RESUMO
BACKGROUND: Cluster headache is characterized by activation of the trigeminovascular pathway with subsequent pain signalling in the meningeal vessels, and inflammation has been suggested to play a role in the pathophysiology. To further investigate inflammation in cluster headache, inflammatory markers were analysed in patients with cluster headache and controls. METHODS: We performed a case-control study, collecting cerebrospinal fluid and serum samples from healthy controls, cluster headache patients in remission, active bout, and during an attack to cover the dynamic range of the cluster headache phenotype. Inflammatory markers were quantified using Target 48 OLINK cytokine panels. RESULTS: Altered levels of several cytokines were found in patients with cluster headache compared to controls. CCL8, CCL13, CCL11, CXCL10, CXCL11, HGF, MMP1, TNFSF10 and TNFSF12 levels in cerebrospinal fluid were comparable in active bout and remission, though significantly higher than in controls. In serum samples, CCL11 and CXCL11 displayed decreased levels in patients. Only one cytokine, IL-13 was differentially expressed in serum during attacks. CONCLUSION AND INTERPRETATION: Our data shows signs of possible neuroinflammation occurring in biological samples from cluster headache patients. Increased cerebrospinal fluid cytokine levels are detectable in active bout and during remission, indicating neuroinflammation could be considered a marker for cluster headache and is unrelated to the different phases of the disorder.
Assuntos
Cefaleia Histamínica , Citocinas , Humanos , Masculino , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Cefaleia Histamínica/sangue , Cefaleia Histamínica/líquido cefalorraquidiano , Adulto , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/líquido cefalorraquidianoRESUMO
BACKGROUND: Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. METHODS: We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n = 104), Alzheimer's disease (AD, n = 76), and neurological controls (NC, n = 27). Measured biomarkers included plasma Aß40/Aß42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n = 90) were stratified according to their CSF Aß profile. RESULTS: DLB patients displayed modified plasma Aß ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aß ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aß ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. CONCLUSIONS: Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aß copathology in DLB.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Doença por Corpos de Lewy , Proteínas tau , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Axônios/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Diagnóstico Diferencial , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/patologia , Glicoproteínas de Membrana , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/diagnóstico , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Receptores Imunológicos/sangue , Estudos Retrospectivos , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidianoRESUMO
Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.
Assuntos
Esclerose Lateral Amiotrófica , Autoanticorpos , Imunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Glicoproteína Mielina-Oligodendrócito/imunologia , Humanos , Autoanticorpos/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/diagnóstico , Imunoglobulina G/sangue , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico , Idoso , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/sangue , Adulto , Esclerose Múltipla/imunologia , Esclerose Múltipla/sangue , AnimaisRESUMO
BACKGROUND: This study aimed to evaluate the utility of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1) and total tau (tTAU) serum concentrations as approximation for cerebrospinal fluid (CSF) concentrations of the respective biomarkers in the context of neuroinflammation and multiple sclerosis (MS). METHODS: NfL, GFAP, UCHL1 and tTAU concentrations in serum and CSF were measured in 183 patients (122 with neuroinflammatory disease and 61 neurological or somatoform disease controls) using the single molecule array HD-1 analyzer (Quanterix, Boston, MA). Spearman's rank correlations were computed between serum and CSF concentrations. In a second step, the effects of age, BMI, gadolinium-enhancing lesions in MRI, integrity of the blood-brain barrier (BBB) and presence of acute relapse were accounted for by computing partial correlations. The analyses were repeated for a subsample consisting of MS phenotype patients only (n = 118). EDSS, MS disease activity and acute relapse were considered as additional covariates. Receiver operating characteristic (ROC) analysis was performed for each serum/CSF biomarker concentration to assess how well the particular biomarker concentration differentiates MS patients from somatoform disease controls. Correlations between serum and CSF levels as well as area under the curve (AUC) values were compared for the different biomarkers using z-test statistics. RESULTS: Serum concentrations correlated positively with CSF levels for NfL (r = 0.705, p < 0.01) as well as for GFAP (r = 0.259, p < 0.01). Correlation coefficients were significantly higher for NfL than for GFAP (z = 5.492, p < 0.01). We found no significant serum-CSF correlations for UCHL1 or tTAU. After adjusting for covariates, the results remained unchanged. In the analysis focusing only on MS patients, the results were replicated. ROC analysis demonstrated similarly acceptable performance of serum and CSF NfL values in differentiating MS phenotype patients from somatoform disease controls. AUC values were significantly higher for serum and CSF NfL compared to other biomarkers. CONCLUSION: NfL and GFAP but not UCHL1 or tTAU serum concentrations are associated with CSF levels of the respective biomarker. NfL exhibits more robust correlations between its serum and CSF concentrations as compared to GFAP independently from BBB integrity, clinical and radiological covariates. Both serum and CSF NfL values differentiate between MS and controls.
Assuntos
Biomarcadores , Proteína Glial Fibrilar Ácida , Esclerose Múltipla , Proteínas de Neurofilamentos , Ubiquitina Tiolesterase , Proteínas tau , Humanos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Feminino , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Masculino , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Ubiquitina Tiolesterase/sangue , Ubiquitina Tiolesterase/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Doenças Neuroinflamatórias/diagnósticoRESUMO
OBJECTIVE: In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1). METHODS: This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1ß, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels. RESULTS: In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01). INTERPRETATION: Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.
Assuntos
Esclerose Lateral Amiotrófica , Progressão da Doença , Osteopontina , Humanos , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/diagnóstico , Osteopontina/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Adulto , Doenças Neuroinflamatórias/sangue , Citocinas/sangueRESUMO
Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.
Assuntos
Envelhecimento , Cognição , Disfunção Cognitiva , Doenças Neuroinflamatórias , Nootrópicos , Fator Plaquetário 4 , Animais , Masculino , Camundongos , Envelhecimento/sangue , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/complicações , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/prevenção & controle , Fator Plaquetário 4/sangue , Fator Plaquetário 4/metabolismo , Fator Plaquetário 4/farmacologia , Fator Plaquetário 4/uso terapêutico , Nootrópicos/sangue , Nootrópicos/metabolismo , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Plasma/química , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Transcrição Gênica/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Neuroinflammation after surgery and its contribution to peri-operative neurocognitive disorders (PND) is not well understood. Studying the association between central and peripheral cytokines and neuroinflammation is a prelude to the development of treatments for PND. Here, we investigate the hypotheses that there is a greater cytokine response in cerebrospinal fluid (CSF) than plasma after orthopaedic surgery, and that plasma cytokine levels are directly related to CSF cytokine levels, indicating that plasma cytokine levels may have potential as biomarkers of neuroinflammation. Patients admitted with a fractured neck of femur were invited to participate in this study. Participants had a spinal catheter inserted just prior to induction of anaesthesia. Samples of blood and CSF were taken before, immediately after, and on the first day following emergency surgery. The catheter was then removed. Samples were analysed for the presence of ten cytokines by immunoassay. A spinal catheter was successfully inserted in 11 participants during the 18-month study period. Five plasma cytokines (IL-4, IL-6, IL-10, IL-12p70 and IL-13) rose significantly following surgery, whereas all ten CSF cytokines rose significantly (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ and TNF-α) (adjusted-p < 0.05). Central (CSF) cytokine levels were consistently higher than their peripheral (plasma) counterparts after surgery, with some patients having a particularly marked neuroinflammatory response. The greatest increases occurred in IL-8 in CSF and IL-6 in plasma. There were significant, strong positive correlations between several of the measured cytokines in the CSF after surgery, but far fewer in plasma. There was no significant correlation between cytokine levels in the plasma and CSF at each of the three time points. To our knowledge, this is the first study to analyse paired samples of plasma and CSF for cytokine levels before and after emergency orthopaedic surgery. This study demonstrates that following surgery for a fractured neck of femur, there is a far greater rise in cytokines in the CSF compared to plasma. The lack of correlation between peripheral and central cytokines suggests measurement of peripheral cytokines are not necessarily related to which patients may have a large neuroinflammatory response.
Assuntos
Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Procedimentos Ortopédicos/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Correlação de Dados , Feminino , Humanos , Londres , Masculino , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Período Perioperatório , Plasma/química , Fatores de TempoRESUMO
BACKGROUND AND OBJECTIVES: Despite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5. METHODS: We identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder. RESULTS: Patients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab. DISCUSSION: Our findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Linfócitos B , Moléculas de Adesão Celular Neuronais/imunologia , Plasmócitos , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/fisiopatologia , Estudos RetrospectivosRESUMO
OBJECTIVE: Neuroinflammatory response is deemed the primary pathogenesis of delayed cerebral ischemia (DCI) caused by aneurysmal subarachnoid hemorrhage (aSAH). Both white blood cell (WBC) count and Hounsfield Unit (HU) are gradually considered can reflect inflammation in DCI. This study aims to identify the relationship between WBC count and HU value and investigate the effects of both indicators in predicting DCI after aSAH. METHODS: We enrolled 109 patients with aSAH admitted within 24 h of onset in our study. A multivariate logistic regression analysis was used to evaluate the admission WBC count, HU value, and combined WBC-HU associated with DCI. The receiver operating characteristic curve and area under the curve (AUC) were used to determine thresholds and detect the predictive ability of these predictors. These indicators were also compared with the established inflammation markers. RESULTS: Thirty-six (33%) patients developed DCI. Both WBC count and HU value were strongly associated with the admission glucose level (ρ = .303, p = .001; ρ = .273, p = .004), World Federation of Neurosurgical Societies grade (ρ = .452, p < .001; ρ = .578; p < .001), Hunt-Hess grade (ρ = .450, p < .001; ρ = .510, p < .001), and modified Fisher scale score (ρ = .357, p < .001; ρ = .330, p < .001). After controlling these public variables, WBC count (ρ = .300, p = .002) positively correlated with HU value. An early elevated WBC (odds ratio [OR] 1.449, 95% confidence interval [CI]: 1.183-1.774, p < .001) count and HU value (OR 1.304, 95%CI: 1.149-1.479, p < .001) could independently predict the occurrence of DCI. However, only these patients with both WBC count and HU value exceeding the cut-off points (OR 36.89, 95%CI: 5.606-242.78, p < .001) were strongly correlated with DCI. Compared with a single WBC count (AUC 0.811, 95%CI: 0.729-0.892, p < .001) or HU value (AUC 0.869, 95%CI: 0.803-0.936, p < .001), the combined WBC-HU (AUC 0.898, 95%CI: 0.839-0.957, p < .001) demonstrated a better ability to predict the occurrence of DCI. Inspiringly, the prediction performance of these indicators outperformed the established inflammatory markers. CONCLUSION: An early elevated WBC count and HU value could independently predict DCI occurrence between 4 and 30 days after aSAH. Furthermore, WBC count was positively correlated with HU value, and the combined WBC-HU demonstrated a superior prediction ability for DCI development compared with the individual indicator.
Assuntos
Isquemia Encefálica/diagnóstico , Doenças Neuroinflamatórias/diagnóstico , Hemorragia Subaracnóidea/diagnóstico , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/imunologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/diagnóstico por imagem , Doenças Neuroinflamatórias/imunologia , Admissão do Paciente , Prognóstico , Estudos Retrospectivos , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/imunologia , Tomografia Computadorizada por Raios XRESUMO
Neuroinflammation is a key process in the pathogenesis of subarachnoid hemorrhage (SAH) and contributes to poor outcome in patients. The purpose of this study is to explore the effect of triggering receptor expressed on myeloid cells 1 (TREM1) in the SAH, as well as its potential mechanism. In our study, plasma levels of soluble TREM1 was increased significantly after SAH and correlated to SAH severity and serum C-reactiveprotein. TREM1 inhibitory peptide LP17 alleviated the neurological deficits, attenuated brain water content, and reduced neuronal damage after SAH. Meanwhile, TREM1 inhibitory peptide decreased neuroinflammation (evidenced by the decreased levels of markers including IL-6, IL-1ß, TNF-α) by attenuating proinflammatory subtype transition of microglia (evidenced by the decreased levels of markers including CD68, CD16, CD86) and decreasing the formation of neutrophil extracellular traps (evidenced by the decreased levels of markers including CitH3, MPO, and NE). Further mechanistic study identified that TREM1 can activate downstream proinflammatory pathways through interacting with spleen tyrosine kinase (SYK). In conclusion, inhibition of TREM1 alleviates neuroinflammation by attenuating proinflammatory subtype transition of microglia and decreasing the formation of neutrophil extracellular traps through interacting with SYK after SAH. TREM1 may be a a promising therapeutic target for SAH.
Assuntos
Armadilhas Extracelulares/imunologia , Microglia/imunologia , Doenças Neuroinflamatórias/imunologia , Hemorragia Subaracnóidea/imunologia , Quinase Syk/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Animais , Antígenos CD/genética , Córtex Cerebral/imunologia , Citocinas/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/sangue , Hemorragia Subaracnóidea/sangue , Receptor Gatilho 1 Expresso em Células Mieloides/sangueRESUMO
BACKGROUND: Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. METHODS: We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell' medium/HG-treated mouse hippocampal HT22 cells. RESULTS: Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood-brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / -) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. CONCLUSIONS: These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.
Assuntos
Disfunção Cognitiva/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Lipocalina-2/sangue , Fatores de Transcrição NFATC/sangue , Doenças Neuroinflamatórias/sangue , Animais , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/psicologia , Dieta Hiperlipídica , Aprendizagem em Labirinto/fisiologia , Camundongos , Doenças Neuroinflamatórias/etiologia , Células RAW 264.7RESUMO
Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood-brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and eclampsia. We included women recruited to the South African Preeclampsia Obstetric Adverse Events (PROVE) biobank. Blood and cerebrospinal fluid (CSF) were collected around delivery. CSF was analyzed for neuroinflammatory markers interleukin 1ß, interleukin 6, interleukin-8 and tumor necrosis factor alpha (TNF-alpha). The CSF to plasma albumin ratio was measured to assess blood-brain barrier function. Women with eclampsia (n = 4) showed increased CSF concentrations of all pro-inflammatory cytokines and TNF-alpha compared to women with normotensive pregnancies (n = 7) and also for interleukin-6 and TNF-alpha compared to women with preeclampsia (n = 4). Women with preeclampsia also showed increases in pro-inflammatory cytokines IL-6 and IL-8 but not TNF-alpha in the CSF compared to women with normotensive pregnancies. In particular, women with eclampsia but also women with preeclampsia showed an increase in the CSF to plasma albumin ratio compared to normotensive women. In conclusion, women with preeclampsia and eclampsia show evidence of neuroinflammation and an injured blood-brain barrier. These findings are seen in particular among women with eclampsia.
Assuntos
Barreira Hematoencefálica/patologia , Eclampsia/sangue , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/complicações , Pré-Eclâmpsia/sangue , Adulto , Albuminas/metabolismo , Biomarcadores/líquido cefalorraquidiano , Eclampsia/líquido cefalorraquidiano , Feminino , Humanos , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Pré-Eclâmpsia/líquido cefalorraquidiano , GravidezRESUMO
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and restricted and repetitive behaviors. Neuroinflammation and abnormal lipid mediators have been identified in multiple investigations as an acknowledged etiological mechanism of ASD that can be targeted for therapeutic intervention. METHODS: In this study, multiple regression and combined receiver operating characteristic (ROC) curve analyses were used to determine the relationship between the neuroinflammatory marker α-synuclein and lipid mediator markers related to inflammation induction, such as cyclooxygenase-2 and prostaglandin-EP2 receptors, in the etiology of ASD. Additionally, the study aimed to determine the linear combination that maximizes the partial area under ROC curves for a set of markers. Forty children with ASD and 40 age- and sex-matched controls were enrolled in the study. Using ELISA, the levels of α-synuclein, cyclo-oxygenase-2, and prostaglandin-EP2 receptors were measured in the plasma of both groups. Statistical analyses using ROC curves and multiple and logistic regression models were performed. RESULTS: A remarkable increase in the area under the curve was observed using combined ROC curve analyses. Moreover, higher specificity and sensitivity of the combined markers were reported. CONCLUSIONS: The present study indicates that measurement of the predictive value of selected biomarkers related to neuroinflammation and lipid metabolism in children with ASD using a ROC curve analysis should lead to a better understanding of the etiological mechanism of ASD and its link with metabolism. This information may facilitate early diagnosis and intervention.
Assuntos
Transtorno do Espectro Autista/sangue , Ciclo-Oxigenase 2/sangue , Receptores de Prostaglandina E Subtipo EP2/sangue , alfa-Sinucleína/sangue , Transtorno do Espectro Autista/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Humanos , Masculino , Doenças Neuroinflamatórias/sangue , Curva ROCRESUMO
Neuroinflammation contributes significantly to the pathogenesis of diabetic peripheral neuropathy (DPN). Quercetin reportedly exerts neuroprotective effects in DPN. Here, we aimed to evaluate the potential anti-inflammatory effects of quercetin in a DPN rat model. Eight weeks after streptozotocin administration, diabetic rats were treated with quercetin (30 and 60 mg/kg/day orally) for 6 weeks. We assessed the mechanical withdrawal threshold (MWT), nerve conduction velocity (NCV) and morphological changes in sciatic nerves. Additionally, we measured the levels of tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, and IL-6 by ELISA and the expression of TLR4, MyD88, and NF-κB in sciatic nerves by western blotting and immunohistochemical assays. Our results revealed that blood glucose levels and body weight were unaltered following quercetin treatment. However, quercetin improved MWT (p < 0.05), NCV (p < 0.05), and pathological changes in the sciatic nerves of DPN rats. Quercetin significantly alleviated the increased expression of TNF-α (p < 0.05) and IL-1ß (p < 0.001). Furthermore, high-dose quercetin administration significantly downregulated the expression of TLR4 (p < 0.001), MyD88 (p < 0.001), and NF-κB (p < 0.001) in sciatic nerves of DPN rats. Our findings revealed that quercetin could reduce the levels of inflammatory factors in DPN rats, possibly mediated via the downregulation of the TLR4/MyD88/NF-κB signalling pathway. Collectively, these results suggest that although quercetin did not decreased blood glucose levels or reversed the reduced body weight, it showed anti-inflammatory and neuroprotective effects, which was beneficial for the treatment of DPN.
Assuntos
Anti-Inflamatórios/farmacologia , Neuropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Quercetina/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Citocinas/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Inflamação/sangue , Inflamação/metabolismo , Masculino , Condução Nervosa/efeitos dos fármacos , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Quercetina/uso terapêutico , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVES: To evaluate the usefulness of CSF and plasma neurofilament light (Nf-L) as a biomarker for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM). METHODS: Nf-L, CXCL10, and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by single molecule array. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein, and HTLV-1 proviral load. RESULTS: Nf-L was detected in all CSF samples (median [range] = 575 [791.8-2,349] pg/mL) and positively correlated with markers of inflammation (CXCL10 (r = 0.733), neopterin (r = 0.499), cell count (r = 0.403), and protein levels (r = 0.693) in CSF; p < 0.0015). There was an inverse correlation between Nf-L and duration of disease (r = -0.584, p < 0.0001). Wheelchair-dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin, and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10, and protein in CSF. CONCLUSIONS: Nf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuroinflammation.
Assuntos
Infecções por HTLV-I/diagnóstico , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Doenças da Medula Espinal/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Feminino , Seguimentos , Infecções por HTLV-I/sangue , Infecções por HTLV-I/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Neopterina/líquido cefalorraquidiano , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/fisiopatologia , Doenças da Medula Espinal/sangue , Doenças da Medula Espinal/líquido cefalorraquidianoRESUMO
Background: The model of neuroinflammation has been proposed as a possible explanation of depression. Investigations of serum levels of tumor necrosis factor-α (TNF-α) in depressed patients have previously shown contradictory results of increased and decreased levels of TNF-α during the treatment of depression. Methods: We compared the serum levels of TNF-α in two cohorts of patients suffering from depression (ICD-10 criteria): one cohort from a psychotherapeutic unit (n = 18), where patients were treated with Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and the other cohort from a psychiatric day care unit (n = 16). Both cohorts were investigated at the beginning and at the end of treatment. The intensity of depression was measured by means of the Beck Depression Inventory, 2nd edition (BDI-II) at both time points. Results: We observed a statistically significant increase of TNF-α in the psychotherapeutic unit at time point 2 compared to time point 1 (T = -14.71, p < 0.001), but not in the psychiatric day care unit. In both cohorts, BDI-II scores at time point 2 were significantly decreased compared to time point 1 (psychiatric day care unit: T = 3.32, p = 0.005; psychotherapeutic unit: T = 6.22, p < 0.001). There was a significant correlation in the psychotherapeutic unit at time point 2 (r = -0.682, p = 0.02). Conclusion: As TNF-α was increased at time point 2 in the psychotherapeutic unit but not in patients of the psychiatric day care unit, we propose the different durations of pretreatments in both cohorts and the associated processes of neuroinflammation as a possible explanation for our results. The lack of information about the time course of TNF-α in depression could in general explain the huge variety of TNF-α levels in different cohorts of depressed patients reported in the literature.
Assuntos
Depressão/sangue , Depressão/terapia , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/terapia , Psicoterapia/métodos , Fator de Necrose Tumoral alfa/sangue , Adulto , Biomarcadores/sangue , Estudos de Coortes , Depressão/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neuroinflamatórias/diagnóstico , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy. Despite intensive research in recent years, it remains unclear, what drives the different clinical disease courses. Due to this missing pathophysiological link, therapy for the childhood cerebral disease course of X-ALD (CCALD) remains symptomatic; the allogenic hematopoietic stem cell transplantation or hematopoietic stem-cell gene therapy is an option for early disease stages. The inclusion of dried blood spot (DBS) C26:0-lysophosphatidylcholine to newborn screening in an increasing number of countries is leading to an increasing number of X-ALD patients diagnosed at risk for CCALD. Current follow-up in asymptomatic boys with X-ALD requires repetitive cerebral MRIs under sedation. A reliable and easily accessible biomarker that predicts CCALD would therefore be of great value. Here we report the application of targeted metabolomics by AbsoluteIDQ p180-Kit from Biocrates to search for suitable biomarkers in X-ALD. LysoPC a C20:3 and lysoPC a C20:4 were identified as metabolites that indicate neuroinflammation after induction of experimental autoimmune encephalitis in the serum of Abcd1tm1Kds mice. Analysis of serum from X-ALD patients also revealed different concentrations of these lipids at different disease stages. Further studies in a larger cohort of X-ALD patient sera are needed to prove the diagnostic value of these lipids for use as early biomarkers for neuroinflammation in CCALD patients.
Assuntos
Adrenoleucodistrofia/diagnóstico , Lisofosfatidilcolinas/análise , Metabolômica/métodos , Triagem Neonatal/métodos , Doenças Neuroinflamatórias/etiologia , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/fisiopatologia , Animais , Biomarcadores/sangue , Teste em Amostras de Sangue Seco , Encefalomielite Autoimune Experimental/sangue , Feminino , Humanos , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/sangue , FosfolipídeosRESUMO
Mechanical ventilation is the cornerstone of the Intensive Care Unit. However, it has been associated with many negative consequences. Recently, ventilator-induced brain injury has been reported in rodents under injurious ventilation settings. Our group wanted to explore the extent of brain injury after 50 h of mechanical ventilation, sedation and physical immobility, quantifying hippocampal apoptosis and inflammation, in a normal-lung porcine study. After 50 h of lung-protective mechanical ventilation, sedation and immobility, greater levels of hippocampal apoptosis and neuroinflammation were clearly observed in the mechanically ventilated group, in comparison to a never-ventilated group. Markers in the serum for astrocyte damage and neuronal damage were also higher in the mechanically ventilated group. Therefore, our study demonstrated that considerable hippocampal insult can be observed after 50 h of lung-protective mechanical ventilation, sedation and physical immobility.
Assuntos
Anestesia/efeitos adversos , Lesões Encefálicas/etiologia , Sedação Consciente/efeitos adversos , Hipocampo/lesões , Imobilização/efeitos adversos , Doenças Neuroinflamatórias/etiologia , Respiração Artificial/efeitos adversos , Ventiladores Mecânicos/efeitos adversos , Animais , Apoptose , Biomarcadores/sangue , Lesões Encefálicas/sangue , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Unidades de Terapia Intensiva , Pulmão/fisiopatologia , Doenças Neuroinflamatórias/sangue , Neurônios/patologia , Suínos , Volume de Ventilação Pulmonar , Fatores de TempoRESUMO
BACKGROUND: The role of dietary interventions in improving the symptoms of Multiple Sclerosis (MS) has always been considered, but few studies have been conducted in this area. This study aimed to investigate the effects of modified anti-inflammatory diet on fatigue, quality of life, and inflammatory markers among patients with Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: This randomized clinical trial was conducted on 100 patients with RRMS. The patients were randomly divided into the diet group (anti-inflammatory diet) or the control group (healthy diet recommendations) for 12 weeks. Fatigue and quality of life were assessed by Modified Fatigue Impact Scale (MFIS) and Multiple Sclerosis Quality of Life (MSQoL-54), respectively. Anthropometric measures and inflammatory biomarkers, including Interleukin 17 (IL-17), Interleukin 4 (IL-4), and high sensitivity C-Reactive Protein (hs-CRP), were assessed at baseline and end of the study. RESULTS: The results showed a significant improvement in MFIS as well as in physical and mental components of MSQoL-54 (p = 0.001, p = 0.015, and p = 0.003, respectively) in the diet group compared to the control group. The results also showed a significant increase in IL-4 level (p = 0.022). However, no significant changes were detected in IL-17 and hs-CRP levels (p = 0.091, 0.418, respectively). CONCLUSION: Modified anti-inflammatory diet could improve fatigue and quality of life and increase IL-4 level.
Assuntos
Proteína C-Reativa/metabolismo , Fadiga/dietoterapia , Interleucina-17/sangue , Interleucina-4/sangue , Esclerose Múltipla Recidivante-Remitente/dietoterapia , Doenças Neuroinflamatórias/dietoterapia , Qualidade de Vida , Adulto , Fadiga/sangue , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/complicações , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/complicações , Avaliação de Resultados em Cuidados de SaúdeRESUMO
It is increasingly reported that a history of concussion may be associated with chronic deleterious consequences. While the pathophysiology that contributes to these consequences is not well understood, neuroinflammation is postulated to be critical. Activation of multi-protein complexes termed inflammasomes, a key component of this inflammatory response, has been reported in more severe TBIs; however, it has not been investigated in milder TBIs, such as concussion. This study investigated serum levels of interleukin (IL)-1ß and IL-18 (key proteins activated downstream of these inflammasomes) at acute, sub-acute, and chronic time-points post-concussion. We recruited 105 Australian footballers (65 male, 40 female) during the pre-season, then prospectively followed these players for the occurrence of concussion during the season. At baseline, 58 footballers reported a previous concussion history, and 47 reported no previous concussion history. Additionally, 25 players sustained a mid-season concussion and were sampled at 2, 6, and 13 days post-concussion. Serum levels of IL-1ß and IL-18 were quantified using highly sensitive Simoa HD-X Analyzer assays. At baseline, IL-1ß levels were higher in male, but not female, footballers with a previous concussion history compared with footballers with no concussion history. There was also a positive correlation between years of collision sport participation and IL-18 levels in males. No evidence was found in males or females to indicate that IL-1ß or IL-18 levels differed at 2, 6, or 13 days post-concussion. These findings provide novel insights into potential sex-specific physiological consequences of concussion, and suggest that neuroinflammation may be persistent chronically following concussion in male athletes.