Common transcriptome, plasma molecules, and imaging signatures in the aging brain and a Mendelian neurovascular disease,
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ORIGINAL ARTICLE
Common transcriptome, plasma molecules, and imaging signatures in the aging brain and a Mendelian neurovascular disease, cerebral cavernous malformation Janne Koskimäki & Sean P. Polster & Yan Li & Sharbel Romanos & Abhinav Srinath & Dongdong Zhang & Julián Carrión-Penagos & Rhonda Lightle & Thomas Moore & Seán B. Lyne & Agnieszka Stadnik & Kristina Piedad & Ying Cao & Robert Shenkar & Alexey V. Dimov & Nick Hobson & Gregory A. Christoforidis & Timothy Carroll & Romuald Girard & Issam A. Awad
Received: 9 March 2020 / Accepted: 7 May 2020 # American Aging Association 2020
Abstract 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: padj < 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: padj < 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
Janne Koskimäki, Sean P. Polster contributed equally to this work as first author. Romuald Girard and Issam A. Awad contributed equally to this work as senior author. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11357-020-00201-4) contains supplementary material, which is available to authorized users. J. Koskimäki : S. P. Polster : Y. Li : S. Romanos : A. Srinath : D. Zhang : J. Carrión-Penagos : R. Lightle : T. Moore : S. B. Lyne : A. Stadnik : K. Piedad : Y. Cao : R. Shenkar : N. Hobson : R. Girard : I. A. Awad (*) Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA e-mail: [email protected]
Y. Li Center for Research Informatics, The University of Chicago, Chicago, IL, USA A. V. Dimov : G. A. Christoforidis : T. Carroll Depart
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