Journal
GEROSCIENCE
Volume 42, Issue 5, Pages 1351-1363Publisher
SPRINGER
DOI: 10.1007/s11357-020-00201-4
Keywords
Neuro-vascular aging; CCM disease; Plasma biomarker; Background brain permeability; Background brain QSM; Transcriptome
Categories
Funding
- National Institutes of Health [R21NS087328, P01 NS092521]
- University of Chicago Comprehensive Cancer Center [P30 CA14599]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000430]
- William and Judith Davis Fund in Neurovascular Surgery Research at the University of Chicago
- Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior at the University of Chicago
- Be Brave for Life Foundation
- Safadi Program at the University of Chicago Translational Fellowship
- Sigrid Juselius Foundation
- Emil Aaltonen foundation
- Maud Kuistila foundation
- American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Cerebrovascular Section Robert J. Dempsey MD Cerebrovascular Research Grant
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Brain senescence is associated with impaired endothelial barrier function, angiogenic and inflammatory activity, and propensity to brain hemorrhage. The same pathological changes occur in cerebral cavernous malformations (CCM), a genetic neurovascular anomaly. We hypothesized common transcriptomic and plasma cytokine signatures in the aging brain and CCM. We identified 320 genes [fold change >= 1.5;p < 0.05; false discovery rate (FDR) corrected] commonly dysregulated in the aging brain and CCM. Ontology and pathway analyses of the common differentially expressed genes were related to inflammation and extracellular matrix organization. Plasma levels of C-reactive protein and angiopoietin-2 were significantly greater in older compared to younger healthy non-CCM subjects and were also greater in CCM (Sporadic and Familial) subjects regardless of age (all:p < 0.05; FDR corrected). Plasma levels of vascular endothelial growth factor were significantly greater in older compared to younger subjects, in both healthy non-CCM and Sporadic-CCM groups (all:p(adj) < 0.05). Plasma levels of vascular endothelial growth factor were also significantly greater in Familial-CCM cases with germ line mutations regardless of age (all:p(adj) < 0.05) compared to both healthy non-CCM and Sporadic-CCM subjects. Brain white matter vascular permeability assessed by MRI followed the same pattern as vascular endothelial growth factor across all groups. In addition, quantitative susceptibility mapping of brain white matter, a measure of iron deposition, was increased in older compared to younger healthy non-CCM subjects. Genetic aberrations, plasma molecules, and imaging biomarkers in a well characterized Mendelian neurovascular disease may also be applicable in the aging brain.
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