RESUMEN
OBJECTIVES: We examined cognitive functions before and in acute phase of stroke studying frequency and profile of cognitive impairment and relationships between cognitive status. METHODS: Seventy-four patients with early phase after stroke and 49 healthy controls were included and examined using the Mini-Mental State Examination (MMSE) and a battery of neuropsychological tests. Cognitive status before stroke-onset was investigated using Cognitive Impairment Questionnaire. RESULTS: Cognitive impairments were present in 96% of patients after stroke onset using the battery of neuropsychological tests and in 39% of patients using the MMSE, but in only 9% of controls. Seventy-six percent exhibited reduced executive function and 75% reduced psychomotor tempo. Cognitive dysfunction was present in 52% before stroke onset without any impact on the frequency of impairment in the various cognitive areas in early phase after stroke. CONCLUSIONS: Cognitive impairment is frequent before the onset of stroke among older people and may partially explain the very high frequency of cognitive impairment observed after stroke onset.
Asunto(s)
Trastornos del Conocimiento/epidemiología , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/psicología , Anciano , Anciano de 80 o más Años , Escalas de Valoración Psiquiátrica Breve , Función Ejecutiva/fisiología , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , Suecia/epidemiologíaRESUMEN
OBJECTIVE: To examine whether there were any differences in the recovery in performance of personal activities of daily living (P-ADL) in elderly persons in relation to cognitive impairments pre- and post-stroke from discharge to 6 and 12 months in elderly persons. METHODS: Forty-five elderly persons after stroke were assessed at discharge from hospital and at 6 and at 12 months after stroke onset. A questionnaire posed to the next of kin was used to evaluate the person's pre- and post-stroke cognitive status. P-ADL was assessed with the Barthel Index. The Mini Mental State Examination and neuropsychological tests were used to measure cognitive functions after stroke. The National Institute of Health Stroke Scale was used to measure neurological deficits. RESULTS: Persons with cognitive impairments before and after stroke did not improve in P-ADL from the acute phase until 6 and 12 months, while persons with intact cognition pre- and post-stroke did. CONCLUSION: Since cognitive problems pre- and post-stroke hinder recovery in P-ADL, it is important to understand the connection between cognitive impairment and activity limitations when planning the optimal rehabilitation, which could include special compensation strategies, learnt by the patients, cognitive assistive devices and/or appropriate personal support trained in meaningful activities in daily life in their natural environment.
Asunto(s)
Actividades Cotidianas , Trastornos del Conocimiento , Recuperación de la Función/fisiología , Accidente Cerebrovascular/complicaciones , Actividades Cotidianas/psicología , Anciano , Anciano de 80 o más Años , Atención/fisiología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Trastornos del Conocimiento/rehabilitación , Función Ejecutiva/fisiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Memoria/fisiología , Escala del Estado Mental , Pruebas Neuropsicológicas , Rehabilitación de Accidente Cerebrovascular , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
This study examines how prestroke dementia and cognitive dysfunction after stroke influence the personal activities of daily living (P-ADL) in elderly patients in the acute phase after stroke. Elderly stroke patients (n=60) referred to geriatric rehabilitation were included. Assessments were carried out at admission and evaluated at discharge from the geriatric ward. The median age of the group was 77 years. Astrand's questionnaire was used to interview a close relative about the patient's prestroke cognitive status. P-ADL was assessed with the Barthel Index (BI). The Mini Mental State Examination (MMSE) and a neuropsychological test battery were used to measure cognitive functions. Analyses were made using non-parametrical methods. In the acute phase after stroke, neither the presence of prestroke dementia nor the cognitive status after stroke onset among these elderly patients influenced P-ADL at admission or at discharge. Prestroke dementia and cognitive dysfunction's were found to be common after stroke onset, however this did not have any impact on dependence in P-ADL in these elderly patients at admission or at discharge.
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Actividades Cotidianas , Trastornos del Conocimiento/epidemiología , Accidente Cerebrovascular/epidemiología , Enfermedad Aguda , Anciano , Trastornos del Conocimiento/diagnóstico , Demencia/diagnóstico , Demencia/epidemiología , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
OBJECTIVE: Immunological mechanisms may be part of the pathophysiological mechanisms in frontotemporal dementia (FTD), but hitherto only vague evidence of such mechanisms has been presented. The aim of this study was to compare the cerebrospinal fluid (CSF) levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha, and the anti-inflammatory cytokine transforming growth factor (TGF)-beta in patients with FTD and normal controls. Furthermore, serum levels of TNF-alpha, TGF-beta, and IL-1beta were measured in FTD patients. METHODS: The CSF levels of IL-1beta, TNFalpha, and TGF-beta were measured using ELISA in 19 patients with FTD and 24 sex and age matched healthy controls. RESULTS: The CSF levels of TNF-alpha (FTD 0.6 pg/mL (median: lower, upper quartile 0.3, 0.7); controls: 0.0 pg/mL (0.0, 0.0); p = 0.008) and TGF-beta (FTD 266 pg/mL (157, 371), controls: 147 pg/mL (119, 156); p = 0.0001) were significantly increased in FTD patients compared with controls. No correlations were found between CSF and serum levels of the cytokines. In the controls, but not in the FTD patients, a positive correlation was found between the CSF levels of TGF-beta and age (r = 0.42, p < 0.05). No correlation was found between any of the cytokines and degree of brain atrophy or white matter changes. No differences between the groups were found for age, gender, or CSF/serum albumin ratio. CONCLUSIONS: The results suggest an increased intrathecal production of both pro- and anti-inflammatory cytokines in FTD. As no correlations were found with the albumin ratio, and no correlations between CSF and serum levels of the cytokines were found, these changes in the CSF cannot be explained by a systemic overproduction of cytokines.
Asunto(s)
Demencia/inmunología , Demencia/fisiopatología , Inflamación , Interleucina-1/líquido cefalorraquídeo , Factor de Crecimiento Transformador beta/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Lóbulo Frontal/inmunología , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Temporal/inmunología , Lóbulo Temporal/patologíaRESUMEN
OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI). METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls. RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD. CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Sistema Nervioso Central/inmunología , Trastornos del Conocimiento/fisiopatología , Inflamación , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/líquido cefalorraquídeo , Humanos , Interleucina-1/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Placa Amiloide , Estudios Prospectivos , Factores de Riesgo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
Normal pressure hydrocephalus (NPH) is associated with periventricular white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine mediating myelin damage, in patients with NPH. TNF-alpha levels were analyzed by ELISA and measured before and after shunt operation in 35 patients with NPH. The levels of this cytokine were related to the symptomatology and to magnetic resonance imaging (MRI) verified white matter lesions. They were also related to intrathecal levels of sulfatide, a marker for white matter degradation and to levels of neurofilament, a marker for neuronal degeneration. The preoperative levels of TNF-alpha were increased in the CSF of NPH patients compared to controls, and correlated to the levels of sulfatide. The intrathecal TNF-alpha levels were higher in NPH patients with impairment of wakefulness than in those without this symptom. The preoperative TNF-alpha levels were significantly correlated to the improvement of psychometrical test scores, and of wakefulness and to the overall improvement of the patients following shunt operation. Importantly, shunt operation led to complete disappearance of intrathecal TNF-alpha. We conclude that NPH is correlated with intrathecal TNF-alpha production being reversed following shunt operation in parallel with the clinical improvement. The positive correlation between preoperative TNF-alpha and sulfatide levels in the CSF suggest that intrathecal TNF-alpha may contribute to the damage of the white matter known to occur in patients with NPH.
Asunto(s)
Hidrocéfalo Normotenso/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Encéfalo/fisiopatología , Mapeo Encefálico , Estudios de Casos y Controles , Derivaciones del Líquido Cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Marcha , Humanos , Hidrocéfalo Normotenso/metabolismo , Hidrocéfalo Normotenso/cirugía , Imagen por Resonancia Magnética/instrumentación , Imagen por Resonancia Magnética/métodos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Psicometría/métodos , Desempeño Psicomotor , Sulfoglicoesfingolípidos/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVES: Subcortical vascular dementia (SVD) is associated with white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of TNF-alpha, a proinflammatory cytokine mediating myelin damage, in SVD patients. The intrathecal TNF-alpha levels were related to the clinical symptoms of dementia, as well as to intrathecal levels of sulfatide, a marker of white matter degradation, and of neurofilament, a marker of neuronal degeneration. METHODS: CSF levels of TNF-a, sulfatide and neurofilament were all analyzed by immunoenzymatic procedures in 17 patients with SVD and in 26 healthy controls. RESULTS: The intrathecal concentration of TNF-alpha was significantly increased in SVD patients compared to healthy controls (p = 0.0001). The intrathecal levels of TNF-alpha were significantly correlated (r = 0.6, p = 0.02) to the levels of sulfatide, but not to the levels of neurofilament, (r = 0.08, NS). CONCLUSIONS: We have demonstrated intrathecal production of TNF-alpha in SVD patients. The correlation between TNF-a and sulfatide levels in the CSF suggests that this apoptosis-inducing cytokine leads to the death of oligodendrocytes, thereby contributing to white matter degeneration, a hallmark of SVD.
Asunto(s)
Encéfalo/metabolismo , Demencia Vascular/líquido cefalorraquídeo , Sulfoglicoesfingolípidos/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Apoptosis , Encéfalo/patología , Estudios de Casos y Controles , Demencia Vascular/inmunología , Demencia Vascular/patología , Femenino , Humanos , Masculino , Neuronas/patologíaRESUMEN
AIM: Posthaemorrhagic ventricular dilatation (PHVD) is closely associated with white matter damage and neurological disability in the preterm infant. Proinflammatory cytokines have been implicated in the pathogenesis of white matter injury and subsequent cerebral palsy. The aim of this study was to determine the levels of proinflammatory cytokines in cerebrospinal fluid (CSF) from preterm infants with PHVD and to correlate the levels to white matter damage and neurodevelopmental outcome. METHODS: CSF samples were obtained from 24 preterm infants with expanding PHVD and 19 preterm infants with normal ultrasound. Tumour necrosis factor-alphaa (TNF-alpha ), interleukin-1beta (IL-1beta), interleukin-8 (IL-8) and interferon-gamma (IFN-gamma) in CSF were measured by enzyme-linked immunosorbent assay, and IL-6 was measured by bioassay. RESULTS: The concentrations of TNF-alpha, IL-1beta, IL-6 and IL-8 were significantly elevated in CSF from infants with PHVD. TNF-alpha was detected in 43% of PHVD infants and 11% of controls (p = 0.04). IL-1beta was detected in 67% of PHVD infants and 0% of controls (p < 0.0001). The concentrations of IL-6 were 368 (145-460) pg ml(-1) in the PHVD group and 30 (25-41) pg ml(-1) in the control group (p < 0.0001), and those of IL-8 were 3000 (1620-3400) pg ml(-1) in the PHVD group and 35 (0-230) pg ml(-1) in the control group (p < 0.0001). Cytokine concentrations did not correlate with white matter lesions on ultrasound, shunt dependence or neurological outcome within the PHVD group. CONCLUSION: There was an intense and prolonged inflammatory reaction in CSF from preterm infants with PHVD and a high risk for subsequent white matter injury and permanent neurological impairment.
Asunto(s)
Hemorragia Cerebral/líquido cefalorraquídeo , Ventrículos Cerebrales/patología , Citocinas/líquido cefalorraquídeo , Recien Nacido Prematuro/líquido cefalorraquídeo , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/patología , Ventrículos Cerebrales/diagnóstico por imagen , Dilatación Patológica , Humanos , Recién Nacido , Interferón gamma/líquido cefalorraquídeo , Interleucina-1/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Interleucina-8/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , UltrasonografíaRESUMEN
A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. In previous studies, we have demonstrated intrathecal production of the proinflammatory cytokine tumor necrosis factor (TNF)alpha in patients with Alzheimer's disease (AD). The aim of the present study was to investigate the downstream products of TNF-alpha expression including interleukin (IL)1beta and its naturally occurring antagonist IL-1 receptor agonist (ra) in patients with AD. The cytokine levels were related to neuronal damage, as measured by intrathecal tau and beta-amyloid concentration and certain clinical features of the disease. Fifty-two patients with AD and 25 healthy controls were analyzed with respect to cerebrospinal fluid (CSF) levels of IL-1beta and IL-1ra. CSF IL-1beta was neither detectable in CSF of AD nor in control CSF. In contrast, a significantly lower (p < 0.01) number of patients (24 of 49) than of controls (20 of 24) showed detectable levels of IL-1ra in the CSF. The intrathecal levels of IL-1ra were significantly lower in patients with AD than in the controls. Our study demonstrates a decreased production of the anti-inflammatory compound IL-1ra, suggesting a propensity towards inflammation in patients with AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Sialoglicoproteínas/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Trastornos del Conocimiento/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Masculino , Persona de Mediana EdadRESUMEN
A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. The aim of the present study was to investigate patterns of local and systemic cytokine release in patients with Alzheimer's disease (AD) and vascular dementia (VAD). The intrathecal levels of cytokines were related to neuronal damage and cerebral apoptosis. Twenty patients with early AD and 26 patients with VAD were analyzed with respect to cerebrospinal fluid (CSF) and serum levels of pro- and anti-inflammatory cytokines. In addition, CSF levels of Fas/APO-1 and bcl-2, a measure for apoptosis, and Tau protein, a marker for neuronal degradation, were studied. Significantly increased CSF levels of GM-CSF but not of other cytokines were observed in both dementia groups. These patients displayed a significant correlation between the GM-CSF levels and the levels of Fas/APO-1 and Tau protein in CSF. Our study demonstrates an intrathecal production of GM-CSF, a cytokine stimulating microglial cell growth and exerting inflammatogenic properties. It is suggested that GM-CSF once secreted induces programmed cell death in the brain tissue of patients with dementia.
Asunto(s)
Enfermedad de Alzheimer/patología , Apoptosis , Encéfalo/patología , Demencia Vascular/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/sangre , Factor Estimulante de Colonias de Granulocitos y Macrófagos/líquido cefalorraquídeo , Anciano , Femenino , Humanos , Masculino , Microglía , Persona de Mediana Edad , Neuronas/patologíaRESUMEN
A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. We have recently demonstrated that patients with Alzheimer's disease (AD) and vascular dementia (VaD) display an intrathecal production of proinflammatory cytokines. TNF-alpha, one of these cytokines, leads to the production of nitric oxide (NO), a potent inflammatory mediator, by induction of inducible NO synthase. The aim of the present study was to investigate the intrathecal levels of nitrate, one of the main metabolites of NO, and to relate its levels to the degree of intellectual impairment, in patients with AD and VaD. Twenty patients with early AD and 26 patients with VaD were analyzed with respect to cerebrospinal fluid levels of nitrate by gas chromatography/mass spectrometry. Interestingly, in patients with AD but not VaD, the intrathecal levels of nitrate were significantly and inversely correlated (r = -0.68, p = 0.002) to the degree of intellectual impairment. Our study demonstrates an inverse correlation between the intrathecal levels of nitrate and the degree of cognitive impairment in patients with AD, suggesting a neuroprotective effect of NO in AD.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Demencia Vascular/líquido cefalorraquídeo , Óxido Nítrico/líquido cefalorraquídeo , Médula Espinal/metabolismo , Anciano , Enfermedad de Alzheimer/psicología , Demencia Vascular/psicología , Femenino , Humanos , Indicadores y Reactivos , Masculino , Persona de Mediana Edad , Nitratos/líquido cefalorraquídeo , Nitratos/metabolismoRESUMEN
OBJECTIVE: To analyze the extent of tumor necrosis factor-alpha (TNFalpha) and TNFbeta gene polymorphism in patients with AD and to relate it to intrathecal levels of these cytokines. METHODS: Analyses of TNFalpha and TNFbeta gene polymorphism were performed using PCR in 52 patients with AD and in 25 control subjects, and the levels of corresponding cytokines were analyzed using ELISA. RESULTS: Patients with AD displayed significantly higher intrathecal levels of TNFalpha, but not TNFbeta, compared with the control subjects. The levels of these cytokines did not differ significantly in patients displaying different alleles of the TNF gene. CONCLUSIONS: Results indicate that increased intrathecal production of TNFalpha in AD is preferentially controlled by environmental stimuli rather than genetic makeup.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Linfotoxina-alfa/líquido cefalorraquídeo , Linfotoxina-alfa/genética , Polimorfismo Genético/genética , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Proteínas tau/líquido cefalorraquídeoRESUMEN
The potential role of inflammatory mechanisms in the pathophysiology of ischemic brain damage has intensely been discussed. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines early after onset of symptoms. IL-1beta, one of these cytokines, stimulates the production of nitric oxide (NO), a potent inflammatory mediator. The aim of the present study was to investigate the intrathecal levels of nitrate, one of the main metabolites of NO in acute stroke and to relate its levels to brain damage. Stroke patients were prospectively studied with clinical evaluation, radiological assessment and analysis of intrathecal levels of nitrate by gas chromatography/mass spectrometry. In addition, simultaneous analyses of cytokines and of soluble Fas/APO-1 and bcl-2, two proteins regulating apoptosis, were performed. The intrathecal levels of nitrate were not significantly different in stroke patients compared to controls throughout the observation period. However, the intrathecal levels of nitrate increased significantly 3 months after stroke onset compared with the first 3 days. Interestingly, the levels of nitrate measured at stroke onset were negatively correlated to the final size of infarct volume (r = -0.69, p < 0.05) measured by MRI. In addition, patients with large infarcts displayed significantly (p = 0.008) lower levels of nitrate in cerebrospinal fluid compared to patients with small infarcts during the first 3 days after stroke onset. In contrast, the intrathecal levels of nitrate were significantly positively correlated (r = 0.79, p < 0. 001) to the neurological deficit and negatively correlated (r = -0. 76, p < 0.05) to bcl-2, a protein downregulating neuronal apoptosis, in the late stage of the stroke. Early NO production is associated with a smaller infarct volume, suggesting a protective effect, whereas late NO production is associated with severer neurological deficits, suggesting a neurotoxic effect. Treatment trials pertaining to modulate NO production in stroke should take into consideration the dual effect of NO on ischemic brain damage.
Asunto(s)
Daño Encefálico Crónico/etiología , Óxido Nítrico/líquido cefalorraquídeo , Accidente Cerebrovascular/líquido cefalorraquídeo , Accidente Cerebrovascular/fisiopatología , Adulto , Anciano , Apoptosis , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Daño Encefálico Crónico/diagnóstico por imagen , Daño Encefálico Crónico/patología , Citocinas/líquido cefalorraquídeo , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nitratos/líquido cefalorraquídeo , Valores de Referencia , Accidente Cerebrovascular/complicaciones , Factores de Tiempo , Tomografía Computarizada por Rayos X , Receptor fas/líquido cefalorraquídeoRESUMEN
The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1 beta, IL-6, TNF-alpha, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF-alpha on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF-alpha compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF-alpha and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF-alpha-exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF-alpha in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF-alpha exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Demencia Vascular/metabolismo , Fármacos Neuroprotectores/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Anciano , Apoptosis , Femenino , Humanos , Interleucina-1/sangre , Interleucina-1/líquido cefalorraquídeo , Interleucina-6/sangre , Interleucina-6/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Neuronas/patología , Proteínas Proto-Oncogénicas c-bcl-2/líquido cefalorraquídeo , Receptores del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Receptor fas/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND AND PURPOSE: The neuronal death that accompanies an ischemic stroke has previously been attributed to a necrotic process. However, numerous studies in experimental models of ischemia have recently indicated that programmed cell death, also called apoptosis, may contribute to neuronal death. The aim of the present study was to investigate the intrathecal levels of proteins regulating apoptosis in acute stroke and to relate these levels to brain damage and to production of proinflammatory and anti-inflammatory cytokines. METHODS: Thirty stroke patients were studied prospectively on days 0 to 4, 7 to 9, 21 to 26, and after day 90 with clinical evaluation, radiological assessment, and analysis of cerebrospinal fluid (CSF) levels of soluble (s) Fas/APO-1 and sbcl-2, 2 proteins that regulate apoptosis. In addition, analysis of the intrathecal levels of cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha was performed. Nineteen CSF samples from healthy subjects were used for control purposes. The patients were examined with MRI 1 to 3 months after stroke onset for measurement of infarct volume RESULTS: Significantly decreased CSF levels of sFas/APO-1 were observed during the entire observation period, with a maximal decrease on day 21 after the onset of stroke. The intrathecal levels of sFas/APO-1 were significantly negatively correlated with the volume of brain infarct and with the neurological deficit 3 weeks and 3 months after the onset of the stroke. In addition, the intrathecal levels of sFas/APO-1 were significantly correlated with the levels of IL-1beta, IL-6, IL-10, and GM-CSF 3 weeks after the onset of the disease. The intrathecal levels of sbcl-2 were significantly decreased during the first 3 days after stroke onset and at the same time were positively correlated with the levels of IL-6 and tumor necrosis factor-alpha. CONCLUSIONS: Our study demonstrates decreased intrathecal levels of proteins with antiapoptotic properties, suggesting that patients with acute stroke display a propensity toward apoptosis. Control of factors regulating apoptosis may lead to decreased delayed brain damage in stroke.
Asunto(s)
Apoptosis , Trastornos Cerebrovasculares/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Proteínas Proto-Oncogénicas c-bcl-2/líquido cefalorraquídeo , Receptor fas/líquido cefalorraquídeo , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Barrera Hematoencefálica , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Albúmina Sérica/metabolismo , Tomografía Computarizada por Rayos XRESUMEN
Experimental studies suggest that cytokine-mediated inflammatory reactions are important in the cascade leading to hypoxic-ischemic brain injury. The purpose was to study the content of pro- and antiinflammatory cytokines in cerebrospinal fluid (CSF) of asphyxiated and control infants. Samples of CSF were obtained from 20 infants who fulfilled the criteria of birth asphyxia and from seven newborn control subjects. The concentrations of IL-1beta, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and granulocyte/monocyte colony-stimulating factor (GM-CSF) were determined with ELISA and of IL-6 using a bioassay. The concentration of IL-6 (pg/mL) was higher in asphyxiated (250, 35-543; median, interquartile range) than in control (0, 0-18) infants (p = 0.001). There was also a significant relationship between IL-6 and the degree of HIE, and between IL-6 and outcome. In addition, the content of IL-8 (pg/mL) was higher (p = 0.009) in the asphyxia group (170, 70-1440), than in the the control group (10, 0-30) and there was an association between IL-8 and degree of HIE. The levels of IL-10, TNF-alpha, GM-CSF, and IL-1beta did not differ between groups. In conclusion, the proinflammatory cytokines IL-6 and IL-8 were markedly elevated in CSF of asphyxiated infants, and the intrathecal levels of these cytokines corresponded to the degree of HIE.
Asunto(s)
Asfixia Neonatal/inmunología , Citocinas/líquido cefalorraquídeo , Puntaje de Apgar , Asfixia Neonatal/líquido cefalorraquídeo , Peso al Nacer , Proteína C-Reactiva/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/análisis , Femenino , Edad Gestacional , Factor Estimulante de Colonias de Granulocitos y Macrófagos/líquido cefalorraquídeo , Humanos , Recién Nacido , Interleucina-1/líquido cefalorraquídeo , Interleucina-10/líquido cefalorraquídeo , Interleucina-8/líquido cefalorraquídeo , Masculino , Valores de Referencia , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeoRESUMEN
We have previously demonstrated that brain lesions caused by stroke led to the lateralization of T-cell dependent inflammation. The purpose of this study was to assess the impact of localization of the brain lesion on lateralization of immune responsiveness. The delayed-type hypersensitivity (DTH) reaction was used as an in vivo measure of antigen specific T-lymphocyte reactivity. All stroke patients were examined with computed scan tomography (CT) of the brain to ascertain the localization and extent of the brain lesion. Patients with right-sided brain lesions displayed significantly larger (P = 0.008) DTH responses on the paretic side compared to the contralateral side. Detailed analysis of the localization of the brain lesion revealed that infarcts encompassing frontal lobe-putamen led to significantly larger (P = 0.007) DTH responses on the paretic side compared to the contralateral side. Localization of the brain lesion affects the lateralization of DTH, supporting an asymmetrical modulation of the immune response. In addition, our study points to the frontal cortex-putamen as a putative brain centre regulating the magnitude of immune responses.
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Encefalopatías/inmunología , Trastornos Cerebrovasculares/inmunología , Dermatitis Alérgica por Contacto/inmunología , Lóbulo Frontal/inmunología , Hipersensibilidad Tardía/inmunología , Putamen/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Encefalopatías/etiología , Trastornos Cerebrovasculares/complicaciones , Epítopos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL-1beta and IL-6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0-3, 7-9, 21-26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL-8 and GM-CSF, and on day 3 for the immunoregulatory cytokine IL-10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL-8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor-alpha (TNF-alpha) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.
Asunto(s)
Trastornos Cerebrovasculares/inmunología , Citocinas/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Trastornos Cerebrovasculares/líquido cefalorraquídeo , Trastornos Cerebrovasculares/diagnóstico por imagen , Citocinas/biosíntesis , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/líquido cefalorraquídeo , Humanos , Interleucina-10/líquido cefalorraquídeo , Interleucina-8/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Radiografía , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeoRESUMEN
Unilateral paresis remaining after poliomyelitis may affect the expression of inflammatory diseases by lateralization of the disease manifestations. The purpose of this study was to assess the impact of the unilateral paresis after poliomyelitis on lateralization of neurogenic inflammation and immune responsiveness. The delayed-type hypersensitivity (DTH) reaction to tuberculin was used as an in vivo measure of antigen-specific T lymphocyte reactivity. Assessment of axon reflex vasodilatation was simultaneously employed to test for neurogenic inflammation. Fourteen of the 16 polio patients displayed a positive DTH reaction to tuberculin. All but two showed weaker DTH reaction on the paretic- compared to the contralateral-side (P = 0.001). Magnitude of electrically evoked axon reflexes significantly correlated to asymmetries of DTH responses. We conclude that damage of lower motor neuron leads to ipsilateral down-regulation of T cell-mediated cutaneous inflammation. This lateralization of DTH responses is related to deficiencies in motor and sympathetic innervation of the paretic extremity.
Asunto(s)
Dermatitis Alérgica por Contacto/fisiopatología , Paresia/inmunología , Poliomielitis/inmunología , Adulto , Anciano , Axones/inmunología , Dermatitis Alérgica por Contacto/complicaciones , Estudios de Evaluación como Asunto , Potenciales Evocados , Femenino , Histamina/farmacología , Humanos , Hipersensibilidad Tardía/inmunología , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Paresia/etiología , Paresia/fisiopatología , Poliomielitis/complicaciones , Poliomielitis/fisiopatología , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Pruebas Cutáneas , Sistema Nervioso Simpático/inmunología , Linfocitos T/inmunología , Vasodilatación/inmunologíaRESUMEN
BACKGROUND AND PURPOSE: We have previously demonstrated that stroke influences systemic immune responses. The aim of the present study was to investigate patterns of local inflammatory response as a consequence of acute stroke. METHODS: Thirty stroke patients were studied prospectively on days 0 to 3, 7 to 9, 21 to 26, and after day 90 with clinical evaluations, radiological assessments, and analysis of serum and cerebrospinal fluid cytokine levels. RESULTS: Significantly increased levels of interleukin-6 (IL-6) in cerebrospinal fluid (P < .001) were observed in virtually all patients studied compared with healthy control subjects. This increase was observed during the whole observation period but was significantly more pronounced within the first days after stroke onset, with a peak level on days 2 and 3. This initial increase was significantly correlated (r = .65, P = .002) with the volume of infarct measured by MRI 2 to 3 months later. Serum levels of IL-6 in stroke patients were significantly lower than cerebrospinal fluid levels of IL-6 (P = .013) and did not display any significant correlation to the size of the brain lesion. Also, increase in intrathecal but not systemic production of IL-1 beta was observed early during the stroke. Only minor increases of cerebrospinal fluid interferon-gamma levels were observed in two patients. CONCLUSIONS: Our study demonstrates an intrathecal production of IL-6 and IL-1 beta in patients with stroke, supporting the notion of localized inflammatory response to acute brain lesion. In addition, the significant correlation between early intrathecal production of IL-6 and the subsequent size of the brain lesion can be used as a prognostic tool, predicting the size of the brain damage before it is possible to accurately visualize it with radiological methods.