Abstract TMP115: Common Transcriptomic and Biomarker Signatures in the Aging Brain and in Mendelian Neurovascular Disease, Cerebral Cavernous Malformation

Abstract

Background: Cellular senescence is associated with gene expression dysregulation affecting endothelial barrier function as well as angiogenic and inflammatory processes. These pathological changes occur in cerebral cavernous malformations (CCMs), a neurovascular anomaly predisposing patients to hemorrhagic stroke. We hypothesize common transcriptomic and biomarker signatures between the aging brain and CCMs. Method: Brain specific genes dysregulate in Younger (age < 30) and Older (age > 50) human brain parenchyma were identified using the Genotype-Tissue Expression database, and compared with differential transcriptome in microdissected neurovascular units of human CCM lesions. Brain white matter vascular permeability in areas devoid of lesions was measured in non-CCM (23 Younger, 27 Older), Sporadic-CCM (S-CCM) (26 Younger, 37 Older) and Familial-CCM (F-CCM) (41 Younger, 17 Older) using dynamic contrast-enhanced quantitative perfusion MRI. Plasma levels of 6 proteins with reported roles in CCMs were quantified, including VEGF, angiopoietin (ANG 1 & 2), CRP, thrombospondin 2 (THBS 2), and endoglin (ENG). All reported correlations were significant at P< 0.05, FDR corrected. Result: We identified 320 genes (absolute fold change≥1.5) commonly dysregulated in aging brain and CCM, related to inflammation and extracellular matrix organization pathways. Brain permeability was greater in Older non-CCM and S-CCM compared to Younger subjects. Brain permeability was higher in Younger F-CCM harboring germ line CCM mutations, than in both Younger non-CCM (p<0.001) and S-CCM (p<0.05) lacking those mutations. No difference was observed in Younger or Older F-CCM and Older S-CCM or controls. Plasma levels of VEGF, ANG-2 and CRP were greater in both Older non-CCM and S-CCM compared to Younger. No difference was found in Older or Younger F-CCM. No differences were observed in THBS2, ENG and ANG1. Conclusion: There are common transcriptomic, and brain permeability and plasma biomarker signatures in the aging brain and CCM, suggesting common dysregulated pathways. Biomarkers and potential therapies identified in a well characterized Mendelian neurovascular disease may be applicable to mitigate the same mechanistic aberrations in the aging brain.