TY - JOUR
T1 - Sexually dimorphic differences in angiogenesis markers are associated with brain aging trajectories in humans
AU - Torres-Espin, Abel
AU - Radabaugh, Hannah L.
AU - Treiman, Scott
AU - Fitzsimons, Stephen S.
AU - Harvey, Danielle
AU - Chou, Austin
AU - Lindbergh, Cutter A.
AU - Casaletto, Kaitlin B.
AU - Goldberger, Lauren
AU - Staffaroni, Adam M.
AU - Maillard, Pauline
AU - Miller, Bruce L.
AU - DeCarli, Charles
AU - Hinman, Jason D.
AU - Ferguson, Adam R.
AU - Kramer, Joel H.
AU - Elahi, Fanny M.
N1 - Publisher Copyright:
Copyright © 2024 The Authors, some rights reserved;.
PY - 2024/11/27
Y1 - 2024/11/27
N2 - Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts (n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.
AB - Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts (n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.
UR - http://www.scopus.com/inward/record.url?scp=85210932992&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adk3118
DO - 10.1126/scitranslmed.adk3118
M3 - Article
C2 - 39602511
AN - SCOPUS:85210932992
SN - 1946-6234
VL - 16
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 775
M1 - eadk3118
ER -