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“Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders

Background and Objective: In the aging brain, increased blood-brain barrier (BBB) leakage and white matter hyperintensity (WMH) on MRI are frequently presumed secondary to cerebral small vessel disease (cSVD) or endotheliopathy. We investigate this association in vivo by quantifying protein cargo fr...

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Autores principales: Elahi, Fanny M., Casaletto, Kaitlin B., Altendahl, Marie, Staffaroni, Adam M., Fletcher, Evan, Filshtein, Teresa J., Glymour, Maria M., Miller, Bruce L., Hinman, Jason D., DeCarli, Charles, Goetzl, Edward J., Kramer, Joel H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244607/
https://www.ncbi.nlm.nih.gov/pubmed/30483114
http://dx.doi.org/10.3389/fnagi.2018.00343
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author Elahi, Fanny M.
Casaletto, Kaitlin B.
Altendahl, Marie
Staffaroni, Adam M.
Fletcher, Evan
Filshtein, Teresa J.
Glymour, Maria M.
Miller, Bruce L.
Hinman, Jason D.
DeCarli, Charles
Goetzl, Edward J.
Kramer, Joel H.
author_facet Elahi, Fanny M.
Casaletto, Kaitlin B.
Altendahl, Marie
Staffaroni, Adam M.
Fletcher, Evan
Filshtein, Teresa J.
Glymour, Maria M.
Miller, Bruce L.
Hinman, Jason D.
DeCarli, Charles
Goetzl, Edward J.
Kramer, Joel H.
author_sort Elahi, Fanny M.
collection PubMed
description Background and Objective: In the aging brain, increased blood-brain barrier (BBB) leakage and white matter hyperintensity (WMH) on MRI are frequently presumed secondary to cerebral small vessel disease (cSVD) or endotheliopathy. We investigate this association in vivo by quantifying protein cargo from endothelial-derived exosomes (EDE), and comparing levels between two groups of functionally normal elders with and without WMH. In addition, we study associations of EDE proteins with upstream and downstream factors, such as inflammation and neurodegenerative changes, respectively. Methods: Twenty six neurologically normal older adults completed general health questionnaires, neuropsychological and physical examinations, and brain MRI. WMH was visually graded with modified Fazekas score of 2 or greater used to classify 11 subjects as cases, and 15 without WMH as controls. Plasma total exosomes were precipitated and EDEs enriched by sequential immuno-precipitations. In addition, we quantified three inflammatory cytokines from plasma and imaging variables on MRI. Group means were compared, the discriminant functions of biomarkers calculated, and the association of EDE biomarkers with plasma inflammatory markers, cognition, and imaging outcomes assessed via regression modeling. Results: Plasma levels of EDE cargo proteins GLUT1, LAT1, P-GP, and NOSTRIN were significantly higher in subjects with WMH in comparison to those without. In contrast, EDE levels of the marker with low expression in brain (VCAM1) were equal between groups. The effect sizes for each of the brain-expressed cargo proteins (GLUT1, LAT1, and P-GP) were such that age-adjusted logistic regressions revealed areas under the curve (AUC) with range of 0.82–0.89, differentiating subjects with WMH from those without. VCAM1 poorly discriminated between groups (AUC:0.55). Higher levels of all brain-expressed EDE proteins were also associated with lower cognitive function, unrelated to burden of WMH. Levels of LAT1 and P-GP were significantly inversely associated with global gray matter volumes, and EDE GLUT1, LAT-1, and P-GP concentrations were significantly associated with systemic IL-6 levels. Conclusion: In a case control study of clinically normal adults with and without WMH, concentrations of EDE proteins were significantly higher in subjects with WMH in comparison to controls. This work is a first step toward in vivo dissection of molecular changes in endothelia of functionally normal subjects with radiographic evidence of age-associated white matter disease.
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spelling pubmed-62446072018-11-27 “Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders Elahi, Fanny M. Casaletto, Kaitlin B. Altendahl, Marie Staffaroni, Adam M. Fletcher, Evan Filshtein, Teresa J. Glymour, Maria M. Miller, Bruce L. Hinman, Jason D. DeCarli, Charles Goetzl, Edward J. Kramer, Joel H. Front Aging Neurosci Neuroscience Background and Objective: In the aging brain, increased blood-brain barrier (BBB) leakage and white matter hyperintensity (WMH) on MRI are frequently presumed secondary to cerebral small vessel disease (cSVD) or endotheliopathy. We investigate this association in vivo by quantifying protein cargo from endothelial-derived exosomes (EDE), and comparing levels between two groups of functionally normal elders with and without WMH. In addition, we study associations of EDE proteins with upstream and downstream factors, such as inflammation and neurodegenerative changes, respectively. Methods: Twenty six neurologically normal older adults completed general health questionnaires, neuropsychological and physical examinations, and brain MRI. WMH was visually graded with modified Fazekas score of 2 or greater used to classify 11 subjects as cases, and 15 without WMH as controls. Plasma total exosomes were precipitated and EDEs enriched by sequential immuno-precipitations. In addition, we quantified three inflammatory cytokines from plasma and imaging variables on MRI. Group means were compared, the discriminant functions of biomarkers calculated, and the association of EDE biomarkers with plasma inflammatory markers, cognition, and imaging outcomes assessed via regression modeling. Results: Plasma levels of EDE cargo proteins GLUT1, LAT1, P-GP, and NOSTRIN were significantly higher in subjects with WMH in comparison to those without. In contrast, EDE levels of the marker with low expression in brain (VCAM1) were equal between groups. The effect sizes for each of the brain-expressed cargo proteins (GLUT1, LAT1, and P-GP) were such that age-adjusted logistic regressions revealed areas under the curve (AUC) with range of 0.82–0.89, differentiating subjects with WMH from those without. VCAM1 poorly discriminated between groups (AUC:0.55). Higher levels of all brain-expressed EDE proteins were also associated with lower cognitive function, unrelated to burden of WMH. Levels of LAT1 and P-GP were significantly inversely associated with global gray matter volumes, and EDE GLUT1, LAT-1, and P-GP concentrations were significantly associated with systemic IL-6 levels. Conclusion: In a case control study of clinically normal adults with and without WMH, concentrations of EDE proteins were significantly higher in subjects with WMH in comparison to controls. This work is a first step toward in vivo dissection of molecular changes in endothelia of functionally normal subjects with radiographic evidence of age-associated white matter disease. Frontiers Media S.A. 2018-11-09 /pmc/articles/PMC6244607/ /pubmed/30483114 http://dx.doi.org/10.3389/fnagi.2018.00343 Text en Copyright © 2018 Elahi, Casaletto, Altendahl, Staffaroni, Fletcher, Filshtein, Glymour, Miller, Hinman, DeCarli, Goetzl and Kramer. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Elahi, Fanny M.
Casaletto, Kaitlin B.
Altendahl, Marie
Staffaroni, Adam M.
Fletcher, Evan
Filshtein, Teresa J.
Glymour, Maria M.
Miller, Bruce L.
Hinman, Jason D.
DeCarli, Charles
Goetzl, Edward J.
Kramer, Joel H.
“Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders
title “Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders
title_full “Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders
title_fullStr “Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders
title_full_unstemmed “Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders
title_short “Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders
title_sort “liquid biopsy” of white matter hyperintensity in functionally normal elders
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244607/
https://www.ncbi.nlm.nih.gov/pubmed/30483114
http://dx.doi.org/10.3389/fnagi.2018.00343
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