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- Jiang, R. C., et al.
(författare)
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Increased CSF-decorin predicts brain pathological changes driven by Alzheimer's A beta amyloidosis
- 2022
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer's disease (AD) which is characterized by amyloid-beta (A beta) amyloidosis. Here, we used two App knock-in mouse models, App(NL-F/NL-F) and App(NL-G-F/NL-G-F), exhibiting AD-like A beta pathology to analyze how the brain pathologies translate to CSF proteomes by label-free mass spectrometry (MS). This identified several extracellular matrix (ECM) proteins as significantly altered in App knock-in mice. Next, we compared mouse CSF proteomes with previously reported human CSF MS results acquired from patients across the AD spectrum. Intriguingly, the ECM protein decorin was similarly and significantly increased in both App(NL-F/NL-F) and App(NL-G-F/NL-G-F) mice, strikingly already at three months of age in the App(NL-F/NL-F) mice and preclinical AD subjects having abnormal CSF-A beta 42 but normal cognition. Notably, in this group of subjects, CSF-decorin levels positively correlated with CSF-A beta 42 levels indicating that the change in CSF-decorin is associated with early A beta amyloidosis. Importantly, receiver operating characteristic analysis revealed that CSF-decorin can predict a specific AD subtype having innate immune activation and potential choroid plexus dysfunction in the brain. Consistently, in App(NL-F/NL-F) mice, increased CSF-decorin correlated with both AP plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human A beta 42 induces decorin secretion from mouse primary neurons. Interestingly, we finally identify decorin to activate neuronal autophagy through enhancing lysosomal function. Altogether, the increased CSF-decorin levels occurring at an early stage of A beta amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects.
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- Boccardi, M., et al.
(författare)
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The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48, s. 2070-2085
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Tidskriftsartikel (refereegranskat)abstract
- Background The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research. Methods We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers. Results The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures. Discussion This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.
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