RESUMO
BACKGROUND: Bipolar disorders (BD) are chronic, debilitating disorders. The blood-brain barrier (BBB) has been increasingly investigated in BD. This systematic review aimed to assess the available evidence on the relationship between BD and markers of BBB dysfunction. METHODS: A systematic search in PubMed, Embase, PsycINFO, CINAHL and Web of Science was run where the primary outcomes were BBB markers such as S100B, albumin ratio, matrix metalloproteinase (MMP), cell adhesion molecule (CAM), and tight junction proteins. Techniques included blood, cerebrospinal fluid (CSF), post-mortem, genetic and imaging methods in BD compared to healthy controls. RESULTS: 55 studies were identified, 38 of which found an association between BD and markers of BBB dysfunction. 16/29 studies found increased blood/CSF albumin ratio, S100B, CAMs or MMP levels in BD participants compared to controls. 5/19 post-mortem studies found increased levels of chondroitin sulphate proteoglycans, intercellular CAM, neurexin or claudin-5 mRNA in distinct locations throughout the brain in BD compared to controls. One imaging study identified extensive BBB leakage in 30 % of BD participants, compared to 0 % in controls. LIMITATIONS: The diversity in methodologies used in the included studies makes direct comparison of results challenging. Furthermore, imaging methods are the gold standard, but only one study used them. Other markers are only indicative of BBB permeability. CONCLUSIONS: This review suggests an association between BD and BBB dysfunction. Further research is needed to provide definite answers considering the existing literature's limitations, and to clarify whether this association provides a pathogenic mechanism, or is an epiphenomenon of BD.
Assuntos
Transtorno Bipolar , Barreira Hematoencefálica , Subunidade beta da Proteína Ligante de Cálcio S100 , Humanos , Biomarcadores/sangue , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/metabolismo , Transtorno Bipolar/sangue , Moléculas de Adesão Celular/genética , Metaloproteinases da Matriz/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Proteínas de Junções Íntimas/metabolismoRESUMO
PURPOSE: Enteroviruses (EV) comprises many different types and are the most common cause of aseptic meningitis. How the virus affects the brain including potential differences between types are largely unknown. Measuring biomarkers in CSF is a tool to estimate brain damage caused by CNS infections. METHODS: A retrospective study was performed in samples from 38 patients with acute neurological manifestations and positive CSF-EV RNA (n = 37) or serum-IgM (n = 1). The EV in 17 samples were typed by sequencing. The biomarkers neurofilament light (NFL), glial fibrillary acidic protein (GFAP), S-100B protein, amyloid-ß (Aß) 40 and Aß42, total-tau (T-tau) and phosphorylated tau (P-tau) were measured and compared with data derived from a control group (n = 19). RESULTS: There were no increased levels of GFAP (p ≤ 0.1) nor NFL (p ≤ 0.1) in the CSF of patients with EV meningitis (n = 38) compared with controls. However, we found decreased levels of Aß42 (p < 0.001), Aß40 (p < 0.001), T-tau (p ≥ 0.01), P-tau (p ≤ 0.001) and S-100B (p ≤ 0.001). E30 (n = 9) and CVB5 (n = 6) were the most frequent EV-types identified, but no differences in biomarker levels or other clinical parameters were found between the infecting virus type. Seven patients who were followed for longer than one month reported remaining cognitive impairment, although no correlations with biomarker concentrations were observed. CONCLUSION: There are no indication of neuronal or astrocyte damage in patients with EV meningitis. Yet, decreased concentrations of Aß40, Aß42, P-tau and T-tau were shown, a finding of unknown importance. Cognitive impairment after acute disease occurs, but with only a limited number of patients analysed, no conclusion can be drawn concerning any association with biomarker levels or EV types.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Infecções por Enterovirus , Enterovirus , Proteína Glial Fibrilar Ácida , Proteínas tau , Humanos , Biomarcadores/líquido cefalorraquidiano , Masculino , Feminino , Enterovirus/genética , Enterovirus/isolamento & purificação , Estudos Retrospectivos , Infecções por Enterovirus/líquido cefalorraquidiano , Infecções por Enterovirus/virologia , Adulto , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Pessoa de Meia-Idade , Adolescente , Criança , Genótipo , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Pré-Escolar , Adulto Jovem , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Infecções do Sistema Nervoso Central/líquido cefalorraquidiano , Infecções do Sistema Nervoso Central/virologia , Idoso , Lactente , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangueRESUMO
Lyme borreliosis (LB) is the most common tick-borne infection in Europe, with Lyme neuroborreliosis (LNB) its second most frequent clinical manifestation. Prognostic factors for clinical outcomes in LNB have not been identified. Elevated serum levels of the brain damage markers neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) have been associated with poor clinical outcomes in other disorders of the central nervous system. The aim of this study is to assess NSE and S100B in serum as prognostic biomarkers for clinical outcomes in paediatric LNB patients. Children evaluated for LNB (n = 121) in Sweden were prospectively included during 2010-2014, serum samples were collected on admission, and all children underwent a 2-month follow-up. Patients with pleocytosis and anti-Borrelia antibodies in cerebrospinal fluid (CSF) were classified as having LNB (n = 61). Controls were age- and gender-matched non-LNB patients (n = 60). NSE was elevated in 38/61 (62%) LNB patients and in 31/60 (52%) controls. S100B was elevated in 3/60 (5%) LNB patients and 0/59 (0%) controls. NSE and S100B concentrations did not differ significantly when comparing LNB patients with controls. No differences were found in the concentrations when comparing the clinical recovery of LNB patients at the 2-month follow-up. NSE was detectable in the majority of LNB patients and controls, whereas S100B was detectable in only a few LNB patients and no controls. NSE and S100B in serum cannot be recommended as prognostic biomarkers for clinical outcomes in children with LNB.
Assuntos
Neuroborreliose de Lyme , Fosfopiruvato Hidratase , Subunidade beta da Proteína Ligante de Cálcio S100 , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Humanos , Neuroborreliose de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/diagnóstico , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Prognóstico , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidianoRESUMO
BACKGROUND: Case-control studies have associated delirium with blood-brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity. METHODS: Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate. RESULTS: The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P<0.001), delirium incidence (CPAR P=0.012; S100B P<0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P<0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01). CONCLUSION: Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB.
Assuntos
Barreira Hematoencefálica , Delírio , Biomarcadores , Delírio/diagnóstico , Humanos , Interleucina-6 , Ácido Láctico , Doenças Neuroinflamatórias , Estudos Prospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidianoRESUMO
Aim: There is a critical need to validate biofluid-based biomarkers as diagnostic and drug development tools for traumatic brain injury (TBI). As part of the TBI Endpoints Development Initiative, we identified four potentially predictive and pharmacodynamic biomarkers for TBI: astroglial markers GFAP and S100B and the neuronal markers UCH-L1 and Tau. Materials & methods: Several commonly used platforms for these four biomarkers were identified and compared on analytic performance and ability to detect gold standard recombinant protein antigens and to pool control versus TBI cerebrospinal fluid (CSF). Results: For each marker, only some assay formats could differentiate TBI CSF from the control CSF. Also, different assays for the same biomarker reported divergent biomarker values for the same biosamples. Conclusion: Due to the variability of TBI marker assay in performance and reported values, standardization strategies are recommended when comparing reported biomarker levels across assay platforms.
Lay abstract Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world. There is a critical need to validate biofluid-based biomarker tests as diagnostic and drug development tools. For this study, we focused on four brain-derived proteins called GFAP, S100B, UCH-L1 and Tau. To measure these biomarker proteins in human biofluid, one relies on either commercial or home-brew assays. Here, we attempted to compare the performance of 24 assay formats for each biomarker. We compared their assay sensitivity, ability to detect 'gold standard' protein analyte we procured, as well as the ability to differentiated pooled TBI cerebrospinal fluid from healthy control cerebrospinal fluid. We found that there are high variabilities among TBI marker assays in assay performance, reported biomarker values and ability to differentiate TBI versus control biofluid. Thus, a standardization strategy is needed when comparing reported biomarker levels across assay platforms.
Assuntos
Bioensaio/normas , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/diagnóstico , Determinação de Ponto Final , Antígenos/metabolismo , Estudos de Casos e Controles , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Humanos , Proteínas Recombinantes/metabolismo , Padrões de Referência , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Ubiquitina Tiolesterase/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: Cerebral injury is a common cause of maternal mortality due to preeclampsia and is challenging to predict and diagnose. In addition, there are associations between previous preeclampsia and stroke, dementia and epilepsy later in life. The cerebral biomarkers S100B, neuron specific enolase, (NSE), tau protein and neurofilament light chain (NfL) have proven useful as predictors and diagnostic tools in other neurological disorders. This case-control study sought to determine whether cerebral biomarkers were increased in cerebrospinal fluid (CSF) as a marker of cerebral origin and potential cerebral injury in preeclampsia and if concentrations in CSF correlated to concentrations in plasma. METHODS: CSF and blood at delivery from 15 women with preeclampsia and 15 women with normal pregnancies were analysed for the cerebral biomarkers S100B, NSE, tau protein and NfL by Simoa and ELISA based methods. MRI brain was performed after delivery and for women with preeclampsia also at six months postpartum. RESULTS: Women with preeclampsia demonstrated increased CSF- and plasma concentrations of NfL and these concentrations correlated to each other. CSF concentrations of NSE and tau were decreased in preeclampsia and there were no differences in plasma concentrations of NSE and tau between groups. For S100B, serum concentrations in preeclampsia were increased but there was no difference in CSF concentrations of S100B between women with preeclampsia and normal pregnancy. CONCLUSION: NfL emerges as a promising circulating cerebral biomarker in preeclampsia and increased CSF concentrations point to a neuroaxonal injury in preeclampsia, even in the absence of clinically evident neurological complications.
Assuntos
Axônios/metabolismo , Encefalopatias/líquido cefalorraquidiano , Pré-Eclâmpsia/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Encefalopatias/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Pré-Eclâmpsia/patologia , GravidezRESUMO
Varicella-zoster virus (VZV) is one of the most common agents causing viral infections of the central nervous system (CNS). VZV encephalitis is associated with severe neurological sequelae, despite antiviral treatment. Cognitive impairment has been reported and VZV has been associated with dementia. Our aim was to investigate the cognitive impairment and cerebrospinal fluid biomarkers in a follow-up study of patients with VZV encephalitis. Thirteen patients with VZV encephalitis, diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF) by PCR and concomitant symptoms of encephalitis, were included. Neuropsychological assessment in parallel with a lumbar puncture to obtain CSF was performed 1.5-7 years after acute disease. The CSF biomarkers neurofilament light chain (NFL), S100B, glial fibrillary acidic protein (GFAP), amyloid-ß (Aß) 40 and Aß42, total tau (t-tau) and phosphorylated tau (p-tau) were analysed and compared to controls (n = 24). Cognitive impairment was shown in the domains of executive functions and speed/attention and to a minor degree in the domains of learning/memory and language, indicated by a significantly poorer performance on seven neuropsychological test variables. No convincing evidence of alterations in concentrations of biomarkers in the CSF were shown. Our results indicate that patients with VZV encephalitis suffer from cognitive impairment long time after acute disease. Importantly, these impairments do not seem to be accompanied by biomarker evidence of ongoing neuronal or astrocytic injury/activation or induction of dementia-related brain pathologies by the infection.
Assuntos
Disfunção Cognitiva/líquido cefalorraquidiano , Encefalite por Varicela Zoster/líquido cefalorraquidiano , Herpesvirus Humano 3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , DNA Viral/líquido cefalorraquidiano , Encefalite por Varicela Zoster/complicações , Feminino , Seguimentos , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Projetos Piloto , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Parkinson's disease (PD) and multiple system atrophy (MSA) have overlapping symptoms, challenging an early diagnosis. Diagnostic accuracy is important because PD and MSA have a different prognosis and response to treatment. Here, we aimed to evaluate the diagnostic value of brain-specific structural proteins in cerebrospinal fluid (CSF) of PD and MSA patients, as well as their association with cognitive decline. METHODS: CSF samples were collected from patients with clear signs of parkinsonism, but with uncertain diagnosis at the time of inclusion. Clinical diagnoses of PD (n = 55) and MSA (n = 22) were established after 3 and 10 years of follow-up and re-evaluated after 12 years, according to the most updated clinical criteria. CSF from controls (n = 118) was studied for comparison. Neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B) and myelin basic protein (MBP) levels in CSF were measured using ELISA. Protein levels were also correlated with cognitive decline, i.e. worsening of the mini mental state examination (MMSE) over a period of three years. RESULTS: MBP concentrations were increased in MSA compared to PD and controls (p < 0.005) and could differentiate MSA and PD with high accuracy (AUC = 0.781; p < 0.001). Concentrations of MPB, GFAP and S100B, but not NSE, were significantly elevated in PD patients compared to controls (p = 0.05). None of the brain-specific structural proteins correlated with MMSE progression. CONCLUSIONS: Our results demonstrate that MBP differentiates PD from MSA at early stages of the disease, indicating that demyelination and axonal damage may already occur in early stages of MSA.
Assuntos
Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/diagnóstico , Proteína Básica da Mielina/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico , Idoso , Biomarcadores , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidianoRESUMO
Specific neuroprotective strategies to minimize cerebral damage caused by severe hypoxia or hypovolemia are lacking. Based on previous studies showing that relaxin-2/serelaxin increases cortical cerebral blood flow, we postulated that serelaxin might provide a neuroprotective effect. Therefore, we tested serelaxin in two emergency models: hypoxia was induced via inhalation of 5% oxygen and 95% nitrogen for 12 min; thereafter, the animals were reoxygenated. Hypovolemia was induced and maintained for 20 min by removal of 50% of the total blood volume; thereafter, the animals were retransfused. In each damage model, the serelaxin group received an intravenous injection of 30 µg/kg of serelaxin in saline, while control animals received saline only. Blood gases, shock index values, heart frequency, blood pressure, and renal blood flow showed almost no significant differences between control and treatment groups in both settings. However, serelaxin significantly blunted the increase of lactate during hypovolemia. Serelaxin treatment resulted in significantly elevated cortical cerebral blood flow (CBF) in both damage models, compared with the respective control groups. Measurements of the neuroproteins S100B and neuron-specific enolase in cerebrospinal fluid revealed a neuroprotective effect of serelaxin treatment in both hypoxic and hypovolemic animals, whereas in control animals, neuroproteins increased during the experiment. Western blotting showed the expression of relaxin receptors and indicated region-specific differences in relaxin receptor-mediated signaling in cortical and subcortical brain arterioles, respectively. Our findings support the hypothesis that serelaxin is a potential neuroprotectant during hypoxia and hypovolemia. Due to its preferential improvement of cortical CBF, serelaxin might reduce cognitive impairments associated with these emergencies.
Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Hipovolemia/tratamento farmacológico , Hipóxia/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Relaxina/farmacologia , Choque/tratamento farmacológico , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Hipovolemia/líquido cefalorraquidiano , Hipovolemia/fisiopatologia , Hipóxia/líquido cefalorraquidiano , Hipóxia/fisiopatologia , Ácido Láctico/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Relaxina/administração & dosagem , Circulação Renal/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Ovinos , Choque/líquido cefalorraquidiano , Choque/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of ≥1.0 compared to patients without long-term cognitive decline at 3 months postsurgery. METHODS: Serum and CSF biomarkers of inflammation and blood-brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. RESULTS: Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48-hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long-term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long-term cognitive decline at 3 months. Patients both with and patients without long-term cognitive decline showed early transient increases of the astroglial biomarkers S-100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). INTERPRETATION: Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long-term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort. Ann Neurol 2020;87:370-382.
Assuntos
Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Complicações Cognitivas Pós-Operatórias/sangue , Complicações Cognitivas Pós-Operatórias/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Idoso , Barreira Hematoencefálica/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/líquido cefalorraquidiano , Masculino , Procedimentos Ortopédicos/efeitos adversos , Permeabilidade , Fatores de TempoRESUMO
The early detection of perinatal brain damage in preterm and term newborns (i.e. intraventricular hemorrhage, periventricular leukomalacia and perinatal asphyxia) still constitute an unsolved issue. To date, despite technological improvement in standard perinatal monitoring procedures, decreasing the incidence of perinatal mortality, the perinatal morbidity pattern has a flat trend. Against this background, the measurement of brain constituents could be particularly useful in the early detection of cases at risk for short-/long-term brain injury. On this scenario, the main European and US international health-care institutions promoted perinatal clinical and experimental neuroprotection research projects aimed at validating and including a panel of biomarkers in the clinical guidelines. Although this is a promising attempt, there are several limitations that do not allow biomarkers to be included in standard monitoring procedures. The main limitations are: (i) the heterogeneity of neurological complications in the perinatal period, (ii) the small cohort sizes, (iii) the lack of multicenter investigations, (iv) the different techniques for neurobiomarkers assessment, (iv) the lack of consensus for the validation of assays in biological fluids such as urine and saliva, and (v), the lack of reference curves according to measurement technique and biological fluid. In the present review we offer an up-to-date overview of the most promising developments in the use of biomarkers in the perinatal period such as calcium binding proteins (S100B protein), vasoactive agents (adrenomedullin), brain biomarkers (activin A, neuron specific enolase, glial fibrillary acidic protein, ubiquitin carboxyl-terminal hydrolase-L1) and oxidative stress markers.
Assuntos
Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas/diagnóstico , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/urina , Humanos , Assistência Perinatal , Gravidez , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/urina , Saliva/metabolismo , Ubiquitina Tiolesterase/sangue , Ubiquitina Tiolesterase/líquido cefalorraquidiano , Ubiquitina Tiolesterase/urinaRESUMO
BACKGROUND: Central nervous system (CNS) may be infected by several agents, resulting in different presentations and outcomes. Analysis of cerebrospinal fluid (CSF) markers could be helpful to differentiate specific conditions and setting an appropriate therapy. METHODS: Patients presenting with signs and symptoms were enrolled if, before receiving a diagnostic lumbar puncture, signed a written informed consent. We analyzed CSF indexes of blood-brain barrier permeability (CSF to serum albumin ratio or CSAR), inflammation (CSF to serum IgG ratio, neopterin), amyloid deposition (1-42 ß-amyloid), neuronal damage (Total tau (T-tau), Phosphorylated tau (P-tau), and 14.3.3 protein) and astrocyte damage (S-100ß). RESULTS: Two hundred and eighty-one patients were included: they were mainly affected by herpesvirus encephalitis, enterovirus meningoencephalitis, bacterial meningitis (Neisseria meningitidis and Streptococcus pneumoniae), and infection by other etiological agents or unknown pathogen. Their CSF features were compared with HIV-negative patients and native HIV-positive individuals without CNS involvement. 14.3.3 protein was found in bacterial and HSV infections while T-tau and neopterin were abnormally high in the herpesvirus group. P-tau, instead, was elevated in enterovirus meningitis. S-100ß was found to be high in patients with HSV-1 and HSV-2 infections but not in those with Varicella Zoster Virus (VZV). Thirty-day mortality was unexpectedly low (2.7%): patients who died had higher levels of T-tau and, significantly, lower levels of Aß1-42. CONCLUSION: This work demonstrates that CSF biomarkers of neuronal damage or inflammation may vary during CNS infections according to different causative agents. The prognostic value of these biomarkers needs to be assessed in prospective studies.
Assuntos
Infecções do Sistema Nervoso Central/líquido cefalorraquidiano , Proteínas 14-3-3/líquido cefalorraquidiano , Adulto , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Infecções do Sistema Nervoso Central/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neopterina/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Análise de Sobrevida , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: Increased expression of the astroglial Ca2+-binding protein S100B has been observed in various neurodegenerative diseases and also seems to play a role in the unfolding of pathophysiological events at early stages of Alzheimer's disease (AD). OBJECTIVE: To examine the association of cerebrospinal fluid (CSF) levels of S100B with 1) established CSF core biomarkers total tau (tau), hyperphosphorylated tau (p-tau), and amyloid ß1-42 (Aß1-42) as well as neuron-specific enolase (NSE) CSF levels and 2) cognition in early AD and mild cognitive impairment (MCI) due to AD (MCI-AD). METHODS: Retrospective study assessing 49 pooled charts of Memory Clinic and inpatients diagnosed with AD (Nâ=â26) and MCI-AD (Nâ=â23) according to the National Institute of Aging and Alzheimer's Disease Association (NIA-AA) criteria. Neuropsychological testing was performed with the Consortium to Establish a Registry for AD (CERAD)-Plus battery. RESULTS: CSF levels of S100B correlated with NSE, but not the other CSF parameters. Stepwise multiple linear regression, adjusted for age, sex, and educational level, revealed that only increased CSF S100B was independently associated with lower CERAD-Plus total and Mini-Mental Status Examination scores together with poorer performance in wordlist learning (delayed recall and overall performance). We found no independent associations with other CSF biomarkers or cognitive domains. CONCLUSION: Our data suggest that CSF S100B may have a diagnostic value particularly at early stages of AD reflecting the significance of neuroinflammatory/astroglial processes. Thus, CSF S100B may complement the established array of available AD biomarkers to improve early stage diagnosis.
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Fragmentos de Peptídeos/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Fosforilação , Sistema de Registros , Estudos RetrospectivosRESUMO
Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.
Assuntos
Proteínas de Neurofilamentos/líquido cefalorraquidiano , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Oligonucleotídeos/farmacologia , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Projetos Piloto , Estudos Prospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Atrofias Musculares Espinais da Infância/líquido cefalorraquidiano , Adulto Jovem , Proteínas tau/sangueRESUMO
Biomarkers classically studied in Alzheimer's disease have been analyzed in numerous central nervous system infections in adults, but there are scarce data on these biomarkers in children. Enteroviruses appear to be the most common cause of aseptic meningitis throughout the world. The aim of the study was to investigate neuroinflammatory properties of non-polio enteroviruses by measuring CSF concentrations of biomarkers that are involved in neuropathological pathways of neurodegenerative disorders. We measured Aß42, t-tau, and S100B concentrations in 42 children with enteroviral meningitis (EM) compared to control group without central nervous system infection. We found enteroviral meningitis (EM) to reduce CSF concentration of Aß42 (median, 1051.1 pg/mL; interquartile range (IQR), 737.6-1559.5 vs. median, 459.4 pg/mL; IQR, 312.0-662.0, p < 0.001). In contrast, CSF concentrations of t-tau and S100B were not affected by EM. There was a correlation between total neutrophil count in CSF and Aß42 (R = - 0.59, p < 0.001). Absolute number of mononuclear cells in the CSF correlated with CSF t-tau (R = 0.41, p < 0.05). Both correlations remained significant after adjustment for age, blood leukocytes, serum CRP, CSF leukocytes, and CSF protein concentration.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Infecções por Enterovirus/líquido cefalorraquidiano , Meningite Viral/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Adolescente , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Enterovirus , Feminino , Hospitalização , Humanos , Masculino , Polônia , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Centros de Atenção Terciária , Proteínas tau/líquido cefalorraquidianoRESUMO
The identification of hypothermia as the cause of death remains challenging in forensic pathology because of unspecific radiological, morphological, and biochemical results. Hyperemia, edema, and petechial hemorrhages within the cerebral parenchyma were described in cases of death by hypothermia. On the other hand, the effect of low temperatures in the brain has been speculated to cause local injuries on a cellular level with potential occurrences of necrosis and inflammation. In the study herein described, endocan, alkaline phosphatase, neuron-specific enolase, S100 protein subunit B, glial fibrillary acidic protein, and C-reactive protein were measured in postmortem serum from femoral blood and cerebrospinal fluid in a series of hypothermia fatalities and control cases. The combination of data collected failed to identify a specific biochemical profile for death by hypothermia in postmortem serum and/or the cerebrospinal fluid, thus suggesting that an alternative panel of brain damage biomarkers indicative of diffuse hypoxic brain injury needs to be defined in hypothermia fatalities.
Assuntos
Hipotermia/sangue , Hipotermia/líquido cefalorraquidiano , Hipóxia-Isquemia Encefálica/diagnóstico , Adulto , Idoso , Fosfatase Alcalina/sangue , Fosfatase Alcalina/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Medicina Legal , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/líquido cefalorraquidiano , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Proteoglicanas/sangue , Proteoglicanas/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Adulto JovemRESUMO
In recent decades a significant scientific effort has focused on projects regarding the use of neurobiomarkers in perinatal medicine with a view to understanding the mechanisms that interfere with physiological patterns of brain development and lead to ominous effects in several human diseases. Numerous potential neurobiomarkers have been proposed for use in monitoring high-risk fetuses and newborns, including markers of oxidative stress, neuroproteins, and vasoactive agents. Nonetheless, the use of these markers in clinical practice remains a matter of debate. Recently, the calcium-binding S100B protein has been proposed as being an ideal neurobiomarker, thanks to its simple availability and easy reproducibility, to the possibility of detecting it noninvasively in biological fluids with good reproducibility, and to the possibility of a longitudinal evaluation in relation to reference curves. The present chapter contains an overview of the most significant studies on the assessment of S100B in different biological fluids as a trophic factor and/or marker of brain damage in high-risk fetuses and newborns.
Assuntos
Biomarcadores/metabolismo , Doenças do Sistema Nervoso Central/diagnóstico , Sistema Nervoso Central/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Doenças do Sistema Nervoso Central/metabolismo , Testes Diagnósticos de Rotina , Feminino , Humanos , Imunoensaio , Recém-Nascido , Estresse Oxidativo , Gravidez , Prognóstico , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/urinaRESUMO
Sepsis-associated encephalopathy (SAE) has significant impact on the neurocognitive outcome of sepsis survivors. This study was conducted to analyze the amino-terminal propeptide of the C-type natriuretic peptide (NT-proCNP) as a biomarker for SAE in comparison to neuron-specific enolase (NSE) and S100B protein. Cerebrospinal fluid (CSF) and plasma samples from twelve septic patients with SAE and nine non-septic controls without encephalopathy were analyzed. The assessment of SAE comprised a neuropsychiatric examination, delirium screening using the confusion assessment method in the ICU (CAM-ICU) and magnetic resonance imaging (MRI) in all participants. NSE, S100B and NT-proCNP were measured in plasma at study days 1, 3 and 7 in sepsis patients, once in controls and once in the CSF of both groups. The long-term outcome was assessed using the validated Barthel index (BI). Plasma NT-proCNP levels were significantly higher in the sepsis cohort compared to controls with peak concentrations at study day 1 (10.1 ± 6.6 pmol/l vs. 3.3 ± 0.9 pmol/l; p < 0.01) and a decrease over time. Plasma NT-proCNP levels at day 7 correlated with NT-proCNP in CSF (r = 0.700, p < 0.05). A comparable decrease of significantly higher plasma S100B values in sepsis patients compared to controls was observed. Plasma NSE levels were not significantly different between both groups. CSF NT-proCNP levels just tended to be higher in sepsis patients compared to controls and tended to be higher in patients with septic brain lesions seen on MRI. In the sepsis cohort CSF NT-proCNP levels correlated with CSF Interleukin-6 (IL-6) levels (r = 0.616, p < 0.05) and systemic inflammation represented by high plasma procalcitonin (PCT) levels at day 3 (r = 0.727, p < 0.05). The high peak concentration of plasma NT-proCNP in the early phase of sepsis might help to predict the emergence of SAE during the further course of disease. NT-proCNP in plasma might, in contrast to CSF, indicate neurological impairment in patients with SAE.
Assuntos
Peptídeo Natriurético Tipo C/sangue , Peptídeo Natriurético Tipo C/líquido cefalorraquidiano , Encefalopatia Associada a Sepse/sangue , Encefalopatia Associada a Sepse/líquido cefalorraquidiano , Encefalopatia Associada a Sepse/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proteínas de Transporte/sangue , Proteínas de Transporte/líquido cefalorraquidiano , Encefalite/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Encefalopatia Associada a Sepse/complicações , Adulto JovemRESUMO
Astrocytic impairment is a pathologic feature of neuromyelitis optica spectrum disorder (NMOSD). S100B and glial fibrillary acidic protein (GFAP) are the two most commonly used astrocytic markers. The aim of this study was to evaluate whether CSF-S100B could serve as a marker of NMOSD. We enrolled 49 NMOSD patients [25 aquaporin-4 antibody (AQP4-Ab)-positive, 8 myelin-oligodendrocyte glycoprotein antibody (MOG-Ab)-positive, and 16 seronegative patients], 12 multiple sclerosis (MS) patients, and 15 other noninflammatory neurological diseases (OND) patients. The CSF levels of S100B and GFAP were measured by ELISA. Both CSF-S100B and GFAP levels significantly discriminated NMOSD from MS [area under curve (AUC) = 0.839 and 0.850, respectively] and OND (AUC = 0.839 and 0.850, respectively). The CSF-S100B levels differentiated AQP4-Ab-positive NMOSD from MOG-Ab-positive NMOSD with higher accuracy than the CSF-GFAP levels (AUC=0.865 and 0.772, respectively). The CSF-S100B levels also significantly discriminated MOG-Ab-positive patients from seronegative patients (AUC = 0.848). Both CSF-S100B and GFAP levels were correlated with the Expanded Disability Status Scale (EDSS) during remission. Only the CSF-S100B levels were correlated with the CSF WBC count and the EDSS during attack. The levels of CSF-S100B seemed to have a longer lasting time than the levels of CSF-GFAP, which may benefit patients who present late. As a result, CSF-S100B might be a potential candidate biomarker for NMOSD in discriminating, evaluating severity, and predicting disability.
Assuntos
Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Neuromielite Óptica/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/patologiaRESUMO
BACKGROUND: S100B is a calcium-binding protein located in glial cells; it is regarded as a potential biomarker in affective disorders. AIM: To review the literature investigating the role of S100B in patients with affective disorders. METHOD: A systematic review of original English language studies investigating S100B in serum, cerebrospinal fluid, plasma and lymphocytes, in patients with affective disorders, was conducted. The literature search was conducted within the PubMed database. Effect sizes were calculated to adjust for systematic measurement effects. RESULTS: Twenty studies were included, with a total of 1292 participants. Of these, 398 patients had or have had depressive disorder, 301 patients had bipolar disorder and 593 were healthy controls. S100B levels in serum were consistently elevated in studies with statistically significant results which investigated acute affective episodes (comprising major depressive episode in major depressive disorder, and both manic and depressive episodes in patients with bipolar disorder), in comparison to healthy controls. There were few studies assessing S100B levels in cerebrospinal fluid, plasma or lymphocytes, and these had inconsistent results. CONCLUSION: The results indicated that elevated S100B levels might be associated with mood episodes in affective disorders. However, the role of S100B, and its possible impact in affective disorders, requires further investigation and at the present S100B does not have a role as clinically biomarker in affective disorder. Future longitudinal multicentre studies with larger transdiagnostic real life patient cohorts are warranted.