Amyloid β peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing

https://doi.org/10.1016/j.expneurol.2009.07.024Get rights and content

Abstract

We measured concentrations of Aβ peptides 1–42 and 1–40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3–3.8% for Aβ1–42, and 1.8–4.1% for Aβ1–40, inter-assay imprecision for Aβ1–42, Aβ1–40, and Aβ1–42/Aβ1–40 concentration ratio in the range of 2.3–11.5%, 2.2–10.4% and 4.2–9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n = 193) had significantly lower Aβ1–42 plasma concentrations (p < 0.007), and Aβ1–42/1–40 ratios (p < 0.003) compared to patients with other dementias and MCI of other types (n = 64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

Introduction

The age-related surge in the number of people with dementia poses urgent public health challenges worldwide (Ferri et al., 2005, Ott et al., 1998). In particular, improvements in early detection and differential diagnosis of more common dementias such as Alzheimer's disease (AD) are sorely needed, along with effective disease-modifying treatments. The availability of robust, validated biomarkers is considered to be one of the essential means to achieve these ends. For AD, such diagnostic markers should not only be quantifiable and reliable, but reflect the central pathogenic processes associated with the disease, namely the degeneration of neurons and their synapses as reflected in their defining characteristic lesions — senile plaques and neurofibrillary tangles (The Working Group on: “Molecular and Biochemical Markers of Alzheimer's Disease”, 1998).

Although cerebrospinal fluid (CSF) biomarker studies based on lumbar puncture have been associated with very low rates of complications (Blennow et al., 1993), such a technique is more invasive, and it poses a practical and psychological barrier to its use as a general screening tool. Alternatively, several studies suggest that concentration of Aβ in plasma may help in the early diagnosis of AD, but results seem conflicting (Freeman et al., 2007, Graff-Radford et al., 2007, van Oijen et al., 2006). These differences may, in part, be related to the use of suboptimally standardized in-house tests. To circumvent this confounding issue, we measured plasma Aβ concentrations in clinically and neurochemically characterized groups using a new standardized multiplexing approach for the first time.

Section snippets

Patients

The study was approved by the ethics committees of all the participating universities, and all patients and/or their relatives gave their informed consent.

Fourteen German psychiatric university departments participated in the project (http://www.kompetenznetz-demenzen.de). 2113 subjects passed the screening examinations and were assigned to one of the relevant diagnostic groups. There were 1870 patients (790 dementia and 1080 MCI patients) and 243 control subjects (201 healthy and 42 disease

Analytical performance of the Aβ multiplexing assay

Coefficients of variation of intra-assay imprecision were in the range of 1.3–3.8% for Aβ1–42, and in the range of 1.8–4.1% for Aβ1–40. Coefficients of variation of inter-assay imprecision were in the range of 2.3–11.5% for Aβ1–42, and in the range of 2.2–10.4% for Aβ1–40. Coefficients of variation of inter-assay imprecision of Aβ1–42/1–40 concentration ratio were in the range of 4.2–9.7%.

Aβ peptides in patients' plasma

We observed highly significant differences in Aβ1–42/1–40 plasma concentration ratios between the groups of

Discussion

The main outcome of our study was the highly significant decreases in plasma Aβ1–42 concentrations and Aβ1–42/Aβ1–40 ratios in patients with early AD or MCI of the AD type compared to patients with other dementia types. Patients were categorized according to rigorous protocol: in the fourteen German gerontopsychiatric university departments well-defined clinical and neuropsychological criteria were used (http://www.kompetenznetz-demenzen.de), and the neurochemical diagnostic procedures were

Acknowledgments

This study was supported by the following grants from the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01 GI 0102), and HBPP-NGFN2 (01 GR 0447), and by the EU grant cNEUPRO (contract no. LSHM-CT-2007-037950). The authors thank Heike Kamrowski-Kruck and Leen Demeyer for analysis, and are grateful to Dirk Wouters (Innogenetics) for his useful comments and support. Drs: E. Vanmechelen, H. Vanderstichele, and F. Shapiro are employees of Innogenetics; Dr. G. De

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