RESUMO
OBJECTIVE: Higher levels of biochemical blood markers of brain injury have been described immediately after tonic-clonic seizures and in drug-resistant epilepsy, but the levels of such markers in epilepsy in general have not been well characterized. We analyzed neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau in a regional hospital-based epilepsy cohort and investigated what proportion of patients have levels suggesting brain injury, and whether certain epilepsy features are associated with high levels. METHODS: Biomarker levels were measured in 204 patients with an epilepsy diagnosis participating in a prospective regional biobank study, with age and sex distribution correlating closely to that of all patients seen for epilepsy in the health care region. Absolute biomarker levels were assessed between two patient groups: patients reporting seizures within the 2 months preceding inclusion and patients who did not have seizures for more than 1 year. We also assessed the proportion of patients with above-normal levels of NfL. RESULTS: NfL and GFAP, but not tau, increased with age. Twenty-seven patients had abnormally high levels of NfL. Factors associated with such levels were recent seizures (p = .010) and epileptogenic lesion on radiology (p = .001). Levels of NfL (p = .006) and GFAP (p = .032) were significantly higher in young patients (<65 years) with seizures ≤2 months before inclusion compared to those who reported no seizures for >1 year. NfL and GFAP correlated weakly with the number of days since last seizure (NfL: rs = -.228, p = .007; GFAP: rs = -.167, p = .048) in young patients. NfL also correlated weakly with seizure frequency in the last 2 months (rs = .162, p = .047). SIGNIFICANCE: Most patients with epilepsy do not have biochemical evidence of brain injury. The association with seizures merits further study; future studies should aim for longitudinal sampling and examine whether individual variations in NfL or GFAP levels could reflect seizure activity.
Assuntos
Lesões Encefálicas , Epilepsia , Humanos , Estudos Prospectivos , Proteína Glial Fibrilar Ácida , Filamentos Intermediários , Proteínas de Neurofilamentos , Biomarcadores , ConvulsõesRESUMO
Ketogenic diets (KD) have received increasing interest in neuro-oncology based on their ability to inhibit glioma growth In Vitro and their established role in medically refractory seizures. This review analyses the methodological aspects of KD treatment alongside standard care for patients with gliomas from a nutritional point of view. A literature search was performed in March 2022 searching PubMed and Scopus. We identified 13 articles including 187 patients with a histological-new or recurrent-diagnosis of glioma and treated by KD during the course of the disease. Dietary treatments were categorized as the classical ketogenic diet (CKD), the Modified Atkins diet (MAD), and the medium-chain triglyceride (MCT) diet. We identified a large variation in dietary characteristics regarding restriction of carbohydrates, ketogenic ratio, and additional dietary support. This striking heterogenicity in the methodological approaches of KD treatments made it problematic to compare effects between the included studies. Therefore, a standardized definition of KD for patients with glioma and a consensus on methodological implementation is needed. It would also be desirable to further investigate to what extent KD treatment can be optimized to secure optimal nutrient status and patient satisfaction.
Assuntos
Dieta Cetogênica , Glioma , Humanos , Dieta com Restrição de Carboidratos , Corpos Cetônicos , Carboidratos da DietaRESUMO
OBJECTIVES: To determine what proportion of our First Seizure referrals reflected true unprovoked first seizures or epilepsy, and to assess the long-term diagnostic accuracy of our First Seizure Clinic (FSC) by quantifying the risk of subsequent seizures in our FSC cohort. METHODS: We prospectively collected data of 200 adult patients referred to the FSC between May 2014 and December 2015. We reviewed clinical notes, electroencephalography (EEG) data and performed telephone follow-up at 28-month post-diagnosis. RESULTS: Of the 200 patients referred to the FSC, 181 attended. At the initial assessment, 39 of these patients were diagnosed with epilepsy, with most of these patients (59%) found to have a history of previous seizures. Fifty patients were diagnosed with a first seizure, of which 28% were labelled as provoked seizures. Sixty nine of the patients received another diagnosis and 23 were labelled as indeterminable. At 28 months follow-up, 11 (22%) of patients who received a diagnosis of first seizure subsequently received a diagnosis of epilepsy. In the remaining groups, only 5 (5%) patients were diagnosed with epilepsy (of these three were in the indeterminable group). CONCLUSIONS: Our study shows that 50% of the patients referred to a FSC had not experienced a seizure but were given an alternative diagnosis. Secondly, our study indicates that the risk of seizure recurrence following a first seizure is quite low (22%). This is because a substantial proportion of the patients were diagnosed with epilepsy already at the first assessment. The high proportion of patients being diagnosed with epilepsy was mainly due to a history of previous seizures. Thirdly, patients who were given an alternative diagnosis at the first assessment had a low probability (5%) for seizure recurrence.
Assuntos
Epilepsia/diagnóstico , Convulsões/diagnóstico , Adolescente , Adulto , Eletroencefalografia , Epilepsia/epidemiologia , Epilepsia/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Encaminhamento e Consulta/estatística & dados numéricos , Convulsões/epidemiologia , Convulsões/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Preliminary evidence suggests that diet manipulation may influence motor and nonmotor symptoms in PD, but conflict exists regarding the ideal fat to carbohydrate ratio. OBJECTIVES: We designed a pilot randomized, controlled trial to compare the plausibility, safety, and efficacy of a low-fat, high-carbohydrate diet versus a ketogenic diet in a hospital clinic of PD patients. METHODS: We developed a protocol to support PD patients in a diet study and randomly assigned patients to a low-fat or ketogenic diet. Primary outcomes were within- and between-group changes in MDS-UPDRS Parts 1 to 4 over 8 weeks. RESULTS: We randomized 47 patients, of which 44 commenced the diets and 38 completed the study (86% completion rate for patients commencing the diets). The ketogenic diet group maintained physiological ketosis. Both groups significantly decreased their MDS-UPDRS scores, but the ketogenic group decreased more in Part 1 (-4.58 ± 2.17 points, representing a 41% improvement in baseline Part 1 scores) compared to the low-fat group (-0.99 ± 3.63 points, representing an 11% improvement) (P < 0.001), with the largest between-group decreases observed for urinary problems, pain and other sensations, fatigue, daytime sleepiness, and cognitive impairment. There were no between-group differences in the magnitude of decrease for Parts 2 to 4. The most common adverse effects were excessive hunger in the low-fat group and intermittent exacerbation of the PD tremor and/or rigidity in the ketogenic group. CONCLUSIONS: It is plausible and safe for PD patients to maintain a low-fat or ketogenic diet for 8 weeks. Both diet groups significantly improved in motor and nonmotor symptoms; however, the ketogenic group showed greater improvements in nonmotor symptoms. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Dieta com Restrição de Gorduras/métodos , Dieta Cetogênica/métodos , Doença de Parkinson/dietoterapia , Adulto , Idoso , Glicemia/metabolismo , Feminino , Seguimentos , Humanos , Cetonas/sangue , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Índice de Gravidade de DoençaRESUMO
Drug-induced hypersensitivity syndrome (DIHS) is a multi-system syndrome resulting from an idiosyncratic reaction to medication. While it commonly results in multi-organ involvement, particularly the liver, there are few reports of DIHS causing cerebral vasculitis and neurological deficits. We report the case of a 63-year old woman with DIHS secondary to allopurinol leading to multiple neurological deficits with magnetic resonance imaging findings consistent with a cerebral vasculitis.
Assuntos
Alopurinol/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/complicações , Supressores da Gota/efeitos adversos , Vasculite do Sistema Nervoso Central/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Exame NeurológicoRESUMO
The aim of this study was to describe the extent of, and risk factors for, non-adherence to anti-seizure medications (ASMs) in adult people with epilepsy (PWE) in Sweden. A cross-sectional multi-centre study was performed of PWEs in western Sweden, with data from medical records, and a questionnaire filled in by the participants including self-reports on how often ASM doses had been forgotten during the past year. Participants were categorized into adherent if they forgot at 0-1 occasion, and non-adherent if they forgot at 2-10 or >10 occasions. Demographic and clinical factors were compared by Chi2- or Fisher's test and a logistic regression model was used to find risk factors for non-adherence. In the cohort of 416 PWE aged median 43, IQR 29-62 years, 398 patients were prescribed ASM treatment at inclusion, and 39 % (n = 154) were in the non-adherent group. Significant factors in the multivariable analysis were: younger age, seizure freedom the past year, valproate treatment and experiencing side effects. The rate of self-reported non-adherence was high, illustrating a need for continuous focus on fundamental aspects of epilepsy care. The identified risk factors could enable quality improvement projects and patient education to be directed to those at risk of non-adherence.
RESUMO
PURPOSE: A biochemical way to measure seizures would greatly benefit epilepsy research and clinical follow-up. Short-term biomarkers like lactate exist, and interest in biomarkers representative of longer-term seizure burden is growing. In this exploratory study, we aimed to identify markers in blood plasma that differentiate persons with recent seizures from persons with epilepsy and long-standing seizure freedom. METHODS: A proteomic analysis was performed on plasma samples of 120 persons with seizures using the Olink Neuro-exploratory panel. Participants were selected from a regional biobank study in Västra Götaland (Sweden) and categorized into two groups: recent seizure and seizure-free. The panel contained 92 proteins linked to neurological diseases and processes, and levels of these proteins were compared between the patient groups to identify potential markers of seizure activity. RESULTS: We identified significant differences in protein levels between the recent seizure and seizure-free patient groups for Cadherin-15 [(CDH15; p = 0.008)], Latent transforming growth factor beta-binding protein 3 [(LTBP3; p = 0.002)], Phosphoethanolamine/phosphocholine phosphatase 1 [(PHOSPHO1; p = 0.011)], and Progestagen associated endometrial protein [(PAEP; p = 0.0005)]. CONCLUSION: The findings in this study present CDH15, LTBP3, PHOSPHO1 and PAEP as candidate markers of seizure activity. Further confirmatory studies are needed.
Assuntos
Epilepsia , Proteômica , Humanos , Convulsões/diagnóstico , Epilepsia/diagnóstico , Biomarcadores , PlasmaRESUMO
PURPOSE: Side effects is one of the major clinical problems in epilepsy care. We assessed the prevalence of ASM side effects in participants in a large regional multicenter observational study in western Sweden and aimed to identify risk factors and inventory the nature of side effects with different ASM regimes. METHODS: Cross-sectional analysis of survey answers and clinical characteristics of 406 adult participants recruited to a regional observational study between December 2020 and March 2023. Half of the participants had been seizure free for one year. Second-generation or newer ASMs were the most common. RESULTS: A total of 164 (40 %, 95 %CI: 36-45) patients reported side effects. Patients reporting side effects were younger (median 41 vs 47 years, p = 0.015), had more frequently experienced a seizure in the last year (p = 0.02), and were more often on ASM polytherapy (p < 0.01). ASM polytherapy and age were significant risk factors in regression models, but the explanatory value was low. The most common side effect was tiredness followed by cognitive symptoms. CONCLUSIONS: Our findings show that side effects are still common in epilepsy care and suggests that unnecessary polypharmacy should be avoided. Apart from number or ASMs, predicting who will experience side effects is difficult and more research on individual vulnerability is needed.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsia , Adulto , Humanos , Suécia/epidemiologia , Prevalência , Estudos Transversais , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Medidas de Resultados Relatados pelo Paciente , Anticonvulsivantes/efeitos adversosRESUMO
SARS-COV-2 frequently cause neurological disorders and is sometimes associated with onset of autoimmune diseases affecting the nervous system. Over recent years, a rare but distinct diagnosis designated myelin oligodendrocyte glycoprotein-associated disorder (MOGAD) has been recognized in patients with attacks of optic neuritis, myelitis, or encephalomyelitis and increased levels of anti-MOG antibodies. The cause of MOGAD is unknown. However, there have been reports of single cases of MOGAD in patients with Covid-19 infection. We report a series of SARS-CoV-2 positive patients that developed MOGAD, but a homology search did not support a cross-reactive immune response to SARS-CoV-2 spike-protein and MOG.
Assuntos
COVID-19 , Neurite Óptica , Autoanticorpos , Humanos , Glicoproteína Mielina-Oligodendrócito , SARS-CoV-2RESUMO
Perry syndrome is a rare neurological condition characterised clinically by depression, sleep disturbance, central hypoventilation and parkinsonism. Perry syndrome is a TAR DNA-binding protein 43 (TDP-43) proteinopathy associated with mutated dynactin-1 protein, inherited in an autosomal dominant manner. Several pathogenic mutations in exon 2 in the dynactin 1 gene have been identified; p. F521, p. G67d, p. G71R, p. G71E, p. G71A, p. T72p, p. Q74p and p. Y78C. We present the second known case Perry syndrome with confirmed DCTN1 mutation (p. Y78C) in New Zealand, who initially was thought to have a depressive illness. Perry syndrome should be considered in the differential diagnosis of young parkinsonism, especially if there is family history of sleep disorders, weight loss and/or marked depression.
Assuntos
Complexo Dinactina/genética , Hipoventilação , Mutação/genética , Transtornos Parkinsonianos , Depressão/diagnóstico , Depressão/genética , Depressão/fisiopatologia , Feminino , Humanos , Hipoventilação/diagnóstico , Hipoventilação/genética , Hipoventilação/fisiopatologia , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , LinhagemRESUMO
Limbic encephalitis (LE) is frequently associated with malignancy. Non-paraneoplastic LE is less common and in this form, voltage-gated potassium channel (VGKC) antibodies are usually found. However in 2007 the spectrum was further extended by a report on four patients with presumed non-paraneoplastic LE in whom neither VGKC-antibodies nor other antibodies could be found (Samarasekera et al. 2007). Despite immunmodulatory treatment all these patients had severe neurological residual symptoms. Here we describe a further patient in whom extensive diagnostic procedures suggested non-paraneoplastic antibody-negative limbic encephalitis. Although this woman had prolonged status epilepticus during seven weeks, her outcome was excellent.
Assuntos
Epilepsia do Lobo Temporal/etiologia , Encefalite Límbica/complicações , Encefalite Límbica/diagnóstico , Estado Epiléptico/etiologia , Adulto , Amnésia/etiologia , Anticonvulsivantes/uso terapêutico , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Doença Crônica , Diagnóstico Diferencial , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/terapia , Feminino , Hipocampo/imunologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Encefalite Límbica/fisiopatologia , Encefalite Límbica/terapia , Imageamento por Ressonância Magnética , Metilprednisolona/uso terapêutico , Transtornos da Personalidade/etiologia , Plasmaferese , Estado Epiléptico/fisiopatologia , Estado Epiléptico/terapia , Resultado do TratamentoRESUMO
OBJECTIVE: To compare long term (10 years) seizure outcome, psychosocial outcome and use of antiepileptic drugs (AED) with the 2 year follow-up in adults after resective epilepsy surgery. METHODS: All adults (n = 70) who underwent resective epilepsy surgery from 1987 to 1995 in the Göteborg Epilepsy Surgery Series were included. Fifty-four had undergone temporal lobe resections and 16 extratemporal resections (12 frontal). A cross-sectional follow-up in the form of a semistructured interview was performed in late 2003. RESULTS: Mean follow-up was 12.4 years (range 8.6-16.2). Of the 70 patients (51% males), five (7%) were dead (three as a result of non-epilepsy related causes). Of the 65 patients interviewed, 38 (58%) were seizure-free at the long term follow-up: 65% of the patients with temporal lobe resections and 36% of the patients with extratemporal resections. Of the 35 patients who were seizure-free at the 2 year follow-up, 3 (9%) had seizures at the long term follow-up. Of the 30 patients who had seizures at the 2 year follow-up, 6 (20%) were seizure-free at the long term follow-up. Of all 65 patients, 45 (69%) had the same seizure status as the 2 year follow-up. Sixteen (25%) had an improved seizure status and 4 (6%) had a worsened status. Of the seizure-free patients, 11 (29%) had ceased taking AED, 28 (74%) were working and 25 (66%) had a driving license. CONCLUSIONS: Adult patients who are seizure-free 2 years after resective epilepsy surgery are most likely to still be seizure-free 10 years later. Most are working and have obtained a driving license.
Assuntos
Epilepsia/psicologia , Epilepsia/cirurgia , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Depressão/etiologia , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Psicologia , Qualidade de Vida , Fatores de Tempo , Resultado do TratamentoRESUMO
Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect. Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles.
Assuntos
Proteoglicanas de Sulfatos de Condroitina/genética , Proteoglicanas de Sulfatos de Condroitina/fisiologia , Hipocampo/metabolismo , Aprendizagem , Potenciação de Longa Duração/fisiologia , Memória , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Animais , Northern Blotting , Western Blotting , Encéfalo/patologia , Encéfalo/fisiologia , Brevicam , Eletrofisiologia , Lectinas Tipo C , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Modelos Genéticos , Rede Nervosa/patologia , Sinapses/patologia , Fatores de TempoRESUMO
Autoimmune neurologic syndromes can be paraneoplastic (associated with malignancies and/or onconeural antibodies), or non-paraneoplastic. Their clinical presentation is often similar. As prognosis is related to malignancy treatment, better biomarkers are needed to identify patients with malignancy. We investigated cerebrospinal fluid (CSF) markers of neuronal (neurofilament light chain, NFL and total tau protein, T-tau) and glial (glial fibrillary acidic protein) damage. CSF-NFL and T-tau were increased in both paraneoplastic and non-paraneoplastic autoimmune syndromes. Patients with manifest malignancies were older, had less epilepsy, more focal central and peripheral neurological signs and symptoms, and worse long-term outcome, than those without malignancy. CSF-NFL-levels predicted long-term outcome but were not diagnostic for malignancy, after age adjustment.
Assuntos
Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/complicações , Neoplasias/líquido cefalorraquidiano , Neoplasias/complicações , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias/diagnóstico por imagem , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
Transient global amnesia (TGA) occurs mostly in middle-aged and elderly individuals, and is generally believed to be very rare in individuals less than 40 years of age. We present three cases of TGA in young persons (16-22 years). They all had a medical history and presented symptoms fulfilling the criteria for TGA. Physical examinations and investigations were all normal. All three presented their symptoms while playing football. Reviewing the literature the suggested causes are partly different for TGA in old and young people, respectively. The present report confirms that TGA may also occur in younger individuals. We propose that single TGA is a benign condition also in younger persons and that the investigation should be similar to that of TGA in older age groups.
Assuntos
Amnésia Global Transitória/diagnóstico , Adolescente , Adulto , Fatores Etários , Amnésia Global Transitória/psicologia , Humanos , Masculino , Transtornos de Enxaqueca/diagnóstico , Esforço Físico , FutebolRESUMO
BACKGROUND AND PURPOSE: Hyperglycemia aggravates brain damage in clinical stroke and in experimental in vivo models of cerebral ischemia. Elevated preischemic glucose levels, lactate production, and intracerebral acidosis correlate with increased brain damage. We have developed a murine hippocampal slice culture model of in vitro ischemia (IVI), suitable for studies of the mechanisms of neuronal death. In this model we investigated the individual contribution of glucose, pH, lactate, and combinations thereof as well as ionotropic glutamate receptor activation to the development of hyperglycemic ischemic cell death. METHODS: Murine organotypic hippocampal slice cultures were exposed to IVI in a medium with an ionic composition similar to that of the extracellular fluid in the brain during ischemia in vivo. Cell death was assessed by propidium iodide uptake. Ionotropic glutamate receptor blockade was accomplished by D-2-amino-5-phosphonopentanoic acid (D-APV) or 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX). RESULTS: The combination of high glucose levels and acidosis (pH 6.8), but not acidosis per se or the combination of lactate and acidosis during IVI, exacerbated damage. Cell death after hyperglycemic IVI was not diminished by blockade of ionotropic glutamate receptors. CONCLUSIONS: Aggravation of brain damage by hyperglycemia in vivo can be reproduced in hippocampal slice cultures in vitro. Our results demonstrate that glucose per se, but not lactate, in combination with acidosis mediates the detrimental hyperglycemic effect through a mechanism independent of ionotropic glutamate receptors.
Assuntos
Acidose/metabolismo , Isquemia Encefálica/metabolismo , Glucose/farmacologia , Ácido Láctico/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/citologia , Concentração de Íons de Hidrogênio , Hiperglicemia/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/citologia , Receptores de Glutamato/efeitos dos fármacos , Receptores de Glutamato/metabolismo , Fatores de TempoRESUMO
Oxygen and glucose deprivation (OGD) in cell cultures is generally studied in a medium, such as artificial cerebrospinal fluid (CSF), with an ion composition similar to that of the extracellular fluid of the normal brain (2 to 4 mmol/L K+, 2 to 3 mmol/L Ca2+; pH 7.4). Because the distribution of ions across cell membranes dramatically shifts during ischemia, the authors exposed mouse organotypic hippocampal tissue cultures to OGD in a medium, an ischemic cerebrospinal fluid, with an ion composition similar to the extracellular fluid of the brain during ischemia (70 mmol/L K+, 0.3 mmol/L Ca2+; pH 6.8). In ischemic CSF, OGD induced a selective and delayed cell death in the CA1 region, as assessed by propidium iodide uptake. Cell death was glutamate receptor dependent since blockade of the N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors mitigated cell damage. Hyperglycemia aggravates ischemic brain damage whereas glucose in artificial CSF prevents oxygen deprivation-induced damage. The authors demonstrate that glucose in ischemic CSF significantly exacerbates cell damage after oxygen deprivation. This new model of "ischemia" can be useful in future studies of the mechanisms and treatment of ischemic cell death, including studies using genetically modified mice.
Assuntos
Isquemia Encefálica/patologia , Glucose/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Cálcio/metabolismo , Líquido Cefalorraquidiano/metabolismo , Técnicas de Cultura/métodos , Maleato de Dizocilpina/farmacologia , Eletrofisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glucose/deficiência , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hidrogênio/metabolismo , Hipóxia/patologia , Íons , Camundongos , Camundongos Endogâmicos BALB C , Potássio/metabolismo , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Long-term potentiation (LTP) was studied in the hippocampal CA1 region of guinea-pigs using a solution containing 0.1 mM magnesium and 10 microM of the non-N-methyl-d-aspartate (non-NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), leaving an NMDA-mediated field excitatory postsynaptic potential (EPSP). Brief high-frequency afferent tetanization induced a substantial synapse-specific potentiation of the NMDA EPSP with a time course closely resembling that previously described for LTP of the non-NMDA-mediated EPSP. This NMDA EPSP potentiation was occluded by prior induction of LTP in normal solution. Using a solution containing 0.1 mM magnesium and 1 microM CNQX, the EPSP was composed of both a non-NMDA- and an NMDA-mediated component which could be measured separately and in parallel. Manipulations that cause increased transmitter release, such as phorbol ester application and changes in stimulation frequency, enhanced the two measures nearly equally. Afferent tetanization induced an increase of both EPSP components, with a similar time course, the NMDA component showing a relative increase of about one-third of that of the non-NMDA one. These results suggest that, to the extent that LTP is based on an increased release of transmitter, the mechanism exhibits features distinct from those underlying other forms of enhanced release.
RESUMO
Tonic GABAergic inhibition regulates neuronal excitability and has been implicated to be involved in both neurological and psychiatric diseases. We have previously shown that the endogenous peptide antisecretory factor (AF) decreases phasic GABAergic inhibition onto pyramidal CA1 neurons. In the present study, using whole-cell patch-clamp recordings, we investigated the mechanisms behind this disinhibition of CA1 pyramidal neurons by AF. We found that application of AF to acute rat hippocampal slices resulted in a reduction of the frequency, but not of the amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. Miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of tetrodotoxin (TTX), were however not affected by AF, neither in CA1 pyramidal cells, nor in stratum radiatum interneurons. Instead, AF caused an increase of the tonic GABAA current in stratum radiatum interneurons, leaving the tonic GABAergic transmission in CA1 pyramidal cells unaffected. These results show that the endogenous peptide AF enhances tonic, but not phasic, GABAergic signaling in CA1 stratum radiatum interneurons, without affecting tonic GABAergic signaling in CA1 pyramidal neurons. We suggest that this increased tonic GABAergic signaling in GABAergic interneurons could be a mechanism for the AF-mediated disinhibition of pyramidal neurons.
RESUMO
IMPORTANCE: Identifying a clinical distinction between the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) and nonprion rapidly progressive dementias is important and sometimes difficult; thus, reliable tools for diagnosis are in great demand. OBJECTIVE: To test the diagnostic performance of dementia cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and the T-tau to P-tau ratio for CJD by analyzing the results from a large database of routine clinical samples in combination with diagnosis information from the Swedish Mortality Registry. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study. We cross-referenced the Swedish Mortality Registry with a data set of CSF measurements of T-tau and P-tau performed in routine clinical testing at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, which serves most of Sweden. The data set consisted of 9765 deceased individuals with CSF measures, including 93 with CJD, with 52 autopsy-verified samples (56%). MAIN OUTCOMES AND MEASURES: For each patient, T-tau and P-tau levels in CSF were measured and the T-tau to P-tau ratio was calculated. Biomarker levels (adjusted for age and sex) were analyzed in relation to the recorded cause of death and time of death. We specifically tested a previously defined CJD biomarker profile (T-tau >1400 ng/L and T-tau to P-tau-ratio >25). RESULTS: Patients who died of CJD had elevated CSF T-tau levels and T-tau to P-tau ratio, but not elevated CSF P-tau levels, compared with patients who died of Alzheimer disease (AD) and other dementias. The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5%, and a positive likelihood ratio of 79.9. When tested against common differential diagnoses, the sensitivity, specificity, and positive likelihood ratio of this profile was 78.5%, 99.6%, and 196.6, respectively, in relation to AD and 78.5%, 99.3%, and 109.3, respectively, in relation to other dementias. In CJD individuals (n = 30) with repeated measurements, but not in those with AD (n = 242) or other dementias (n = 258), T-tau levels and T-tau to P-tau ratios increased over time. CONCLUSIONS AND RELEVANCE: In this routine clinical setting, the combination of increased T-tau levels and increased T-tau to P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD and may serve as a clinically useful diagnostic test.