About

Issam Awad is a Professor of Neurological Surgery at the University of Chicago, where he leads the Neurovascular Surgery Program and is tenured in the Biological Sciences Division. He holds the title of John Harper Seeley Professor of Neurological Sciences and is also a Professor of Neurology, Neurological Surgery, the Grossman Institute of Neuroscience, and the Committee on Neurobiology. Since his recruitment in 2010, Dr. Awad has been actively involved in advancing the understanding and treatment of cerebrovascular diseases, hemorrhagic stroke, and neurovascular malformations. His research focuses on molecular mechanisms, biomarkers, and therapeutic targets in cavernous angiomas, the pathobiology of brain hemorrhage, and minimally invasive techniques for treating hemorrhagic stroke. Dr. Awad has authored over 400 scientific papers and book chapters, edited twelve books on cerebrovascular surgery, and has presented extensively at major meetings. His scientific contributions include characterizing subcortical ischemic lesions in the aged, understanding the natural history of vascular malformations, and developing technical advances in neurovascular and epilepsy surgery. Recognized as an expert in his field, he has received numerous honors, including the Bucy Award for Excellence in Neurosurgical Education and the Arnold Award for Mentoring. He has been continuously funded by the National Institutes of Health since 1998, with current projects including studies on cerebral cavernous angiomas, brain hemorrhage, and minimally invasive surgical techniques. Dr. Awad has served on the United States National Advisory Council for Neurological Disorders and Stroke and was elected to the Association of American Physicians in 2019. His work is characterized by a focus on translating scientific discoveries into clinical practice to improve outcomes for patients with neurovascular diseases.

Research topics

• Medicine
• Biology
• Neuroscience
• Pathology
• Bioinformatics
• Computer Science
• Surgery
• Cancer research
• Internal medicine
• Medical physics
• Intensive care medicine
• Cell biology
• Medical emergency
• Endocrinology
• Engineering
• General surgery
• Psychology
• Genetics

Selected publications

• Recurrent somatic copy number alterations in resected cerebral cavernous malformations

  Human Genomics · 2025-12-09

  articleOpen access

  Cerebral Cavernous Malformations (CCMs) are brain vascular lesions that occur in sporadic or inherited (autosomal dominant) forms. The malformations are driven by mutations in KRIT1, CCM2, PDCD10 or MAP3K3. Known oncogenic variants in PIK3CA accompany CCM-specific variants in lesions. While the primary genetic etiology of CCM lesions is relatively well understood, a subset of lesions does not yet have an identified molecular genetic etiology. Moreover, whether large genomic alterations occur somatically in CCM lesion tissue has been largely unexplored. In PIK3CA + cancers, large somatic copy number alterations ('CNAs') are frequent, with whole genome doubling and aneuploidy identified in most tumors. Such CNA events are known to be associated with course of disease and therapeutic response. In this study, using whole genome SNP-genotyping and Mosaic Chromosome Alteration (MoChA) analysis, we identify the presence of large (> 1 MB) somatic CNAs in CCMs, with specific enrichment of events in chromosome arms 16p,19p,17q, 20q. We also identify additional chromosome arm level events encompassing known CCM genes in a subset of lesions. Thus, we characterize a pattern of large genomic events that had remained hidden by the insensitivity of the molecular and analytical methods previously used. Finally, we propose that similar events may be found in other vascular malformations or PIK3CA overgrowth syndromes that have yet to be analyzed in this manner.

  PublisherDOI

• Integration of artificial intelligence and high-content screening enabled identification of drugs for long-term treatment of cerebral cavernous malformation disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-11

  articleOpen access

  Abstract Background Adults and children with cerebral cavernous malformations (CCMs) are at risk of experiencing lifelong complications such as hemorrhagic strokes, neurological deficits, and epileptic seizures. These complications can severely reduce quality of life. At present, there is no safe or effective therapeutic option for the long-term treatment of CCMs. Methods Using advanced artificial intelligence (AI) and machine learning models, powered by the Benevolent Platform™, we aimed to identify therapeutic drug targets for CCM pathology (e.g., CCM1, CCM2, CCM3). An AI integrative approach utilized various data types from biomedical entities, including diseases, genes, tissues, and biological mechanisms, together with CCM transcriptomic experimental data. High-throughput drug screening of AI-selected FDA-approved medications, analyses of mitochondrial morphology, and studies on pharmacokinetics, pharmacodynamics, and toxicology were conducted in CCM animal models to identify drugs that could potentially be repurposed for the long-term treatment of CCM disease. Results AI predicted the AMPK (AMP-activated protein kinase) and mTOR (mammalian target of rapamycin) pathways as potential therapeutic targets that contribute to CCM pathology. High-content screening validation revealed that the FDA-approved drug metformin, which acts as an AMPK agonist and mTOR inhibitor, can reverse changes in cell-cell junction organization and increase KLF4 expression, a marker for CCM, in human CCM endothelial cells in cultured assays. In addition, pharmacodynamic markers of metformin were observed in CCM mouse models ( Slco1c1-iCreERT2;Krit1 fl/fl ;Pten fl/wt and Slco1c1-iCreERT2;Pdcd10 fl/fl ) including reduced S6 kinase or ribosomal protein phosphorylation, a marker of decrease mTOR signaling, and increased AMPK phosphorylation, a marker of AMPK activation, that corresponded to reduced lesion burden. Pharmacokinetic and toxicological studies in CCM animal models showed that that metformin penetrates the brain and long-term administration has a favorable safety profile. We also demonstrated that brain endothelial cells in chronic CCM mouse models exhibit increased levels of the inflammatory marker VCAM-1, which is associated with altered mitochondrial phenotypes, as observed by immunofluorescence, MITO-tagging, and electron microscopy analysis. Additionally, we discovered that metformin and a potent AMPK activator, PF-06409577, can reverse mitochondrial phenotypic changes in brain endothelial cells and reduce the elevation of VCAM-1 expression associated with chronic CCM disease. Therefore, metformin can provide cytoprotection and may reverse the CCM endothelial phenotype by activating AMPK. Conclusions Predictions using AI technology and high-throughput drug screening, combined with pharmacokinetic, pharmacodynamic, and toxicological studies in CCM animal models, identified metformin as a promising drug candidate for repurposing for the long-term treatment of CCM disease. We propose that metformin enhances metabolic adaptation to brain vascular malformations by activating AMPK, which helps reverse mitochondrial fragmentation in brain endothelial cells. Graphical abstract

  PublisherDOI

• Safety and efficacy of atorvastatin for rebleeding in cerebral cavernous malformations (AT CASH EPOC): a phase 1/2a, randomised placebo-controlled trial

  The Lancet Neurology · 2025-03-19 · 8 citations

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Abstract TP200: Association Between Hematoma Evacuation and Risk of Subsequent Ischemic Stroke and Coronary Ischemic Events by Hematoma Location: A MISTIE III and ATACH-2 Analysis

  Stroke · 2025-01-30

  article

  Background: Nontraumatic intracerebral hemorrhage (ICH) especially in deep locations is independently associated with a long-term increased risk of major arterial ischemic events. Minimally invasive surgery (MIS) has not been shown to improve outcomes for deep ICH. Whether ischemic events modify the effect of MIS on outcomes for deep ICH has not been studied. Methods: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was ICH location (deep vs. lobar). The outcome was a symptomatic, clinically overt ischemic stroke or coronary ischemic event, adjudicated centrally within each trial. We evaluated the association between ICH location and risk of an ischemic event using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. We used logistic regression to assess whether ischemic events modified the effect of MIS with end of treatment volume (EOT) <15mL on modified Rankin scale (mRS) 0-3 at one year in MISTIE III. Results: Of 1470 patients with ICH, mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2–35.7) and 1186 (80.7%) were deep. During a median follow-up of 110 days (iqr 110-365), a total of 70 ischemic events occurred, 60 (5.0% cumulative incidence) in patients with deep ICH and 10 in patients with lobar ICH (cumulative incidence 3.2%). In adjusted analysis, deep ICH location, but not MIS was associated with increased risk of ischemic events (hazard ratio, 2.1 [95% CI, 1.07–4.3]). In the full MISTIE cohort, in patients without ischemic events during follow-up, MIS with EOT<15 mL was significantly associated with favorable one year outcome (OR 1.90 (95% CI: 1.16-3.12; Pinteraction = 0.04). There was no effect modification for deep location (Pinteraction = 0.13) and for lobar ICH, achieving EOT<15 with MIS was associated with good outcome regardless of ischemic events in adjusted analyses. Conclusions: In a heterogeneous cohort of patients with ICH, deep ICH location was associated with increased risk of ischemic events over the short term, but this appears to have low impact on one-year outcomes with successful surgery and does not help to explain worse outcomes of deep (vs. lobar) ICH with MIS.

  PublisherDOI

• The Infundibulum-Aneurysm Conundrum: A Longitudinal Single-Center Analysis

  American Journal of Neuroradiology · 2025-12-12

  articleOpen access

  BACKGROUND AND PURPOSE: This study aims to characterize the natural history and diagnostic variability of unequivocal intracranial infundibula and diagnostically uncertain outpouchings labeled "aneurysm vs infundibulum." MATERIALS AND METHODS: We retrospectively analyzed 665 intracranial outpouchings detected on CTA, MRA, or DSA at a single center (2013-2018). Radiology reports classified lesions as unequivocal infundibula (n=321) or as conundrums with an explicit label of "aneurysm vs infundibulum" (n=344). Follow-up imaging through December 2023 was reviewed for growth, rupture or aneurysmal transformation. Ten conundrums with later DSA follow-up also underwent blinded image re-review. A logistic model tested clinical and radiographic predictors of diagnostic ambiguity, and a literature review contextualized anatomic prevalence. RESULTS: Of 321 unequivocal infundibula, 146 (45%) had follow-up imaging. Among 344 conundrums, 208 (61%) were followed, yielding 1040 lesion-years of surveillance across both cohorts. No complications or morphological changes were observed in either group. Median follow-up among followed infundibula and conundrums was 2.26 (IQR 0.32 - 5.34) and 2.31 (IQR 0.20 - 5.43) years, respectively. Conundrums were more likely than unequivocal infundibula to undergo follow-up imaging (p<0.001). Non-Pcomm location (OR 7.4; 95% CI 5.11 - 10.63) and presence of comorbid aneurysms (OR 1.9; 95% CI 1.15 - 2.96) independently predicted a conundrum label. Surveillance declined steeply after 5 years, with only 13.4% of infundibula and 17.2% of conundrums still imaged at that horizon. Secondary reassessment of 10 conundrums revealed 100% concordance with DSA when morphological criteria were rigorously applied. Literature review reaffirmed the predominance of infundibula at the posterior communicating artery but highlighted inconsistent terminology and sparse long-term outcome data. CONCLUSIONS: In the largest single-center cohort to date, both classic infundibula and radiologically ambiguous conundrums remained stable over medium-term follow-up. Diagnostic uncertainty appears to stem mainly from interpretive variability rather than true biological risk. Structured reporting combined with location-informed heuristics could reduce unnecessary surveillance. ABBREVIATIONS: Acomm＝ anterior communicating artery; CE-MRA＝ contrast-enhanced MRA; Pcomm = posterior communicating artery.

  PublisherDOI

• Abstract WMP14: Spatial Transcriptomics Glean Homologous Mechanisms in the Pathophysiology of Human and E4FAD Mouse Cerebral Microbleeds

  Stroke · 2025-01-30

  articleSenior author

  Introduction: Cerebral microbleeds (CMBs) are age-related manifestations of microangiopathies predisposing patients to hemorrhagic stroke (HS) and cognitive decline. Little work has currently been done to elucidate mechanisms in the pathophysiology of CMBs. Herein, we report transcriptomic signatures of CMBs, as well as important location/etiological and sex-specific differences, to glean mechanistic insights in human autopsy tissue and a murine E4FAD model. Methods: Fourteen human CMB lesions were identified at autopsy by a neuropathologist (n=9 lobar and n=5 deep brain lesions). In addition, 6 CMB lesions were identified from E4FAD mice (n=3 male and n=3 female) sacrificed at 8 months. For each lesion, contralateral control brain tissue was also obtained from the same brain. Serial sections were obtained for each lesional and control region. The first section was stained for non-heme iron to localize CMB and control regions. The second section was then used for paired GeoMx bulk spatial transcriptomics. Downstream differential expression analyses were completed using DeSeq2, with enriched pathway analyses using Ingenuity pathway analysis (IPA). Results: Spatial transcriptomics identified 781 differentially expressed genes (DEGs) in human CMB and 448 in E4FAD mouse lesions compared with controls (p&lt;0.05, FDR corrected). Pathway enrichment identified 110 homologous pathways between human and E4FAD mouse CMBs, related to vascular permeability, senescence and neuroinflammation (p&lt;0.05, FDR corrected). Furthermore, lobar compared to deep microbleeds showed 52 IPA pathways related to similar functions, particularly in relation to extracellular matrix deposition (p&lt;0.05, FDR corrected). Notable differences identified etiologic-specific pathways, such as arteriolosclerosis and amyloid processing. Male compared with female mouse CMBs identified 12 common mechanisms involved in blood brain barrier dysfunction and neuroinflammation with differences related to sex-specific neurotransmitter and hormonal variances (p&lt;0.05, FDR corrected). Conclusions: This is the first report to address transcriptomic changes within the CMB microenvironment, while addressing mechanistic differences by sex and lesional location. Further studies shall aim to delineate mechanisms that lead CMBs to develop into larger HS. The results also pave the way for identification of mechanistically linked circulating molecules in biomarker discovery as well as for potential therapeutic targets.

  PublisherDOI

• Abstract WP389: Unraveling Cerebral Cavernous Malformation Pathogenesis: Insights from a Radiation-Induced Endothelial Dysmorphism Model

  Stroke · 2025-01-30

  article

  Introduction: Mouse models have been a valuable tool for studying the molecular mechanisms driving cerebral cavernous malformation (CCM) pathogenesis. However, genetically modified mouse models do not fully recapitulate human CCM disease, and endothelial dysfunction is implicated in multiple disease processes of the brain. Herein, we provide a radiation-induced platform of endothelial dysmorphism and physiologic dysfunction similar to that observed in CCM disease. By analyzing gene expression and pathway alterations in endothelial cells, this model enhances our understanding of the fundamental biological processes at play that are common and different between CCM and endothelial leak. Methods: Ten-week-old female C57BL/6 mice underwent irradiation with 40 Gy (@50% isodose) to a 5mm target within the left cerebral hemisphere. Brain parenchymal changes were assessed using contrast-enhanced CT imaging and histology. Endothelial cell RNA extraction and transcriptomic analysis were performed on formalin-fixed, paraffin-embedded coronal tissue sections from radiated and control hemispheres using the a digital spatial profiler system. Ingenuity Pathway Analysis (IPA) was employed to identify affected molecular pathways. Results: CT imaging revealed increased blood-brain barrier permeability within the irradiated area. Histologic analysis identified telangiectasias and microhemorrhages, consistent with dysmorphic endothelium and capillary malformations. Gene expression profiles between radiated vs. non-radiated endothelium demonstrated a clear distinction by principal component analysis. Differentially expressed genes were primarily associated with extracellular matrix organization, regulation of the actin cytoskeleton, and pro-inflammatory cytokine response pathways. Upstream analysis predicted TGFB1, TNF, lipopolysaccharide, dexamethasone, and angiotensinogen as potential regulators underlying the observed changes. Conclusion: This study elucidates a signature of dysmorphic endothelium in a non-genetically modified mouse model, revealing potential key molecular pathways and regulators that lead to endothelial leak. This model can guide mechanistic-based experimental studies and provide a platform for targeted interventions directed at critical components of CCM pathophysiology and the blood-brain barrier.

  PublisherDOI

• Abstract WMP99: Circulating Plasma Biomarkers Associated with Familial Cerebral Cavernous Malformation, Hereditary Hemorrhagic Telangiectasia and Sturge-Weber Syndrome

  Stroke · 2025-01-30

  article

  Introduction: Circulating plasma protein profiling in individuals with brain vascular disorders may aid in the identification of robust diagnostic biomarkers, stratification of high-risk patients for treatment, and monitoring of disease progression or treatment response. This Brain Vascular Malformation Consortium (BVMC) study aimed to identify circulating inflammatory and angiogenic proteins that associate with familial Cerebral Cavernous Malformation (FCCM), Hereditary Hemorrhagic Telangiectasia (HHT), or Sturge-Weber Syndrome (SWS). Methods: We used the Angiome multiplex ELISA biomarker panel to assess the circulating plasma levels of 22 proteins related to inflammation and angiogenesis in 234 individuals enrolled in the BVMC, including 114 FCCM, 101 HHT and 19 SWS cases. Protein levels were measured in duplicate and absolute measurements obtained. We tested for biomarker associations between disease states using linear regression models adjusting for age at blood collection and sex. We calculated the intraclass correlation coefficient (ICC) to describe the similarity in replicates, and report proportional increase (PI) for protein levels for statistically significant results with Bonferroni-corrected P-values &lt;0.05 (adjusted for 22 markers). Results: All 22 proteins were successfully measured in the 114 FCCM (39% male, median age 52 years), 101 HHT (49% male, median age 42 years, 36% with brain arteriovenous malformation), and 19 SWS (53% male, median age 15 years). The ICC was high for all markers (range 0.904-0.990). As expected, HHT cases with endoglin mutations had ~50% lower endoglin. We observed increased levels of endoglin (PI=1.38, 95% CI:1.27-1.50, P=6.50E-13) and IL10 (PI=1.48, 95% CI:1.16-1.91, P=0.04) in CCM compared to HHT cases, and decreased IL8 (PI=0.60, 95% CI:0.43-0.83, P=0.04) and OPN (PI=0.63, 95% CI:0.47-0.84, P=0.04) in CCM compared to SWS cases. We also observed higher levels of endoglin (PI=1.45, 95% CI:1.24-1.71, P=1.47E-04), GP130 (PI=1.24, 95% CI:1.11-1.38, P=2.91E-03), and OPN (PI=1.80, 95% CI:1.36-2.40, P=1.13E-03), and lower levels of IL1β (PI=0.30, 95% CI:0.15-0.59, P=0.01) in SWS compared to HHT cases. Conclusions: We identified circulating plasma biomarkers associated with FCCM, HHT and SWS. Larger ongoing work will confirm whether these inflammatory/angiogenic markers are relevant as potential diagnostic or therapeutic targets or have broader implications as clinical biomarkers in other brain vascular diseases.

  PublisherDOI

• A Systematic Review of MicroRNAs in Hemorrhagic Neurovascular Disease: Cerebral Cavernous Malformations as a Paradigm

  International Journal of Molecular Sciences · 2025-04-17 · 4 citations

  reviewOpen accessSenior authorCorresponding

  Hemorrhagic neurovascular diseases, with high mortality and poor outcomes, urge novel biomarker discovery and therapeutic targets. Micro-ribonucleic acids (miRNAs) are potent post-transcriptional regulators of gene expression. They have been studied in association with disease states and implicated in mechanistic gene interactions in various pathologies. Their presence and stability in circulating fluids also suggest a role as biomarkers. This review summarizes the current state of knowledge about miRNAs in the context of cerebral cavernous malformations (CCMs), a disease involving cerebrovascular dysmorphism and hemorrhage, with known genetic underpinnings. We also review common and distinct miRNAs of CCM compared to other diseases with brain vascular dysmorphism and hemorrhage. A systematic search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, queried all peer-reviewed articles published in English as of January 2025 and reported miRNAs associated with four hemorrhagic neurovascular diseases: CCM, arteriovenous malformations, moyamoya disease, and intracerebral hemorrhage. The PubMed systematic search retrieved 154 articles that met the inclusion criteria, reporting a total of 267 unique miRNAs identified in the literature on these four hemorrhagic neurovascular diseases. Of these 267 miRNAs, 164 were identified in preclinical studies, while 159 were identified in human subjects. Seventeen miRNAs were common to CCM and other hemorrhagic diseases. Common and unique disease-associated miRNAs in this systematic review motivate novel mechanistic hypotheses and have potential applications in diagnostic, predictive, prognostic, and therapeutic contexts of use. Much of current research can be considered hypothesis-generating, reflecting association rather than causation. Future areas of mechanistic investigation are proposed alongside approaches to analytic and clinical validations of contexts of use for biomarkers.

  PublisherOA PDFDOI

• Abstract WP40: Common and Distinct Circulating MicroRNAs Across Four Neurovascular Disorders

  Stroke · 2025-01-30

  articleSenior author

  Introduction: Familial cerebral cavernous malformations (FCCM), Sturge-Weber Syndrome (SWS), and hereditary hemorrhagic telangiectasia with brain arteriovenous malformations (HHT) are neurovascular disorders driven by genetic mutations while cerebral microbleeds (CMBs) are primarily associated with the aging process. All are associated with different vascular dysmorphisms and/or propensity to bleed. Hypothesis: We hypothesized that common and distinct circulating microribonucleic acids (miRNAs), reflecting shared and different pathobiology, can serve as potential biomarkers and therapeutic targets. Methods: Plasma miRNAs from patients with FCCM (n=10), SWS (n=10), and HHT (n=10) compared to age and sex-propensity-matched healthy young (HY) subjects (n=10) were extracted and sequenced. Similarly, CMB patients (n=10) were age and sex propensity-matched with healthy old (HO) subjects (n=10). Differentially expressed (DE) miRNAs of each disorder were identified (p&lt;0.05, FDR corrected, absolute fold change [|FC|]&gt;1.5]). Ingenuity Pathway Analysis (IPA) was conducted to determine gene targets and pathways of DE miRNAs. DE genes based on the transcriptome of each disorder were identified and utilized to filter gene targets of circulating miRNAs. Results: Eleven DE miRNAs were identified in FCCM, 40 in SWS, 41 in HHT, and 26 in CMB (p&lt;0.05, FDR-corrected, [|FC|]&gt;1.5]). Further analyses showed that 18 miRNAs were commonly dysregulated in two of the studied neurovascular disorders. IPA identified 17 genes targeted by at least two DE miRNAs in each of the four cerebrovascular disorders. Functional enrichment of those shared gene targets showed that PTEN, CDKN1A, NCL2L1, and CCND2 were involved in the PI3K-Akt Signaling Pathway. Moreover, the ROBO SLIT Signaling Pathway was identified as an involved pathway across all four disorders. Conclusion: The common dysregulated miRNAs across the disorders underscore their potential as biomarkers and therapeutic targets, reflecting their mechanistic involvement in shared pathophysiological pathways. Furthermore, the commonly targeted genes and implicated pathways suggest shared functionality of the miRNAs. These findings pave the way for further exploration of these miRNAs, aiming at the clinical application for disease monitoring and therapeutic intervention.

  PublisherDOI

Recent grants

• Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

  NIH · $25.9M · 2015–2025

• NIH Grant R21NS052285

  NIH · $367k · 2008

• Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage

  NIH · $3.8M · 2017–2023

• Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

  NIH · $3.9M · 2018–2025

• NIH Grant R01NS060748

  NIH · $2.0M · 2013

Frequent coauthors

• Daniel F. Hanley

  1021 shared

• Wendy Ziai

  Johns Hopkins University

  749 shared

• Nichol McBee

  Johns Hopkins University

  563 shared

• Santosh B. Murthy

  Cornell University

  555 shared

• Robert Shenkar

  University of Chicago

  447 shared

• Radhika Avadhani

  440 shared

• Romuald Girard

  407 shared

• Kevin N. Sheth

  Yale University

  406 shared

Labs

• University of Chicago Neurovascular Surgery ProgramPI

Education

• M.D.

  University of Chicago

• Ph.D., Neurological Surgery

  University of Chicago

Awards & honors

• Bucy Award for Excellence in Neurosurgical Education
• Arnold Award for Mentoring at Pritzker School of Medicine