Image: A Matrix-Assisted Laser Desorption/Ionization (MALDI) time-of-flight mass spectrometer (Photo courtesy of JEOL).
Aggregation and accumulation of beta-amyloid (Aβ), particularly Aβ42, is implicated in the pathogenesis of Alzheimer's disease (AD) with overproduction in autosomal-dominant AD and impaired clearance in the presence of amyloidosis contributing to the cause of AD.
Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical beta-amyloid (Aβ) biomarker for central nervous system amyloid deposition.
An international team of scientists working with the Japanese National Center for Geriatrics and Gerontology (Obu, Japan) used immunoprecipitation followed by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to measure levels of the three markers, APP669-711, Aβ42, and Aβ40 in two cohorts, a discovery set consisting of 121 Japanese patients and a validation set consisting of 252 Australian patients. Both sets included a mix of cognitively normal individuals, subjects with mild cognitive impairment, and subjects with clinically diagnosed Alzheimer's disease with dementia. All patients also had Aβ- positron-emission tomography (PET) imaging data, providing an assessment of their brain Aβ burdens. A subset of the Australian patients also had measurements taken of their cerebrospinal fluid Aβ levels.
The tem tested ratios of the three markers to develop a composite blood-based marker corresponding to brain Aβ levels as assessed by PET and cerebrospinal fluid (CSF) measurements. They used ratios as opposed to absolute measurements to account for individual variation in blood Aβ42 levels across individuals. A composite of the three plasma protein ratios corresponded well with both patient Aβ42 CSF levels and brain Aβ42 levels as determined by PET. Using PET measurements as the gold standard, the investigators found their plasma measurements had comparable performance to the CSF measurements, with both showing accuracy of 80.4% and areas under the curve of 83.8% and 87.4% for the blood and CSF measurements, respectively. Using the CSF measurements as the gold standard, the composite plasma markers performed with an accuracy of 80.4% and an AUC of 87.6.
The authors concluded that their results demonstrated the potential clinical utility of plasma biomarkers in predicting brain beta-amyloid burden at an individual level. These plasma biomarkers also have cost–benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening. The study was published on January 31, 2018, in the journal Nature.
Japanese National Center for Geriatrics and Gerontology