Tania Nikolcheva

Multi analyte profiling and variability of inflammatory markers in blood and induced sputum in patients with stable COPD

BackgroundWe analyzed serial concentrations of multiple inflammatory mediators from serum and induced sputum obtained from patients with stable COPD and controls. The objective was to determine which proteins could be used as reliable biomarkers to assess COPD disease state and severity.MethodsForty-two subjects; 21 with stable COPD and 21 controls, were studied every 2 weeks over a 6-week period. Serum and induced sputum were obtained at each of 3 visits and concentrations of 19 serum and 22 sputum proteins were serially assessed using multiplex immunoassays. We used linear mixed effects models to test the distribution of proteins for an association with COPD and disease severity. Measures of within- and between-subject coefficients of variation were calculated for each of the proteins to assess reliability of measurement.ResultsThere was significant variability in concentrations of all inflammatory proteins over time, and variability was greater for sputum proteins (median intra-subject coefficient of variation 0.58) compared to proteins measured in serum (median intra-subject coefficient of variation 0.32, P = 0.03). Of 19 serum proteins and 22 sputum proteins tested, only serum CRP, myeloperoxidase and VEGF and sputum IL-6, IL-8, TIMP-1, and VEGF showed acceptable intra and inter-patient reliability and were significantly associated with COPD, the severity of lung function impairment, and dyspnea.ConclusionsLevels of many serum and sputum biomarkers cannot be reliably ascertained based on single measurements. Multiple measurements over time can give a more reliable and precise estimate of the inflammatory burden in clinically stable COPD patients.

Deconvoluting post-transplant immunity: cell subset-specific mapping reveals pathways for activation and expansion of memory T, monocytes and B cells.

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO+CD62L− effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant.

Revolutionizing Alzheimer's disease and clinical trials through biomarkers

The Alzheimers Associations Research Roundtable met in May 2014 to explore recent progress in developing biomarkers to improve understanding of disease pathogenesis and expedite drug development. Although existing biomarkers have proved extremely useful for enrichment of subjects in clinical trials, there is a clear need to develop novel biomarkers that are minimally invasive and that more broadly characterize underlying pathogenic mechanisms, including neurodegeneration, neuroinflammation, and synaptic dysfunction. These may include blood‐based assays and new neuropsychological testing protocols, as well as novel ligands for positron emission tomography imaging, and advanced magnetic resonance imaging methodologies. In addition, there is a need for biomarkers that can serve as theragnostic markers of response to treatment. Standardization remains a challenge, although international consortia have made substantial progress in this area and provide lessons for future standardization efforts.

Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease

Importance A reliable method of detecting Alzheimer disease (AD) in its prodromal state is needed for patient stratification in clinical trials or for personalizing existing or potential upcoming therapies. Current cerebrospinal fluid (CSF)- or imaging-based single biomarkers for AD offer reliable identification of patients with underlying AD but insufficient prediction of the rate of AD progression. Objective To optimize prediction of progression from mild cognitive impairment (MCI) to AD dementia by combining information from diverse patient variables. Design, Setting, and Participants This cohort study from the Alzheimer Disease Neuroimaging Initiative (ADNI) enrolled 928 patients with MCI at baseline and 249 selected variables available in the ADNI data set. Variables included clinical and demographic data, cognitive scores, magnetic resonance imaging-based brain volumetric data, the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes, and analyte levels measured in the CSF and plasma. Data were collected in July 2012 and analyzed from July 1, 2012, to June 1, 2015. Main Outcomes and Measures Progression from MCI to AD within 1 to 6 years. To determine whether combinations of markers could predict progression from MCI to AD within 1 to 6 years, the elastic net algorithm was used in an iterative resampling of a training- and test-based variable selection and modeling approach. Results Among the 928 patients with MCI in the ADNI database, 94 had 224 of the required variables available for the modeling. The results showed the contributions of age, Clinical Dementia Rating Sum of Boxes composite test score, hippocampal volume, and multiple plasma and CSF factors in modeling progression to AD. A combination of apolipoprotein A-II and cortisol levels in plasma and fibroblast growth factor 4, heart-type fatty acid binding protein, calcitonin, and tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) in CSF allowed for reliable prediction of disease status 3 years from the time of sample collection (80% classification accuracy, 88% sensitivity, and 70% specificity). Conclusions and Relevance These study findings suggest that a combination of markers measured in plasma and CSF, distinct from β-amyloid and tau, could prove useful in predicting midterm progression from MCI to AD dementia. Such a large-scale, multivariable-based analytical approach could be applied to other similar large data sets involving AD and beyond.

Efficacy and safety of gantenerumab in prodromal Alzheimer’s disease: Results from scarlet road—a global, multicenter trial

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr

Challenges in the development of companion diagnostics for neuropsychiatric disorders

There are few examples of successful CNS diagnostics owing to our poor understanding of the mechanisms of disease. This article will discuss this and other challenges facing CNS diagnostic development with a focus on Alzheimer’s disease, along with a discussion of potential future diagnostic assays that may help in the development of new CNS medications.

Biomarker data from scarlet road: A global phase 3 study of gantenerumab in patients with prodromal Alzheimer's disease

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr

Sembragiline in Moderate Alzheimer’s Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD)

Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD). Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. Methods: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p = 0.014; 1 mg) and – 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

IDENTIFICATION OF PREDICTORS OF DISEASE PROGRESSION IN AN AMYLOID-BETA 42 (Aβ42)-POSITIVE, PRODROMAL ALZHEIMER’S DISEASE COHORT: ANALYSIS OF THE SCARLET ROAD STUDY

Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; 2 University of Leicester, Leicester, United Kingdom; 3 Global Innovative Pharma Business – Clinical Sciences Pfizer, Paris, France; Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; 5 VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: l.vermunt@vumc.nl

Correction to: A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows: