without surgery, even in older adults, did not provoke an inflammatory state or neuronal injury at a concentration that is detectable by an acute elevation of measured plasma biomarkers in the early hours after exposure. CLINICAL TRIAL REGISTRATION: NCT02275026.


Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/efeitos dos fármacos , Estudos de Coortes , Feminino , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/efeitos dos fármacos , Estudos Prospectivos , Valores de Referência , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/efeitos dos fármacos
14.
Neurology ; 95(12): e1754-e1759, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32546655

RESUMO

OBJECTIVE: To test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury. METHODS: We 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. RESULTS: The 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. CONCLUSION: We 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.


Assuntos
Astrócitos/metabolismo , Infecções por Coronavirus/sangue , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Neurônios/metabolismo , Pneumonia Viral/sangue , Adulto , Fatores Etários , Idoso , Betacoronavirus , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Índice de Gravidade de Doença , Imagem Individual de Molécula
15.
Neurology ; 95(9): e1126-e1133, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32571850

RESUMO

OBJECTIVE: To determine whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment (CogI). METHODS: We enrolled 155 veterans from 2 veterans' retirement homes: 90 without TBI and 65 with TBI history. Participants were further separated into CogI groups: controls (no TBI, no CogI), n = 60; no TBI with CogI, n = 30; TBI without CogI, n = 30; and TBI with CogI, n = 35. TBI was determined by the Ohio State University TBI Identification Method. CogI was defined as impaired cognitive testing, dementia diagnosis, or use of dementia medication. Blood specimens were enriched for CNS-derived exosomes. Proteins (neurofilament light [NfL], total tau, glial fibrillary acidic protein [GFAP], α-synuclein, ß-amyloid 42 [Aß42], and phosphorylated tau [p-tau]) and cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-10) were measured using ultrasensitive immunoassays. RESULTS: Veterans were, on average, 79 years old. In participants with TBI history, 65% had mild TBI; average time from most recent TBI was 37 years. In adjusted analyses, the TBI and CogI groups differed on CNS-enriched exosome concentration of p-tau, NfL, IL-6, TNF-α (all p < 0.05), and GFAP (p = 0.06), but not on Aß42 or other markers. Adjusted area under the curve (AUC) analyses found that all significantly associated biomarkers combined separated TBI with/without CogI (AUC, 0.85; 95% confidence interval [CI], 0.74-0.95) and CogI with/without TBI (AUC, 0.88; 95% CI, 0.77-0.99). CONCLUSIONS: Increased levels of blood-based, CNS-enriched exosomal biomarkers associated with TBI and CogI can be detected even decades after TBI. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in veterans with a history of TBI, CNS-enriched exosome concentration of p-tau, NfL, IL-6, and TNF-α are associated with CogI.


Assuntos
Lesões Encefálicas Traumáticas/sangue , Disfunção Cognitiva/sangue , Interleucina-6/sangue , Proteínas de Neurofilamentos/sangue , Fator de Necrose Tumoral alfa/sangue , Veteranos , Proteínas tau/sangue , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Exossomos/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/sangue , Humanos , Interleucina-10/sangue , Masculino , Testes de Estado Mental e Demência , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Testes Neuropsicológicos , Fragmentos de Peptídeos/sangue , Fosforilação , alfa-Sinucleína/sangue
16.
Neuron ; 106(6): 881-883, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32553204
17.
PLoS One ; 15(6): e0234519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530970

RESUMO

Axonal damage leads to the release of neurofilament light chain (NFL), which enters the CSF or blood. In this work, an assay kit for plasma NFL utilizing immunomagnetic reduction (IMR) was developed. Antibodies against NFL were immobilized on magnetic nanoparticles to develop an IMR NFL kit. The preclinical properties, such as the standard curve, limit of detection (LoD), and dynamic range, were characterized. Thirty-one normal controls (NC), fifty-two patients with Parkinson's disease (PD) or PD dementia (PDD) and thirty-one patients with Alzheimer's disease (AD) were enrolled in the study evaluating the plasma NFL assay using an IMR kit. T-tests and receiver operating characteristic (ROC) curve analysis were performed to investigate the capability for discrimination among the clinical groups according to plasma NFL levels. The LoD of the NFL assay using the IMR kit was found to be 0.18 fg/ml. The dynamic range of the NFL assay reached 1000 pg/ml. The NC group showed a plasma NFL level of 7.70 ± 4.00 pg/ml, which is significantly lower than that of the PD/PDD (15.85 ± 7.82 pg/ml, p < 0.001) and AD (19.24 ± 8.99 pg/ml, p < 0.001) groups. A significant difference in plasma NFL levels was determined between the PD and AD groups (p < 0.01). Through ROC curve analysis, the cut-off value of the plasma NFL concentration for differentiating NCs from dementia patients (AD and PD/PDD) was found to be 12.71 pg/ml, with a clinical sensitivity and specificity of 73.5% and 90.3%, respectively. The AUC was 0.868. Furthermore, the cut-off value of the plasma NFL concentration for discriminating AD from PD/PDD was found to be 18.02 pg/ml, with a clinical sensitivity and specificity of 61.3% and 65.4%, respectively. The AUC was 0.630. An ultrasensitive assay for measuring plasma NFL utilizing IMR technology was developed. Clear differences in plasma NFL concentrations were observed among NCs and PD and AD patients. These results imply that the determination of plasma NFL is promising not only for screening dementia but also for differential diagnosis.


Assuntos
Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Axônios/metabolismo , Axônios/patologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Feminino , Humanos , Separação Imunomagnética , Filamentos Intermediários/genética , Filamentos Intermediários/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/genética , Doença de Parkinson/patologia
18.
J Clin Neurosci ; 78: 307-312, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32376155

RESUMO

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease. Neurofilament light chain (NFL) is a novel adverting biomarker of axonal damage that suggested as a useful assistant in the monitoring of MS patients. It has been shown that the auto/mitophagy associated with MS pathogenesis. In this study, we aimed to study correlation between ATG5 and Parkin, as markers of autophagy and mitophagy respectively, with NFL and ANT1 in serum and cerebrospinal fluid (CSF) in MS subjects. ATG5, Parkin, NFL, and ANT1 levels were measured in a cross-sectional study of 40 MS patients compared with gender, age and BMI matching healthy volunteers. Based on our results, levels of ATG5, Parkin, and NFL significantly were elevated in both serum and CSF of MS patients comparing control individuals (p < 0.0001) but ANT1 levels significantly was decreased in both serum and CSF of MS patients comparing control individuals (p < 0.0001). The correlation indices between NFL, ANTI1, ATG5 and Parkin in both case and control groups showed a direct and moderate the correlation between ANTI1 and ATG5 in the CSF level of the control group (r = 0.554, P = 0.011). Our data support the feasibility of quantifying of NFL as a sensitive and clinically meaningful serum/CSF biomarker to follow-up nerve tissue injury in MS condition.


Assuntos
Autofagia , Mitofagia , Esclerose Múltipla/patologia , Translocador 1 do Nucleotídeo Adenina/sangue , Translocador 1 do Nucleotídeo Adenina/líquido cefalorraquidiano , Adulto , Proteína 5 Relacionada à Autofagia/sangue , Proteína 5 Relacionada à Autofagia/líquido cefalorraquidiano , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Ubiquitina-Proteína Ligases/sangue , Ubiquitina-Proteína Ligases/líquido cefalorraquidiano
19.
Neurology ; 94(23): e2457-e2467, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434867

RESUMO

OBJECTIVE: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening. METHODS: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS). RESULTS: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant. CONCLUSIONS: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.


Assuntos
Esclerose Múltipla/sangue , Proteínas de Neurofilamentos/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Biomarcadores , Estudos de Casos e Controles , Avaliação da Deficiência , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Suécia/epidemiologia , Adulto Jovem
20.
Neurology ; 94(23): e2412-e2423, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461282

RESUMO

OBJECTIVE: To measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms. METHODS: Exosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1-2 mTBIs, and repetitive (3 or more) mTBIs. RESULTS: Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF. CONCLUSION: Repetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.


Assuntos
Concussão Encefálica/sangue , Exossomos/química , Proteínas de Neurofilamentos/sangue , Saúde dos Veteranos , Veteranos , Adulto , Biomarcadores , Traumatismos por Explosões/sangue , Traumatismos por Explosões/complicações , Concussão Encefálica/complicações , Estudos Transversais , Depressão/sangue , Depressão/etiologia , Feminino , Seguimentos , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Síndrome Pós-Concussão/sangue , Síndrome Pós-Concussão/etiologia , Prognóstico , Degeneração Retrógrada , Índice de Gravidade de Doença , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/etiologia , Fator de Necrose Tumoral alfa/análise , Fator A de Crescimento do Endotélio Vascular/sangue , Guerra
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