Abstract TMP2: A Framework For The Study Of Hemorrhagic Microangiopathy With Cerebral Cavernous Malformation As A Paradigm

Abstract

Introduction: Hemorrhagic microangiopathies (HMAs) are age-related cerebral microbleeds associated with an increased risk of cognitive decline and intracerebral hemorrhage (ICH). HMAs share a strikingly similar appearance on MRI to cerebral cavernous malformations (CCMs), which are clusters of leaky capillaries predisposing patients to brain bleeding. We hypothesize that HMAs and CCMs share common dysregulated genes and pathways reflecting hemorrhagic failure of the neurovascular unit. Thus, biomarkers developed in CCM may be applicable to HMA. Methods: Extracted mRNA from 5 HMA lesions collected at autopsy along with 3 non-lesional brain sections from the same patients was sequenced, and differentially expressed genes (DEGs) were identified. Enrichment analyses were performed using the Reactome database. Pathways related to postulated mechanisms of HMA were identified, as well as those overlapping pathways with a previously published CCM transcriptome. Dynamic Contrast-Enhanced Quantitative Perfusion (DCEQP) and Quantitative Susceptibility Mapping (QSM) MRIs were performed on 11 HMA patients, 12 age-matched, and 22 young healthy subjects assessing vascular permeability and iron content, as previously done in CCM. Mean permeability and QSM values were calculated for white and gray matter in the frontal, temporal, parietal, and occipital lobes. Results: Differential analyses of the HMA transcriptome identified 376 DEGs ( p <0.05), including 46 common with the CCM transcriptome. The Reactome database identified 231 enriched pathways ( p <0.05) in HMAs, 8 of which overlapped with CCM, primarily relating to endothelial permeability, cell junctions, and the extracellular matrix. Additional inflammatory pathways with mechanistic links to plasma compounds were identified in HMA as in CCM. We further demonstrate feasibility of background brain QSM and DCEQP acquisition in the brain of HMA patients and controls. Conclusion: Transcriptomic commonalities suggest that similar pipelines for plasma and imaging biomarkers developed in CCM research may be adapted for risk assessment and monitoring of HMA. These will help improve the understanding of HMA pathogenesis and assist in patient management, offering a large public health impact.