RESUMEN
Alzheimer's disease (AD) has been recognized as the most common cause of sporadic dementia. It represents both a medical and social problem, as it affects 10% of over-65 population. Even if the elderly are the most involved population, aging alone cannot be considered as the only cause of this disease. In this review we wanted to focus on the last hypotheses on the possible causes of this neuronal affection. We focused in particular on the role of inflammation and alteration of the inflammatory status that is typical of the elderly and may lead to chronic inflammation. The inflammation seems to be a cause of neuronal impairment and loss. Some studies have proposed a protective role of antiinflammatory drugs. Then we analyzed the role of genetic polymorphisms of some pro-inflammatory substances that seem to be linked to some cases of dementia. The complement system seems to have a role too, as some factors have been found in senile plaques, representing a possible involvement of classical complement pathway. One of the latest hypotheses is about the role of blood-brain barrier (BBB), as its loss of integrity may lead to a passage of proteins in cerebro spinal fluid (CSF), causing a compromised role of BBB in preserving the brain as an "immune sanctuary".
Asunto(s)
Enfermedad de Alzheimer/inmunología , Barrera Hematoencefálica/inmunología , Encéfalo/inmunología , Proteínas del Sistema Complemento/metabolismo , Inflamación/inmunología , Neuronas/inmunología , Placa Amiloide/metabolismo , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Apolipoproteínas E/genética , Apolipoproteínas E/inmunología , Autoinmunidad/efectos de los fármacos , Autoinmunidad/inmunología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Proteínas del Sistema Complemento/inmunología , Humanos , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/genética , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/inmunología , Memoria Inmunológica , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Placa Amiloide/inmunología , Polimorfismo Genético , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunología , alfa 1-Antiquimotripsina/genética , alfa 1-Antiquimotripsina/inmunologíaRESUMEN
The integrity of neuroprotection is an important component against the development of cognitive disorders and AD. Within this context, DHEAS would seem to have some positive metabolic and endocrine effects to delay brain aging by recovering the impairment of neuroprotective growth factors. In the present study we measured by ELISA the secretion of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and transforming growth factor-beta1 (TGFbeta1) in the supernatants of cultured circulating peripheral blood mononuclear cells (PBMC) from which natural killer cells (NK) were separated (PBMC-NK) (pg/ml/7.75x10(6) cells) in healthy subjects and in age-matched patients with mild to moderate AD. The growth factors were measured in spontaneous conditions and after stimulation with growth hormone (GH) 1 microg/ml (IGF-1), lipopolysaccharide (LPS) 1 microg/ml (VEGF) and glucose 10 microM (TGF(beta1). AD group demonstrated at baseline a severe reduction of IGF-1 (3.7+1.2 pg/ml after GH), VEGF (63+/-18 pg/ml spontaneous and 210+/-65 pg/ml after LPS) and TGF(beta1 (33+/-10 pg/ml spontaneous and 75+/-12 pg/ml after glucose) secretions compared to healthy elderly subjects (IGF-1, 9.5+/-2.8 pg/ml after GH, p<0.001; VEGF, 117+/-38 pg/ml spontaneous, p<0.001 and 690+/-120 pg/ml after LPS, p<0.001; and TGF(beta1, 73+/-21 pg/ml spontaneous, p<0.001 and 169+/-53 pg/ml after glucose, p<0.001). Significant positive correlations between IGF-1 and VEGF concentrations were found both in healthy subjects (r=0.87, p<0.001) and in AD subjects (r=0.87, p<0.001). The co-incubation of NK cells with DHEAS (10(6) M/ml/cells) significantly increase IGF-1, VEGF and TGF (beta1 production, reaching in AD group the normal concentrations found in healthy subjects (IGF-1, 7.9 + 2.4 pg/ml after GH; VEGF, 105+/-31 pg/ml spontaneous and 670+/-112 pg/ml after LPS; and TGFfbeta1, 68+/-18 pg/ml spontaneous and 155+/-48 pg/ml after glucose). These data suggested that DHEAS is able to increase the immunoendocrine production of neuroprotective growth factors, which is reduced in AD subjects, so suggesting a new approach in the treatment of dementia.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Sulfato de Deshidroepiandrosterona/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/sangre , Anciano , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Sulfato de Deshidroepiandrosterona/administración & dosificación , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Factor de Crecimiento Transformador beta1/sangre , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Among the age-related diseases, the development of cognitive impairments, in particular dementia, is the most devastating for the individual and has great social and healthcare costs. Accurate information is needed about the prevalence and incidence of cognitive disorders and the physiology of the aging brain. In particular, only scarce data are available about the relationship between aging, cognitive status and nutritional factors. In order to address these issues, we planned the Conselice Study, a longitudinal study of physiological and pathological brain aging. The center involved in the study was the municipality of Conselice, (Province of Ravenna), in the Northern-Italian Region Emilia-Romagna. A total of 1,016 subjects aged 65 years and over was enrolled at baseline. Information about cognitive status at 4-years of follow-up was collected from 940 of them. These data have been used to estimate prevalence and incidence of dementia in the elderly Italian population and to investigate the possible role of homocysteine as a predictor of dementia.
Asunto(s)
Envejecimiento/fisiología , Encéfalo/fisiopatología , Demencia/fisiopatología , Anciano , Áreas de Influencia de Salud , Trastornos del Conocimiento/epidemiología , Demencia/epidemiología , Estudios de Seguimiento , Humanos , Hiperhomocisteinemia/epidemiología , Incidencia , Italia , Prevalencia , Factores de Riesgo , Deficiencia de Vitamina B/epidemiologíaRESUMEN
BACKGROUND: Moderately elevated levels of homocysteine have been associated with an increased cardiovascular risk in type 2 diabetic patients. The role of methylenetetrahydrofolate reductase gene polymorphism is less clear. MATERIALS AND METHODS: We investigated the contribution of plasma homocysteine levels and the methylenetetrahydrofolate reductase gene polymorphism to the variability of carotid intima-media thickness in 124 consecutive Italian patients with type 2 diabetes mellitus. Fasting plasma homocysteine was measured by high-pressure liquid chromatography with an electrochemical detector; methylenetetrahydrofolate reductase genotypes were determined by polymerase chain reaction and restriction enzyme digestion. The carotid intima-media thickness was evaluated with high-resolution B-mode ultrasonography. RESULTS: Age, creatinine and plasma homocysteine levels showed a positive correlation with mean carotid intima-media thickness values, but only age and creatinine levels were still associated with mean carotid intima-media thickness values in the multivariate analysis. Plasma homocysteine levels were significantly higher in the patients bearing the 677T/677T genotype of the methylenetetrahydrofolate reductase polymorphism; mean carotid intima-media thickness values were not different in the three different methylenetetrahydrofolate reductase genotypes. CONCLUSION: In 124 Italian patients with type 2 diabetes mellitus, basal levels of plasma homocysteine, as well as methylenetetrahydrofolate reductase gene polymorphism, did not explain the variability of mean carotid intima-media thickness.
Asunto(s)
Arterias Carótidas/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Homocisteína/sangre , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Polimorfismo de Nucleótido Simple , Anciano , Arterias Carótidas/diagnóstico por imagen , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/patología , Femenino , Genotipo , Humanos , Italia , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Túnica Íntima/patología , UltrasonografíaRESUMEN
Plasma azopigments derived from conjugated bilirubin were analyzed by thin-layer chromatography according to HEIRWEGH et al. in 14 cases of obstructive jaundice and in 11 of acute hepatitis. The chromatographic patterns were compared with those obtained from azopigments derived from 8 normal bile samples. The plasma pigment patterns did not differ from those of the bile in number and chromatographic mobility of the spots. However, the quantitative percentages of the plasma azopigments were significantly modified: the alpha 0 fraction (free azodipyrrolic pigment) increased in both icteric syndromes, while the delta fraction (mainly glucuronide azopigment) decreased. Moreover, the behavior of two closed components of the delta group showed significant differences in both icteric syndromes. It can be postulated that the synthesis of bilirubin diconjugates decreases both in hepatocellular and cholestatic jaundice, while monoglucuronidated as well as saccharide and glucoside conjugates increase. In cholestatic jaundice the conjugation with glucuronic acid mainly takes place in the normal way, whereas compounds with different features are formed in hepatitis.