Intracerebral hemorrhage (ICH), bleeding into the brain from a ruptured blood vessel, remains the most devastating stroke subtype, with 30-day mortality approaching 40% and severe functional impairments in the majority of survivors. The amount of blood that exits the ruptured vessel is the most powerful determinant of outcome in ICH, and while there are currently no proven treatments for acute ICH, the observation that continued bleeding and hematoma growth commonly occur points to an inviting therapeutic target. Two interventions (hemostatic and antihypertensive therapy) appear to slow hematoma growth, but this reduced expansion has thus far failed to translate into clinical benefit in clinical trials. These observations underscore the importance of clarifying the relationship between hematoma expansion and clinical outcome. Motivating the current proposal is the idea that improved predictive markers and biological characterization of hematoma growth will lead to efficient, personalized selection of optimal therapy. The goal of this approach is to target treatment to patients at highest risk for expansion and likeliest to respond to a specific therapy. We focus on two neuroimaging markers characterized by our group and others: 1) pooling of contrast or """"""""spot sign"""""""" on contrast CT angiography (CTA), a widely used extension of the standard emergency head CT;and 2) demonstration of cerebral microbleeds (CMB) on sensitive T2*-weighted MRI sequences, also part of the routine diagnostic evaluation of acute ICH. Accumulating evidence strongly supports CTA spot sign findings as powerful predictors of likelihood of expansion. Data from MRI imaging, though less definitive, also implicate CMB as markers of microvascular structure and associated risk of hematoma growth. As these two methods detect distinct aspects of ICH pathogenesis, our expectation is that they will provide complementary biological and predictive information regarding risk of expansion. Our overall goal is to apply CTA and MRI to identify patients at highest risk for hematoma expansion. Partnering with the Antihypertensive Treatment in Acute Cerebral Hemorrhage-2 (ATACH-2) trial, we will determine whether CTA and MRI can identify patients at high risk for hematoma growth and whether these imaging techniques can select patients more likely to benefit from early, intensive antihypertensive treatment. Our proposal takes advantage of three specific factors: 1) the tremendous leverage obtained from building on the wealth of data to be collected in ATACH-2, 2) the widespread use of CTA and T2*-weighted MRI by tertiary stroke centers in the clinical evaluation of ICH (thus necessitating no separate consent process for enrollment in our substudy), and 3) our research group's widely recognized expertise in the interpretation of both of these techniques. Successful completion of the proposed studies will be a major step towards optimizing the application of current and future approaches to hematoma growth and establishing tangible improvements in ICH outcome.

Public Health Relevance

Intracerebral hemorrhage (ICH), bleeding into the brain from a ruptured blood vessel, is the deadliest stroke subtype and there are currently no proven effective treatments for patients with ICH. The Antihypertensive Treatment in Acute Cerebral Hemorrhage-2 (ATACH-2) trial will determine whether urgently administered aggressive blood pressure control can improve ICH outcome. The proposed studies will investigate whether routinely obtained brain imaging studies can select the patients most likely to benefit from this intervention.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Janis, Scott
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Massachusetts General Hospital
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Morotti, Andrea; Goldstein, Joshua N (2016) Diagnosis and Management of Acute Intracerebral Hemorrhage. Emerg Med Clin North Am 34:883-899
Morotti, A; Romero, J M; Jessel, M J et al. (2016) Effect of CTA Tube Current on Spot Sign Detection and Accuracy for Prediction of Intracerebral Hemorrhage Expansion. AJNR Am J Neuroradiol :
Morotti, Andrea; Marini, Sandro; Jessel, Michael J et al. (2016) Lymphopenia, Infectious Complications, and Outcome in Spontaneous Intracerebral Hemorrhage. Neurocrit Care :
Morotti, Andrea; Jessel, Michael J; Brouwers, H Bart et al. (2016) CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage. Neurocrit Care 25:79-85
Morotti, Andrea; Phuah, Chia-Ling; Anderson, Christopher D et al. (2016) Leukocyte Count and Intracerebral Hemorrhage Expansion. Stroke 47:1473-8
Boulouis, Gregoire; Morotti, Andrea; Brouwers, H Bart et al. (2016) Noncontrast Computed Tomography Hypodensities Predict Poor Outcome in Intracerebral Hemorrhage Patients. Stroke 47:2511-6
Raffeld, Miriam R; Biffi, Alessandro; Battey, Thomas W K et al. (2015) APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage. Neurology 85:349-56
Brouwers, H Bart; Battey, Thomas W K; Musial, Hayley H et al. (2015) Rate of Contrast Extravasation on Computed Tomographic Angiography Predicts Hematoma Expansion and Mortality in Primary Intracerebral Hemorrhage. Stroke 46:2498-503
Radmanesh, Farid; Falcone, Guido J; Anderson, Christopher D et al. (2015) Rare Coding Variation and Risk of Intracerebral Hemorrhage. Stroke 46:2299-301
Biffi, Alessandro; Anderson, Christopher D; Battey, Thomas W K et al. (2015) Association Between Blood Pressure Control and Risk of Recurrent Intracerebral Hemorrhage. JAMA 314:904-12

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