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

Vascular contributions to cognitive impairment are increasingly recognized1-5 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-beta (A beta)(3,11,14), and more recently tau(15). Animal studies suggest that A beta 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 A beta 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-beta(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 A beta and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of A beta and tau.