RESUMEN
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
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 effect of neonatal brain infection of herpes simplex virus type 1 (HSV-1) on the development of sensorimotor function in the rat was investigated using an acoustic startle paradigm. Intracerebral inoculation of HSV-1 at day 2 after birth, but not at day 4, caused a significant delay in the development of prepulse inhibition of acoustic startle. A decrease in prepulse inhibition was shown at 37, 46 and 58 days of age in these rats compared to control rats. No evidence was obtained for other behavioural dysfunctions such as differences in sensorimotor reactivity, sensorimotor response habituation, spontaneous locomotor activity, rearing activity or stereotyped behaviour. Prepulse inhibition of acoustic startle is an accepted model of sensorimotor gating in the CNS, a function which has been shown diminished in schizophrenic persons. The present results suggest that early viral infections during a neurone-susceptible period may contribute to the development of this deficit.
Asunto(s)
Encéfalo/fisiopatología , Encéfalo/virología , Encefalitis por Herpes Simple/fisiopatología , Herpesvirus Humano 1/fisiología , Desempeño Psicomotor/fisiología , Esquizofrenia/fisiopatología , Esquizofrenia/virología , Factores de Edad , Animales , Animales Recién Nacidos , Peso Corporal/fisiología , Encéfalo/patología , ADN Viral/análisis , ADN Viral/metabolismo , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Femenino , Actividad Motora/fisiología , Inhibición Neural/fisiología , Neuroglía/patología , Neuroglía/virología , Neuronas/patología , Neuronas/virología , Reacción en Cadena de la Polimerasa , Embarazo , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/fisiología , Esquizofrenia/patología , Tasa de Supervivencia , Factores de Tiempo , Carga ViralRESUMEN
Infection of the CNS by herpes simplex type 1 (HSV-1) via the trigeminal route to the brain stem was elucidated in a rat model. In contrast to the earlier described cortical and hippocampal infection after intracranial injection, the CNS showed a profound resistance to HSV-1 infection when the virus was administered by nose inoculation, as judged by histopathology and immunohistochemistry. In contrast, when the distribution of HSV-1 in the brain was investigated after nose inoculation by polymerase chain reaction, viral DNA was detected at all levels from the ganglia to the cortex. When replication of HSV-1 was assayed in primary cell cultures of rat astrocytes derived from brain stem, striatum, hippocampus and cerebral cortex, significantly lower virus yields were obtained in brain stem-derived astrocytes cultures as compared with in cortex-derived astrocytes. This finding was independent of whether HSV-1 strains used originated from brains of patients suffering from herpes simplex encephalitis or from patients with oral cutaneous lesions and lacking neurological symptoms. Also, by immunocytochemistry of cultures after HSV-1 infection, a lower number of plaques were seen in brain stem-derived astrocytes as compared with cortex-derived astrocytes. The observed relative resistance of brain stem-derived astrocytes to replicate HSV-1 might contribute to the ability of the brain stem to withstand infection during reactivation of this virus in the trigeminal neurons.