Assuntos
Biomarcadores/sangue , Lesões Encefálicas/sangue , Degeneração Neural/sangue , Voo Espacial , Peptídeos beta-Amiloides/sangue , Lesões Encefálicas/etiologia , Proteína Glial Fibrilar Ácida/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/etiologia , Proteínas de Neurofilamentos/sangue , Fragmentos de Peptídeos/sangueRESUMO
Microglial activation is a central player in the pathophysiology of Alzheimer's disease (AD). The soluble fragment of triggering receptor expressed on myeloid cells 2 (sTREM2) can serve as a marker for microglial activation and has been shown to be overexpressed in AD. However, the relationship of sTREM2 with other AD biomarkers has not been extensively studied. We investigated the relationship between cerebrospinal fluid (CSF) sTREM2 and other AD biomarkers and examined the correlation of plasma sTREM2 with CSF sTREM2 in a cohort of individuals with AD and without AD. Participants were consecutively recruited from Asan Medical Center from 2018 to 2020. Subjects were stratified by their amyloid positivity and clinical status. Along with other AD biomarkers, sTREM2 level was measured in the plasma as well as CSF. In 101 patients with either amyloid-positive or negative status, CSF sTREM2 was closely associated with CSF T-tau and P-tau and not with Abeta42. CSF sTREM2 levels were found to be strongly correlated with CSF neurofilament light chain. The comparison of CSF and plasma sTREM2 levels tended to have an inverse correlation. Plasma sTREM2 and P-tau levels were oppositely influenced by age. Our results suggest that neuroinflammation may be closely associated with tau-induced neurodegeneration.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/líquido cefalorraquidiano , Receptores Imunológicos/sangue , Fatores Etários , Idoso , Amiloide/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Bases de Dados como Assunto , Feminino , Humanos , Masculino , Degeneração Neural/sangue , Fosforilação , Solubilidade , Proteínas tau/líquido cefalorraquidianoRESUMO
Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays ß1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1-3] vs. 21[16-52] ng/mL, p < 0.01). In this preclinical model, ß1-blockade during CPR did not facilitate VF termination but provided neuroprotection.
Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca/tratamento farmacológico , Neurônios/patologia , Propanolaminas/uso terapêutico , Animais , Gasometria , Encéfalo/patologia , Modelos Animais de Doenças , Parada Cardíaca/sangue , Parada Cardíaca/complicações , Parada Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Degeneração Neural/sangue , Degeneração Neural/complicações , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Perfusão , Fosfopiruvato Hidratase/sangue , Pressão , Propanolaminas/farmacologia , SuínosRESUMO
Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. Exposure to early life trauma (ELT) has been associated with higher relapse rates in MS patients; however, the underlying mechanisms are not well-defined. Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-ß resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement. These phenotypic changes are observed in control EAE mice treated with ß1 adrenergic receptor antagonist. Conversely, ß1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell ß1 adrenergic receptor function. Our results indicate that ELT alters EAE phenotype via downregulation of ß1 adrenergic signaling in immune cells. These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.
Assuntos
Regulação para Baixo , Interferon beta/metabolismo , Esclerose Múltipla/complicações , Degeneração Neural/complicações , Receptores Adrenérgicos beta 1/metabolismo , Transdução de Sinais , Estresse Psicológico/complicações , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Biomarcadores/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/patologia , Feminino , Complexo de Golgi/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Degeneração Neural/sangue , Degeneração Neural/imunologia , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Norepinefrina/sangue , Fenótipo , Índice de Gravidade de Doença , Regulação para Cima/efeitos dos fármacosRESUMO
The availability of blood-based assays detecting Alzheimer's disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. This is especially true for markers that capture the risk of decline in pre-symptomatic stages of AD, as this would allow one to focus interventions on participants maximally at risk and at a stage prior to widespread synapse loss and neurodegeneration. Here we quantify plasma concentrations of an N-terminal fragment of tau (NT1) in a large, well-characterized cohort of clinically normal elderly who were followed longitudinally. Plasma NT1 levels at study entry (when all participants were unimpaired) were highly predictive of future cognitive decline, pathological tau accumulation, neurodegeneration, and transition to a diagnosis of MCI/AD. These predictive effects were particularly strong in participants with even modestly elevated brain ß-amyloid burden at study entry, suggesting plasma NT1 levels capture very early cognitive, pathologic and neurodegenerative changes along the AD trajectory.
Assuntos
Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Degeneração Neural/sangue , Degeneração Neural/complicações , Proteínas tau/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Feminino , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória Episódica , Degeneração Neural/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Encefalopatias Metabólicas/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Catepsina D/sangue , Glutaril-CoA Desidrogenase/deficiência , Degeneração Neural/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Biomarcadores/sangue , Encefalopatias Metabólicas/complicações , Criança , Pré-Escolar , Feminino , Glutaril-CoA Desidrogenase/sangue , Humanos , Lactente , Recém-Nascido , Masculino , Degeneração Neural/sangue , Degeneração Neural/etiologia , Moléculas de Adesão de Célula Nervosa/sangue , Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Irradiation of food at 50-55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain. There is no evidence of oligodendrocyte death. The spinal cord dorsal column is initially spared yet eventually becomes severely demyelinated with subsequent loss of axons in the core and then surface of the fasciculus gracilis. However remyelination of the sub-pial axons in the dorsal column results in their protection. While there was a lack of biochemical evidence of Vitamin B12 deficiency, the pathological similarities of FIDID with sub-acute combined degeneration (SCD) led us to explore treatment with Vitamin B12. Treatment led to recovery or improvement in some cats and neurologic relapse on cessation of B12 therapy. While the reason that irradiated food is myelinotoxic in the cat remains unresolved, nonetheless the neuropathological changes match exactly what is seen in SCD and its models and provide an ideal model to study the cellular and molecular basis of remyelination.
Assuntos
Doenças Desmielinizantes/patologia , Dieta , Degeneração Neural/patologia , Radiação , Doença Aguda , Animais , Axônios/patologia , Gatos , Doença Crônica , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Macrófagos/patologia , Masculino , Metaboloma , Microglia/patologia , Bainha de Mielina/metabolismo , Degeneração Neural/sangue , Degeneração Neural/fisiopatologia , Neuropatologia , Remielinização , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Fatores de Tempo , Vitamina B 12/sangueRESUMO
OBJECTIVE: Identifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA. METHODS: We examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 (SMN2) copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE). RESULTS: Patients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93-2.49; p < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52-1.82; p < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31-1.58; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.8-fold (95% CI 1.57-2.11; p < 0.0001) higher Crn levels compared to patients with SMA with 2 SMN2 copies and 1.4-fold (95% CI 1.24-1.58; p < 0.0001) higher Crn levels compared to patients with SMA with 3 SMN2 copies. Patients with SMA with 3 SMN2 copies had 1.4-fold (95% CI 1.21-1.56; p < 0.0001) higher Crn levels than patients with SMA with 2 SMN2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters (p < 0.0001) and positive associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, SMN2 copies, HFMS, CMAP, and MUNE. CONCLUSIONS: These findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.
Assuntos
Creatinina/sangue , Atrofia Muscular Espinal/diagnóstico , Degeneração Neural/diagnóstico , Potenciais de Ação/fisiologia , Biomarcadores/sangue , Contagem de Células , Criança , Variações do Número de Cópias de DNA/genética , Progressão da Doença , Feminino , Humanos , Lactente , Masculino , Neurônios Motores/patologia , Músculo Esquelético/fisiologia , Atrofia Muscular Espinal/sangue , Atrofia Muscular Espinal/genética , Degeneração Neural/sangue , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-ß deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Progressão da Doença , Degeneração Neural/sangue , Proteínas de Neurofilamentos/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Humanos , Mutação/genética , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/genéticaRESUMO
Introduction: There is alarming evidence about the involvement of general anaesthesia in the development of postoperative cognitive dysfunction. Aim: To clarify the impact of general anaesthesia on cognitive function and to study the possible effect of general anaesthesia on serum S100B, the marker of neuronal degeneration. Methods: This is a prospective randomised controlled study carried out on 50 patients undergoing elective laparoscopic cholecystectomy under conventional general anaesthesia. Cognitive assessment for selected patients was done preoperative and 1 week postoperative using Paired Associate Learning test (PALT) for assessment of verbal memory and Benton Visual Retention test (BVRT) for assessment of visual memory. Quantitative determination of serum S100B was done for all patients in the basal sample and postoperative sample by applying an enzyme- linked immunoabsorbent assay technique on am automated ELISA platform. Results: Regarding cognitive tests, there was a statistically significant difference between the mean value of preoperative PALT and postoperative PALT (p-value = .012). There was also a statistically significant difference between the mean value of preoperative BVRT and postoperative BVRT (p-value = .011). Regarding S100B, there was a statistically significant difference between preoperative and postoperative serum level (p-value = .002). There was also a statistically significant negative correlation between postoperative S100B serum level and the postoperative scores of both PALT and BVRT. Conclusion: General anaesthesia is incriminated in the development of postoperative verbal and visual memory impairment and in the postoperative increase in serum S100B, the markers of neuronal degeneration.
Assuntos
Anestesia Geral/efeitos adversos , Disfunção Cognitiva/etiologia , Degeneração Neural/etiologia , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto , Colecistectomia Laparoscópica/efeitos adversos , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/sangue , Estudos ProspectivosRESUMO
BACKGROUND: A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer's disease (AD). METHODS: With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid ß (Aß)1-42, Aß42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. RESULTS: NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant association between NfL and age (ρ = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = -0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. CONCLUSIONS: This study confirms increased concentrations of plasma NfL in patients with Alzheimer's disease compared with nondemented controls.
Assuntos
Doença de Alzheimer/complicações , Degeneração Neural/sangue , Degeneração Neural/etiologia , Proteínas de Neurofilamentos/sangue , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Análise em Microsséries , Pessoa de Meia-Idade , Degeneração Neural/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Curva ROCRESUMO
BACKGROUND: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions. METHODS: We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis. RESULTS: NF-L concentrations increased with age (Spearman's rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status. CONCLUSIONS: NF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia.
Assuntos
Síndrome de Down/complicações , Degeneração Neural/sangue , Degeneração Neural/etiologia , Proteínas de Neurofilamentos/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Demência/sangue , Demência/diagnóstico , Demência/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Adulto JovemRESUMO
Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer's disease (AD) in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs) in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i) the presence/absence of AD, (ii) the risk of developing AD, (iii) the progression of AD, or (iv) AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons) is universally present. Current consensus is that the earlier the diagnosis, the better the chance to develop treatments that influence disease progression. In this article we provide a detailed review and analysis of the role of the blood-brain barrier (BBB) and damage-associated molecular patterns (DAMPs) as well as coagulation molecules in the onset and progression of these neurodegenerative disorders.
Assuntos
Doença de Alzheimer/fisiopatologia , Biomarcadores , Barreira Hematoencefálica , Degeneração Neural/fisiopatologia , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Humanos , Degeneração Neural/sangue , Degeneração Neural/líquido cefalorraquidiano , Degeneração Neural/genética , Placa Amiloide/sangue , Placa Amiloide/líquido cefalorraquidiano , Placa Amiloide/fisiopatologiaRESUMO
AIM: To investigatethe association of plasma epoxyeicosatrienoic acids (EETs) with early neurologic deterioration (END), and whether EETs are mediated by EPHX2 variants in patients with minor ischemic stroke (MIS). METHOD: This was a prospective, multi-center observational study in patients with acute MIS in the Chinese population.Plasma EETs levels were measured on admission. Single nucleotide polymorphisms (SNPs) of EPHX2 rs751141 were genotyped using mass spectrometry. The primary outcome was END within 10 days after admission. END was defined as an increase in NIHSS of 2 or more points. The degree of disability was assessed using the modified Rankin Scale (mRS) at 3 months after admission. RESULTS: A total of 322 patients were enrolled, of which 85 patients (26.4%) experienced END. The mean EETs level was 64.1±7.5 nmol/L. EETs levels were significantly lower in patients with END compared to patients without END. Frequency of EPHX2 rs751141 GG was higher in patients with END than in patients without END, and EPHX2 rs751141 GG genotype was associated with lower EETs levels. Low level (ï¼64.4 nmol/L) of EETs was an independent predictor of END (first and second quartiles) in multivariate analyses. END was associated with a higher risk of poor outcome (mRS scores 3-6) at 3 months. CONCLUSION: END is fairly common and associated with poor outcomes in acute MIS. EPHX2 variants may mediate EETs levels, and low levels of EETs may be a predictor for END in acute MIS.
Assuntos
Biomarcadores/sangue , Isquemia Encefálica/complicações , Epóxido Hidrolases/genética , Ácidos Hidroxieicosatetraenoicos/sangue , Degeneração Neural/diagnóstico , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/complicações , Idoso , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Degeneração Neural/sangue , Degeneração Neural/etiologia , Prognóstico , Estudos ProspectivosRESUMO
The purpose of this work was to determine whether changes in cholesterol profiles after interferon-ß (IFN-ß)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-ß1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-ß1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-ß1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-ß1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.
Assuntos
Interferon beta-1a/administração & dosagem , Lipídeos/sangue , Esclerose Múltipla/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Degeneração Neural/sangue , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/patologiaRESUMO
As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3ß,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3ß-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3ß-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3ß,7α-dihydroxycholest-5-en-26-oic acid.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Ácidos e Sais Biliares/isolamento & purificação , Colesterol/isolamento & purificação , Lipídeos/isolamento & purificação , Idoso , Esclerose Lateral Amiotrófica/patologia , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/líquido cefalorraquidiano , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Colesterol/sangue , Colesterol/líquido cefalorraquidiano , Feminino , Humanos , Lipídeos/sangue , Lipídeos/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Degeneração Neural/sangue , Degeneração Neural/líquido cefalorraquidiano , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologiaRESUMO
Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-ß-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.
Assuntos
Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Modelos Animais de Doenças , Progressão da Doença , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Inibidores de Histona Desacetilases/sangue , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/uso terapêutico , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Mutação/genética , Degeneração Neural/sangue , Degeneração Neural/complicações , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Doença de Niemann-Pick Tipo C/sangue , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/patologia , Polietilenoglicóis/química , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/efeitos dos fármacos , Baço/patologia , Análise de Sobrevida , Vorinostat , beta-Ciclodextrinas/químicaRESUMO
Tissue non-specific alkaline phosphatase (TNAP) is present on neuronal membranes and induces neuronal toxicity via tau dephosphorylation; a mechanism which could play a role in the neuronal loss seen in Alzheimer's disease (AD). TNAP increases in the plasma following brain injury and cerebrovascular disease. In this chapter we summarise our previous work which looked at changes in TNAP activity in the brain and plasma of AD individuals and discuss whether these changes may be reflective of neuronal loss. Our data demonstrate that TNAP activity is significantly increased in the brain in both the sporadic and familial forms of AD and that TNAP activity is significantly increased in the plasma in AD patients. In addition, we describe a significant inverse correlation between plasma TNAP activity and cognitive function in AD. Using these data we propose a model for TNAP-induced neurodegeneration in AD resulting from tau dephosphorylation following secretion of tau from neuronal cells.
Assuntos
Fosfatase Alcalina/fisiologia , Doença de Alzheimer/enzimologia , Doenças Neurodegenerativas/enzimologia , Fosfatase Alcalina/sangue , Fosfatase Alcalina/líquido cefalorraquidiano , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Apoptose , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas/sangue , Lesões Encefálicas/líquido cefalorraquidiano , Humanos , Degeneração Neural/sangue , Degeneração Neural/líquido cefalorraquidiano , Degeneração Neural/etiologia , Proteínas tau/metabolismoRESUMO
Neurotoxicity of silver nanoparticles has been confirmed in both in vitro and in vivo studies. However, the mechanisms of the toxic action have not been fully clarified. Since nanoparticles are likely to have the ability to enter the brain and significantly accumulate in this organ, it is important to investigate their neurotoxic mechanisms. Here we examine the effect of prolonged exposure of rats to small (10nm) citrate-stabilized silver nanoparticles (as opposed to the ionic silver) on synapse ultrastructure and specific proteins. Administration of both nanosilver and ionic silver over a two-week period resulted in ultrastructural changes including blurred synapse structure and strongly enhanced density of synaptic vesicles clustering in the center of the presynaptic part. Disturbed synaptic membrane leading to liberation of synaptic vesicles into neuropil, which testifies for strong synaptic degeneration, was characteristic feature observed under AgNPs exposure. Also a noteworthy finding was the presence of myelin-like structures derived from fragmented membranes and organelles which are associated with neurodegenerative processes. Additionally, we observed significantly decreased levels of the presynaptic proteins synapsin I and synaptophysin, as well as PSD-95 protein which is an indicator of postsynaptic densities. The present study demonstrates that exposure of adult rats to both forms of silver leads to ultrastructural changes in synapses. However, it seems that small AgNPs lead to more severe synaptic degeneration, mainly in the hippocampal region of brain. The observations may indicate impairment of nerve function and, in the case of hippocampus, may predict impairment of cognitive processes.
Assuntos
Encéfalo/patologia , Nanopartículas/toxicidade , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Compostos de Prata/toxicidade , Sinapses/efeitos dos fármacos , Administração Oral , Análise de Variância , Animais , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Relação Dose-Resposta a Droga , Tomografia com Microscopia Eletrônica , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Espectrometria de Massas , Proteínas de Membrana/metabolismo , Nanopartículas/metabolismo , Nanopartículas/ultraestrutura , Degeneração Neural/sangue , Ratos , Ratos Wistar , Compostos de Prata/sangue , Sinapses/patologia , Sinapses/ultraestrutura , Sinapsinas/metabolismo , Sinaptofisina/metabolismo , Fatores de TempoRESUMO
Transforming growth factor (TGF)-ß1, a cytokine that can be expressed in the brain, is a key regulator of the brain's responses to injury and inflammation. Alzheimer's disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-ß (Aß) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-ß1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-ß1 via the intracerebroventricle (ICV) in AD model rats, by Aß1-42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-ß1. The TGF-ß1 administration after the Aß1-42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aß1-42 injection alone. These findings demonstrate that TGF-ß1 provides protection against AD neurodegeneration and suggest that the TGF-ß1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.