The Biomarker Core (Core B) of the P01 ?Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer?s Disease? will provide services, resources and expertise on biomarkers of the neurovascular unit (NVU) for Projects 1-3 and all P01 investigators. Since the overall design of this program includes individuals with genetic risk for late-onset AD (APOE4 carriers) and early, autosomal dominant AD (ADAD) (PSEN1 mutation carriers) and a novel rat model of AD with early vascular changes (line TgF344-AD) and controls during aging and/or different experimental conditions, this core will provide the essential, quantified molecular measures relatable to the imaging and cognitive measures collected as part of this program. The Biomarker Core has developed a novel panel of multiple molecular biomarkers that integrate NVU cell- and system-specific biomarkers with established AD biomarkers (A?, tau, pTau) to simultaneously determine biomarkers of vascular/blood-brain barrier (BBB) injury in relation to inflammatory, neuronal injury, and A? and tau biomarkers in both human and rat cerebrospinal fluid (CSF) and plasma (Projects 1 and 3). Existing strengths of our core include decades of experience and knowledge in studying the NVU, BBB and cerebrovascular system, and a more recent experience over the past two years working closely with the Meso Scale Discovery (MSD) scientists to develop reliable and simultaneous measurements of multiple NVU biomarkers in human and rat biofluid for all pilot data analyses in Projects 1 and 3 using the ultrasensitive electrochemiluminescent MSD multiplex platform that is up to 2-3 orders of magnitude more sensitive than ELISA or other multiplex platforms. Our strengths also include existing and established collaborations with clinical site investigators participating in the P01 including: 1) USC ADRC (Chui, Schneider, Law); 2) Washington University Knight ADRC (Morris, Fagan, Benzinger); 3) Huntington Medical Research Institutes (HMRI) (Harrington); and 4) Dominantly Inherited Alzheimer?s Network (DIAN) including Washington University site (Morris, Fagan) and USC site (Ringman, former UCLA site moved to USC 5/15); as well as with Project 1, 2, and 3 investigators - laboratories of Drs. Zlokovic, Nation, Pa, Toga, Town, Thompson, Dong and Jacobs (CalTech). Core B has provided simultaneous measurements of different NVU biomarker categories in CSF for all pilot data analyses in APOE4 and PSEN1 mutation carriers and non-carriers and TgF344-AD rats and controls, and has determined subjects? APOE genotype. Under the leadership of Dr. Zlokovic and the resources available at USC Zilkha Neurogenetic Institute, Core B will 1) Coordinate and standardize collection, processing, and delivery of biofluid samples at different sites; 2) Assay CSF and plasma simultaneously for NVU biomarkers and conduct APOE genotyping; 3) provide further technological developments, and 4) facilitate data management, requests and distribution to projects to support the scientific goals of this program project, all investigators and research Projects 1-3.
| Nation, Daniel A; Tan, Alick; Dutt, Shubir et al. (2018) Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion. J Alzheimers Dis 61:91-101 |
| Sweeney, Melanie D; Kisler, Kassandra; Montagne, Axel et al. (2018) The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21:1318-1331 |
| Nation, Daniel A (2018) Blood Pressure and Cerebral Blood Flow in Alzheimer Disease. Hypertension 72:68-69 |
| Netto, Joao Prola; Iliff, Jeffrey; Stanimirovic, Danica et al. (2018) Neurovascular Unit: Basic and Clinical Imaging with Emphasis on Advantages of Ferumoxytol. Neurosurgery 82:770-780 |
| Montagne, Axel; Nikolakopoulou, Angeliki M; Zhao, Zhen et al. (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 24:326-337 |
| Sweeney, Melanie D; Zlokovic, Berislav V (2018) A lymphatic waste-disposal system implicated in Alzheimer's disease. Nature 560:172-174 |
| Li, Junning; Gahm, Jin Kyu; Shi, Yonggang et al. (2018) Topological false discovery rates for brain mapping based on signal height. Neuroimage 167:478-487 |
| Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133-150 |
| Amar, Arun Paul; Sagare, Abhay P; Zhao, Zhen et al. (2018) Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C. Neuropharmacology 134:293-301 |
| Ho, Jean K; Nation, Daniel A; Alzheimer’s Disease Neuroimaging Initiative (2018) Neuropsychological Profiles and Trajectories in Preclinical Alzheimer's Disease. J Int Neuropsychol Soc 24:693-702 |
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