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.

Additional Information

© 2015 Elsevier Inc. Accepted 10 December 2014, Available online 21 January 2015. We would like to thank the National Institutes of Health for grants R37NS34467 (B.V.Z.), R37AG23084 (B.V.Z.), R01AG039452 (B.V.Z.), Zilkha Senior Scholar support (B.V.Z.), R21EB013456 (M.L.), UL1TR000130 (M.L.), L.K. Whittier Foundation (M.G.H), P50AG05142 (H.C.C.), 7P41EB015922 (A.W.T.), and EB000993 (R.E.J.). Author Contributions: A.M. and B.V.Z. designed research and analyzed and interpreted data; A.M., S.R.B., M.D.S., M.R.H., A.P.S., and Z.Z. performed experiments and analyzed data; A.M., S.R.B., and R.E.J. contributed to a new analytic software; C.Y.L., H.C.C., M.L., L.A., and M.G.H. recruited participants and performed and provided imaging scans; S.R.B., A.W.T., R.E.J., H.C.C., M.L., and M.G.H. provided critical reading of the manuscript; A.M. contributed to manuscript writing; and B.V.Z. wrote the manuscript.

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Supplemental Material - mmc1.pdf

Accepted Version - nihms651289.pdf

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