RESUMEN
To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/inmunología , Trastornos del Conocimiento/terapia , Inmunoterapia Activa , Fragmentos de Péptidos/inmunología , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Animales , Anticuerpos/administración & dosificación , Anticuerpos/sangre , Anticuerpos/líquido cefalorraquídeo , Cognición , Trastornos del Conocimiento/inmunología , Trastornos del Conocimiento/patología , Progresión de la Enfermedad , Femenino , Hipocampo/inmunología , Hipocampo/patología , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Pruebas Neuropsicológicas , Pacientes Desistentes del Tratamiento , Fragmentos de Péptidos/análisis , Placa Amiloide/inmunología , Placa Amiloide/patología , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
BACKGROUND: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy. OBJECTIVE: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD. METHODS: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects. RESULTS: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%). CONCLUSION: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas Serina-Treonina Quinasas/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Anticuerpos Monoclonales/inmunología , Apolipoproteínas E/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Genotipo , Glucógeno Sintasa Quinasa 3 , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proteínas Serina-Treonina Quinasas/inmunología , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain. OBJECTIVE: To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD. DESIGN: Alzheimer disease traits (beta-amyloid load, beta-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations. SETTING: Specialized centers for memory disorders in Switzerland, Greece, and Italy. PARTICIPANTS: Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies. RESULTS: A polymorphism of CYP46 was associated with increased beta-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CI], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E epsilon4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CI, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E epsilon4 alone (95% CI, 2.8-6.8; P<.001). CONCLUSION: CYP46 influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Esteroide Hidroxilasas/genética , Proteínas tau/líquido cefalorraquídeo , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/patología , Colesterol/líquido cefalorraquídeo , Colesterol 24-Hidroxilasa , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Humanos , Hidroxicolesteroles/líquido cefalorraquídeo , Intrones/genética , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , Polimorfismo Genético , Factores de RiesgoRESUMEN
The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Agonistas Muscarínicos/uso terapéutico , Fragmentos de Péptidos/líquido cefalorraquídeo , Quinuclidinas/uso terapéutico , Receptor Muscarínico M1/agonistas , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , PlacebosRESUMEN
Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Polimorfismo Genético , Inhibidor Tisular de Metaloproteinasa-1/líquido cefalorraquídeo , Inhibidor Tisular de Metaloproteinasa-1/genética , Regiones no Traducidas 5'/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Mapeo Cromosómico , Cromosomas Humanos X , ADN/sangre , ADN/genética , Femenino , Frecuencia de los Genes , Variación Genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Valores de ReferenciaRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.
Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 10/genética , Esteroide Hidroxilasas/genética , Regiones no Traducidas 5'/genética , Anciano , Alelos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/patología , Colesterol/sangre , Femenino , Regulación Enzimológica de la Expresión Génica , Marcadores Genéticos , Genotipo , Haplotipos , Humanos , Masculino , Placa Amiloide/genética , Placa Amiloide/patología , Polimorfismo de Nucleótido Simple , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , RiesgoRESUMEN
We report the association of long-term clozapine and clomipramine therapy with severe esophageal dilation and hypomotility in a patient with chronic schizophrenia leading to life threatening aspiration pneumonia. Severe aspiration pneumonia manifested suddenly and required intubation and intensive care. Gross impairment of swallowing function with esophageal dilation and hypomotility was detected on videofluoroscopy and manometry. The patient recovered well following a reduction in the dose of clozapine and the withdrawal of clomipramine. The restoration of esophageal function was documented by manometry. The reported side effects and possible pharmacological actions of clozapine, an atypical neuroleptic, and clomipramine, a tricyclic antidepressant, on esophageal motility are discussed.
Asunto(s)
Enfermedades del Esófago/inducido químicamente , Psicotrópicos/efectos adversos , Esquizofrenia/complicaciones , Enfermedades del Esófago/patología , Humanos , Masculino , Manometría/métodos , Persona de Mediana Edad , Psicotrópicos/uso terapéutico , Estudios Retrospectivos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/patología , Tórax/patología , Tomografía Computarizada por Rayos X/métodosRESUMEN
Amyloid-beta peptides (Abeta) are major components of amyloid plaques in the Alzheimer's disease (AD) brain and have been proposed as diagnostic markers in cerebrospinal fluid (CSF). Abeta derived from brain may be processed into fragments before emerging in CSF. Therefore, we determined mass profiles of Abeta peptides in CSF of patients with AD and age-matched healthy control subjects (CTR) by using protein biochip technology. Abeta peptides were captured on the chip surfaces (spots) by the specific monoclonal antibody 6E10 and were then analyzed by integrated surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS). We found Abeta species with mean molecular masses at 1,583.3 Da (corresponding to Abeta2-14), 2,068.5 Da (Abeta1-17), 2,166.4 Da (Abeta1-18), 3,676.6 Da (Abeta1-33), 3,789.4 Da (Abeta1-34), 4,076.9 Da (Abeta1-37), 4,134.0 Da (Abeta1-38), 4,233.3 Da (Abeta1-39), 4,332.4 Da (Abeta1-40) and 4,516.8 Da (Abeta1-42) in both AD (n = 24) and CTR (n = 24) subjects. Abeta1-38 appeared to be a major Abeta species in human CSF along with Abeta1-40. Quantitation revealed that CSF levels of Abeta1-38 were significantly decreased in AD as compared to CTR subjects. The CSF profile of Abeta peptides may be used for diagnostic and therapeutic purposes in clinical studies.