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Authors: Andriuta, Daniela | Moullart, Véronique | Schraen, Susanna | Devendeville, Agnes | Meyer, Marc-Etienne | Godefroy, Olivier | for the Alzheimer’s Disease Neuroimaging

Article Type: Research Article

Abstract: The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer’s disease (AD) (Aβ1–42 , t-tau, and p-tau) and 18 Fluorodeoxyglucose 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 Aβ1–42 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 (Aβ1–42 , 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 Aβ1–42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aβ1–42 level (t-tau: R2  = 0.044, p  = 0.001; p-tau: R2  = 0.02, p  = 0.03). In the latter patients, CSF p-tau was the most frequently (p  = 0.0001) 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 (R2  = 0.149; p  = 0.0001) 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. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, FDG-PET metabolism, neurodegeneration markers, tau

DOI: 10.3233/JAD-150829

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 793-800, 2016

Authors: Gabelle, Audrey | Richard, Florence | Gutierrez, Laure-Anne | Schraen, Susanna | Delva, Fleur | Rouaud, Olivier | Buée, Luc | Dartigues, Jean-François | Touchon, Jacques | Lambert, Jean-Charles | Berr, Claudine

Article Type: Research Article

Abstract: Studies of plasma amyloid-β (Aβ) levels as potential biomarkers for incident Alzheimer's disease (AD) have yielded contradictory results. We explored the associations between plasma Aβ40 , Aβ42 , and truncated Aβ levels, and prognosis of dementia in participants of the prospective 3-City Study. 120 aged individuals diagnosed with 2-year incident dementia were followed up for seven years. The associations between Aβ plasma levels and baseline cognitive score, cognitive decline, and death were examined. A higher level of baseline plasma Aβ was associated with worse cognitive status two years prior to incident dementia diagnosis. In incident AD patients, the association was …only significant for Aβ40 and Aβn-42 . In the fast cognitive decliners group, especially in AD cases, a higher level of 5 pg/ml of baseline Aβ42 , Aβn-42 , Aβn-42 /Aβn-40 , and Aβ42 /Aβ40 ratios were associated with a lower risk of fast cognitive decline based on the Isaacs Set Test score. There was no association between peptide levels and mortality in demented subjects. When assayed at prodromal stage, plasma Aβ levels may be potentially useful markers of fast cognitive decline in individuals who subsequently become demented. Show more

Keywords: Alzheimer's disease, cohort studies, mild cognitive impairment, plasma amyloid-β peptides

DOI: 10.3233/JAD-2012-121147

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 381-391, 2013

Authors: Gabelle, Audrey | Dumurgier, Julien | Vercruysse, Olivier | Paquet, Claire | Bombois, Stéphanie | Laplanche, Jean-Louis | Peoc'h, Katell | Schraen, Susanna | Buée, Luc | Pasquier, Florence | Hugon, Jacques | Touchon, Jacques | Lehmann, Sylvain

Article Type: Research Article

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, Lille 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. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid biomarkers, cohort studies, dementia, p-tau

DOI: 10.3233/JAD-121549

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 297-305, 2013

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