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 Buennagel; 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; Berislav V Zlokovic

doi:10.1038/s41591-018-0297-y

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 Buennagel, 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, Berislav V Zlokovic

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	270-276
Number of pages	7
Journal	Nature Medicine
Volume	25
Issue number	2
DOIs	https://doi.org/10.1038/s41591-018-0297-y
Publication status	Published - Feb 2019

Keywords / Materials (for Non-textual outputs)

Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/metabolism
Blood-Brain Barrier/pathology
Cognitive Dysfunction/cerebrospinal fluid
Humans
Imaging, Three-Dimensional
Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid
tau Proteins/cerebrospinal fluid

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10.1038/s41591-018-0297-y

Cite this

Nation, D. A., Sweeney, M. D., Montagne, A., Sagare, A. P., D'Orazio, L. M., Pachicano, M., Sepehrband, F., Nelson, A. R., Buennagel, D. P., Harrington, M. G., Benzinger, T. L. S., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Chui, H. C., Law, M., Toga, A. W., & Zlokovic, B. V. (2019). Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature Medicine, 25(2), 270-276. https://doi.org/10.1038/s41591-018-0297-y

@article{b1d20ff4b77140b08618b4204333822c,

title = "Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction",

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.",

keywords = "Amyloid beta-Peptides/cerebrospinal fluid, Biomarkers/metabolism, Blood-Brain Barrier/pathology, Cognitive Dysfunction/cerebrospinal fluid, Humans, Imaging, Three-Dimensional, Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid, tau Proteins/cerebrospinal fluid",

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

year = "2019",

month = feb,

doi = "10.1038/s41591-018-0297-y",

language = "English",

volume = "25",

pages = "270--276",

journal = "Nature Medicine",

issn = "1078-8956",

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Nation, DA, Sweeney, MD, Montagne, A, Sagare, AP, D'Orazio, LM, Pachicano, M, Sepehrband, F, Nelson, AR, Buennagel, DP, Harrington, MG, Benzinger, TLS, Fagan, AM, Ringman, JM, Schneider, LS, Morris, JC, Chui, HC, Law, M, Toga, AW & Zlokovic, BV 2019, 'Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction', Nature Medicine, vol. 25, no. 2, pp. 270-276. https://doi.org/10.1038/s41591-018-0297-y

TY - JOUR

T1 - Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction

AU - Nation, Daniel A

AU - Sweeney, Melanie D

AU - Montagne, Axel

AU - Sagare, Abhay P

AU - D'Orazio, Lina M

AU - Pachicano, Maricarmen

AU - Sepehrband, Farshid

AU - Nelson, Amy R

AU - Buennagel, David P

AU - Harrington, Michael G

AU - Benzinger, Tammie L S

AU - Fagan, Anne M

AU - Ringman, John M

AU - Schneider, Lon S

AU - Morris, John C

AU - Chui, Helena C

AU - Law, Meng

AU - Toga, Arthur W

AU - Zlokovic, Berislav V

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - Amyloid beta-Peptides/cerebrospinal fluid

KW - Biomarkers/metabolism

KW - Blood-Brain Barrier/pathology

KW - Cognitive Dysfunction/cerebrospinal fluid

KW - Humans

KW - Imaging, Three-Dimensional

KW - Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid

KW - tau Proteins/cerebrospinal fluid

U2 - 10.1038/s41591-018-0297-y

DO - 10.1038/s41591-018-0297-y

M3 - Article

C2 - 30643288

SN - 1078-8956

VL - 25

SP - 270

EP - 276

JO - Nature Medicine

JF - Nature Medicine

IS - 2

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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