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BACKGROUND AND OBJECTIVES: To elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging. METHODS: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF ß-amyloid (Aß) peptide biomarkers. These Aß cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients. RESULTS: A total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%. DISCUSSION: The proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification.
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Enfermedad de Alzheimer , Biomarcadores , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Fragmentos de Péptidos , Tomografía de Emisión de Positrones , Proteínas tauRESUMEN
INTRODUCTION: There is increasing interest in plasma amyloid beta (Aß) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aß levels may elucidate important biological processes that determine plasma Aß measures. METHODS: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aß1-40, Aß1-42 levels and Aß1-42/Aß1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aß deposition and AD risk. RESULTS: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aß1-42 and Aß1-42/Aß1-40 ratio, and BACE1 for Aß1-40. Gene-based analysis of Aß1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aß deposition. DISCUSSION: Identification of variants near/in known major Aß-processing genes strengthens the relevance of plasma-Aß levels as an endophenotype of AD.
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Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Amiloide , Apolipoproteínas E/genética , Ácido Aspártico Endopeptidasas/genética , Estudio de Asociación del Genoma Completo , Voluntarios Sanos , Presenilina-2/genética , Enfermedad de Alzheimer/genética , Amiloide/sangre , Amiloide/metabolismo , Encéfalo/metabolismo , Humanos , Tomografía de Emisión de PositronesRESUMEN
SCOPE: Type 2 diabetes (T2D) induces organ damage associated with glycation, among other metabolic pathways. While therapeutic strategies have been tested to reduce the formation and impact of glycation products, results remain equivocal. Anti-diabetic therapies using probiotics have been proposed, but their effect upon glycation has not been reported. Here, the effects of the bacterial strain Lactobacillus fermentum ME-3 on glycation and T2D-related complications in a mouse model of T2D are investigated. METHODS & RESULTS: Wild-type LepRdb/+ and diabetic LepRdb/db littermates receive a daily gavage of either water or the probiotic ME-3 strain (1010 CFU). Glycation markers, fructoselysine-derived furosine (FL-furosine) and carboxymethyllysine (CML), are quantified in four major organs and plasma using stable-isotope dilution LC-MS/MS. After 12 weeks of ME-3 treatment, diabetic mice gain less weight and exhibit an apparently improved glucose tolerance. The ME-3 treatment reduces median renal levels of FL-furosine in both genotypes by 12-15%, and renal and pulmonary free-CML in diabetic mice by 30% and 18%, respectively. Attenuated hepatic steatosis and an improved plasma lipid profile are also observed with treatment in both genotypes, while the gut microbiota profile is unchanged. CONCLUSION: L. fermentum ME-3 has therapeutic potential for reducing the formation/accumulation of some glycation products in kidneys and attenuating some common diabetes-related complications.
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Complicaciones de la Diabetes/dietoterapia , Productos Finales de Glicación Avanzada/metabolismo , Limosilactobacillus fermentum , Probióticos/farmacología , Animales , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/dietoterapia , Microbioma Gastrointestinal/fisiología , Hemoglobina Glucada/análisis , Riñón/metabolismo , Lípidos/sangre , Hígado/metabolismo , Hígado/fisiología , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Receptores de Leptina/genética , Aumento de Peso/efectos de los fármacosRESUMEN
PURPOSE: A cross-sectional study was conducted in a group of Algerian welders to study the relationship between the exposure to metal particles from welding fumes and the concentration of three circulating miRNAs, miR-21, miR-146a and miR-155, as markers of renal function injury. METHODS: Characteristics of the subjects and the curriculum laboris were determined by questionnaires. We measured the concentrations of metals in blood and urine samples using ICP-MS. The three circulating miRNAs studied were measured by quantitative PCR. Associations between miRNAs and internal exposure markers were assessed by simple and multiple regression analyses. RESULTS: miR-21 was significantly lower among welders (p = 0.017), compared with controls, adjusted for age, body mass index, smoking status and seniority. Significant adjusted associations were observed between miR-21 or miR-155 and urinary chromium (p = 0.005 or p = 0.041, respectively), miR-146a and urinary nickel (p = 0.019). The results of the multivariate analysis showed that duration of employment was the main factor responsible for the variation of miRNAs among welders. CONCLUSION: In conclusion, a recent exposure to certain metals, mainly chromium and nickel, appears to be associated to a decrease in plasma expression of miR-21, miR-146a and miR-155. Further larger studies would help to determine the mechanisms of action of metal particles on miRNA expression.
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Contaminantes Ocupacionales del Aire/efectos adversos , Metales/toxicidad , MicroARNs/sangre , Exposición Profesional/efectos adversos , Soldadura , Adulto , Argelia , Biomarcadores/orina , Estudios de Casos y Controles , Cromo/sangre , Cromo/toxicidad , Cromo/orina , Estudios Transversales , Humanos , Enfermedades Renales/inducido químicamente , Masculino , Metales/sangre , Metales/orina , Persona de Mediana Edad , Níquel/sangre , Níquel/toxicidad , Níquel/orinaAsunto(s)
Alcaptonuria/diagnóstico , Errores Diagnósticos , Proteinuria/diagnóstico , Orina/química , Preescolar , Humanos , Masculino , UrinálisisRESUMEN
OBJECTIVES: New diagnostic criteria for Alzheimer's disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics. DESIGN: We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey. SETTING: 29 secondary and tertiary memory clinics in France. PARTICIPANTS: Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP. PRIMARY AND SECONDARY OUTCOME MEASURES: Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine. RESULTS: 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4). CONCLUSION: This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.
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Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Francia , Humanos , Masculino , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Streptococcus pneumoniae infection causes morbidity and mortality in multiple myeloma patients. Pneumococcal vaccination is commonly given to immunocompromised myeloma patients; however response data are sparse. Here, we present longitudinal response data to pneumococcal vaccination in multiple myeloma patients. METHOD: Twenty-eight multiple myeloma patients were included, 25 of whom were newly diagnosed. All the patients received two vaccines Prevnar13® and Pneumo23®. Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline, and then sequentially at different time points postvaccination until treatment ended. Response to vaccination is available for 20 patients. The primary endpoint was the incidence rate of patients who obtained an isotype response serum concentration after vaccination. Secondary endpoints included detailed isotype increase, time to first increase, further assessment of a decreased anti-pneumococcal serum concentrations following treatment including autologous stem cell transplantation (ASCT), rate of infection with a special attention to pneumococcal infection. RESULTS: The median age was 66 years and the male to female ratio was 0.6. Anti-pneumococcal capsular polysaccharide (anti-PCP23) IgG, IgG2, IgA, and IgM responses were detected within 1 week postvaccination. Response to at least one subtype of antibody was obtained in 85% (n = 17) of patients, for at least two subtypes in 65% (n = 13), for at least three subtypes in 55% (n = 11), and 2 patients responded to all four subtypes. The median increase in the concentration of anti-PCP23 isotypes was threefold following vaccination, with the highest increase observed when Pneumo23® was given more than 30 days after Prevnar13®. The anti-pneumococcal geometric mean concentration decreased significantly for all subtypes over time independently of treatment approaches. CONCLUSION: Myeloma has the ability to demonstrate a response to pneumococcal vaccine, independently of preexisting hypogammaglobulinemia and possibly of treatment-induced immunodepression. We also observed a drop in the serum response overtime and following autologous transplantation. Further studies in larger sample are needed to understand the benefit of vaccination strategies in these patients.
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Mieloma Múltiple/complicaciones , Infecciones Neumocócicas/etiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/inmunología , Adulto , Anciano , Anticuerpos Antibacterianos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Vacunas Neumococicas/administración & dosificación , VacunaciónRESUMEN
INTRODUCTION: Patients with positive tauopathy but negative Aß42 (A-T+) in the cerebrospinal fluid (CSF) represent a diagnostic challenge. The Aß42/40 ratio supersedes Aß42 and reintegrates "false" A-T+ patients into the Alzheimer's disease spectrum. However, the biomarker and clinical characteristics of "true" and "false" A-T+ patients remain elusive. METHODS: Among the 509 T+N+ patients extracted from the databases of three memory clinics, we analyzed T+N+ patients with normal Aß42 and compared "false" A-T+ with abnormal Aß42/40 ratio and "true" A-T+ patients with normal Aß42/40 ratio, before CSF analysis and at follow-up. RESULTS: 24.9% of T+N+ patients had normal Aß42 levels. Among them, 42.7% were "true" A-T+. "True" A-T+ had lower CSF tauP181 than "false" A-T+ patients. 48.0% of "true" A-T+ patients were diagnosed with frontotemporal lobar degeneration before CSF analysis and 64.0% at follow-up, as compared with 6% in the "false" A-T+ group (P < .0001). DISCUSSION: Frontotemporal lobar degeneration is probably the main cause of "true" A-T+ profiles.
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PURPOSE: One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer's disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients. METHODS: Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain 18F-FDG PET and MRI. A cluster analysis was performed, with the CSF biomarkers for AD as variables. Vertex-wise, partial-volume-corrected metabolic maps were computed for the patients and compared between the clusters of patients. Linear correlations between each CSF biomarker and the metabolic maps were assessed. RESULTS: Three clusters emerged. The "Aß42" cluster contained 32 patients with low levels of Aß42, while tau and p-tau remained within the normal range. The "Aß42 + tau" cluster contained 41 patients with low levels of Aß42 and high levels of tau and p-tau. Lastly, the "tau" cluster contained 12 patients with very high levels of tau and p-tau and low-normal levels of Aß42. There were no inter-cluster differences in age, sex ratio, educational level, APOE genotype, disease duration or disease severity. The "Aß42 + tau" and "tau" clusters displayed more marked frontal hypometabolism than the "Aß42" cluster did, and frontal metabolism was significantly negatively correlated with the CSF tau level. The "Aß42" and "Aß42 + tau" clusters displayed more marked hypometabolism in the left occipitotemporal region than the "tau" cluster did, and metabolism in this region was significantly and positively correlated with the CSF Aß42 level. CONCLUSION: The CSF biomarkers can be used to identify metabolically distinct subgroups of patients with EOAD. Future research should seek to establish whether these biochemical differences have clinical consequences.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Encéfalo/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Análisis por Conglomerados , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosfoproteínas/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is not straightforward, especially in the early stages of disease. We compared AD biomarkers (phospho-Tau181, total-Tau, Aß42 and Aß40) in cerebrospinal fluid (CSF) of patients with DLB and AD, focusing especially on the prodromal stage. METHODS: A total of 1221 CSF were collected in different memory centres (ePLM network) in France and analysed retrospectively. Samples were obtained from patients with prodromal DLB (pro-DLB; n=57), DLB dementia (DLB-d; n=154), prodromal AD (pro-AD; n=132) and AD dementia (n=783), and control subjects (CS; n=95). These centres use the same diagnostic procedure and criteria to evaluate the patients. RESULTS: In patients with pro-DLB, CSF Aß42 levels appeared much less disrupted than in patients at the demented stage (DLB-d) (P<0.05 CS>pro-DLB; P<0.001 CS>DLB-d). On average, Aß40 levels in patients with DLB (pro-DLB and DLB-d) were much below those in patients with pro-AD (P<0.001 DLB groupsAsunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo
, Enfermedad de Alzheimer/diagnóstico
, Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo
, Enfermedad por Cuerpos de Lewy/diagnóstico
, Síntomas Prodrómicos
, Anciano
, Péptidos beta-Amiloides/líquido cefalorraquídeo
, Biomarcadores/líquido cefalorraquídeo
, Estudios de Casos y Controles
, Diagnóstico Diferencial
, Femenino
, Humanos
, Masculino
, Persona de Mediana Edad
, Fragmentos de Péptidos/líquido cefalorraquídeo
, Estudios Retrospectivos
, Proteínas tau/líquido cefalorraquídeo
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BACKGROUND: Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD). OBJECTIVE: The aim of this study was to test the hypothesis of misdiagnoses for these patients. METHOD: Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aß1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis. RESULTS: In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology. CONCLUSION: AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fosforilación , Estudios RetrospectivosRESUMEN
Automated serum heavy + light chain (HLC) immunoassays can measure the intact immunoglobulins of each light chain type separately. We though to compare HLC assays with electrophoretic techniques in determining International Myeloma Working Group (IMWG) response criteria. 114 myeloma patients from 2 trials were included. HLC measurements were made utilizing archived sera and response assessments compared with those based on electrophoretic analysis at the time of the trials. Assessments at â¼90 days and maximal response were compared as was the power of the 2 techniques for predicting later responses, overall survival, and progression. The kappa statistic indicated good agreement between the 2 methods for determining IMWG response criteria, although HLC measurements might give better predictions of subsequent responses and frequently gave an earlier indication of change. HLC measurements could represent an alternative to electrophoretic techniques in determining IMWG response. Validation with a greater range of patient responses is needed for confirmation.
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Biomarcadores de Tumor/sangre , Inmunoensayo/normas , Cadenas Pesadas de Inmunoglobulina/sangre , Cadenas Ligeras de Inmunoglobulina/sangre , Monitorización Inmunológica/métodos , Mieloma Múltiple/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/patología , Pronóstico , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
The diagnostic accuracy of hexamethylpropyleneamine oxime (HMPAo) single-photon emission computed tomography (SPECT) in Alzheimer disease (AD) remains undetermined in a "real-life" clinical population. The objective was to determine the HMPAo SPECT hypoperfusion pattern in cognitively impaired patients with positive CSF AD biomarker and to evaluate its diagnostic accuracy. This study included 120 patients referred to a university memory clinic assessed using HMPAo SPECT, MRI, and CSF biomarkers. Three biomarker signatures suggestive of AD were analyzed (1, Aß1-42; 2, Aß1-42+t-tau and/or p-tau; 3, Aß1-42/p-tau). The clinical diagnoses were possible AD (n=29) or other causes of cognitive impairment (n=91). All CSF AD signatures were significantly (1, P=0.004; 2, P=0.017; 3, P=0.024) associated with the difference between inferior parietal perfusion and lateral dorsal frontal cortex perfusion. The hypoperfusion pattern discriminated between patients with positive CSF AD biomarkers and those with other cognitive impairments with a sensitivity of 67% to 71% and a specificity of 63% to 65% and a greatest negative predictive value (NPV) of 90%. Inferior parietal cortex hypoperfusion was the most sensitive and specific feature in AD patients diagnosed using clinical and CSF biomarker criteria. This hypoperfusion pattern was associated with an NPV of 90% and therefore discriminated sharply between AD and other cognitive disorders.
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Enfermedad de Alzheimer/diagnóstico por imagen , Biomarcadores/líquido cefalorraquídeo , Lóbulo Parietal/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Femenino , Francia , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios RetrospectivosRESUMEN
Immunoglobulin G (IgG) metabolism has received much attention in the literature for two reasons: (i) IgG homeostasis is regulated by the neonatal Fc receptor (FcRn), by a pH-dependent and saturable recycling process, which presents an interesting biological system; (ii) the IgG-FcRn interaction may be exploitable as a means for extending the plasma half-life of therapeutic monoclonal antibodies, which are primarily IgG-based. A less-studied problem is the importance of endogenous IgG metabolism in IgG multiple myeloma. In multiple myeloma, quantification of serum monoclonal immunoglobulin plays an important role in diagnosis, monitoring and response assessment. In order to investigate the dynamics of IgG in this setting, a mathematical model characterizing the metabolism of endogenous IgG in humans is required. A number of authors have proposed a two-compartment nonlinear model of IgG metabolism in which saturable recycling is described using Michaelis-Menten kinetics; however it may be difficult to estimate the model parameters from the limited experimental data that are available. The purpose of this study is to analyse the model alongside the available data from experiments in humans and estimate the model parameters. In order to achieve this aim we linearize the model and use several methods of model and parameter validation: stability analysis, structural identifiability analysis, and sensitivity analysis based on traditional sensitivity functions and generalized sensitivity functions. We find that all model parameters are identifiable, structurally and taking into account parameter correlations, when several types of model output are used for parameter estimation. Based on these analyses we estimate parameter values from the limited available data and compare them with previously published parameter values. Finally we show how the model can be applied in future studies of treatment effectiveness in IgG multiple myeloma with simulations of serum monoclonal IgG responses during treatment.
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BACKGROUND: Immunomodulatory drugs, IMid compounds, are active in Waldenström's macroglobulinemia (WM), although in a lesser extent than multiple myeloma, where it was initially developed. We hypothesized WM tumour cells might develop mechanisms of resistance, and sought to identify and describe these mechanisms. MATERIAL AND METHOD: MM and WM-derived cell lines, and Waldenström's CD19+ cells were treated using both lenalidomide and pomalidomide. Stable CRBN expressing cells were generated. RESULTS: WM-derived cells were resistant to IMid compounds. We demonstrated a modulation of the downstream targets of IRF4, despite low expression of cereblon, and hypothesized IRF4 was the cause for resistance to IMid compounds. We ruled out the role of various IRF4 regulatory mechanisms, and other pathways activating WM tumor cells, such as B cell activators. CONCLUSION: This study demonstrated that mechanisms of resistance to IMid compounds could be not related to cereblon. IRF4 was identified as the potential mechanism of resistance to lenalidomide and pomalidomide in WM. It potentially explains the lesser activity observed in the clinic in WM. Interestingly, some WM patients benefited strongly to lenalidomide and pomalidomide, and future studies will have to describe the indirect mechanisms of IMid compounds in WM, possibly related to an immune-mediated process.
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BACKGROUND: Affective and psychotic disorders are mental or behavioural patterns resulting in an inability to cope with life's ordinary demands and routines. These conditions can be a prodromal event of Alzheimer's disease (AD). The prevalence of underlying AD lesions in psychiatric diseases is unknown, and it would be helpful to determine them in patients. AD cerebrospinal fluid (CSF) biomarkers (amyloid ß, tau and phosphorylated tau) have high diagnostic accuracy, both for AD with dementia and to predict incipient AD (mild cognitive impairment due to AD), and they are sometimes used to discriminate psychiatric diseases from AD. Our objective in the present study was to evaluate the clinical utility of CSF biomarkers in a group of patients with psychiatric disease as the main diagnosis. METHODS: In a multicentre prospective study, clinicians filled out an anonymous questionnaire about all of their patients who had undergone CSF biomarker evaluation. Before and after CSF biomarker results were obtained, clinicians provided a diagnosis with their level of confidence and information about the treatment. We included patients with a psychiatric disorder as the initial diagnosis. In a second part of the study conducted retrospectively in a followed subgroup, clinicians detailed the psychiatric history and we classified patients into three categories: (1) psychiatric symptoms associated with AD, (2) dual diagnosis and (3) cognitive decline not linked to a neurodegenerative disorder. RESULTS: Of 957 patients, 69 had an initial diagnosis of a psychiatric disorder. Among these 69 patients, 14 (20.2 %) had a CSF AD profile, 5 (7.2 %) presented with an intermediate CSF profile and 50 (72.4 %) had a non-AD CSF profile. Ultimately, 13 (18.8 %) patients were diagnosed with AD. We show that in the AD group psychiatric symptoms occurred later and the delay between the first psychiatric symptoms and the cognitive decline was shorter. CONCLUSIONS: This study revealed that about 20 % of patients with a primary psychiatric disorder diagnosis before undergoing a CSF exploration for cognitive disorder displayed a CSF biomarker AD profile. In memory clinics, it seems important to consider AD as a possible diagnosis before finalizing a diagnosis of a psychiatric disorder.
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Trastornos Mentales/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Trastornos Mentales/complicaciones , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/complicaciones , Estudios Prospectivos , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) (Aß1-42, t-tau, and p-tau) and 18Fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism in subjects from the Alzheimer's Disease Neuroimaging Initiative, and specifically to determine which index of neurodegeneration was most frequently affected. The secondary objective was to determine the most frequently hypometabolic region in patients with a CSF AD signature (abnormal Aß1-42 and abnormal p-tau). We included the 372 subjects (85 normal subjects, 212 patients with mild cognitive impairment, and 75 patients with AD) with a CSF biomarker dosage (Aß1-42, t-tau, and p-tau) and brain FDG-PET. The relationship between FDG-PET metabolism (in five regions of interest (ROI) known to be damaged in AD) and CSF t-tau and p-tau levels was studied as a function of CSF Aß1-42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aß1-42 level (t-tau: R2â=â0.044, pâ=â0.001; p-tau: R2â=â0.02, pâ=â0.03). In the latter patients, CSF p-tau was the most frequently (pâ=â0.0001) abnormal neurodegeneration marker (p-tau: 92.8%; FDG-PET: 56.5%; CSF t-tau: 59.1%). Within the five ROI of FDG PET, the angular gyrus metabolism (R2â=â0.149; pâ=â0.0001) was selected as the most tightly associated with CSF AD signature. The relation between CSF markers of neurodegeneration (p-tau and t-tau) and brain hypometabolism (in FDG-PET) is conditioned by presence of amyloid abnormality. This finding supports the current physiopathological model of AD. P-tau is the most frequently impaired biomarker. Using FDG PET angular gyrus hypometabolism is the most sensitive to CSF-biomarker-defined AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/epidemiología , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/epidemiología , Bases de Datos Factuales , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Fosforilación , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
BACKGROUND: Apolipoprotein E (Apo E) is a 36 Kda glycoprotein involved in lipid transport. It exists in 3 major isoforms: E2, E3 and E4. ApoE status is known to be a major risk factor for late-onset Alzheimer's and cardiovascular diseases. Genotyping is commonly used to obtain ApoE status but can show technical issues with ambiguous determinations. Phenotyping can be an alternative, not requiring genetic material. We evaluated the ability to accurately type ApoE isoforms by 2 phenotyping tests in comparison with genotyping. METHODS: Two phenotyping techniques were used: (1) LC-MS/MS detection of 4 ApoE specific peptides (6490 Agilent triple quadripole): After its denaturation, serum was either reduced and alkylated, or only diluted, and then trypsin digested. Before analysis, desalting, evaporation and resuspension were performed. (2) Isoelectric focusing and immunoprecipitation: serum samples were neuraminidase digested, delipidated and electrophoresed on Hydragel ApoE (Sebia agarose gel) using Hydrasys 2 Scan instrument (Sebia, Lisses, France). ApoE isoforms bands were directly immunofixed in the gel using a polyclonal anti human ApoE antibody. Then, incubation of the gel with HRP secondary antibody followed by TTF1/TTF2 substrate allowed the visualization of ApoE bands. The results of the two techniques were compared to genotyping. RESULTS: Sera from 35 patients previously genotyped were analyzed with the 2 phenotyping techniques. 100% concordance between both phenotyping assays was obtained for the tested phenotypes (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4). When compared to genotyping, 3 samples were discordant. After reanalyzing them by both phenotyping tests and DNA sequencing, 2/3 discrepancies were confirmed. Those can be explained by variants or rare ApoE alleles or by unidentified technical issues. 102 additional samples were then tested on LC-MS/MS only and compared to genotyping. The data showed 100% concordance. CONCLUSION: Our 2 phenotyping methods represent a valuable alternative to genotyping. LC-MS/MS has the advantage of being fully specific, with identification of the different isoforms and can be considered as a reference method. Sebia isofocusing technique was concordant with LC-MS/MS. Plus, it is a rapid, semi-automated assay that can be easily implemented in clinical laboratories.