Olivier Vercruysse

Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: a multicentric study

IntroductionThe cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ), tau and phosphorylated tau (p-tau181) are now used for the diagnosis of Alzheimer’s disease (AD). Aβ40 is the most abundant Aβ peptide isoform in the CSF, and the Aβ 42/40 ratio has been proposed to better reflect brain amyloid production. However, its additional value in the clinical setting remains uncertain.MethodsA total of 367 subjects with cognitive disorders who underwent a lumbar puncture were prospectively included at three French memory centers (Paris-North, Lille and Montpellier; the PLM Study). The frequency of positive, negative and indeterminate CSF profiles were assessed by various methods, and their adequacies with the diagnosis of clinicians were tested using net reclassification improvement (NRI) analyses.ResultsOn the basis of local optimum cutoffs for Aβ42 and p-tau181, 22% of the explored patients had indeterminate CSF profiles. The systematic use of Aβ 42/40 ratio instead of Aβ42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (NRI = −2.1%; P = 0.64). In contrast, the use of Aβ 42/40 ratio instead of Aβ42 levels alone in patients with a discrepancy between p-tau181 and Aβ42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003).ConclusionsIn patients with a discrepancy between CSF p-tau181 and CSF Aβ42, the assessment of Aβ 42/40 ratio led to a reliable biological conclusion in over 50% of cases that agreed with a clinician’s diagnosis.

Impact of harmonization of collection tubes on Alzheimer's disease diagnosis

The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimers disease (AD) diagnosis.

Intersite variability of CSF Alzheimer’s disease biomarkers in clinical setting

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 Alzheimers disease (AD). Although these measurements have shown some variability, little is known about their intersite variability in clinical settings.

Impact of the 2008-2012 French Alzheimer Plan on the Use of Cerebrospinal Fluid Biomarkers in Research Memory Center: The PLM Study

The French Alzheimers 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, Lille and Montpellier) study has emerged through collaboration between these memory centers, already involved in this field. The revised Alzheimers 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.

Exacerbated CSF abnormalities in younger patients with Alzheimer's disease

Increasing age is the most important risk factor for developing Alzheimers 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.

Relevance of Follow-Up in Patients with Core Clinical Criteria for Alzheimer Disease and Normal CSF biomarkers

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 Aβ1-42, 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.

Beyond interest and limits of CSF biomarkers in clinical practice: The PLM study

Background: We aimed to assess the impact of CSF biomarkers on diagnosis and management of memory clinic patients in the daily practice. In addition we took into account the considerations and views of the neurologists when using CSF biomarkers. Methods: All patients visiting the VUmc Alzheimer center for cognitive screening were consecutively included from 06-2011 till 05-2012. Clinical diagnoses were made in a multidisciplinary team without knowledge of the CSF biomarkers. Neurologists filled out questionnaires before and after disclosure of CSF results, with change of diagnosis and confidence in diagnosis as primary outcome measures. In addition, neurologists expressed their diagnostic considerations, reasons for wishing to know the CSF biomarker results, interpretation of the biomarker concentrations and impact on patient management. Results: 438 patients were included, of which 80% (351 patients) underwent lumbar puncture. Before disclosure of CSF results neurologists wished to know the results in 74% of all cases. Reasons included: confirm (46%) or exclude Alzheimer’s disease (AD) (36%), reassure the patient (11%), assess the prognosis (24%), or preselection for clinical trials (11%). Diagnostic confidence level was higher when neurologists thought not to need CSF results (90% vs 82%, p< 0.001). After disclosure of CSF results, diagnosis changed in 23 cases (7% of patients with CSF). In cases where the diagnosis remained unchanged, confidence level increased from 84 to 89% (p<0.001). The increase was significant in AD (6%, p<0.001), other dementia (4%, p< 0.01) and MCI patients (6%, p< 0.001). In 40 patients (13% of patients with CSF and unchanged diagnosis) level of confidence decreased substantially because CSF was not in accordance with the clinical diagnosis. These cases often underwent more intensive clinical follow-up or further investigations, such as FDGand PiB-PET, or consultation of other specialists. Conclusions: In this study in a tertiary referral setting, CSF biomarkers did not change the diagnosis markedly, but the clinician’s confidence in the underlying neuropathology. In cases where CSF results contradicted clinical diagnosis, they prompted further investigation or follow-up. We conclude that CSF biomarkers may aid clinicians in the diagnostic process, even in a setting where pre-CSF confidence in the diagnosis is high.

Comparison of diagnostic power of cerebrospinal fluid Aß and Tau variables for Alzheimer's disease diagnosis: proposition of a simple decision tree

Background: Advanced glycations endproducts (AGE) are known to cause increased oxidant stress, inflammation, and neurotoxicity; serum levels are increased in diabetes and aging. We examined the relationship between levels of serum methylglyoxal (sMG), an AGE precursor, and cognitive decline in elderly. Methods: Subjects were 266 initially non-demented elderly who had complete data including at least two MMSEs. Tobit mixed regression models assessed the association of baseline MG with cognitive decline in the Mini Mental State Exam (MMSE) score over time, controlling for sociodemographic factors (age, sex, and years of education), and cardiovascular risk factors (diabetes and presence of anAPOE4 allele). sMGwas assessed by ELISA. Results: The sample averaged 83.5 years of age, 14.3 years of education, 36 months of follow up, and 0.93 nmol/ml of sMG. Average baseline MMSE of 28.2 reflected this cognitively normal sample. Seventy six percent of the sample was male since a major source of recruitment was the Mount Sinai affiliate James J. Peters Veterans Affairs Medical Center; 18% had diabetes and 20% carried an APOE4 allele. The fully adjusted model showed an annual decline of 0.33 MMSE points per unit increase in baseline sMG (p 1⁄4 0.015). Significance improved as additional risk factors were added to the model. The interactions of sMGwith diabetes, sex, age, and APOE4 genotype were not significant and did not substantially improve the model fit. In a small replication sample of 49 younger elderly (average age 70, education 14.6, 18 months of follow up, sMG1⁄4 0.91 nmol/ml, baselineMMSE 28.8, 53%males, 13% had diabetes, 9% carried an APOE4 allele), who had a broad neuropsychological battery, results were essentially identical: for the fully adjusted model: p 1⁄4 0.01 when using the MMSE as outcome measure and p 1⁄4 0.03 when using an overall cognition outcome measure. Conclusions: Higher levels of circulating MG were associated with a faster rate of cognitive decline, after adjusting for several sociodemographic and clinical characteristics. This relationship did not differ by sex, APOE4 genotype, or diabetes status suggesting its generality. Since subjects were cognitively normal at the beginning of the study, elevated circulating MG may be indicative of brain cell injury initiated before clinically evident cognitive compromise. Because levels of MG in blood correlate with those consumed with diet, lowering MG by AGE restricted diet has potential for preventing cognitive compromise.

P2a-13 Biomarqueurs Tau, p-Tau et Aβ 1-42 dans le LCR : Proposition d’arbres décisionnels pour l’aide au diagnostic des démences et de la MA

Introduction Dans la Maladie d’Alzheimer (MA), des alterations specifiques du metabolisme cerebral conduisent a la formation et l’agregation de proteines anormales : les proteines Tau hyperphosphorylees et le peptide amyloide Ab42, qui constituent donc des marqueurs biologiques privilegies. La concentration de ces marqueurs dans le LCR est alteree chez les patients MA : les proteines intraneuronales Tau totales et hyperphosphorylees (phospho-Tau), voient leurs concentrations augmenter ; par contre le peptide Ab42 voit ses concentrations diminuer. Dans cette etude, nous avons recherche parmi ces trois parametres quels etaient les indicateurs majeurs pour separer les sujets dements des non-dements d’une part, et pour separer les sujets MA des autres demences d’autre part. Methodes La proteine tau totale (Tau), tau phosphorylee (Threonine 181, P-Tau) et le peptide Aβ 1-42 sont doses prospectivement depuis 2004 dans le liquide cephalo-rachidien. • Inclusion : patients de la clinique neurologique et du CMRR de Lille : 38 cas controles, 91 cas de maladie d’Alzheimer probable (MA), 57 cas ayant un trouble cognitif leger (MCI), 104 cas de demences non Alzheimer (nMA : demences vasculaires, demences a corps de Lewy, paralysies supranucleaires progressives, degenerescences corticobasales, demences fronto-temporales, demences d’autre etiologie). • Le diagnostic clinique a ete pose selon les criteres consensuels internationaux etablis grâce a l’interrogatoire, l’examen clinique, le bilan neuropsychologique et l’imagerie cerebrale. L’interrogatoire et l’examen clinique ont permis d’exclure une demence chez les controles. • Dosages : par technique ELISA (Innogenetics®, Belgique). Resultats Pour distinguer les sujets dements des controles, l’indicateur majeur est P-tau (pour une valeur seuil de 53 pg/ml), avec un apport plus mineur de la valeur d’Aβ 1-42. Pour distinguer les sujets MA des autres demences, l’indicateur majeur est P-tau (pour une valeur seuil de 70 pg/ml). Conclusion En fonction du contexte clinique, nous proposons 2 arbres decisionnels avec des valeurs seuil de p-Tau distinctes pour l’aide au diagnostic des demences et de la MA.