Udo Eichenlaub

Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of β-amyloid (1-42) in human cerebrospinal fluid.

Available assays for quantitation of the Alzheimers disease (AD) biomarker amyloid‐beta 1–42 (Aβ [1–42]) in cerebrospinal fluid demonstrate significant variability and lack of standardization to reference measurement procedures (RMPs). We report analytical performance data for the novel Elecsys β‐amyloid (1–42) assay (Roche Diagnostics).

CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts

We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort.

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

DETECTING BRAIN AMYLOID STATUS USING FULLY AUTOMATED PLASMA Aβ BIOMARKER ASSAYS

baseline. The median percentage change was -42% in the IVarm and -48% in the SC arm, with 21% and 13% of patients falling below the LLoQ after treatment. In contrast, no systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change (54% of the placebo patients had lower AbO levels at week 69). The difference in proportions of patients with decreasing levels was significant for both treatment arms: p1⁄40.001 for SC, and p1⁄40.01 for IV crenezumab vs. placebo. Conclusions:Crenezumab lowers AbO levels in CSF in the large majority of tested patients. These results strongly suggest engagement of the principal target and recommend assaying CSF AbO in future trials of anti-Ab agents.

A UNIFIED PRE-ANALYTICAL PROTOCOL FOR HANDLING OF CSF SAMPLES BEFORE ANALYSES OF AD BIOMARKER LEVELS

O2-09-01 CSF, PLASMA AND MRI BIOMARKER TRAJECTORIES DURING THE DEVELOPMENT OFALZHEIMER’S DISEASE Sebastian Palmqvist, Niklas Mattsson, Olof Strandberg, Philip Insel, Shorena Janelidze, Erik Stomrud, Oskar Hansson, Department of Neurology, Sk ane University Hospital, Lund, Sweden; Clinical Memory Research Unit, Lund University, Malm€o, Sweden; Department of Neurology, Lund, Sweden; Clinical Memory Research Unit, Lund University, Lund, Sweden; Center for Imaging of Neurodegenerative Diseases, San Francisco Veterans Administration Medical Center, San Francisco, CA, USA; Lund University, Lund, Sweden. Contact e-mail: sebastian.palmqvist@med.lu.se

CSF BIOMARKERS IN THE GENERAL POPULATION: ASSOCIATIONS WITH DEMOGRAPHICS AND APOE GENOTYPE

Gender (female/male) 8/3 9/10 5/13 Age, years (mean, SD) 38.9 (9.5) 36.0 (5.7) 46.5 (9.4) EYO. years (mean, SD) N/A -9.6 (5.5) +3.3 (3.3) Baseline MMSE/30 (median, IQR) 30 (30-30) 29 (29-30) 20.0(19-25) CDR Global (median, IQR) 0 (0-0) 0 (0-0) 0.5 (0.5-1.0) CDR SOB (median. IQR) 0 (0-0) 0 (0-0) 3.75 (2.0-4.75) Baseline NfL, pg/mL (mean, SD) 12.75 (7.18) 16.68 (7.70) 45.71 (20.89) Rate of change in NfL. pg/mL/year (mean. SD) 0.32(1.55) (n1⁄49) 1.11 (3.46) (n1⁄411 ) 1.88 (9.30) (n1⁄46)

Derivation of cutoffs for the Elecsys® amyloid β (1–42) assay in Alzheimer's disease

An Elecsys® Amyloid β (Aβ [1–42]) immunoassay cutoff for classification of patients with Alzheimers disease was investigated.

STABILITY OF AMYLOID-BETA (1–42) IN FRESH VERSUS FROZEN HUMAN CEREBROSPINAL FLUID SAMPLES AS MEASURED WITH THE ELECSYS® B-AMYLOID(1–42) IMMUNOASSAY

trol have a very low score; the one outlier is currently cognitively normal but is homozygous for the ApoE4 allele placing her at much higher risk of developing AD in the future. All other controls were E2/E3, E3/E3 and E3/E4. Most but not all MCls are positive, again underscoring the potential for distinguishing between AD relatedMCI vs. MCI due to other pathophysiology (e.g. vascular). P values calculated comparing against the common control using Dunnett’s with the one control outlier excluded. Means (black bars, all points included) tend to be higher in the MCI vs. AD groups. (Tsutsui, Roychoudhury, Poulin, Smith, Barber & Stys,unpublished).

COMMUTABILITY OF THE CANDIDATE CERTIFIED REFERENCE MATERIALS FOR THE STANDARDIZATION OF Aβ1-42 MEASUREMENTS IN HUMAN CEREBROSPINAL FLUID

collection, handling and storing procedures. For all subjects, Ab1-42, T-Tau and P-Tau in CSF, MMSE and MOCA scores were determined. Using a highly sensitive semi-targeted MS assay, more than 40’000 low-concentration molecules were quantified in serum, including 111 biomarker candidates taken from the literature. Results: Out of the 111 candidates from the literature, 31 were found to be significantly different in AD versus CON however none presented an AUC>80%. In the larger pool of 40’000 compounds, we found new low-concentration molecules highly sensitive to AD (AUC>80%) and/or presenting a high correlation with MOCA and MMSE. Combining these biomarkers to distinguish AD and MCI from CON while minimizing overfitting, a panel of 7 molecules was derived. The resulting score was found to be highly correlated to MOCA>19(p1⁄41.e-8; R21⁄40.42) and MMSE>24 (p1⁄44.e-8; R21⁄40.40), mildly correlated to CSF markers. AUCs of 87% and 92% were found to distinguish MCI from CON and AD from CON, respectively. The score increases with the progression of the disease CON/MCI-/MCI+/AD. This score did not allow the distinction of AD from the other dementias although it remains correlated to MOCA and MMSE in these groups. This score distinguishes subjects with MMSE<28 from those with MMSE>28(AUC1⁄488%) as well as the subjects with MOCA<25 from those with MOCA>25(AUC1⁄495%). Conclusions:This panel of 7 new blood biomarkers is sensitive to AD and other dementias while correlated to MOCA and MMSE. This blood cognition score is highly effective for detecting molecular alterations associated to cognitive decline especially in early phases. The proposed cognition score still needs to be validated on other cohorts, especially on blood samples collected longitudinally which has included subjects with early or mild cognitive decline (e.g., clinical trials).

Multicentre performance evaluation of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of Aβ(1–42) in human cerebrospinal fluid

Background: By the year 2050, it is projected the majority of nearly 14 million people living with dementia in the United States will be racial/ethnic minorities. Survival after dementia diagnosis is not well characterized for multiethnic communitybased populations with equal access to healthcare. Delineating if there are racial/ethnic differences in survival time after dementia diagnosis is important for public health planning and would shed light on whether there are differences in severity of disease at time of diagnosis, care received by patients, or pace of progression of underlying disease. We compared survival after dementia diagnosis in five racial/ethnic groups among members of a large healthcare delivery system. Methods: We studied N1⁄459,494 dementia patients receiving care in the Kaiser Permanente Northern California medical system who were age 64 years and diagnosed with dementia between January 1, 2000 and December 31, 2013 (n1⁄43,847 Asian Americans, n1⁄44,942 African Americans, n1⁄44,371 Latinos, n1⁄41,224 Native Americans, and n1⁄445,110 non-Latino whites). Age at diagnosis and date of death were identified from medical records and the California Automated Mortality Linkage System through December 31, 2013. We estimated median post-diagnosis Kaplan-Meier survival times and sex-adjusted Cox proportional hazards models with age as the timescale. Results:Dementia patients were followed for up to 14 years after dementia diagnosis, during which 64.1% (n1⁄438,159) died. Non-Latino whites were older at dementia diagnosis (mean 83.7 years) and Latinos and African Americans were youngest at dementia diagnosis (mean 82.2 years and 82.1 years, respectively). Median survival time after dementia diagnosis was shortest among non-Latino whites (3.09 years). Relative to non-Latino whites, median survival time was 0.35 years longer for Native Americans, 0.65 years longer for African Americans, 1.0 year longer for Latinos, and 1.29 years longer for Asian Americans (Table 1). Conclusions: Our results suggest non-Latino whites are diagnosed with dementia at older ages and have shorter survival times after dementia diagnosis than other racial/ethnic groups. These differences in post-diagnosis survival should be taken into account for public health planning and when interpreting evidence on racial/ethnic disparities in dementia.