Cerebrovascular Diseases

Different parts of the brain control everything from the beating of the heart to the ability to see and hear; from the ability to breathe to the ability to think, walk, talk and make sense of the world. Cerebrovascular disease can damage the brain by altering its blood supply, depriving brain cells of the oxygen necessary to their survival. Cerebrovascular disorders are common and potentially devastating. They include cerebral infarction and other types of stroke, cerebral or intercranial aneurysms (widening and weakening of an artery), and vascular malformations (tangled vessels in the brain). Even without a major event such as a stroke, cerebrovascular disease can impair the brain's normal function by reducing its blood flow.

Damaged brain cells do not regenerate on their own, and so it is critical to contain and repair damage once it occurs, and equally critical to prevent it before it happens. Advances in diagnosis, treatment, and prevention are the foundation of Mayo Clinic's cerebrovascular disease research program.

In an coordinated effort across its three sites in Rochester, MN, Scottsdale, AZ, and Jacksonville, FL, over 30 neurologists as well as researchers and practioners in radiology, anesthesiology, molecular medicine, neurocritical care, neurosurgery, pharmacology, and physical medicine and rehabilitation, and speech pathology contribute to Mayo's cerebrovascular research. Mayo Clinic's renowned culture of collaboration ensures that discoveries in basic science transfer efficiently from the laboratory to clinical application at a rate that few, if any, institutions can match.

Mayo Clinic believes that the best cure for cerebrovascular disease is prevention--preventing the degree of impairment following stroke and preventing cerebrovascular disorders themselves. To do that Mayo is focused on several lines of research that impact on one another. These initiatives include:

  • identifying the genetic causes of cerebrovascular disease, stroke and stroke disability
  • identifying biological and behavioral risk factors for cerebrovascular disease
  • developing improved diagnostic, treatment, and rehabilitation techniques

What is a stroke?

Blood carries oxygen via blood vessels to the brain, and a stroke occurs when blood supply to the brain is compromised. In a cerebral

infarction or ischemic stroke, blood supply is cut off by a blocked blood vessel. In a transient ischemic attack (TIA), blood supply is temporarily reduced. Ischemic strokes are the most common form of stroke.

In a cerebral hemorrhage, a blood vessel leaks or bursts. Hemorrhagic strokes can occur in the brain itself (an intracerebral hemorrhage) or within the spaces that line the surface of the brain (subarachnoid hemorrhage and subdural hemorrhage).

A cerebral aneurysm is an artery with a weak spot that balloons out. If it bursts, it creates a hemorrhagic stroke. Cerebral aneurysms are silent killers with a fatality rate of 30 to 40 percent when they rupture. They occur in the young as well as the old and are present in two percent of the U.S population.

Vascular malformations can also lead to stroke if the tangled vessels in the brain cut off blood supply or burst, causing bleeding in the brain.

Whether from infarction or hemorrhage, stroke leads to brain cell death in the affected area. In a chain reaction called the ischemic cascade, other cells near the affected area begin to die too, increasing the potential for damage and subsequent functional deficits.

Of the nearly 5 million stroke survivors in this country, over one million have functional limitations that reduce or prevent their ability to carry out every day activities. They may not be able to eat, groom or bathe independently. They may not be able to walk. They may not be able to plan and problem solve. Vision may be altered. Short term memory can be affected. Speech problems can range from mildly slurred speech to the inability to understand and produce language in spoken or written form. Depression is common.

The Framington Heart Study found that 26 percent of stroke survivors over age 65 end up in a nursing home. The annual direct and indirect cost of strokes in this country is approximately 50 billion dollars.

The symptoms of stroke differ in type and severity according to the location and size of the affected area or lesion in the brain. Regardless of individual differences in outcome, stroke remains the single greatest cause of long-term disability in this country. It is the third leading cause of death. In the United States someone has a stroke every 45 seconds. Every three minutes someone dies of one.

Cardiovascular epidemiology — Identifying risk factors in the population

As a premier center for neurologic diseases, Mayo attracts thousands of patients from diverse age groups and ethnic backgrounds with both rare and common disorders to its three geographic locations. In addition, it has a repository of meticulously documented medical records going back over 100 years. This precious resource--unique in the world--combined with its vast banks of tissue and blood samples enables researchers to track and define new risk factors for cerebrovascular disease and to readily access medical histories for prospective and retrospective research.

Stroke epidemiology

Large scale population studies identify risk factors, incidence of occurrence, and outcomes. Mayo Clinic has the longest-term and largest ongoing population studies of stroke anywhere in the world. The Rochester Epidemiologic Project has been collecting population data for over fifty years across several generations. Its patient record-linkage system provides the setting to evaluate stroke type and subtypes for clinically detailed population-based studies. It is the resource used by The American Heart Association and the American Stroke Association to define the impact of stroke on our population--its recurrence, mortality and disability rates.

Mayo's epidemiology research is looking at long term changes in the prevalence, duration, odds ratios and risks of specific stroke risk factors for each type of stroke. This knowledge will help define how various stroke risk factors influence individual underlying mechanisms of stroke. It will also assist investigators in designing future drug trials for stroke prevention.

In addition, Mayo Clinic is working on innovative methods of health care delivery to ensure that risk factors in patients are adequately monitored over the long term so as to reduce recurrent ischemic events. Among the initiatives in this area is the development of standardized guidelines for monitoring patients with known risk factors and standardized treatment and follow-up plans for continued risk-factor monitoring in patients who have had a first stroke or TIA.

Determining the factors that influence outcome as well as the onset of stroke is an equally important goal of Mayo's epidemiology research. Investigators are focused on differing outcomes that may be associated with subtypes of ischemic stroke. This information will help health policy planners and practicing physicians in monitoring changes in the societal and economic burden of differing types of stroke, and in devising strategies to prevent, treat and improve outcomes for all types of stroke.

Current areas of the epidemiology of stroke also include:

  • Longitudinal assessment of trans-esophageal echocardiogram-based monitoring for cardiovascular and cerebrovascular disease, an National Institutes of Health (NIH) funded study on Stroke Prevention and Risk in the Community (SPARC).
  • Assessment of new metabolic and inflammatory markers (e.g., leptin, Homocysteine, cytokines, Chalmydia pneumoniae Ab and C-reactive protein) for future stroke risk
  • Risk of chronic hypertension and stroke in women with hypertension during pregnancy
  • Determining if left atrial volume in the heart and other cardiac conditions are independent risk factors for subsequent death.
  • Etiology and natural history of cerebral Venous Sinus Thrombosis
  • Clinical and radiology manifestations and long term outcome in isolated central nervous system vasculitis.

Vascular malformation epidemiologic research

Mayo's goal for epidemiologic research in vascular malformation is to define the natural course and management outcome of intracranial vascular malformation. Among the initiatives in this area are:

  • The association of intracranial aneurysms and intracranial arteriovenous malformation (AVM)
  • Radiosurgery (use of radiation to destroy affected tissue during surgery): Evaluation of a radiosurgery-based AVM grading system based on pre-operative clinical findings and AVM characteristics to predict outcomes following a single-session AVM radiosurgery
  • Examination of the usefulness of this grading system with pediatric patients
  • The natural course and best management for intracranial cavernous malformations

Genetic and molecular mechanisms of stroke and stroke recovery

Genetic research holds promise not only of identifying who is at risk for cardiovascular disorders, but also for producing gene treatments to protect the brain against stroke and reduce its impact when it occurs.

Genetics of ischemic stroke

Mayo Clinic leads two multi-center studies of stroke genetics, both funded by the National Institutes of Health (NIH):

  • the Siblings with Ischemic Stroke Study (SWISS)
  • the Ischemic Stroke Genetics Study (ISGS).

These studies elevate the promise of finding rational gene targets for neuroprotectants -- drugs that provide immediate protection against impairment following ischemic strokes.

Neurovascular genetics

Changes in the lining of the arteries as we age (atherosclerosis) make us more vulnerable to stroke and heart attack. Mayo Clinic, considered a world leader in neurovascular genetics, is focused on the molecular structures and mechanisms responsible for these changes. Years of research at Mayo Clinic investigating the role of nitric oxide have contributed to the finding that loss of nitric oxide is a key component. Specifically, they are investigating Tetrahydrobiopterin (BH4), an essential factor in the activity of nitric oxide--looking into how BH4 is metabolized in the vascular system and means of controlling its biosynthesis and degradation in cerebral arteries. Mayo Clinic researchers were the first to demonstrate that in vivo gene delivery of a form of nitric oxide has beneficial effects on vascular function and may be important as a future treatment.

Other projects are focused on analyzing the role of progenitor cells in maintaining normal cerebrovascular function. Progenitor cells, made in the bone marrow and circulating through the blood stream, were only recently identified as important in repairing injured blood vessels. Depletion of these cells is considered a risk factor for cerebrovascular disease, but their specific effect on vascular dysfunction in the brain has not been well studied. For this reason, Mayo cerebrovascular research is actively investigating their activity in the brain's blood supply, work ultimately aimed at cell-based treatments as an option in preventing and reversing the atherosclerotic vessel damage associated with aging.

Mayo investigators have recently demonstrated that transplantation of progenitor cells does have a therapeutic effect on injured arteries The next step is to translate this body of work into human studies where it will have the potential not only to help prevent stroke, but also to improve blood supply to the brain, the heart, and the rest of the body as we age.

Neuroprotection: Preventing the ischemic cascade

Researchers at Mayo Clinic have determined that genes and gene products are key factors in the ischemic cascade. They suspect that genetic variability among the population (individual differences in genetic make-up) translates to significant differences among patients in stroke outcome. They are working to identify the genes responsible for making the brain more susceptible to injury in older people as well as those responsible for protecting it in younger people. Discovering these neuroprotectants is a first step toward using them to reduce damage following stroke. Mayo Clinic is the only institution addressing ischemic intolerance in the aging brain and attempting to define the genes that help make injured brain tissue salvageable.

Genetics of intracranial aneurysms Mayo researchers are investigating chromosomal regions related to the formation, enlargement, and rupture of intracranial aneurysms. They are in a leadership role in the design and implementation of the NIH-funded Familial Intracranial Aneurysm Study (FIA) designed to identify the genetic impact on aneurysm formation.

They are correlating findings from molecular biology and genomics with imaging techniques, including computational fluid dynamics (CFD) which allows the computation of blood flow during aneurysm growth and rupture. This work is leading to improved ability to determine a patient's risk of rupture from an existing aneurysm.