P4‐473: A NOVEL MASS SPECTROMETRIC METHOD FOR THE ABSOLUTE QUANTIFICATION OF SIX Aβ PEPTIDES IN HUMAN CEREBROSPINAL FLUID
Year: 2019
Type: article
Study design: Observational Study
Abstract: The main hypothesis on the pathogenesis of Alzheimer's disease (AD) is currently the amyloid cascade hypothesis, which postulates that Aβ peptide aggregates in the form of soluble oligomers or amyloid plaques, which in turn leads to tau pathology, neurodegeneration and cognitive symptoms. It is therefore important with more detailed understanding of the amylogenic pathway and the role of different Aβ peptide species. For that purpose, we developed and validated a novel mass spectrometric method to quantify six endogenous Aβ species of different lengths, namely Aβ1-34, Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40 and Aβ1-42. The aim of the study was to investigate if absolute concentrations and/or ratios of these Aβ peptides are different in CSF from clinically diagnosed AD patients compared with control subjects. Absolute quantification of the above-mentioned six Aβ peptides was performed using parallel reaction monitoring on a hybrid quadrupole-orbitrap mass spectrometer. In this first study, 97 CSF samples were analyzed, of which 47 samples were from clinically diagnosed AD patients and 50 samples were from cognitively normal control subjects. Group analyses were performed using unpaired t-test, as well as ROC and correlation analyses. There was a significant decrease in the CSF concentration of Aβ1-42, as well as in all ratios involving this peptide divided by the concentration of any of the C-terminally truncated Aβ forms (Aβ1-42/Aβ1-40, Aβ1-42/Aβ1-39, Aβ1-42/Aβ1-38,Aβ1-42/Aβ1-37 and Aβ1-42/Aβ1-34), in AD patients compared with controls (P <0.0001 for all comparisons). CSF concentrations of the C-terminally truncated Aβ forms were similar in the two groups and highly correlated. The best-performing biomarker combination for distinguishing AD patients from controls was Aβ1-42/Aβ1-40 with an area under the curve of 0.9632 (P <0.0001). These results show that, in contrast to Aβ1-42, the Aβ1-34, Aβ1-37, Aβ1-38, Aβ1-39 and Aβ1-40 peptide concentrations in CSF are unaffected by cerebral Aβ pathology in patients with the sporadic form of AD. Instead, assessment of these peptides may be useful in studies on familial AD (FAD), to further understand the effects of different mutations, and in pharmacodynamic studies to assess biochemical effects of AD therapies targeting amyloid precursor protein-processing in clinical trials.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2981157542