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

Daniel A. Nation, Melanie D. Sweeney, Axel Montagne, Abhay P. Sagare, Lina M. D’Orazio, Maricarmen Pachicano, Farshid Sepehrband, Amy R. Nelson, David P. Buennage, Michael G. Harrington, Tammie L. S. Benzinger, Anne M. Fagan, John M. Ringman, Lon S. Schneider, John C. Morris, Helena C. Chui, Meng Law, Arthur W. Toga, and Berislav V. Zlokovic.

Nature Medicine 2019. (14 January 2019).

Vascular contributions to cognitive impairment are increasingly recognized as shown by neuropathological, neuroimaging, and cerebrospinal fluid biomarker 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). Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ), and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown. Although neurovascular dysfunction and BBB breakdown develop early in AD, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia, 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, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging. 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.