Diagnostic Validity Comparison Between Criteria Based on CSF Alzheimer's Disease Biomarkers.

AIM: To compare the diagnostic validity of NIA-AA criteria, for AD CSF biomarkers, with our own new criteria. MATERIALS AND METHODS: Between 2008 and 2011, 170 patients with Mild Cognitive Impairment (MCI) were included. CSF levels of Aß1-42, T-tau, P-tau181, and ratios of T-tau/Aß1-42 and P-tau181/Aß1-42 were analyzed. In our criteria, we considered 3 or more abnormal variables indicative of a high likelihood of MCI due to AD. RESULTS: After a clinical follow-up of 4.5 ± 1.2 years, 44 patients remained stable, 95 developed AD, 15 other forms of dementia, 7 died and 9 received other diagnoses. Using the NIA-AA criteria and our own criteria, the diagnostic validity of the CSF biomarkers was 58% versus 85%, specificity 84% versus 72%, PPV 82% versus 79% and NPV 61% versus 79%. CONCLUSION: The inclusion of the ratios in diagnostic criteria increases sensitivity and NPV for the diagnosis of MCI due to AD.

Non-AIDS Kaposi sarcoma in the external ear / Sarcoma de Kaposi del oído externo, no asociado con SIDA

No disponible

Influence of APOE Genotype on Alzheimer's Disease CSF Biomarkers in a Spanish Population.

OBJECTIVES: To evaluate the association between apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) levels of Alzheimer's disease (AD) biomarkers and to study the influence of APOE genotype on the development of AD in a Spanish population. MATERIAL AND METHODS: The study comprised 29 amnestic mild cognitive impairment (MCI) patients and 27 control subjects. Using ELISA methodology, CSF biomarkers and tau/Aß ratios were obtained. ANOVA and adjusted odds ratios were calculated. RESULTS: We observed the effect of APOE genotype and age on CSF AD variables. The progression to AD was more clearly influenced by CSF AD variables than by age or APOE status. CONCLUSIONS: APOE status influences CSF AD variables. However, the presence of APOE ε4 does not appear to be a deterministic factor for the development of AD, because CSF variables have a greater influence on progression to the disease. These results confirm previous observations and, to our knowledge, are the first published in a Spanish population.

Comparación de la capacidad diagnóstica precoz de los biomarcadores de la enfermedad de Alzheimer en resonancia magnética cerebral y líquido cefalorraquídeo / A comparison of early diagnostic utility of Alzheimer disease biomarkers in brain magnetic resonance and cerebrospinal fluid

Introducción: Nuestros objetivos fueron comparar la capacidad de diagnóstico precoz de los biomarcadores (BMC) de enfermedad de Alzheimer (EA) en LCR y RM cerebral, en condiciones posibles de nuestra práctica clínica y, además, conocer la precisión diagnóstica de la combinación de ambas técnicas. Métodos: Entre 2008 y 2009, estudiamos a 30 pacientes con deterioro cognitivo leve (DCL) mediante RM cerebral de 1,5 teslas y análisis de BMC de EA en el LCR. Las RM fueron valoradas por 2 neurorradiólogos, atendiendo a la escala visual de Korf (2004). Los BMC de EA en LCR se analizaron mediante reactivos INNOTEST para proteínas A 1-42, total-tau y fosfo-tau. Se evaluó la evolución clínica (según criterios NINCDS-ADRDA) a los 2 a˜nos tras la inclusión. Resultados: Entre los 30 pacientes iniciales, 15 evolucionaron a EA (criterios NINCDS-ADRDA) a los 2 a˜nos de la inclusión. La capacidad predictiva de los BMC en LCR (RR 2,7; IC del 95%, 1,1-6,7; p < 0,01) es superior a los de RM (RR 1,5; IC del 95%, 0,7-3,4; p < 0,2), y la combinación de ambas técnicas alcanza una sensibilidad y valor predictivo negativo del 100%. La normalidad de ambas pruebas complementarias descartó al 100% el desarrollo de EA, en los 2 a˜nos siguientes a la realización de las mismas. Conclusiones: Siguiendo nuestra metodología, la precisión diagnóstica de los BMC en LCR es superior a los de la RM para el diagnóstico precoz de EA. La combinación de ambas técnicasconsigue una precisión diagnóstica muy alta, tanto para diagnosticar como para excluir precozmente EA, en pacientes con DCL

Introduction: The goals of this study were to compare the early diagnostic utility of Alzheimer disease biomarkers in the CSF with those in brain MRI in conditions found in our clinical practice, and to ascertain the diagnostic accuracy of both techniques used together. Methods: Between 2008 and 2009, we included 30 patients with mild cognitive impairment (MCI) who were examined using 1.5 Tesla brain MRI and AD biomarker analysis in CSF. MRI studies were evaluated by 2 radiologists according to the Korf s visual scale. CSF biomarkers were analysed using INNOTEST reagents for A 1-42, total-tau and phospho-tau181p. We evaluated clinical changes 2 years after inclusion. Results: By 2 years after inclusion, 15 of the original 30 patients (50%) had developed AD (NINCDS-ADRA criteria). The predictive utility of AD biomarkers in CSF (RR 2.7; 95% CI, 1.1-6.7; P < .01) was greater than that of MRI (RR 1.5; 95% CI 95%, 0.7-3.4; P < .2); using both techniques together yielded a sensitivity and a negative predictive value of 100%. Normal results on both complementary tests ruled out progression to AD (100%) within 2 years of inclusion. Conclusions: Our results show that the diagnostic accuracy of biomarkers in CSF is higher than that of biomarkers in MRI. Combined use of both techniques is highly accurate for either early diagnosis or exclusion of AD in patients with MCI

A comparison of early diagnostic utility of Alzheimer disease biomarkers in brain magnetic resonance and cerebrospinal fluid.

INTRODUCTION: The goals of this study were to compare the early diagnostic utility of Alzheimer disease biomarkers in the CSF with those in brain MRI in conditions found in our clinical practice, and to ascertain the diagnostic accuracy of both techniques used together. METHODS: Between 2008 and 2009, we included 30 patients with mild cognitive impairment (MCI) who were examined using 1.5 Tesla brain MRI and AD biomarker analysis in CSF. MRI studies were evaluated by 2 radiologists according to the Korf́s visual scale. CSF biomarkers were analysed using INNOTEST reagents for Aß1-42, total-tau and phospho-tau181p. We evaluated clinical changes 2 years after inclusion. RESULTS: By 2 years after inclusion, 15 of the original 30 patients (50%) had developed AD (NINCDS-ADRA criteria). The predictive utility of AD biomarkers in CSF (RR 2.7; 95% CI, 1.1-6.7; P<.01) was greater than that of MRI (RR 1.5; 95% CI 95%, 0.7-3.4; P<.2); using both techniques together yielded a sensitivity and a negative predictive value of 100%. Normal results on both complementary tests ruled out progression to AD (100%) within 2 years of inclusion. CONCLUSIONS: Our results show that the diagnostic accuracy of biomarkers in CSF is higher than that of biomarkers in MRI. Combined use of both techniques is highly accurate for either early diagnosis or exclusion of AD in patients with MCI.

Pacientes con deterioro cognitivo leve y reducción de la proteína Aβ 1-42 en LCR evolucionan rápidamente a enfermedad de Alzheimer / Patients with mild cognitive impairment and a reduced CSF A_1-42 protein progress rapidly to Alzheimer’s disease

Introducción: En muchos artículos recientes, el análisis de las proteínas Aβ 1-42, tau total (T-tau) y tau fostorilada (P-tau) en LCR puede discriminar entre los pacientes con deterioro cognitivo leve (DCL) estables y aquellos otros que van a progresar a enfermedad de Alzheimer (EA). Nuestro objetivo fue comprobar la capacidad de estas proteínas del LCR para discriminar, entre nuestros pacientes DCL, según la evolución clínica en el año siguiente a la punción lumbar. Material y métodos: Se incluyó a 36 pacientes DCL amnésico (criterios de Petersen 2006) procedentes de la consulta de deterioro cognitivo del Hospital General de Alicante. Usando los reactivos INNO-BIA Alzbio-3 (Innogenetics), cuantificamos las proteínas Aβ1-42, T-tau, P-tau181p en LCR, y calculamos los cocientes T-tau/Aβ1-42 y P-tau181p/Aβ1-42. El estudio fue aprobado por el comité ético de investigación del Hospital General de Alicante. Resultados: En los 12 meses posteriores a la punción lumbar, 14 pacientes DCL (38%) evolucionaron a EA. Estos pacientes, presentaron menores niveles de Aβ1-42 (285,3 vs. 377,7 ng/ml, p<0,02), y un aumento en el valor del cociente P-tau181p/Aβ1-42 (0,25 vs. 0,16, p<0,02) que los pacientes que se mantuvieron estables. No hubo diferencias significativas en el resto de las variables estudiadas. Conclusiones: Nuestros pacientes DCL que presentaron niveles reducidos de la proteína Aβ1-42 y elevación del cociente P-tau181p/Aβ1-42 en LCR, evolucionaron rápidamente a EA. Estos resultados pueden ayudar a conseguir el objetivo de identificar de forma precoz a los pacientes DCL con peor pronóstico (AU)

Introduction: Some studies have shown that CSF amyloid-beta 1-42 (A_1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau181p) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheimer's disease (AD). Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture. Material and methods: A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF A_1-42, T-tau and P-tau181p proteins, and calculated the T-tau/A_1-42 y P-tau181p/A_1-42 ratios. Thisproject was approved by the local ethics committee. Results: One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower A_ 1-42 protein levels (285.3 vs 377 ng/ml, P < .02) and higher P-tau181p/A_1-42 ratio (0,25 vs 0,16, p < .02) than the clinically stable patients. Conclusions: Our MCI patients with lower A_1-42 protein levels and an increased P-tau181p /A_1-42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis (AU)

[Patients with mild cognitive impairment and a reduced CSF Aß1₋42 protein progress rapidly to Alzheimer's disease]. / Pacientes con deterioro cognitivo leve y reducción de la proteína Aß(1-42) en LCR evolucionan rápidamente a enfermedad de Alzheimer.

INTRODUCTION: Some studies have shown that CSF amyloid-beta 1-42 (Aß1₋42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau(181p)) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheimers disease (AD). Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture. MATERIAL AND METHODS: A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF Aß1₋42, T-tau and P-tau(181p) proteins, and calculated the T-tau/Aß1₋42 y P-tau(181p)/Aß1₋42 ratios. This project was approved by the local ethics committee. RESULTS: One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower Aß1₋42 protein levels (285.3 vs 377 ng/ml, P<.02) and higher P-tau(181p)/Aß1₋42 ratio (0,25 vs 0,16, p<.02) than the clinically stable patients. CONCLUSIONS: Our MCI patients with lower Aß1₋42 protein levels and an increased P-tau(181p) /Aß1₋42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis.

Biomarkers of Alzheimer's disease in the cerebrospinal fluid of Spanish patients with mild cognitive impairment.

The study of biomarkers in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) is a technique used with increasing frequency in the early diagnosis of Alzheimers disease (AD). Our objectiv was to gain an own experience while evaluating the reliability, sensitivity, and reproducibility of this technique in Spanish patients. Thirty-seven patients with MCI and twenty-four control subjects were studied by means of AD biomarker analysis in CSF. xMAP Luminex and INNO-BIA Alzbio3 reagents of Innogenetics were used. The study variables assessed were levels of Aß(1-42), T-tau and P-tau(181p) proteins as well as the ratios of T-tau/Aß(1-42) and P-tau(181p)/Aß(1-42). Samples from nineteen patients were examined twice. Intra-class correlation coefficients for the three biomarkers used showed values higher than 0.95. We observed significant differences between the control group and the MCI groups. In the 6 months following lumbar puncture (LP), eleven (29%) patients with MCI developed AD. These patients showed significant lower levels in Aß(1-42) protein (276.35 ± 78 vs. 367.13 ± 123.49, P < 0.03) and higher ratios (T-tau/Aß(1-42) [0.38 ± 0.2 vs. 0.22 ± 0.14, P < 0.01] and P-tau(181p)/Aß(1-42) [0.27 ± 0.13 vs. 0.16 ± 0.1, P < 0.008]) to those in the same group who remained stable. We obtained similar results to those in the most recent reliable literature with our ROC curves, especially with our P-tau(181p) values and T-tau/Aß(1-42) ratio in order to differentiate between control and AD groups. Our experience showed that the analysis of CSF-AD biomarkers in patients with MCI is reliable, sensitive and reproducible. In our knowledge, this is the first experience in Spanish patients.

Biomarcadores en el líquido cefalorraquídeo de pacientes con deterioro cognitivo leve: metaanálisis de su capacidad predictiva para el diagnóstico de la enfermedad de Alzheimer / Biomarkers in the cerebrospinal fluid of patients with mild cognitive impairment: a meta-analysis of their predictive capacity for the diagnosis of Alzheimer’s disease

Introducción. Varios estudios han descrito alteraciones en los biomarcadores del líquido cefalorraquídeo (proteínas Abeta- 42, T-tau y P-tau), tanto en la enfermedad de Alzheimer (EA) como en el deterioro cognitivo leve (DCL). Objetivo. Realizar un metaanálisis sobre la rentabilidad diagnóstica de esta técnica para la predicción de los pacientes con DCL que van a progresar a EA. Materiales y métodos. Tras una búsqueda en PubMed y Embase de los artículos publicados entre 1999 y septiembre de 2008, se incluyeron sólo estudios prospectivos para la revisión sistemática. Se estudió la sensibilidad y especificidad para cada biomarcador por separado y también de forma conjunta.Resultados. De los 12 estudios incluidos, 6 cuantificaron la proteína Abeta-42, 11 la proteína T-tau y 7 la proteína P-tau. En tres estudios se pudieron obtener los datos de los tres biomarcadores de forma combinada. La sensibilidad de la cuantificación de las proteínas T-tau y P-tau es del 82%, con una odds ratio diagnóstica de 12,09 (intervalo de confianza al 95%, C 95% = 7,71-18,99; p = 0,1) y 16,29 (IC 95% = 9,69-27,4; p = 0,9), respectivamente. La alteración de alguno de los tres biomarcadores tiene una especificidad del 87%, con una odds ratio diagnóstica de 35,97 (IC 95% = 7,8-164,6; p = 0,04). Conclusiones. La alteración aislada de los niveles de T-tau o P-tau en el líquido cefalorraquídeo es muy sensible para diferenciar entre los pacientes con DCL que van a desarrollar EA de los que van a permanecer estables. La normalidad de los tres biomarcadores es muy fiable para descartar la evolución a EA en pacientes con DCL (AU)

Introduction. Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau and P-tau proteins), both in Alzheimer’s disease (AD) and in mild cognitive impairment (MCI). Aim. To perform a meta-analysis of the diagnostic yield of this technique for the prediction of patients with MCI who are going to progress to AD. Materials and methods. A search was conducted in PubMed and Embase of papers published between 1999 and September 2008, and as a result only prospective studies were included for the systematic review. The sensitivity and specificity for each biomarker were studied separately and also jointly. Results. Of the 12 studies that were included, 6 quantified the Abeta-42 protein, 11 the T-tau protein and seven the P-tau protein. In three of the studies data was obtained from the three biomarkers in combination. The sensitivity of the quantification of the T-tau and P-tau proteins is 82%, with a diagnostic odds ratio of 12.09 (confidence interval 95%, CI 95% = 7.71-18.99; p = 0.1) and 16.29 (CI 95% = 9.69-27.4; p = 0.9), respectively. Alteration of any of the three biomarkers has a specificity of 87%, with a diagnostic odds ratio of 35.97 (CI 95% = 7.8-164.6; p = 0.04). Conclusions. The isolated alteration of T-tau or P-tau levels in cerebrospinal fluid is very sensitive for differentiating between patients with MCI who are going to develop AD and those who are going to remain stable. Normality of the three biomarkers is a very reliable way of ruling out the progression of AD in patients with MCI (AU)

Cyclical hypereosinophilia with skin manifestations and a clonal T cell population.

Hypereosinophilia is a common biological finding in clinical practice, in some cases without an identifiable cause. We describe the case of a 59-year-old woman with recurrent attacks of facial angioedema, fever, pruritic cutaneous nodules, and eosinophilia that reached up to 12.7 x 10(9) cells/L during outbreaks. She had experienced 2 episodes every month for the last 12 years, and the episodes resolved with systemic corticosteroids. Other causes of eosinophilia were ruled out. The patient showed an aberrant T cell population with a CD3-CD4+ TCR- phenotype that accounted for up to 22% of circulating lymphocytes. Analysis of the T-cell receptor (TCR) gene showed evidence of clonal rearrangement. During the episodes, this cell population produced high levels of interleukin-5, which returned to normal levels between the outbreaks. However the aberrant T cell population remained unaffected after the treatment. We suggest that lymphocyte immunophenotyping analysis should be included in the diagnostic workup of patients with hypereosinophilic syndrome, including the variant type of episodic angioedema and eosinophilia (Gleich syndrome).

Monitoring trough plasma concentrations of mycophenolate mofetil in patients with uveitis.

BACKGROUND: Mycophenolate mofetil (MMF) has been used successfully in patients with various forms of uveitis not responsive to other immunosuppressants. Nevertheless, for these patients neither recommendations for optimal dosage of MMF nor data concerning drug exposure of MMF are available. OBJECTIVE: To describe the results of the therapeutic drug monitoring (TDM) of MMF trough concentrations in a cohort of patients with uveitis, with the aim of optimizing the dosage of this drug, by maintaining a target concentration to achieve adequate immunosuppression with a minimal risk of therapeutic failure or toxicity. PATIENTS AND METHODS: This study describes the results of monitoring trough plasma concentrations of MMF in 12 patients with uveitis during a mean period of 21.4 months. Patients included one with Stevens-Johnson syndrome, one with Graves-Basedow's disease, one with Behcet's disease, one with idiopathic thrombocytopenic purpura and the rest with idiopathic uveitis. All patients were treated with steroids and additional therapy prior to treatment with MMF. RESULTS: Pharmacokinetic monitoring of mycophenolic acid (MPA) was performed with 108 trough plasma samples using an EMIT assay. Mean daily MMF dose was 24.5 +/- 6.3 mg/kg and mean trough MPA concentration was 2.9 +/- 1.9 microg/mL. Therapy was effective in 10 patients (83%). There were few side-effects: diarrhoea, excitement, agitation and cough that disappeared with daily dose reduction of MMF. CONCLUSIONS: MMF was effective in the majority of patients with uveitis with an acceptable profile of side-effects. TDM of MMF in patients with uveitis is clinically practicable and may help to optimize individual immunosuppressive therapy. We estimated that MMF dosages in the range of 0.5-1.5 g/day might be sufficient for treating uveitis and we recommend an initial target range of 2-4 microg/mL, which included 50% of our results. Randomized controlled trials are essential to confirm the efficacy of MMF in uveitis.

[Neurological involvement following triple virus vaccine]. / Implicación neurológica tras immunización con vacuna triple vírica.

INTRODUCTION: Prophylactic immunization against measles, rubella and mumps is carried out using a trivalent vaccine. The second dose is recommended at 11-12 years-old. Neurological complications have been described after vaccination for measles and rubella. All cases occurred several days after vaccination. CLINICAL CASES: We describe four girls aged between 10 and 11 years old who were vaccinated on the same day. Almost immediately they complained of symptoms in the vaccinated arm. These were pain, paresthesia, coldness, pallor and sweating of the hand. On the following days there was loss of strength and alterations in sensation. All laboratory, radiological, neurophysiological and psychiatric studies were normal. Immunological study showed changes in the immunohumeral response to the vaccine. Complete recovery was made. CONCLUSIONS: The different types of post-vaccination complications described to date are reviewed, together with conditions showing features such as those described, particularly the reflex sympathetic syndrome. Possible reasons for the poor immunohumoral response to the vaccine in these patients are discussed.

[Bactericidal effect of hydrated lime in aqueous solution]. / Efecto bactericida de la cal hidratada en solución acuosa.

This study determined the bactericidal effect of the supernatants of saturated solutions of common lime and of micronized calcium hydroxide (Ca(OH)2) (1500 mg/L), which was used as a control, compared with disinfectants made of solutions of 0.33% colloidal silver (0.0016 mg/L), toluene sulfachloramine (41 mg/L) with sodium bicarbonate (9 mg/L), and sodium hypochlorite (5 mg/L). The test involved four strains of Vibrio cholerae 01, V. parahaemolyticus, Escherichia coli, Salmonella typhimurium, Shigella flexneri, Sh. sonnei, and Sa. enterititidis. These bacteria were inoculated into the bactericidal substances listed above and, after different incubation times, the number of surviving bacteria was determined in vitro by using a counting plate. The results were expressed in colony-forming units (CFU). An in situ estimate was made of the amount of V. cholerae on 35 strawberries and 35 radishes (having a weight of about 10 g per unit) after they were washed under a flow of potable water, submerged in the supernatant of the saturated lime solution (1.5 g/L), or both. The greatest bactericidal effect was obtained against V. cholerae 01 and was observed in 3 minutes. Other enterobacteria were resistant to the effect for up to 30 minutes.