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2.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769052

RESUMO

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRß in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Encéfalo/virologia , COVID-19/fisiopatologia , Encefalite Viral/virologia , Pericitos/virologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Barreira Hematoencefálica , Encéfalo/patologia , COVID-19/etiologia , Estudos de Casos e Controles , Encefalite Viral/patologia , Fibrinogênio/metabolismo , Humanos , Imuno-Histoquímica/métodos , Camundongos , Pericitos/metabolismo , Pericitos/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano
3.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641541

RESUMO

Glioblastoma Multiforme (GBM) is a brain tumor with a poor prognosis and low survival rates. GBM is diagnosed at an advanced stage, so little information is available on the early stage of the disease and few improvements have been made for earlier diagnosis. Longitudinal murine models are a promising platform for biomarker discovery as they allow access to the early stages of the disease. Nevertheless, their use in proteomics has been limited owing to the low sample amount that can be collected at each longitudinal time point. Here we used optimized microproteomics workflows to investigate longitudinal changes in the protein profile of serum, serum small extracellular vesicles (sEVs), and cerebrospinal fluid (CSF) in a GBM murine model. Baseline, pre-symptomatic, and symptomatic tumor stages were determined using non-invasive motor tests. Forty-four proteins displayed significant differences in signal intensities during GBM progression. Dysregulated proteins are involved in cell motility, cell growth, and angiogenesis. Most of the dysregulated proteins already exhibited a difference from baseline at the pre-symptomatic stage of the disease, suggesting that early effects of GBM might be detectable before symptom onset.


Assuntos
Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/líquido cefalorraquidiano , Glioblastoma/sangue , Glioblastoma/líquido cefalorraquidiano , Proteômica/métodos , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/líquido cefalorraquidiano , Proteínas Sanguíneas/análise , Proteínas do Líquido Cefalorraquidiano/análise , Vesículas Extracelulares/patologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/sangue , Neoplasias Experimentais/líquido cefalorraquidiano , Neoplasias Experimentais/patologia , Fluxo de Trabalho
4.
PLoS One ; 16(10): e0257372, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34618817

RESUMO

AIM: Several pathophysiological processes are involved in Parkinson's disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer's Disease, in a PD cohort. METHODS: Longitudinal cerebrospinal fluid (CSF) samples from PPMI (252 PD, 115 healthy controls, HC) were analyzed at six timepoints (baseline, 6, 12, 24, 36, and 48 months follow-up) using Elecsys® electrochemiluminescence immunoassays to quantify neurofilament light chain (NfL), soluble TREM2 receptor (sTREM2), chitinase-3-like protein 1 (YKL40), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), S100, and total α-synuclein (αSyn). RESULTS: αSyn was significantly lower in PD (mean 103 pg/ml vs. HC: 127 pg/ml, p<0.01; area under the curve [AUC]: 0.64), while all other biomarkers were not significantly different (AUC NfL: 0.49, sTREM2: 0.54, YKL40: 0.57, GFAP: 0.55, IL-6: 0.53, S100: 0.54, p>0.05) and none showed a significant difference longitudinally. We found significantly higher levels of all these markers between PD patients who developed cognitive decline during follow-up, except for αSyn and IL-6. CONCLUSION: Except for αSyn, the additional biomarkers did not differentiate PD and HC, and none showed longitudinal differences, but most markers predict cognitive decline in PD during follow-up.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Neuroglia/patologia , Doença de Parkinson/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia , alfa-Sinucleína/líquido cefalorraquidiano
5.
PLoS One ; 16(10): e0258165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34597351

RESUMO

Brain aquaporin 1 (AQP1) and AQP4 are involved in cerebrospinal fluid (CSF) homeostasis and might participate in the origin of hydrocephalus. Studies have shown alterations of perivascular AQP4 expression in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD). Due to the overlapping of clinical signs between iNPH and certain neurological conditions, mainly AD, specific biomarkers might improve the diagnostic accuracy for iNPH. The goal of the present study was to analyze and quantify the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant's demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH.


Assuntos
Doença de Alzheimer/diagnóstico , Aquaporina 1/líquido cefalorraquidiano , Aquaporina 4/líquido cefalorraquidiano , Diagnóstico Diferencial , Hidrocefalia de Pressão Normal/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/genética , Hidrocefalia de Pressão Normal/patologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/genética
7.
Cell Rep ; 37(5): 109942, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34706272

RESUMO

Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Envelhecimento/imunologia , Animais , COVID-19/líquido cefalorraquidiano , COVID-19/complicações , COVID-19/imunologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/virologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Feminino , Humanos , Ativação Linfocitária , Macaca mulatta , Masculino , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/prevenção & controle , Profilaxia Pré-Exposição , Linfócitos T/imunologia , Replicação Viral/imunologia
8.
BMC Neurol ; 21(1): 387, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615471

RESUMO

BACKGROUND: Hepatocyte growth factor (HGF) plays a role in neuronal survival and development, and has been implicated in neurodegenerative diseases. We sought to examine the associations of the CSF HGF with Alzheimer's disease (AD) pathology and cognitive function. METHODS: A total of 238 participants (including 90 cognitively normal (CN) and 148 mild cognitive impairment (MCI)) who had measurements of CSF HGF were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Multiple linear regression models were utilized to explore the cross-sectional associations of CSF HGF with AD biomarkers (including Aß42, pTau, and tTau proteins) in non-demented participants. Moreover, linear mixed-effects regression models were utilized to explore the longitudinal associations of HGF subgroups with cognitive function. Mediation analyses were utilized to explore the mediation effects of AD markers. RESULTS: MCI individuals had significantly increased CSF HGF compared with the CN individuals. Results of multiple linear regressions showed significant correlations of CSF HGF with CSF Aß42, pTau, and tTau in non-demented participants. Higher level of baseline CSF HGF was associated with faster cognitive decline. Influences of the baseline CSF HGF on cognition were partially mediated by Aß42, pTau, and tTau pathologies. CONCLUSIONS: High concentrations of HGF in CSF may be related to faster cognitive decline. The cognitive consequences of higher CSF HGF partly stem from AD pathology, which suggests that the CSF HGF may be an attractive biomarker candidate to track AD progression.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Fator de Crescimento de Hepatócito/metabolismo , Peptídeos beta-Amiloides , Biomarcadores , Cognição , Estudos Transversais , Fator de Crescimento de Hepatócito/líquido cefalorraquidiano , Humanos , Fragmentos de Peptídeos , Proteínas tau
9.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638953

RESUMO

Tick-borne encephalitis (TBE) is an acute disease caused by the tick-borne encephalitis virus. Due to the viral nature of the condition, there is no effective causal treatment for full-blown disease. Current and nonspecific TBE treatments only relieve symptoms. Unfortunately, the first phase of TBE is characterized by flu-like symptoms, making diagnosis difficult during this period. The second phase is referred to as the neurological phase as it involves structures in the central nervous system-most commonly the meninges and, in more severe cases, the brain and the spinal cord. Therefore, it is important that early markers of TBE that will guide clinical decision-making and the choice of treatment are established. In this review, we performed an extensive search of literature reports relevant to biomarkers associated with TBE using the MEDLINE/PubMed database. We observed that apart from routinely determined specific immunoglobulins, free light chains may also be useful in the evaluation of intrathecal synthesis in the central nervous system (CNS) during TBEV infection. Moreover, selected metalloproteinases, chemokines, or cytokines appear to play an important role in the pathogenesis of TBE as a consequence of inflammatory reactions and recruitment of white blood cells into the CNS. Furthermore, we reported promising findings on tau protein or Toll-like receptors. It was also observed that some people may be predisposed to TBE. Therefore, to understand the role of selected tick-borne encephalitis biomarkers, we categorized these factors and discussed their potential application in the diagnosis, prognosis, monitoring, or management of TBE.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos/sangue , Encefalite Transmitida por Carrapatos/líquido cefalorraquidiano , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Barreira Hematoencefálica/patologia , Quimiocinas/sangue , Quimiocinas/líquido cefalorraquidiano , Encefalite Transmitida por Carrapatos/diagnóstico , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/virologia , Predisposição Genética para Doença , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina M/sangue , Imunoglobulina M/líquido cefalorraquidiano , Cadeias lambda de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/líquido cefalorraquidiano , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/líquido cefalorraquidiano
10.
Int J Mol Sci ; 22(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34638664

RESUMO

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice.


Assuntos
Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Esclerose Múltipla/patologia , Progressão da Doença , Humanos , Inflamação/sangue , Inflamação/líquido cefalorraquidiano , Inflamação/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Prognóstico , Reprodutibilidade dos Testes
11.
Neurosci Bull ; 37(11): 1570-1582, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34487324

RESUMO

Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50-59 year group. Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt-Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese.


Assuntos
Proteínas 14-3-3/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Proteínas Priônicas/genética , Príons , Proteínas tau/líquido cefalorraquidiano , China , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/epidemiologia , Síndrome de Creutzfeldt-Jakob/genética , Humanos , Mutação/genética , Doenças Priônicas/epidemiologia , Doenças Priônicas/genética , Príons/genética
12.
Cancer Sci ; 112(11): 4702-4710, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34523186

RESUMO

The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non-surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell-free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Biópsia Líquida/métodos , Linfoma/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Nucleicos Livres/líquido cefalorraquidiano , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/isolamento & purificação , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico , DNA de Neoplasias/líquido cefalorraquidiano , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linfoma/líquido cefalorraquidiano , Linfoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/líquido cefalorraquidiano , Reação em Cadeia da Polimerase/métodos , Sensibilidade e Especificidade
13.
Chemotherapy ; 66(4): 134-138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34515081

RESUMO

A patient with a therapy-related acute myeloid leukaemia (AML), NPM1mut, and FLT3-ITD+ was treated with induction and consolidation with CPX-351, obtaining a complete response (CR) but minimal residual disease persisted positive. Later, she complained progressive burning leg pain, weakening of the right hand and leg muscles, associated with absence of osteotendinous leg reflexes. Examination of cerebrospinal fluid (CSF) showed a meningeal relapse of AML. Moreover, a magnetic resonance imaging (MRI) showed 2 right meningeal implants of myeloid sarcoma and bone marrow revealed haematologic relapse of disease. She was treated with medicated lumbar punctures (LPs) followed by an FLA-Ida scheme, and she achieved a 2nd CR. Unfortunately, the patient developed hyperleucocytosis and reappearance of meningeal myeloid sarcoma at MRI. For this reason, a monotherapy with gilteritinib (an FLT3 inhibitor) was started: after 3 months of therapy, central nervous system (CNS)-disease shrunken and then faded, while AML in the bone marrow achieved only a partial response. This is the 1st report of a positive biological effect of gilteritinib on CNS (meningeal) myeloid sarcoma. There are no studies of gilteritinib concentration into CSF and penetration of gilteritinib into the blood-brain barrier should be further studied, given the paucity of drugs active on CNS relapse of AML. In patients receiving CPX-351 only, diagnostic LP should be considered after induction.


Assuntos
Compostos de Anilina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Compostos de Anilina/líquido cefalorraquidiano , Medula Óssea/patologia , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Mutação , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Pirazinas/líquido cefalorraquidiano , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
14.
Neurology ; 97(17): e1681-e1694, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34493616

RESUMO

BACKGROUND AND OBJECTIVES: Phosphorylated tau (p-tau) in CSF is considered an important biomarker in Alzheimer disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including p-tau at threonines 181 (p-tau181), 217 (p-tau217), and 231 (p-tau231). However, no studies have compared their diagnostic performance or association to ß-amyloid (Aß) and tau-PET. Understanding which p-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of p-tau181, p-tau217, and p-tau231 in CSF for AD and their association with Aß and tau-PET. METHODS: A total of 629 participants in the Swedish BioFINDER-2 study were included (cognitively unimpaired, n = 334; Aß-positive mild cognitive impairment, n = 84; AD dementia, n = 119; and non-AD disorders, n = 92). In addition to p-tau181 and p-tau217 measured using assays with the same detector antibodies from Eli Lilly (p-tau181Lilly, p-tau217Lilly) and p-tau231, we also included p-tau181 measurements from 2 commonly used assays (Innotest and Elecsys). RESULTS: Although all p-tau variants increased across the AD continuum, p-tau217Lilly showed the greatest dynamic range (13-fold increase vs 1.9-5.4-fold increase for other p-tau variants for AD dementia vs non-AD). P-Tau217Lilly showed stronger correlations with Aß- and tau-PET (p < 0.0001). P-Tau217Lilly exhibited higher accuracy than other p-tau variants for separating AD dementia from non-AD (area under the curve [AUC], 0.98 vs 0.88 [p < 0.0001] - 0.96 [p < 0.05]) and for identifying Aß-PET (AUC, 0.86 vs 0.74 [p < 0.0001] and 0.83 [p < 0.001]) and tau-PET positivity (AUC, 0.94 vs 0.80-0.92, p < 0.0001). Finally, p-Tau181Lilly generally performed better than the other p-tau181 assays (e.g., AD dementia vs non-AD, AUC, 0.96 vs 0.88 [p-tau181Innotest] and 0.89 [p-tau181Elecsys]; p < 0.0001). DISCUSSION: CSF p-tau217Lilly seems to be more useful than other included p-tau assays in the workup of AD. Varied results across p-tau181 assays highlights the importance of anti-tau antibodies for biomarker performance. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that p-tau217 provides higher diagnostic accuracy for diagnosis of AD dementia than p-tau181 or p-tau231.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoensaio/métodos , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/líquido cefalorraquidiano , Sensibilidade e Especificidade , Suécia
15.
PLoS One ; 16(9): e0257946, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587214

RESUMO

BACKGROUND: Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls. METHODS: We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME). DISCUSSION: This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options. TRIAL REGISTRATION: The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).


Assuntos
Anticorpos Antinucleares/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Transtornos Psicóticos/imunologia , Adulto , Idade de Início , Anticorpos Antinucleares/sangue , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transtornos Psicóticos/líquido cefalorraquidiano , Qualidade de Vida , Albumina Sérica Humana/líquido cefalorraquidiano , Adulto Jovem
16.
J Immunol Methods ; 499: 113150, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34560071

RESUMO

Anti-N-methyl-d-aspartate receptor (NMDAR) antibodies are most frequently detected in autoantibody-related autoimmune encephalitis. Anti-NMDAR encephalitis mainly affects young women with ovarian teratoma, including acute to subacute onset of psychosis, seizures, consciousness disturbance, dyskinetic involuntary movements, autonomic dysfunction, and others. Diagnosis is based on the detection of anti-NMDAR autoantibodies in cerebrospinal fluid (CSF). The autoantibody recognizes the conformational epitope of the NMDA receptor. NMDA receptors contain hetero-tetramers of GluN1 (NR1) and GluN2/3 (NR2/3), in which GluN1 is essential to form functional receptors on the synaptic membrane in the brain. Thus, the autoantibodies are detected using neurons or culture cells expressing conformational receptors on their cell membrane, the natural form in the brain. The antibodies detected using artificial GluN1 monosubunit expressing cells as the antigens have been widely used for anti-NMDAR-antibody test. In the present study two detection systems were compared, a live-cell-based assay using human embryonic kidney (HEK) 293 cells expressing both of GluN1 and GluN2B, and a commercially available GluN1-monotransfected HEK cell biochip system. As the result, both the methods were equivalent, and the clinical features of both groups were similar, suggesting both tests have equal clinical significance.


Assuntos
Autoanticorpos/análise , Adulto , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/imunologia , Feminino , Células HEK293 , Humanos , Masculino , Receptores de N-Metil-D-Aspartato/imunologia
17.
Sci Rep ; 11(1): 18528, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535701

RESUMO

To investigate whether cerebrospinal fluid (CSF) markers differ between pediatric-onset multiple sclerosis (PoMS, onset < 18 years) and adult-onset (AoMS), and whether these markers are associated with clinical outcomes among PoMS. Prospective nationwide registry study of incident MS, including persons with a CSF sample < 3 years post-MS onset. We compared CSF oligoclonal band (OCB) status, immunoglobulin G (IgG) index levels, and mononuclear cell count between PoMS and AoMS. Within the PoMS cohort we analyzed the association between CSF markers, relapse rate and Expanded Disability Status Scale (EDSS) score, using negative binomial regression and generalized estimating equations, respectively. The cohort consisted of 130 PoMS and 3228 AoMS cases. The PoMS group had higher odds of OCB-positivity (odds ratio: 2.70; 95% CI 1.21-7.67). None of the CSF markers were associated with relapse rate in the PoMS cohort; however, OCB-positivity was associated with higher EDSS scores. This study suggested that PoMS more commonly display CSF evidence for intrathecal IgG production than AoMS. Further, we found evidence of a relationship between OCB-positivity and subsequent disability, suggesting that they could play a role in the prognostication of MS in children.


Assuntos
Esclerose Múltipla/líquido cefalorraquidiano , Adolescente , Adulto , Idade de Início , Biomarcadores/líquido cefalorraquidiano , Criança , Feminino , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Masculino , Esclerose Múltipla/etiologia , Bandas Oligoclonais/líquido cefalorraquidiano , Estudos Prospectivos
18.
J Prev Alzheimers Dis ; 8(4): 477-482, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34585223

RESUMO

BACKGROUND: Recent biomarker studies demonstrated that the central nervous system (CNS) environment can be observed from peripherally-derived samples. In a previous study, we demonstrated significant hypomethylation of the BRCA1 promoter region in neuronal cells from post-mortem brains of Alzheimer's disease patients through neuron-specific methylome analysis. Thus, we investigate the methylation changes in the BRCA1 promoter region in the blood samples. OBJECTIVES: To analyze the methylation level of the BRCA1 promoter in peripheral blood from AD patients and normal controls. DESIGN, SETTING, PARTICIPANTS: Genomic DNA samples from peripheral blood were obtained from the J-ADNI repository, and their biomarker data were obtained J-ADNI from the National Bioscience Database Center. Genomic DNA samples from an independent cohort for validation was obtained from Niigata University Hospital (Niigata, Japan). Amyloid positivity was defied by visual inspection of amyloid PET or a CSF Aß42 value ≤ 333 pg/mL at the baseline. MEASUREMENTS: Methylation level of the BRCA1 promoter was analyzed by pyrosequencing. RESULTS: Compared to normal controls, methylation of the BRCA1 promoter in AD patients was not significantly changed; however, in AD patients, it showed a positive correlation with AD risk factors. CONCLUSIONS: Our data confirmed the importance of cell-type specific methylome analysis and also suggested that environmental changes in the CNS can be detected by observing the peripheral blood, implying that the peripheral BRCA1 methylation level can be a surrogate for AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Proteína BRCA1/genética , Metilação de DNA , Regiões Promotoras Genéticas , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Amiloide , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Japão , Masculino , Tomografia por Emissão de Pósitrons , Fatores de Risco
19.
J Prev Alzheimers Dis ; 8(4): 495-502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34585225

RESUMO

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.


Assuntos
Doença de Alzheimer , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Carbolinas , Disfunção Cognitiva/líquido cefalorraquidiano , Humanos , Japão , Imageamento por Ressonância Magnética , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo
20.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575909

RESUMO

Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of hydrocephalus by hypoxia in aged mice, reproducing such principal characteristics of the disease. Here, we explore whether these alterations associated with the hydrocephalic state are permanent or can be reverted by reexposure to normoxia. Alterations such as ventriculomegaly, elevated intracranial pressure, and cognitive deficits were reversed, whereas deficits in CSF outflow and ventricular distensibility were not recovered, remaining impaired even one month after reestablishment of normoxia. Interestingly, in AQP4-/- mice, the impairment in CSF drainage and ventricular distensibility was completely reverted by re-normoxia, indicating that AQP4 has a structural role in the chronification of those alterations. Finally, we show that aged mice subjected to two hypoxic episodes experience permanent ventriculomegaly. These data reveal that repetitive hypoxic events in aged cerebral tissue promote the permanent alterations involved in hydrocephalic pathophysiology, which are dependent on AQP4 expression.


Assuntos
Aquaporina 4/genética , Suscetibilidade a Doenças , Hidrocefalia/etiologia , Hidrocefalia/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Fatores Etários , Animais , Aquaporina 4/líquido cefalorraquidiano , Aquaporina 4/metabolismo , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Hidrocefalia/diagnóstico , Hidrocefalia/patologia , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Camundongos , Fenótipo
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