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

Autor: Nation DA; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Psychology, University of Southern California, Los Angeles, CA, USA., Sweeney MD; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Montagne A; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Sagare AP; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., D'Orazio LM; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Pachicano M; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Sepehrband F; Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Nelson AR; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Buennagel DP; Huntington Medical Research Institutes, Pasadena, CA, USA., Harrington MG; Huntington Medical Research Institutes, Pasadena, CA, USA., Benzinger TLS; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.; The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St. Louis, MO, USA., Fagan AM; The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St. Louis, MO, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.; The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA., Ringman JM; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Schneider LS; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA., Morris JC; The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St. Louis, MO, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA., Chui HC; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Law M; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Toga AW; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Zlokovic BV; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2019 Feb; Vol. 25 (2), pp. 270-276. Date of Electronic Publication: 2019 Jan 14.
DOI: 10.1038/s41591-018-0297-y
Abstrakt: Vascular contributions to cognitive impairment are increasingly recognized 1-5 as shown by neuropathological 6,7 , neuroimaging 4,8-11 , and cerebrospinal fluid biomarker 4,12 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 tau 15 . Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown 14-16 . Although neurovascular dysfunction 3,11 and BBB breakdown develop early in AD 1,4,5,8-10,12,13 , how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia 17 , 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-β 8,18 , and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging 8-10 . 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.
Databáze: MEDLINE
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