[Show abstract][Hide abstract] ABSTRACT: Introduction: The relevance of the cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer's disease (AD) and related disorders is clearly established. However, the question remains on how to use these data, which are often heterogeneous (not all biomarkers being pathologic). The objective of this study is to propose to physicians in memory clinics a biologic scale of probabilities that the patient with cognitive impairments has an Alzheimer's disease (AD) pathologic process. Methods: For that purpose, we took advantage of the multicenter data of our Paris-North, Lille, and Montpellier (PLM) study, which has emerged through the initial sharing of information from these memory centers. Different models combining the CSF levels of amyloid-β 42, tau, and p-tau(181) were tested to generate categories of patients with very low (<10%), low (<25%), high (>75%), and very high predictive values (>90%) for positive AD. In total, 1,273 patients (646 AD and 627 non-AD) from six independent memory-clinic cohorts were included. Results: A prediction model based on logistic regressions achieved a very good stratification of the population but had the disadvantages of needing mathematical optimization and being difficult to use in daily clinical practice. Remarkably, a simple and intuitive model based on the number (from zero to three) of three pathologic CSF biomarkers resulted in a very efficient predictive scale for AD in patients seen in memory clinics. The scale's overall predictive value for AD for the different categories were as follows: class 0, 9.6% (95% confidence interval (CI), 6.0% to 13.2%); class 1, 24.7% (95% CI, 18.0% to 31.3%); class 2, 77.2% (95% CI, 67.8% to 86.5%); and class 3, 94.2% (95% CI, 90.7% to 97.7%). In addition, with this scale, significantly more patients were correctly classified than with the logistic regression. Its superiority in model performance was validated by the computation of the net reclassification index (NRI). The model was also validated in an independent multicenter dataset of 408 patients (213 AD and 195 non-AD). Conclusions: In conclusion, we defined a new scale that could be used to facilitate the interpretation and routine use of multivariate CSF data, as well as helping the stratification of patients in clinical research trials. Introduction Intense research efforts have been conducted to develop and validate biomarkers to predict, detect, and follow up the progression of the disease or impact of potential new disease-modifying treatments of Alzheimer's disease (AD). Brain imaging and biologic biomarkers are now included in the recommended AD diagnostic criteria [1-3]. Various scales or tools are available to physicians involved in AD research for better interpreting the positive or negative re-sults of biomarkers for establishing a clinical diagnosis, such as the detection of hippocampal atrophy with the Scheltens' scale  and the positivity of amyloid load on functional brain imaging via the Jack's visual scale . Although biologic cerebrospinal fluid (CSF) bio-markers are among the most studied and validated in clinical practice [6-8], no sort of "visual" scale concerning
Alzheimer's Research and Therapy 06/2014; 6(3). · 4.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer's disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1-42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1-42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1-42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies.
Journal of Neurology 04/2014; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are well validated in clinical research but less in clinical practice. Using a questionnaire, we evaluated the reasons for prescriptions and clinician's expectations concerning CSF biomarkers. The results show that CSF AD biomarkers are mainly required in case of atypical dementia and diagnosis uncertainty that are different from indications in clinical research. In the future, clinicians wish to get new biomarkers that could improve differential diagnosis and could have a good pronostic value. Further studies in routine practice are necessary to precise the role of these biomarkers in the management of patients.
Journal of Alzheimer's disease: JAD 02/2014; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer's disease (AD). Objective: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). Methods: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). Results: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. Conclusions: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD.
Journal of Alzheimer's disease: JAD 11/2013; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CSF biomarkers of Alzheimer's disease are well validated in clinical research; however, their pragmatic utility in daily practice is still unappreciated. These biomarkers are used in routine practice according to Health Authority Recommendations. In 604 consecutive patients explored for cognitive disorders, questionnaires were prospectively proposed and filled. Before and after CSF biomarker results, clinicians provided a diagnosis and an estimate of their diagnostic confidence. Analysis has compared the frequency of diagnosis before and after CSF biomarker results using the net reclassification improvement (NRI) method. We have evaluated external validity comparing with data of French Bank National of AD (BNA). A total of 561 patients [Alzheimer's disease (AD), n = 253; non-AD, n = 308] were included (mean age, 68.6 years; women, 52 %). Clinically suspected diagnosis and CSF results were concordant in 65.2 % of cases. When clinical hypothesis and biological results were discordant, a reclassification occurred in favour of CSF biomarkers results in 76.9 %. The NRI was 39.5 %. In addition, the results show a statistically significant improvement in clinician confidence for their diagnosis. In comparison with BNA data, patients were younger and more frequently diagnosed with AD. Clinicians tend to heavily rely on the CSF AD biomarkers results and are more confident in their diagnoses using CSF AD biomarkers. Thus, these biomarkers appear as a key tool in clinical practice.
Journal of Neurology 10/2013; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimer's disease (AD) diagnosis.
We analyzed data from French memory centers that switched from different CSF collection tubes to a common one. A total of 1966 patients were included in the study. CSF concentrations of β-amyloid 1-42 (Aβ42), total tau, and phosphorylated tau (p-tau181) were measured in each center using the same commercial enzyme-linked immunoabsorbent assay (ELISA) kits. The diagnostic value of CSF biomarkers according to the type of tube used was then assessed using different cutoffs.
The predictive value of Aβ42 was highly affected by the type of collection tube used. The optimal cutoff value for p-tau181 appeared not to be affected by the type of collection tube whereas that of total tau was slightly changed. New optimal cutoff values were then computed.
In a routine clinical environment, the selection of the collection tube and biomarker cutoff value makes a major difference in AD biological diagnosis. The use of a common collection tube among different centers will reduce the risk of misdiagnosis and incorrect patient stratification.
Alzheimer's & dementia: the journal of the Alzheimer's Association 10/2013; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIMS: This study aimed to assess the relationship between blood pressure and cognitive function in elderly patients with diabetes mellitus (DM). METHODS: A total of 32 patients with DM aged≥65 years (seven women and 25 men; mean±SD age: 74.3±6.4 years) were included in this cross-sectional study. Relationships between blood pressure and neuropsychological tests were determined using Spearman's rank correlations (ρ) and multivariable linear regression models. RESULTS: Lower diastolic blood pressure was associated with lower scores on the Frontal Assessment Battery (ρ=0.32, P=0.02), longer times to complete the Trail Making Test Part B (ρ=0.51, P=0.003), lower scores for the Finger Tapping Test (ρ=0.36, P=0.046) and less verbal fluency (ρ=0.36, P=0.047). In multivariable models, these relationships were attenuated after adjusting for levels of education. CONCLUSION: There was an association between lower diastolic blood pressure and poorer executive function in this cohort of elderly DM patients. These results underline the importance of systematic cognitive evaluation in elderly patients with DM, and suggest that a too-low diastolic blood pressure may have deleterious effects on mental function. Larger studies in the future are required to confirm these preliminary results.
[Show abstract][Hide abstract] ABSTRACT: Increasing age is the most important risk factor for developing Alzheimer's disease (AD). The aim of this study was to investigate the relationships between age and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ 1-42), total Tau and phosphorylated Tau (pTau-181), in AD and non-AD patients explored for cognitive disorders. 966 patients (AD, n=528; non-AD, n=438) were included between January 2008 and December 2010 (mean age, 69.5years; mean MMSE, 20.2) from three French memory centers. Multivariable linear regression models were used to study the relationship between CSF biomarker levels and age in AD and non-AD patients. The capacity of each CSF biomarker in discriminating patients was evaluated using the area under the receiver-operating characteristic (ROC) curves by quartile of distribution of age. In AD patients, older age was associated with higher CSF Aβ 1-42 and lower Tau levels. Conversely, in non-AD patients, age was associated with lower CSF Aβ 1-42, higher Tau, and higher pTau-181 levels. In sex-stratified analysis, these relationships were significant only in women. Using ROC curve analysis, CSF AD biomarkers were more discriminant in younger patients than in older ones. In this clinically-based study, younger patients with AD had exacerbated CSF anomalies compared to older patients with AD. CSF biomarkers were more discriminant in younger patients than in older ones for the diagnosis of AD, especially in women. These results support the idea of an overlap in AD neuropathological lesions in oldest subjects with or without AD.
Neurobiology of Disease 02/2013; · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer's disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years. In AD patients, linear mixed models adjusted for age and sex were used to assess the cross-sectional and longitudinal associations between MMSE scores and baseline CSF levels of Aβ peptide (Aβ 1-42), Tau, phosphorylated Tau (p-Tau 181), PKR and pPKR. The mean (SD) MMSE at baseline was 20.5 (6.1) and MMSE scores declined over the follow-up (-0.12 point/month, standard error [SE] = 0.03). A lower MMSE at baseline was associated with lower levels of CSF Aβ 1-42 and p-Tau 181/Tau ratio. pPKR level was associated with longitudinal MMSE changes over the follow-up, higher pPKR levels being related with an exacerbated cognitive deterioration. Other CSF biomarkers were not associated with MMSE changes over time. In aMCI patients, mean CSF biomarker levels were not different in patients who converted to AD from those who did not convert.These results suggest that at the time of AD diagnosis, a higher level of CSF pPKR can predict a faster rate of cognitive decline.
PLoS ONE 01/2013; 8(1):e53587. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The French Alzheimer's Disease Plan aims, in an unprecedented national effort, to develop research, promote optimal diagnosis, and take better care of patients. In order to evaluate the clinical interest and use of cerebrospinal fluid (CSF) biomarkers, a data-sharing project, the PLM (Paris-North, Lillem and Montpellier) study has emerged through collaboration between these memory centers, already involved in this field. The revised Alzheimer's disease (AD) diagnosis criteria include CSF biomarkers, but little is known about their use in routine clinical practice. To evaluate their interest and diagnostic accuracy in routine AD diagnosis, a cohort of 677 patients from Montpellier was first analyzed. The results were then validated through the analysis of a second cohort of 638 patients from Lille and Paris-Nord. Diagnoses of AD and other dementias were established by multidisciplinary expert teams, based on neuropsychological exams and structural brain imaging, blinded from CSF results. CSF amyloid-β, tau, and p-tau concentrations were measured for all patients. Receiver-operating characteristic curves were used to define cut-offs and evaluate the ability of each biomarker to discriminate AD from other diagnoses. We showed that p-tau outperformed other biomarkers for discriminating AD from non-AD patients and presents a clear clinical interest. The other biomarkers also showed relevant variations especially when the differential AD diagnoses were taken into account. Altogether we could demonstrate in both mono-centric and multi-centric cohorts from memory clinics the capacity of CSF biomarkers to discriminate AD from non-AD patients in clinical routine with a high sensitivity and specificity.
Journal of Alzheimer's disease: JAD 11/2012; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The assessment of total tau, phosphorylated tau (pTau-181) and amyloid beta (Aβ 1-42) concentrations in the cerebrospinal fluid (CSF) of subjects has been validated for the diagnosis of Alzheimer's disease (AD). Although these measurements have shown some variability, little is known about their intersite variability in clinical settings. METHODS: A total of 880 subjects (AD, n = 515; non-AD, n = 365) from three French memory centers were included. Receiver-operating characteristic analyses were performed to computerized area under curves (AUCs) and optimal thresholds for each biomarker in the three centers. A test-retest study was performed in a group of 32 CSF samples by repeated blind analysis of the three biomarkers using the same immunoassay batches in the three centers. RESULTS: In the three centers, tau (AUC, 0.82-0.88) and pTau-181 (AUC, 0.83-0.89) outperformed Aβ 1-42 (AUC, 0.70 -0.73) to discriminate subjects with AD from those without AD. An intersite variation of mean levels and cutoffs was observed for the three biomarkers. This variation was higher for Aβ 1-42 (range of cutoff, 368-582 pg/mL) than for tau (range of cutoff, 289-353 pg/mL). In a test-retest study, the mean interlaboratory coefficients of variation were 12.2% for Aβ 1-42, 11.3% for tau, and 11.5% for pTau-181. CONCLUSION: Intercenter variability of CSF biomarkers has been confirmed in a multisite cohort of subjects and can be improved in clinical settings. Efforts on harmonization of procedures should be encouraged to optimize the accuracy of CSF biomarkers in AD.
Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2012; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals. METHODS: We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients. RESULTS: Patients were divided into three similarly sized groups (CPE ≤ 1, CPE between 1.5 and 2.5, and CPE ≥ 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients. CONCLUSION: These results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART.
[Show abstract][Hide abstract] ABSTRACT: Amyloid precursor protein (APP), a key molecule in Alzheimer's disease (AD), is metabolized in two alternative cleavages, generating either the amyloidogenic peptides involved in AD pathology or the soluble form of APP (sAPPα). The level of amyloidogenic peptides in human cerebrospinal fluid (CSF) is considered to be a biomarker of AD, whereas the level of sAPPα in CSF as a biomarker has not been clearly established. sAPPα has neurotrophic and neuroprotective properties. Stimulating its formation and secretion is a promising therapeutic target in AD research. To this end, very sensitive tests for preclinical and clinical research are required.
The tests are based on homogenous time-resolved fluorescence and require no washing steps.
We describe two new rapid and sensitive tests for quantifying mouse and human sAPPα. These 20 μl-volume tests quantify the levels of: i) endogenous mouse sAPPα in the conditioned medium of mouse neuron primary cultures, as well as in the CSF of wild-type mice, ii) human sAPPα in the CSF of AD mouse models, and iii) human sAPPα in the CSF of AD and non-AD patients. These tests require only 5 μl of conditioned medium from 5 × 10(4) mouse primary neurons, 1 μl of CSF from wild-type and transgenic mice, and 0.5 μl of human CSF.
The high sensitivity of the mouse sAPPα test will allow high-throughput investigations of molecules capable of increasing the secretion of endogenous sAPPα in primary neurons, as well as the in vivo validation of molecules of interest through the quantification of sAPPα in the CSF of treated wild-type mice. Active molecules could then be tested in the AD mouse models by quantifying human sAPPα in the CSF through the progression of the disease. Finally, the human sAPPα test could strengthen the biological diagnosis of AD in large clinical investigations. Taken together, these new tests have a wide field of applications in preclinical and clinical studies.
[Show abstract][Hide abstract] ABSTRACT: We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.
[Show abstract][Hide abstract] ABSTRACT: Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.
[Show abstract][Hide abstract] ABSTRACT: Beta-site APP cleaving enzyme 1 (BACE1) is the rate limiting enzyme for accumulation of amyloid β (Aβ)-peptide in the brain in Alzheimer's disease (AD). Oxidative stress (OS) that leads to metabolic dysfunction and apoptosis of neurons in AD enhances BACE1 expression and activity. The activation of c-jun N-terminal kinase (JNK) pathway was proposed to explain the BACE1 mRNA increase under OS. However, little is known about the translational control of BACE1 in OS. Recently, a post-transcriptional increase of BACE1 level controlled by phosphorylation of eIF2α (eukaryotic translation initiation factor-2α) have been described after energy deprivation. PKR (double-stranded RNA dependant protein kinase) is a pro-apoptotic kinase that phosphorylates eIF2α and modulates JNK activation in various cellular stresses. We investigated the relations between PKR, eIF2α and BACE1 in AD brains in APP/PS1 knock-in mice and in hydrogen peroxide-induced OS in human neuroblastoma (SH-SY5Y) cell cultures. Immunoblotting results showed that activated PKR (pPKR) and activated eIF2α (peIF2α) and BACE1 levels are increased in AD cortices and BACE1 correlate with phosphorylated eIF2α levels. BACE1 protein levels are increased in response to OS in SH-SY5Y cells and specific inhibitions of PKR-eIF2α attenuate BACE1 protein levels in this model. Our findings provide a new translational regulation of BACE1, under the control of PKR in OS, where eIF2α phosphorylation regulates BACE1 protein expression.
Biochimica et Biophysica Acta 01/2012; 1822(6):885-96. · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathological hallmarks of Alzheimer's disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1-42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation.
In a prospective cohort study, the CSF of 91 patients were studied (AD: 45; amnestic mild cognitive impairment: 11; neurological disease control subjects [NDC]: 35). The levels of total PKR (T-PKR), phosphorylated PKR (pPKR), Aß 1-42, T-tau, and p181tau were assessed by immunoblotting or enzyme-linked immunosorbent assay methods. Receivers operating characteristic curves were used to examine the discriminatory power of T-PKR, pPKR, and pPKR/T-PKR ratio between AD and NDC patients.
Total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects. We have determined a pPKR value (optical density units) that could discriminate AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, T-PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal T-PKR and pPKR levels.
The evaluation of CSF T-PKR and pPKR can discriminate between AD patients and NDC and could help to improve the biochemical diagnosis of AD.
[Show abstract][Hide abstract] ABSTRACT: IntroductionCerebrospinal fluid (CSF) biomarkers have been extensively studied as diagnostic markers for Alzheimer's disease (AD). However, results are variable probably due to lumbar puncture (LP) procedure, CSF collection and transport. This intercenter variability highlights the need for an efficient standardization of clinical and technical procedures. The aims of this study were firstly to compare the LP procedure and CSF transport process in all French Memory Centers and secondly to evaluate the incidence of LP side effects in 100 patients with cognitive disturbances.MethodsLP practice and side effect prospective questionnaires were sent to all French Memory Centers in May 2010. Memory Centers were asked about their LP procedure. The prospective study over a three-week-period has evaluated the LP feasibility and side effects. All data were collected until the end of July 2010.ResultsThe answers of 18 out of 26 Memory Centers were collected. Although, these centers did not have the same LP procedure and CSF transport, the majority of them proceeded according to Innogenetics's advices concerning the use of polypropylene tubes and transport duration but not sample conditioning. Polypropylene tubes were different from one center to the other. CSF volume, pharmacological premedication and prevention of post-LP syndrome were variable in all responding centers. The prospective study carried out in 100 patients revealed a very good LP acceptability (93/100 patients). LP feasibility was 97 % (90/93) and failed LP were consequently performed with success using radiological scopes. Three minor complications were observed.Discussion and conclusionAll French Centers complied with Innogenetics’ recommendations for pretechnical CSF procedures; however each Center put in place its own procedure that was different one center to the other. It will be very interesting to compare cut-off and result values for Aβ, tau and phosphorylated tau protein on threonine 181 between several centers that used their own procedures. Acceptability and safety were very good in our short but significant prospective study. These results confirm the data of Zetterberg et al., 2010.