Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to ischemic stroke?
A stroke is a sudden interruption of blood flow to the brain which deprives the brain of oxygen and nutrients. Approximately two millions brain cells die each minute during a stroke. This can lead to brain damage, physical and mental disability and death.
An ischemic stroke is a sudden blockage of a blood vessel in the brain, usually the result of a blood clot or fatty deposit called plaques inside the blood vessels. The death of cells in the brain results in a loss of the ability to control functions in those areas like memory, speech and body movement. Ischemic stroke accounts for 85% of all strokes.
How does an ischemic stroke differ from other types of stroke?
There are two main types of strokes, ischemic stroke and hemorrhagic stroke. A hemorrhagic stroke is cause by a blood vessel bursting in the brain. This leads to an accumulation of blood in and around the brain. A transient ischemic stroke “TIA” or “mini-stroke” is a temporary blockage which does not result in brain cell death and results in no long-term damage. It can, however, serve as a warning sign for stroke.
How many people suffer ischemic strokes each year?
Stroke is the leading cause of death in the United States. Each year, over 800,000 people have a stroke, resulting in 133,000 deaths. There are currently about 7,000,000 stroke survivors living in the U.S. which makes stroke one of the leading causes of long-term disability. As a result, stroke costs American approximately $60 billion dollars in treatment, rehabilitation, medication and lost work time, annually.
How are ischemic strokes currently diagnosed?
Current stroke diagnosis requires prompt medical intervention. The diagnostic regiment includes getting a medical history, a neurological exam by a physician, a series of blood tests and getting a CT or MRI scan of the patient. Currently, there is no widely-accessible, non-invasive diagnostic test for ischemic stroke.
How are ischemic strokes currently treated?
Current treatments for ischemic stroke include first, prevention. There are a number of what are termed “controllable” and non-controllable” risk factors for stroke that should be monitored regularly. Non-controllable risk factors include age, sex and heredity. Controllable risk factors include smoking, obesity, high cholesterol, physical inactivity, excessive alcohol consumption and illegal drug use. There are also medical conditions that are risk factors for stroke, including hypertension, diabetes and heart disease.
The second stage of treatment attempts to stop the stroke once it has occurred by removing the block. Currently, tissue plasminogen activator (tPA) is the only FDA approved drug to treat an ischemic stroke. The “clot buster” drug, tPA, works to restart blood flow by dissolving the clot. The third stage of treatment is post-stroke rehabilitation, which may help stroke patients and minimize permanent disability.
How successful are current treatments for ischemic strokes?
tPA, the only drug currently available to treat an ischemic stroke does have its limitations. First, tPA must be administered IV by a doctor and within three-hours of the onset of symptoms, which can be difficult to determine. The exact time of onset must therefore be 100% confirmed. If given outside of the 3-hour window, tPA administration can lead to brain bleeding.
Because of the risk of giving tPA, many hospitals are hesitant. Some even require a two-doctor team, including a neurologist, to make the decision to administer. As a consequence, less that 4% of the ischemic stroke victims are treated with tPA.
How did your research into ischemic strokes originate?
My interest in stroke research stems from the fact that I live in a region of the country known as the “stroke belt”. This Mississippi Valley and Southeastern region of the U.S., where I’m conducting my research at Morehouse College (Atlanta, GA), is recognized by public health authorities for having a disproportionately high number of stroke sufferers compared to the rest of the country. Furthermore, stroke disproportionately affects minorities and especially African Americans. African Americans are twice as likely to die from stroke than Caucasians.
I began my work in acute brain injury through collaboration with my brother, Dr. Byron Ford, at Morehouse School of Medicine almost 10 years ago. We work with a growth factor, Neuregulin-1, which we found to be neuroprotective in a number of acute brain injury models including traumatic brain injury, exposure to neurotoxins and stroke. Through collaboration of Morehouse College, Morehouse School of Medicine and the University of Puerto Rico, our work expanded into development of a non-human primate (NHP) model for stroke and the development of a biomarker panel for the diagnosis and evaluation of stroke. Based on the relatively short therapeutic window for stroke, there is clearly an unmet need for biomarkers for stroke detection. Our work has produced a number of publications, 2 full patents and 10 patent applications.
What animal models have traditionally been used to yield information on the causes of ischemic strokes?
Previous studies have used rodent models to study stroke, but the results obtained for treatment and neuroprotection have been disappointing. Aside from tPA, all of the clinical trials for stroke treatments that have been completed have failed. To better understand the disease and treatment, there is a need for a larger animal model for stroke that is more similar to humans. Non-human primates are an ideal model for stroke research because of the similarities to human biology, behavior and physiology.
What animal model did your recent research use?
Our recent work characterized acute neuronal injury in a novel NHP ischemic stroke. We used juvenile rhesus monkeys (Macaca mulata) acquired from the Caribbean Primate Research Center (University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico).
What did your research involve?
In this study, we occluded the monkeys’ middle cerebral artery (MCA) by using silk sutures to illicit a stroke response. Occlusion of the M1 segment of the MCA was accomplished by injecting 6 to 8 (length, 2 mm) 3-0 silk sutures in saline into the MCA through the catheter in the femoral artery navigated through the abdominal thoracic aorta until the aortic arch, the brachiocephalic trunk, common carotid artery and the internal carotid artery. Animals were monitored, MRI was performed and blood was collected prior to procedure and 1-, 2- and 24-hours post-occlusion. MRI and histological sections were analyzed to assess the infarct as well as multiple physiological outcome measures.
What did your research find?
The rhesus monkey endovascular silk suture MCA occlusion techniques we used here allowed for the development of a minimally invasive stroke model. The important characteristic of this model is consistently produced infarcts that expanded during the acute phase of ischemia. The NHP stroke model we described will likely support the elucidation of mechanisms associated with stroke progression and the development of brain and blood biomarkers of stroke. Genome array technology to assess expression of numerous genes was increased or decreased by 2-fold or more at each time point after ischemia compared with that of control (baseline) samples.
The data revealed that many genes had distinct expression patterns at different time points during acute ischemic injury. These patterns of gene expression may lead to the development of a biomarker or biomarker panel for the evaluation of stroke. This will be important for determining onset of stroke for treatment and monitoring outcome.
What impact do you think your research will have?
This NHP stroke model likely will facilitate the elucidation of mechanisms associated with acute neuronal injury after ischemia. In addition, the ability to identify candidate blood biomarkers in NHP after ischemia may prompt the development of new strategies for the diagnosis and treatment of ischemic stroke in humans.
Do you have any plans for further research into this area?
The next steps in these studies are to validate our potential biomarkers in human patient samples. I recently received a pilot grant award through the United Negro College Fund (UNCF) to begin carrying out these studies at Morehouse College. We will also begin testing the therapeutic effects of Neureulin-1 on ischemic stroke in this new primate model.
Would you like to make any further comments?
For individuals with a family history or suffering from risk factors of stroke, the best method of prevention is to manage the “controllable” risk factors and monitor the “uncontrollable” risk factors. Also, know the signs and symptoms of stroke whether you are a victim or you see someone who may be having a stroke. Finally, you should never try to diagnose a stroke yourself, call 9-1-1 immediately! Time is of the essence and is the difference between life and death as well as recovery and quality of life.
Where can readers find more information?
About Dr Gregory Ford
Dr. Gregory Ford is an Assistant Professor of Biology at Morehouse College in Atlanta, Georgia.
Gregory’s research activities focus on the identification of the common cellular, molecular and genetic factors underlying acute brain injuries (ABIs), including nerve agent exposure, traumatic brain injury (TBI) and stroke. His lab utilizes an integrated systems approach to elucidate biochemical pathways (metabolomics), gene regulation (transcriptomics), gene-gene networks and interactions (genomics) and peptide/protein identification (proteomics) among acute brain injury models.
Dr. Ford employs this approach to identify novel therapeutic targets as well as diagnostic/prognostic biomarkers of these complex ABIs.
Dr. Ford is also interested in the role of Neuregulin-1 in the regulation of the inflammatory response resulting from ischemic stroke. Current work includes investigating a role for Neuregulin-1 in a number of inflammatory diseases.