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An automated clinical mass spectrometric method for identification and quantification of variant and wild-type amyloid-? 1-40 and 1-42 peptides in CSF.

ABSTRACT: Introduction:We developed an automated liquid chromatography-tandem mass spectrometry high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for multiplex quantification of wild-type (wt) amyloid ? (A?) peptides 1-40 (A?40) and 1-42 (A?42) and detection of variant A? peptides in cerebrospinal fluid. Methods:The multiplex A? HPLC-MS/MS assay was validated in a clinically accredited laboratory following regulatory guidelines, with A?42 calibration assigned to the ERM/IFCC certified reference material; sequence variants were additionally multiplexed into the method. Results:Sample preparation was fully automated on a liquid handler. The assay quantified wt-A?42 and wt-A?40 and detected sequence variants, when present, within the A?42 sequence. Discussion:Extension of the HPLC-MS/MS approach for quantification of wt-A?42 and wt-A?40 to include known sequence variants increases analytical accuracy of the mass spectrometric approach and enables identification of cases of autosomal dominant Alzheimer's disease. Development of an automated workflow and selection of appropriate instrumentation enabled deployment of this method in routine clinical testing.

SUBMITTER: DeMarco ML

PROVIDER: S-EPMC7327131 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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An automated clinical mass spectrometric method for identification and quantification of variant and wild-type amyloid-β 1-40 and 1-42 peptides in CSF.

DeMarco Mari L ML Nguyen Quyen Q Fok Alice A Hsiung Ging-Yuek Robin GR van der Gugten J Grace JG

Alzheimer's & dementia (Amsterdam, Netherlands) 20200630 1

<h4>Introduction</h4>We developed an automated liquid chromatography-tandem mass spectrometry high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for multiplex quantification of wild-type (wt) amyloid β (Aβ) peptides 1-40 (Aβ40) and 1-42 (Aβ42) and detection of variant Aβ peptides in cerebrospinal fluid.<h4>Methods</h4>The multiplex Aβ HPLC-MS/MS assay was validated in a clinically accredited laboratory following regulatory guidelines, with Aβ42 calibration assign ...[more]

PMID: 32617385

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Project description:ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A?42/A?40 and A?42/A?38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A?42 alone.MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of A?42, A?40, and A?38 were assessed. CSF A?s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients.ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A?42/A?40 and A?42/A?38 ratios were significantly better predictors of abnormal amyloid PET than CSF A?42. Lower A?42, A?42/A?40, and A?42/A?38 ratios, but not A?40 and A?38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A?38, A?40, and A?42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A?42/A?40 and A?42/A?38 ratios showed increased accuracy compared to A?42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A?s (including A?42) were decreased.InterpretationThe CSF A?42/A?40 and A?42/A?38 ratios are significantly better than CSF A?42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF A?42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A?42 should be used in the clinical work-up of AD.

Dataset Information

An automated clinical mass spectrometric method for identification and quantification of variant and wild-type amyloid-? 1-40 and 1-42 peptides in CSF.

Publications

An automated clinical mass spectrometric method for identification and quantification of variant and wild-type amyloid-β 1-40 and 1-42 peptides in CSF.

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