Significant progress has been made in using neuroimaging and cerebrospinal fluid (CSF) protein measurements as Alzheimer disease (AD) biomarkers. However, there is still a critical need to identify more reliable and reproducible biomarkers with further improved diagnostic accuracy, especially to differentiate AD from other dementias, to track or monitor the disease progression and to objectively evaluate drug effects. There is also a growing interest in developing novel biomarkers that could reflect different aspects of AD pathology and accurately detect pathogenic components of AD before appearance of significant cognitive decline, thereby assisting with AD diagnosis at early symptomatic and even preclinical stages. This proposal is designed to meet several major challenges of current biomarker research, specifically: 1) difficulties in development of antibody-based, quantitative protein assays for most novel candidates identified by proteomic profiling and significant variations associated with most existing immunoassays, 2) low sensitivity and specificity of blood- based markers, and 3) detection of AD at early or even preclinical stages. To address the problems of antibody-based assays, our strategy is development of targeted mass spectrometry-based techniques, such as selected reaction monitoring (SRM), to identify unique peptide markers derived from proteins either showing promise in previous proteomics profiling, or known to be critical to AD pathogenesis in human cerebrospinal fluid (CSF). To facilitate discovery and validation of blood based biomarkers, a specific population of central nervous system derived plasma exosomes, the cargo-carrying microvesicles recognized recently to transport biomolecules among different cells or organ systems, will be isolated before SRM analysis. The unique peptide markers will be tested in several large, well-established cohorts, with cross-sectional and longitudinal samples collected, along with extensive clinical characterization. In addition, because a few recent studies have suggested that Asian populations may have lower levels of some markers (e.g., A?42), we will recruit a subgroup of Asian-American subjects, to help determine whether such a difference might be due to racial or environmental differences. Using this group, we will compare the Asian and non-Asian subjects, using the new Lumipulse system. The studies designed for this project, if successful, have the potential to result in a panel(s) of biomarkers that are robust, with less variation than can currently be achieved, and in a body fluid that is readily accessible in a regular clinical setting. Markers for early diagnosis and progression of AD are critical in understanding how to arrest or slow AD progression.
Alzheimer disease (AD) affects millions of Americans and many more worldwide and is a significant source of disability and a major burden to society. This study aims to use novel mass spectrometry- based technologies to identify and validate key biomarkers related to AD pathogenesis in human cerebrospinal fluid and blood, as well as identify a potential source of confounding factors, by examining whether Asian race affects CSF marker level. Successful identification of such biomarkers will help to improve the AD diagnosis accuracy and enhance the disease progression monitoring as well as assessment of treatment effects.
| Shi, Min; Tang, Lu; Toledo, Jon B et al. (2018) Cerebrospinal fluid ?-synuclein contributes to the differential diagnosis of Alzheimer's disease. Alzheimers Dement 14:1052-1062 |
| Cilento, Eugene M; Jin, Lorrain; Stewart, Tessandra et al. (2018) Mass Spectrometry: A Platform for Biomarker Discovery and Validation for Alzheimer's and Parkinson's Diseases. J Neurochem : |
