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Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.

ABSTRACT: 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 amyloid ? (A?) biomarker for central nervous system amyloid deposition.We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of A?38, A?40, and A?42 in human plasma.A? isoforms have a half-life of approximately 3 hours in plasma. A?38 demonstrated faster turnover kinetics compared with A?40 and A?42. Faster fractional turnover of A?42 relative to A?40 and lower A?42 and A?42/A?40 concentrations in amyloid-positive participants were observed.Blood plasma A?42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of A?. The stability and sensitivity of plasma A? measurements suggest this may be a useful screening test for central nervous system amyloidosis.

SUBMITTER: Ovod V

PROVIDER: S-EPMC5567785 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.

Ovod Vitaliy V Ramsey Kara N KN Mawuenyega Kwasi G KG Bollinger Jim G JG Hicks Terry T Schneider Theresa T Sullivan Melissa M Paumier Katrina K Holtzman David M DM Morris John C JC Benzinger Tammie T Fagan Anne M AM Patterson Bruce W BW Bateman Randall J RJ

Alzheimer's & dementia : the journal of the Alzheimer's Association 20170719 8

<h4>Introduction</h4>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 amyloid β (Aβ) biomarker for central nervous system amyloid deposition.<h4>Methods</h4>We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aβ38, Aβ40, and Aβ42 in human plasma.<h4>Results</h4>Aβ ...[more]

PMID: 28734653

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Project description:Importance:Recent studies found that the concentration of amyloid-? (A?) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of A? kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied. Objective:To determine the association between A? kinetics, age, amyloid levels, and the A? day/night pattern in humans. Design, Setting, and Participants:We measured A? concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of A?40 and A?42 were measured. Interventions:Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of 13C6-leucine. Main Outcomes and Measures:The amplitude, linear increase, and other cosinor measures of each participant's serial cerebrospinal fluid A? concentrations and A? turnover rates. Results:Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in A? concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: A?40, -7.42 pM; P?<?.001; A?42, -3.72 pM; P?<?.001). Amyloid deposition diminished day/night amplitude and linear increase of A?42 but not of A?40. Increased age diminished day/night amplitude of both A?40 and A?42. After controlling for amyloid deposition, amplitude of A?40 was positively associated with production rates (r?=?0.42; P?<?.001), while the linear rise was associated with turnover rates (r?=?0.28; P?<?.05). The amplitude and linear rise of A?42 were both associated with turnover (r?=?-0.38; P?<?.001) and production (r?=?0.238; P?<?.05) rates. Conclusions and Relevance:Amyloid deposition is associated with premature loss of normal A?42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on A?42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night A? patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease.

Dataset Information

Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.

Publications

Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.

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