Accurately balancing the competing risks of interventional treatment and natural history - primarily intracranial hemorrhage (ICH) - is necessary for optimal management of patients harboring brain arteriovenous malformations (bAVMs). The overarching theme of this project is to develop novel risk-stratification biomarkers and provide a decision-analysis framework for their use. As a class, unruptured patients are at higher risk for treatment-related injury but at lower risk for ICH. Accordingly, treatment of unruptured bAVMs-half of all cases- is becoming increasingly controversial. The ongoing randomized clinical trial (NCT00389181), A Randomized Trial of Unruptured Brain AVMs (ARUBA), is comparing best intervention (either surgery, embolization and/or radiosurgery) vs. non-intervention. If non-intervention is found superior-or even non- inferior-then there will be even greater demand to risk-stratify unruptured cases, as good ICH risk predictors are lacking in this group. Taken together, there is a pressing need to improve risk assessment.
Aim 1 will demonstrate that Silent Intralesional Microhemorrhage (SIM) is a novel risk factor for bAVM rupture. We will show that microscopic evidence of hemosiderin (hemosiderin positivity) in resected bAVM tissue is associated with index ICH (clinical presentation with ICH. Further we will show that macrophage infiltration is highly correlated with hemosiderin positivity, which represents an additional potential biomarker. In addition to use as risk markers, both SIM and macrophage infiltration might also serve as surrogate endpoints for clinical trials.
Aim 2 will develop a MR biomarker for SIM, showing that hemosiderin positivity in resected tissue is correlated with susceptibility effect on pre-treatment iron-sensitive imaging (ISI). Using a prospective cohort with a mean follow-up of 2.5 years, we will estimate SIM incidence and compare it to known symptomatic ICH rates. A potential additional marker, macrophage infiltration, can also be imaged in patients using ferumoxytol, an UltraSmall Particles of Iron Oxide (USPIO);MR imaging of ferumoxytol uptake will predict tissue macrophages burden in resected tissue.
In Aim 3, we will demonstrate that (a) genetic variants in IL1ss and TNF are predictors of new ICH after diagnosis;(b) endoglin (ENG) genotype is associated with worsened outcome after index ICH;(c) BDNF genotype is associated with worsened functional outcome after surgical resection in unruptured cases;and (d) Using our existing Genome-Wide Association Study dataset, we will identify novel risk predictors for new ICH, outcome after ICH and outcome after resection. We will sequence novel loci to identify variants associated with these outcomes and test in our entire cohort.
Aim 4 will construct a practical system to balance risks and benefits to optimally inform bAVM management and contextually evaluate and combine new knowledge from Aims 1-3 with established risk markers. We hypothesize that addition of novel risk factors will provide further improvement in discrimination of risk. The proposed project will undergird future multi-center efforts to improve care for bAVM patients.

Public Health Relevance

Brain arteriovenous malformations (AVMs) are an important cause of hemorrhagic stroke in young adults. Although surgical therapy can be curative, there are high costs and inherent morbidity and mortality associated with treatment that may outweigh the benefits, especially for patients with unruptured lesions. This project can provide biomarkers for risk stratification to aid rational choice of therapy to maximize benefit and minimize risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034949-18
Application #
8440219
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Moy, Claudia S
Project Start
1995-09-30
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
18
Fiscal Year
2013
Total Cost
$448,379
Indirect Cost
$162,787
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pekmezci, Melike; Nelson, Jeffrey; Su, Hua et al. (2016) Morphometric characterization of brain arteriovenous malformations for clinical and radiological studies to identify silent intralesional microhemorrhages. Clin Neuropathol 35:114-21
Weinsheimer, Shantel; Bendjilali, Nasrine; Nelson, Jeffrey et al. (2016) Genome-wide association study of sporadic brain arteriovenous malformations. J Neurol Neurosurg Psychiatry 87:916-23
Alexander, M D; Cooke, D L; Nelson, J et al. (2015) Association between Venous Angioarchitectural Features of Sporadic Brain Arteriovenous Malformations and Intracranial Hemorrhage. AJNR Am J Neuroradiol 36:949-52
Kim, Helen; Abla, Adib A; Nelson, Jeffrey et al. (2015) Validation of the supplemented Spetzler-Martin grading system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients. Neurosurgery 76:25-31; discussion 31-2; quiz 32
Abla, Adib A; Nelson, Jeffrey; Kim, Helen et al. (2015) Silent arteriovenous malformation hemorrhage and the recognition of ""unruptured"" arteriovenous malformation patients who benefit from surgical intervention. Neurosurgery 76:592-600; discussion 600
Potts, Matthew B; Lau, Darryl; Abla, Adib A et al. (2015) Current surgical results with low-grade brain arteriovenous malformations. J Neurosurg 122:912-20
Kremer, P H C; Koeleman, B P C; Pawlikowska, L et al. (2015) Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain. J Neurol Neurosurg Psychiatry 86:524-9
Abla, Adib A; Nelson, Jeffrey; Rutledge, W Caleb et al. (2014) The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs. Neurosurg Focus 37:E6
Guo, Yi; Tihan, Tarik; Kim, Helen et al. (2014) Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation. Neuroimmunol Neuroinflamm 1:147-152
Shen, Fanxia; Degos, Vincent; Chu, Pei-Lun et al. (2014) Endoglin deficiency impairs stroke recovery. Stroke 45:2101-6

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