France Will No More Reimburse Available Symptomatic Drugs Against Alzheimer’s Disease
Authors: Krolak-Salmon, Pierre | Dubois, Bruno | Sellal, François | Delabrousse-Mayoux, Jean-Philippe | Vandel, Pierre | Amieva, Hélène | Jeandel, Claude | Andrieu, Sandrine | Perret-Liaudet, Armand
Article Type: Editorial
Abstract: The French Minister of Health published a decree on May 29th of 2018 removing the drugs used to fight against symptoms due to Alzheimer’s disease (donepezil, rivastigmine, galantamine, memantine) from the list of available reimbursed drugs. This follows the advice delivered by the High Authority for Health in 2016 and 2018 stating an “insufficient medical benefit and dangerousness because of significant side effects”. The main French scientific and medical societies and professional associations want to state here their deep disagreement regarding this unfair decision. The evidence-based medicine related to these drugs reaches a high level in literature, whereas the clinical …relevance of these treatments must be considered with co-prescription of psychosocial interventions and related approaches. As no serious pharmacovigilance signal has been provided by health authorities, the ratio of benefits/risks favors these drugs. Show more
Keywords: Alzheimer’s disease, drug, health policy, reimbursement
DOI: 10.3233/JAD-180843
Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 425-427, 2018
Risk of Alzheimer's Disease Biological Misdiagnosis Linked to Cerebrospinal Collection Tubes
Authors: Perret-Liaudet, Armand | Pelpel, Mathieu | Tholance, Yannick | Dumont, Benoit | Vanderstichele, Hugo | Zorzi, Willy | ElMoualij, Benaissa | Schraen, Susanna | Moreaud, Olivier | Gabelle, Audrey | Thouvenot, Eric | Thomas-Anterion, Catherine | Touchon, Jacques | Krolak-Salmon, Pierre | Kovacs, Gabor G. | Coudreuse, Arnaud | Quadrio, Isabelle | Lehmann, Sylvain
Article Type: Research Article
Abstract: Tau proteins and amyloid-β (Aβ) peptides are the current recognized cerebrospinal fluid (CSF) biomarkers used as an aid in the diagnosis of Alzheimer's disease (AD). However, there is no consensus on their clinical use due to non-qualified cut-off values, probably related to the observed high pre-analytical and analytical variability. Standardized pre-analytical protocols have therefore been proposed. Importantly, these recommend the use of polypropylene collection/sampling tubes while, to date, no broad comparison of these types of tubes has been conducted. In this study, we first compared, as part of a real clinical workflow, the impact of four different collection tubes on …the CSF concentration of Aβ peptides (Aβ42 , Aβ40 ) and total (hTau) and phosphorylated (P-Tau181P) tau proteins measured using routine ELISA kits. We then extended this study to 11 polypropylene tubes used by different clinical laboratories, and investigated their plastic polymer composition using differential scanning calorimetry and Fourier Transformed Infrared spectroscopy. Significant concentration variations linked solely to the use of different types of tubes were observed. This was particularly marked for Aβ peptides, with >50% disparity occurring in less than five minutes. Polymer composition analysis revealed that most polypropylene tubes were in fact copolymers with at least polyethylene. There was no clear correlation between tube composition and pre-analytical behavior. Our results show that the use of polypropylene tubes does not guarantee satisfactory pre-analytical behavior. They also point to collection/sampling tubes being a major pre-analytical source of variability that could impact the significance of AD biological diagnosis. Show more
Keywords: Alzheimer's disease, cerebrospinal fluid, collection tubes, standardization
DOI: 10.3233/JAD-2012-120361
Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 13-20, 2012
Decreased sAβPPβ, Aβ 38, and Aβ 40 Cerebrospinal Fluid Levels in Frontotemporal Dementia
Authors: Gabelle, Audrey | Roche, Stéphane | Gény, Christian | Bennys, Karim | Labauge, Pierre | Tholance, Yannick | Quadrio, Isabelle | Tiers, Laurent | Gor, Baptiste | Boulanghien, Justine | Chaulet, Chloé | Vighetto, Alain | Croisile, Bernard | Krolak-Salmon, Pierre | Perret-Liaudet, Armand | Touchon, Jacques | Lehmann, Sylvain
Article Type: Research Article
Abstract: To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38 , Aβ40 , Aβ42 , sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC …curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38 , and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38 , are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia. Show more
Keywords: Alzheimer's disease, frontotemporal dementia, CSF biomarkers, CSF amyloid peptides, Aβ38
DOI: 10.3233/JAD-2011-110515
Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 553-563, 2011
Initial Memory Deficit Profiles in Patients with a Cerebrospinal Fluid Alzheimer's Disease Signature
Authors: Xie, Jing | Gabelle, Audrey | Dorey, Aline | Garnier-Crussard, Antoine | Perret-Liaudet, Armand | Delphin-Combe, Floriane | Bathsavanis, Anthony | Dauphinot, Virginie | Lehmann, Sylvain | Mercier, Bernadette | Desestret, Virginie | Roullet-Solignac, Isabelle | Vighetto, Alain | Krolak-Salmon, Pierre
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) clinical onset is usually characterized by a memory complaint and a progressive memory deficit. The proportion of typical medial-temporal amnesia revealing AD remains unknown. Objective: The present study explores the episodic memory impairment profiles by the Free and Cued Selective Recall Reminding Test (FCSRT) in patients with initial memory complaint and a cerebrospinal fluid (CSF) biomarker signature of AD. Methods: Seventy-three patients referred for memory complaint to the Centers for Memory, Resource and Research of Lyon and Montpellier (France) were included consecutively. All patients underwent an extensive neuropsychological examination and had a Mini-Mental State Examination (MMSE) …score ≥20 and a positive CSF AD signature. The patients were classified as having mild dementia or prodromal AD. Verbal episodic memory was assessed using the French version of the FCSRT exploring encoding, storage/consolidation, and cued delayed retrieval phases of memorization. Three different memory profiles were identified according to the results of FCSRT. Results: The median age was 72 year-old [interquartiles: 65–76]. The median MMSE score was 23 [interquartiles: 21–25]. 88% of the patients (n = 64) presented with a medial temporal amnesia profile. The dysexecutive amnesia and normal verbal episodic memory profiles represented respectively 5% (n = 4) and 7% (n = 5). There were no significant differences in term of age, gender, and MMSE score between the three profile groups. Conclusion: In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT. Show more
Keywords: Alzheimer's disease, cerebrospinal fluid, memory
DOI: 10.3233/JAD-131916
Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1109-1116, 2014
Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer’s Disease: Analytical and Diagnostic Characterization
Authors: Lewczuk, Piotr | Lelental, Natalia | Lachmann, Ingolf | Holzer, Max | Flach, Katharina | Brandner, Sebastian | Engelborghs, Sebastiaan | Teunissen, Charlotte E. | Zetterberg, Henrik | Molinuevo, José Luis | Mroczko, Barbara | Blennow, Kaj | Popp, Julius | Parnetti, Lucilla | Chiasserini, Davide | Perret-Liaudet, Armand | Spitzer, Philipp | Maler, Juan Manuel | Kornhuber, Johannes
Article Type: Research Article
Abstract: Background: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF). Objective: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF. Methods: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method. Results: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. …Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6–15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% – 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer’s disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. Conclusion: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF. Show more
Keywords: Biomarkers, cerebrospinal fluid, phosphorylation, tau
DOI: 10.3233/JAD-160448
Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 159-170, 2017
Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics
Authors: Lelental, Natalia | Brandner, Sebastian | Kofanova, Olga | Blennow, Kaj | Zetterberg, Henrik | Andreasson, Ulf | Engelborghs, Sebastiaan | Mroczko, Barbara | Gabryelewicz, Tomasz | Teunissen, Charlotte | Mollenhauer, Brit | Parnetti, Lucilla | Chiasserini, Davide | Molinuevo, Jose Luis | Perret-Liaudet, Armand | Verbeek, Marcel M. | Andreasen, Niels | Brosseron, Frederic | Bahl, Justyna M.C. | Herukka, Sanna-Kaisa | Hausner, Lucrezia | Frölich, Lutz | Labonte, Anne | Poirier, Judes | Miller, Anne-Marie | Zilka, Norbert | Kovacech, Branislav | Urbani, Andrea | Suardi, Silvia | Oliveira, Catarina | Baldeiras, Ines | Dubois, Bruno | Rot, Uros | Lehmann, Sylvain | Skinningsrud, Anders | Betsou, Fay | Wiltfang, Jens | Gkatzima, Olymbia | Winblad, Bengt | Buchfelder, Michael | Kornhuber, Johannes | Lewczuk, Piotr
Article Type: Research Article
Abstract: Background: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. Objective: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. Methods: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with …an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. Results: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at – 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. Conclusion: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements. Show more
Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cerebrospinal fluid, laboratory diagnostics, quality control, tau
DOI: 10.3233/JAD-150883
Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 51-64, 2016