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1.
Pediatr Infect Dis J ; 39(3): 239-243, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32032308

RESUMEN

BACKGROUND: Borrelia burgdorferi and tick-borne encephalitis (TBE) virus are 2 types of tick-borne pathogens that can cause central nervous system infection. Routine diagnostics have so far included analysis of cerebrospinal fluid (CSF) cell numbers, CSF serology for Borrelia burgdorferi and serum serology for TBE virus. However, early diagnosis may be difficult based on antibody detection which takes time to analyze, and with the possibility of false negative results, thus delaying treatment. Cytokine analyses are becoming increasingly available in clinical routine care and may offer important information. METHODS: Fifteen cytokines and chemokines were measured in the CSF from the diagnostic lumbar puncture of 37 children with TBE, 34 children with neuroborreliosis and 19 children without evidence of central nervous system infection, using Luminex technology. RESULTS: Significantly higher levels of proinflammatory interleukin-6 were detected in the samples from TBE-infected children, when compared with neuroborreliosis or controls. In comparison, children with neuroborreliosis had significantly higher levels of interleukin-7, interleukin-8, interleukin-10, and interleukin-13 when compared with TBE infected or controls. Furthermore, the ratio between interleukin-6 and interleukin-10 was significantly different between the 2 types of tick-borne infections. CONCLUSIONS: The interleukin-6/interleukin-10 ratio can be used as a rapid diagnostic cue upon suspected tick-borne infection, enabling fast and correct treatment. Also, in serology-negative results, such information may strengthen a clinical suspicion.


Asunto(s)
Virus de la Encefalitis Transmitidos por Garrapatas , Encefalitis Transmitida por Garrapatas/líquido cefalorraquídeo , Encefalitis Transmitida por Garrapatas/diagnóstico , Interleucina-10/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Biomarcadores , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Encefalitis Transmitida por Garrapatas/virología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico
2.
Brain Dev ; 42(2): 185-191, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31787380

RESUMEN

BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.


Asunto(s)
Encefalopatías/inmunología , Encefalopatías/patología , Citocinas/análisis , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Quimiocinas/análisis , Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Preescolar , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Encefalitis/líquido cefalorraquídeo , Femenino , Humanos , Lactante , Oxidorreductasas Intramoleculares/sangre , Oxidorreductasas Intramoleculares/líquido cefalorraquídeo , Factor Inhibidor de Leucemia/sangre , Factor Inhibidor de Leucemia/líquido cefalorraquídeo , Factores Inhibidores de la Migración de Macrófagos/sangre , Factores Inhibidores de la Migración de Macrófagos/líquido cefalorraquídeo , Masculino , Osteopontina/sangre , Osteopontina/líquido cefalorraquídeo , Convulsiones/etiología , Convulsiones Febriles/complicaciones , Convulsiones Febriles/inmunología , Convulsiones Febriles/patología
3.
PLoS One ; 14(7): e0219987, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31356620

RESUMEN

BACKGROUND: The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses. METHODS: C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis. RESULTS: Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed. CONCLUSIONS: The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.


Asunto(s)
Biomarcadores/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/diagnóstico , Quimiocinas/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Adolescente , Biomarcadores/sangre , Recuento de Células Sanguíneas , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/inmunología , Quimiocina CCL2/sangre , Quimiocina CCL2/líquido cefalorraquídeo , Quimiocina CXCL10/sangre , Quimiocina CXCL10/líquido cefalorraquídeo , Quimiocina CXCL13/sangre , Quimiocina CXCL13/líquido cefalorraquídeo , Quimiocinas/sangre , Niño , Preescolar , Femenino , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Interleucina-8/líquido cefalorraquídeo , Masculino , Curva ROC
4.
Infect Immun ; 87(9)2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31262978

RESUMEN

Staphylococcus epidermidis cerebrospinal fluid (CSF) shunt infection is a common complication of hydrocephalus treatment, creating grave neurological consequences for patients, especially when diagnosis is delayed. The current method of diagnosis relies on microbiological culture; however, awaiting culture results may cause treatment delays, or culture may fail to identify infection altogether, so newer methods are needed. To investigate potential CSF biomarkers of S. epidermidis shunt infection, we developed a rat model allowing for serial CSF sampling. We found elevated levels of interleukin-10 (IL-10), IL-1ß, chemokine ligand 2 (CCL2), and CCL3 in the CSF of animals implanted with S. epidermidis-infected catheters compared to sterile controls at day 1 postinfection. Along with increased chemokine and cytokine expression early in infection, neutrophil influx was significantly increased in the CSF of animals with infected catheters, suggesting that coupling leukocyte counts with inflammatory mediators may differentiate infection from sterile inflammation. Mass spectrometry analysis revealed that the CSF proteome in sterile animals was similar to that in infected animals at day 1; however, by day 5 postinfection, there was an increase in the number of differently expressed proteins in the CSF of infected compared to sterile groups. The expansion of the proteome at day 5 postinfection was interesting, as bacterial burdens began to decline by this point, yet the CSF proteome data indicated that the host response remained active, especially with regard to the complement cascade. Collectively, these results provide potential biomarkers to distinguish S. epidermidis infection from sterile postoperative inflammation.


Asunto(s)
Infecciones Relacionadas con Catéteres/líquido cefalorraquídeo , Infecciones Estafilocócicas/líquido cefalorraquídeo , Staphylococcus epidermidis/aislamiento & purificación , Animales , Biomarcadores/líquido cefalorraquídeo , Infecciones Relacionadas con Catéteres/microbiología , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Modelos Animales de Enfermedad , Inflamación/líquido cefalorraquídeo , Neutrófilos/citología , Ratas , Infecciones Estafilocócicas/microbiología
5.
Am J Trop Med Hyg ; 101(2): 343-349, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31264559

RESUMEN

In this study, we investigated the diagnostic utility of the cytokine profile of the cerebrospinal fluid (CSF) and enzyme-linked immunospot (ELISPOT) assays of patients with suspected tuberculous meningitis (TBM). We prospectively enrolled adult patients with suspected TBM, and CSF specimens were analyzed for 18 cytokines/chemokines and soluble programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1). Enzyme-linked immunospot assays were performed on mononuclear cells from the CSF (CSF-MCs) and peripheral blood (PBMCs). A total of 87 patients with meningitis, including 42 TBM-suspected patients and 45 non-TBM patients, were enrolled. Excluding the 32 patients with possible TBM, 10 patients with TBM and 45 patients with non-TBM were finally analyzed. Levels of adenosine deaminase (ADA), interleukin 12 subunit ß (IL-12p40), IL-13, macrophage inflammatory protein α (MIP-1α), and soluble PD-1 and PD-L1 in the CSF were significantly higher in the TBM group than in the non-TBM group (P < 0.05). The optimal cutoff values for the sensitivities and specificities of the test methods for diagnosing TBM with small samples of 10 cases of definite or probable TBM were as follows: ADA > 6.95 U/L, 70% and 81%; IL-12p40 > 52.04 pg/mL, 80% and 73%; IL-13 > 0.44 pg/mL, 90% and 47%; MIP-1α > 8.83 pg/mL, 80% and 62%; soluble PD-1 > 35.87 pg/mL, 80% and 63%; soluble PD-L1 > 24.19 pg/mL, 80% and 61%; CSF-MC ELISPOT > 13.5 spots/250,000 CSF-MC, 30% and 91%; and PBMC ELISPOT > 14 spots/250,000 PBMCs, 50% and 78%, respectively. Therefore, CSF IL-12p40, IL-13, MIP-1α, and soluble PD-1 and PD-L1 concentrations appear to be useful adjuncts for diagnosing TBM.


Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Tuberculosis Meníngea/diagnóstico , Anciano , Ensayo de Immunospot Ligado a Enzimas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Sensibilidad y Especificidad , Tuberculosis Meníngea/líquido cefalorraquídeo
6.
Epilepsia ; 60(8): 1678-1688, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31283843

RESUMEN

OBJECTIVE: To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures. METHODS: We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection-related epilepsy syndrome (FIRES)/FIRES-related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD. RESULTS: The median age of onset of seizures was 2.4 years (range = 0.08-12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1-2 days of onset of seizures (P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1-associated cytokines/chemokines (TNF-α, CXCL9, CXCL10, CXCL11), IL-6, CCL2, CCL19, and CXCL1 (P < .05) were elevated in FIRES, in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The cytokines/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF testing in relation to seizures. Chronic epilepsy generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures. The median concentrations of the cytokines/chemokines rapidly declined on serial testing during the course of illness in all three FIRES/FRD cases. SIGNIFICANCE: We identify significant differences in CSF cytokine/chemokine profile between FIRES/FRD and encephalitis. The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent FSE highlights that the cytokine/chemokine elevation is significantly associated with the etiology of the underlying process rather than purely reactive. However, it is unclear whether the immune activation contributes to the disease process.


Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Epilepsia/líquido cefalorraquídeo , Fiebre/complicaciones , Estado Epiléptico/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Niño , Preescolar , Epilepsia/etiología , Femenino , Fiebre/líquido cefalorraquídeo , Humanos , Lactante , Inflamación/líquido cefalorraquídeo , Inflamación/complicaciones , Masculino , Convulsiones/líquido cefalorraquídeo , Convulsiones/etiología , Estado Epiléptico/etiología
7.
Biol Res Nurs ; 21(4): 366-376, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31142128

RESUMEN

Preterm infants are at risk of brain injury and poor neurodevelopmental outcomes including impairments in cognition, behavioral functioning, sensory perception, and motor performance. Systemic inflammation has been identified as an important, potentially modifiable precursor of neurologic and neurodevelopmental impairments. Inflammation is typically measured by quantifying circulating cytokines and chemokines. However, it is unclear which specific cytokines/chemokines most consistently predict neurodevelopment in preterm infants. In this integrative review, we evaluated and analyzed the literature (N = 37 publications) to determine the cytokines/chemokines most predictive of neurodevelopment in preterm infants, the optimal timing for these measurements, and the ideal source for collecting cytokines/chemokines. Synthesis of the findings of these studies revealed that interleukin (IL)-6, IL-1ß, IL-8, and tumor necrosis factor (TNF)-α collected during the first 3 weeks of life are most predictive of subsequent neurodevelopment. Methodological variation among studies hinders more specific analysis, including the evaluation of cytokine thresholds and meta-analyses, that would allow for the use of cytokines/chemokines to predict neurodevelopment. Future research should focus on identifying explicit cytokine values, specifically for IL-6, IL-1ß, IL-8, and TNF-α, that are most predictive for identifying preterm infants most at risk of impairment, keeping in mind that longitudinal measures of cytokines/chemokines may be more predictive of future outcomes than single-time point measures.


Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Recien Nacido Prematuro/líquido cefalorraquídeo , Inflamación/inmunología , Humanos , Lactante , Recién Nacido , Mediadores de Inflamación/líquido cefalorraquídeo
8.
J Neuroimmunol ; 330: 38-43, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30784775

RESUMEN

Hypertrophic pachymeningitis (HP) is a rare neurologic disease causing inflammatory fibrous thickening of the brain and spinal dura mater. We investigated the cerebrospinal fluid cytokine profile of HP by measuring 28 cytokines/chemokines/growth factors with a multiplexed fluorescent immunoassay in 8 patients with HP (6 idiopathic, 1 IgG4-related, 1 anti-neutrophil cytoplasmic antibody-related), and 11 with other non-inflammatory neurologic diseases (OND). Interleukin (IL)-4, IL-5, IL-9, IL-10, TNF-α, and CXCL8/IL-8 levels were significantly higher in idiopathic HP (IHP) than OND. Cluster analyses disclosed two major clusters: one mainly consisted of IHP and the other of OND, suggesting a unique cytokine profile in IHP.


Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Péptidos y Proteínas de Señalización Intercelular/líquido cefalorraquídeo , Meningitis/líquido cefalorraquídeo , Meningitis/diagnóstico , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Quimiocinas/sangre , Citocinas/sangre , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Meningitis/sangre , Persona de Mediana Edad , Células Th2/metabolismo
9.
J Neuroinflammation ; 16(1): 42, 2019 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-30777092

RESUMEN

BACKGROUND: Varicella-zoster virus (VZV) is a common viral agent causing central nervous system (CNS) infections including encephalitis, meningitis, and Ramsay Hunt syndrome. Neurological complications occur frequently despite antiviral treatment. Matrix metalloproteinases (MMPs) and cytokines are involved in the neuroinflammatory response during CNS infection. Their role in VZV CNS infections and how they differ between different CNS entities caused by VZV are poorly investigated. METHODS: We analyzed the levels of 30 chemokines and 9 MMPs in cerebrospinal fluid (CSF) and serum from 66 patients with VZV CNS infections diagnosed by detection of VZV DNA in CSF and concomitant neurological symptoms and compared with a control group (n = 24). RESULTS: Levels of CCL19, CXCL8, CXCL9, and CXCL10 were significantly increased and surpassing the levels in serum when analyzing all patients with VZV CNS infections whereas CXCL11 was only increased in CSF of patients with VZV meningitis. MMP-2-levels were highly elevated in CSF of all 66 VZV patients. The patients with encephalitis had the most significantly increased levels of MMPs in CSF, and MMP-3, MMP-8, and MMP-12 were exclusively increased in this group, whereas MMP-9 in CSF was increased in the patients with VZV meningitis. CONCLUSIONS: We show that both chemokines and MMPs are elevated in the CSF of patients with VZV CNS infections. Encephalitis and meningitis patients differed with respect to other chemokines (CXCL11) and MMPs (MMP-3, MMP-8, MMP-9, and MMP-12), indicating that different location of the virus gives rise to qualitative differences in the ensuing inflammatory response. In addition, the pronounced increase of MMPs in CSF of the patients with encephalitis suggests an association to the severity of this manifestation, compared to VZV meningitis and Ramsay Hunt syndrome. The role of MMPs in association to chemokines should be further investigated to evaluate their significance in the neuropathogenesis of VZV CNS infections and as a potential target for new treatment alternatives.


Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Encefalitis por Varicela Zóster/líquido cefalorraquídeo , Herpesvirus Humano 3/patogenicidad , Metaloproteinasas de la Matriz/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Herpes Zóster Ótico/líquido cefalorraquídeo , Herpes Zóster Ótico/virología , Herpesvirus Humano 3/genética , Humanos , Masculino , Meningitis/líquido cefalorraquídeo , Meningitis/virología , Persona de Mediana Edad , Suecia , Carga Viral , Adulto Joven
10.
Int J Stroke ; 14(2): 154-158, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30209990

RESUMEN

AIM: To determine the role of inflammation in pediatric transient focal cerebral arteriopathy using cerebrospinal fluid cytokine/chemokines as biomarkers. METHODS: We measured 32 cytokine/chemokines in acute cerebrospinal fluid collected from children with stroke due to focal cerebral arteriopathy (n = 5) using multiplex immunoassay and compared with two patients with arterial ischemic stroke due to other causes (non-focal cerebral arteriopathy group, vertebral dissection, n = 1; cryptogenic, n = 1), pediatric encephalitis (n = 43), and non-inflammatory neurological disease controls (n = 20). RESULTS: Median age in the focal cerebral arteriopathy group was 9.3 years (range, 2.8-13 years). In the focal cerebral arteriopathy group (n = 5), four patients had middle cerebral ± distal carotid arteriopathy; one patient had posterior circulation arteriopathy. The median time from symptom onset to cerebrospinal fluid sampling was four days (range, 0.6-7 days). Only IL-6, IL-8, CXCL1, and CXCL10 levels were significantly higher in the acute cerebrospinal fluid of focal cerebral arteriopathy patients compared to non-inflammatory neurological disease controls and non-focal cerebral arteriopathy stroke. In contrast to focal cerebral arteriopathy, a broad array of Th1, Th2, Treg, Th17, B-cell related, and other broad spectrum cytokine/chemokines were elevated in encephalitis. CONCLUSION: The elevated cerebrospinal fluid cytokine/chemokines support innate, T cell, and granulocyte inflammatory mechanisms in children with focal cerebral arteriopathy. This warrants larger cohort studies to discriminate primary inflammatory signals of the arteriopathy from secondary inflammation due to the stroke itself.


Asunto(s)
Biomarcadores/líquido cefalorraquídeo , CADASIL/diagnóstico , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Granulocitos/inmunología , Linfocitos T/inmunología , Adolescente , Niño , Preescolar , Femenino , Humanos , Inmunidad Innata , Inflamación , Masculino , Regulación hacia Arriba
11.
J Neuroinflammation ; 15(1): 209, 2018 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-30021640

RESUMEN

BACKGROUND: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. METHODS: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI®) were recorded during 4 years of follow-up. RESULTS: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p < 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. CONCLUSIONS: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.


Asunto(s)
Encéfalo/diagnóstico por imagen , Esclerosis Múltiple , Proteínas de Neurofilamentos/sangre , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Adulto , Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Evaluación de la Discapacidad , Femenino , Estudios de Seguimiento , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico por imagen , Curva ROC , Estudios Retrospectivos , Adulto Joven
12.
J Neural Transm (Vienna) ; 125(10): 1487-1494, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30039507

RESUMEN

Delirium is a common complication seen after surgery and anesthesia, in particular in older patients. Although the etiology of postoperative delirium is only incompletely understood, various lines of evidence suggest that proinflammatory signaling from the peripheral site of inflammation to central nervous system results in a decrease of cerebral acetylcholine (ACh) levels thereby inducing neuroinflammation. To corroborate this theory, we applied an animal model for characterization of the neuroinflammatory response after partial hepatectomy (HPx). In this model, the surgery-induced decrease in cerebral ACh levels can be prevented by intraoperative application of physostigmine. Thus, ACh-associated changes in the expression and secretion of inflammation-related compounds can be assessed by comparing the results obtained after surgery, in physostigmine-treated and untreated controls. This way we were able to show that the decrease of cerebral ACh triggers increased secretion of IL-1ß, IL-6, TNFα, MIP-2 (CCL3), RANTES, MCP1, IFNgamma, and IP-10. A gene array covering the expression of 370 inflammation-related genes indicated 13 candidates that are induced upon cerebral ACh decrease after HPx. Quantification of the changes in the expression of these candidates by the comparative CT method revealed a significant increase (> 1.5-fold) in the expression of IL-1ß, IL-6, TNFα, MIP2, RANTES, MCP1, TLR2, TLR4, HMGB1, TNFSF6, TNFSF12, IL1R1 and ILR6. Thus, our results suggest that peripheral surgery induces a reduction of cerebral ACh levels which trigger a complex neuroinflammatory response. From a clinical point of view, manipulating cerebral ACh levels by procholinergic drugs such as physostigmine could become an option to therapeutically target this kind of neuroinflammation.


Asunto(s)
Acetilcolina/metabolismo , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , Encefalitis/etiología , Complicaciones Intraoperatorias/etiología , Fisostigmina/uso terapéutico , Complicaciones Posoperatorias/etiología , Acetilcolina/líquido cefalorraquídeo , Animales , Encéfalo/efectos de los fármacos , Quimiocinas/biosíntesis , Quimiocinas/líquido cefalorraquídeo , Quimiocinas/genética , Inhibidores de la Colinesterasa/farmacología , Citocinas/biosíntesis , Citocinas/líquido cefalorraquídeo , Citocinas/genética , Delirio/etiología , Encefalitis/genética , Encefalitis/prevención & control , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Hepatectomía/efectos adversos , Complicaciones Intraoperatorias/líquido cefalorraquídeo , Complicaciones Intraoperatorias/prevención & control , Masculino , Ratones , Modelos Animales , Fisostigmina/farmacología , Complicaciones Posoperatorias/líquido cefalorraquídeo , Complicaciones Posoperatorias/prevención & control , Ratas , Ratas Wistar
13.
PLoS One ; 13(5): e0196487, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29723220

RESUMEN

OBJECTIVE: To determine if cognitive dysfunction in patients with systemic lupus erythematosus (SLE) derives from an inflammatory process with continuing disease activity, and increased levels of autoantibodies and inflammatory molecules in serum and cerebrospinal fluid (CSF). METHODS: 100 randomly selected patients participating in an inception SLE cohort were studied. At entry into the cohort, a standardized medical history and extensive laboratory tests profile, including autoantibodies were completed. Follow-up occurred every 3-6 months with assessment of lupus characteristics, comorbidities, and treatment. After a mean follow-up of six-years, cross-sectional evaluation of cognitive function was done with standardized tests, and in a subset of patients an extended profile of autoantibodies, cytokines and chemokines was measured in serum and CSF. RESULTS: At enrollment into the cohort, patients were 26.4±8.2 years of age and lupus duration 5.3±3.7 months. Moderate/severe cognitive dysfunction was diagnosed in 16 patients; in comparison to patients with normal cognitive function, they had lower education 9 vs. 12 years (P = 0.006), higher body mass index 26.7 vs. 24.3 (P = 0.03), positive IgG anticardiolipin antibodies 50% vs 18% (P = 0.009), and a higher median number of concomitant NPSLE syndromes 3 vs. 1, (P = 0.04). The prevalence of cardiovascular-risk factors, other auto-antibodies, lupus activity, treatment, and incidence of critical events did not differ. In serum and CSF, the levels of autoantibodies, cytokines and chemokine were similar, only CCL2 was elevated in CSF [886.1 (374.9-1439.7) vs. 515.8 (3.2-1958.2) pg/mL, P = 0.04]. CONCLUSION: Scant evidence of inflammation in SLE patients with cognitive dysfunction was observed. Only a higher prevalence of IgG anticardiolipin antibodies in serum and increased levels of CCL2 in CSF were detected.


Asunto(s)
Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Mediadores de Inflamación/sangre , Mediadores de Inflamación/líquido cefalorraquídeo , Lupus Eritematoso Sistémico/complicaciones , Adolescente , Adulto , Anticuerpos Anticardiolipina/sangre , Quimiocina CCL2/líquido cefalorraquídeo , Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Disfunción Cognitiva/inmunología , Estudios de Cohortes , Estudios Transversales , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Femenino , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven
14.
Front Immunol ; 9: 557, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29670611

RESUMEN

The concept and recognized components of "neuroinflammation" are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron-glia interactions and other mechanisms affecting neurotransmission. They issue the "help me" cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells-often subtype specific-that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules ("neutraligands") that are not receptor antagonists, high-affinity neuroligands ("decoy molecules"), as well as neutralizing "nanobodies" (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. "Fusokines" (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.


Asunto(s)
Biomarcadores/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/terapia , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Adulto , Astrocitos/inmunología , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/inmunología , Quimiocinas/inmunología , Niño , Citocinas/inmunología , Humanos , Linfocitos/inmunología , Neuronas/inmunología
15.
Mol Neurobiol ; 55(8): 6387-6435, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29307081

RESUMEN

Autism spectrum disorders (ASD) are characterized by impairments in language and communication development, social behavior, and the occurrence of stereotypic patterns of behavior and interests. Despite substantial speculation about causes of ASD, its exact etiology remains unknown. Recent studies highlight a link between immune dysfunction and behavioral traits. Various immune anomalies, including humoral and cellular immunity along with abnormalities at the molecular level, have been reported. There is evidence of altered immune function both in cerebrospinal fluid and peripheral blood. Several studies hypothesize a role for neuroinflammation in ASD and are supported by brain tissue and cerebrospinal fluid analysis, as well as evidence of microglial activation. It has been shown that immune abnormalities occur in a substantial number of individuals with ASD. Identifying subgroups with immune system dysregulation and linking specific cellular immunophenotypes to different symptoms would be key to defining a group of patients with immune abnormalities as a major etiology underlying behavioral symptoms. These determinations would provide the opportunity to investigate causative treatments for a defined patient group that may specifically benefit from such an approach. This review summarizes recent insights into immune system dysfunction in individuals with ASD and discusses the potential implications for future therapies.


Asunto(s)
Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/terapia , Trastorno del Espectro Autista/líquido cefalorraquídeo , Quimiocinas/líquido cefalorraquídeo , Humanos , Sistema Inmunológico/patología , Péptidos y Proteínas de Señalización Intercelular/metabolismo
16.
J Clin Lab Anal ; 32(1)2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28303609

RESUMEN

BACKGROUND: In this study, the pathologies of acute meningitis and encephalopathy were investigated, and biomarkers useful as prognostic indices were searched for. METHODS: The subjects were 31 children with meningitis, 30 with encephalopathy, and 12 with convulsions following gastroenteritis. Control group consisted of 24 children with non-central nervous system infection. Cerebrospinal fluid cytokine analysis was performed. RESULTS: Chemokines significantly increased in the bacterial meningitis group compared with those in viral meningitis and encephalopathy groups. On comparison of interleukin(IL)-17, it increased in cases with status epilepticus in influenza-associated encephalopathy group. In the rotavirus encephalopathy and convulsions following gastroenteritis groups, IL-17 particularly increased in the convulsions following gastroenteritis group. IL-8 increased in all cases irrespective of the causative virus. CONCLUSIONS: In the encephalopathy group, IL-8 may serve as a neurological prognostic index. IL-17 was increased in the convulsions following gastroenteritis group, particularly in cases with status epilepticus, suggesting its involvement as a convulsion-related factor.


Asunto(s)
Biomarcadores/líquido cefalorraquídeo , Encefalopatías/líquido cefalorraquídeo , Quimiocinas/líquido cefalorraquídeo , Interleucina-17/líquido cefalorraquídeo , Meningitis/líquido cefalorraquídeo , Encefalopatías/diagnóstico , Encefalopatías/epidemiología , Estudios de Casos y Controles , Preescolar , Femenino , Humanos , Lactante , Masculino , Meningitis/diagnóstico , Meningitis/epidemiología , Pronóstico
17.
Fluids Barriers CNS ; 14(1): 35, 2017 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-29228970

RESUMEN

BACKGROUND: Neuroinflammation has been implicated in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF). METHODS: Lumbar CSF levels of key cytokines (IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-ß1, IFN-γ) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined. RESULTS: Total protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1α, IL-4, IL-6, IL-12, TNF-α, CCL-3, CCL-19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1α, IL-1ß, IL-10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1ß and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils. CONCLUSIONS: Neuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH.


Asunto(s)
Hemorragia Cerebral Intraventricular/complicaciones , Encefalitis/líquido cefalorraquídeo , Hidrocefalia/líquido cefalorraquídeo , Recien Nacido Prematuro/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Encefalitis/etiología , Femenino , Humanos , Hidrocefalia/etiología , Recién Nacido , Enfermedades del Prematuro/líquido cefalorraquídeo , Mediadores de Inflamación/líquido cefalorraquídeo , Masculino , Médula Espinal
18.
Pain ; 158(12): 2487-2495, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28930774

RESUMEN

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.


Asunto(s)
Quimiocinas/líquido cefalorraquídeo , Dolor Crónico/líquido cefalorraquídeo , Inflamación/líquido cefalorraquídeo , Neuralgia/líquido cefalorraquídeo , Adulto , Quimiocina CCL11/líquido cefalorraquídeo , Quimiocinas CC/líquido cefalorraquídeo , Estudios Transversales , Depresión/líquido cefalorraquídeo , Fatiga/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad
19.
PLoS Negl Trop Dis ; 11(8): e0005854, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28821016

RESUMEN

BACKGROUND: Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease. METHODOLOGY/PRINCIPAL FINDINGS: The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness. CONCLUSIONS/SIGNIFICANCE: The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis.


Asunto(s)
Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Encefalitis/parasitología , Sueño , Tripanosomiasis Africana/sangre , Tripanosomiasis Africana/líquido cefalorraquídeo , Animales , Biomarcadores , Encéfalo/parasitología , Encéfalo/patología , Interferón gamma/sangre , Interferón gamma/líquido cefalorraquídeo , Masculino , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Análisis de Regresión , Trypanosoma brucei brucei
20.
J Neuroinflammation ; 14(1): 89, 2017 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-28438224

RESUMEN

BACKGROUND: The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however, cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). METHODS: We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons was studied by magnetic resonance imaging. RESULTS: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1ß and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C. CONCLUSIONS: Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.


Asunto(s)
Cerebelo/metabolismo , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Médula Espinal/diagnóstico por imagen , Médula Espinal/metabolismo
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