title: Blood-brain barrier breakdown in the aging human hippocampus.
abstract: The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Montagne
authors.affiliation: Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, CA 91101, USA.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Barnes
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Sweeney
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Halliday
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Abhay P
authors.initials: AP
authors.lastname: Sagare
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Institute for Neuroimaging & Informatics, Department of Neurology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, CA 91101, USA.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Jacobs
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Department of Radiology, Neuroradiology Division, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Collin Y
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lilyana
authors.initials: L
authors.lastname: Amezcua
authors.affiliation: Huntington Medical Research Institute, Pasadena, CA 91101, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Harrington
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Chui
authors.affiliation: Department of Radiology, Neuroradiology Division, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Law
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: zlokovic@usc.edu.
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000418:Albumins / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D056654:CA3 Region, Hippocampal / Q000378:metabolism*; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism; D010539:Permeability; D012709:Serum Albumin; D013788:Thalamus / Q000378:metabolism; D055815:Young Adult
chemical_list: D000418:Albumins; D012709:Serum Albumin