Determinants of Delayed Ischemic Neurological Deficits and Infarction after Aneurysmal Subarachnoid Hemorrhage

Rose Du, M.D., Ph.D.

Brigham and Women's Hospital

Department of Neurosurgery
Funded in December, 2015: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Study may help to improve outcomes following a ruptured brain aneurysm

 In a two-phase exploration, neurosurgeons will seek to identify factors that may predispose certain patients with ruptured brain aneurysms to experience complications leading to poor neurological outcomes. Doing so may lead to new approaches to avoiding these complications.

When brain aneurysms (weaknesses in brain artery walls) rupture, blood shoots out into the space between the brain and skull. This situation is called “aneurysmal subarachnoid hemorrhage” (aSAH) and it kills nearly 50% of patients. Many of those who survive develop delayed ischemic neurological deficits and infarction. Scientists have suspected that these cognitive deficits and stroke occur when spasms narrow the large arteries supplying the brain and then blood flow to the brain is reduced. Therapies that prevent vasospasm, though, have not improved blood supply to the brain or prevented stroke. So the investigators instead suggest involvement of an alternative pathway.    

They hypothesize that the delayed ischemic neurological deficits and stroke following aSAH may arise from tiny blood clots that form in the small vessels (“microemboli”) in the brain and induce intense electrical changes in the brain. They further hypothesize that variations in certain genes may underlie formation of microemboli and electrical changes. Their hypotheses are based in part on similar observations of a genetic predisposition to microemboli and electrical changes that can occur in some people with migraine.    

In this two-phase research, the investigators first will undertake studies to better characterize the electrical changes (called “cortical spreading depression”) and microemboli formation. They also will examine the role that these two factors may play in the delayed neurological deficits and infarction following aSAH, and how these processes interact.  

Thereafter, in Phase II, they will conduct genetic studies in more than 200 aSAH survivors, to try to identify genes that make some of the survivors more susceptible to forming the microemboli and electrical brain changes that are associated with poor outcomes.  They will determine whether variations in specific genes are associated with delayed neurologic deficits and stroke, and then will see if the genetic and physiologic data are linked.

Significance :  The findings could enable clinicians to identify patients at high risk for delayed neurological deficits and stroke following aSAH, and facilitate efforts to develop new therapeutic and genetic interventions to improve their outcomes.

ABSTRACT

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Aneurysmal subarachnoid hemorrhage (aSAH) is caused by ruptured brain aneurysms and is associated with high mortality and poor neurologic outcome in a predominantly young population. It was previously thought that the main cause of poor outcome after aSAH was due to ischemia secondary to the narrowing of the large intracranial arteries known as cerebral vasospasm. However, despite many clinical trials on drugs that ameliorate vasospasm, outcome was not improved. Novel mechanisms underlying delayed neurological deficits and stroke after aSAH have therefore been proposed. It has been noted that clots form and propagate in the microvessels of the brain after aSAH (microemboli), that cortical spreading depression (CSD) occurs in aSAH patients and is associated with poor outcome, and that microemboli may induce CSD. We thus hypothesize that poor neurological outcome and stroke (delayed ischemic neurological deficits and infarction, DINDI) after aSAH may be caused by microemboli-induced CSD. In the first phase of this proposal, we will evaluate the interaction between microemboli and CSD, and the effect of these manifestations on the severity and rate of DINDI. In the second phase, we will focus on the role of genetic determinants in the development of and susceptibility to DINDI, microemboli and CSD. Genetic factors underlying microemboli formation and CSD development have been demonstrated in other diseases such as migraines. We propose to elucidate the genetic basis of susceptibility of DINDI after aSAH by performing whole transcriptome analysis via RNA sequencing. RNA sequencing is a means of obtaining information regarding gene expression via next-generation sequencing technology. We will use novel computational techniques that will also allow us to derive genetic variations based on RNA sequencing data. The results of this study will not only provide insight into the pathophysiology of DINDI and facilitate the development of a model for predicting the risk of developing DINDI, but also provide the targets for novel therapeutic strategies.

INVESTIGATOR BIOGRAPHIES

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Rose Du, M.D., Ph.D.

Rose Du, MD, PhD is Associate Professor of Neurosurgery at Harvard Medical School and Director of Cerebrovascular Surgery at the Brigham and Women’s Hospital. She received her PhD in physics from the Massachusetts Institute of Technology and her MD from Harvard Medical School. She later completed her neurosurgical residency at the University of California at San Francisco and her fellowship in cerebrovascular surgery at the Brigham and Women’s Hospital. After completing her training, she joined the faculty at the Brigham and Women’s Hospital/Harvard Medical School where she specializes in the treatment of patients with cerebrovascular diseases including subarachnoid hemorrhage. Dr. Du’s research focuses on both the genetics and clinical outcome in stroke and subarachnoid hemorrhage. She has received a K08 research award from NIH to study the integrative genomics of stroke susceptibility using both mouse and human models, the results of which have been published in the journal Stroke. She has published over 100 peer-reviewed manuscripts and is an Associate Editor for the journal Neurosurgery.

KEYWORDS


Anatomy: Cerebral cortex
Cortex
Conditions: Brain injury
Stroke
Function:
Technology: Neurosurgery