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Nat Med. 2019 Feb;25(2):270-276. doi: 10.1038/s41591-018-0297-y. Epub 2019 Jan 14.

Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.

Author information

1
Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
2
Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
3
Department of Psychology, University of Southern California, Los Angeles, CA, USA.
4
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
5
Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
6
Huntington Medical Research Institutes, Pasadena, CA, USA.
7
Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
8
The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St. Louis, MO, USA.
9
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
10
The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
11
Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
12
Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
13
Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.
14
Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.

Abstract

Vascular contributions to cognitive impairment are increasingly recognized1-5 as shown by neuropathological6,7, neuroimaging4,8-11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown14-16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8-10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.

PMID:
30643288
PMCID:
PMC6367058
[Available on 2019-07-14]
DOI:
10.1038/s41591-018-0297-y

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