A stroke is an emergency medical condition that occurs when a blood vessel in the brain is blocked or ruptures resulting in interrupted blood supply to part of the brain. There are three major types of strokes: ischemic, hemorrhagic, and transient. Ischemic strokes, the most common type, occur when there is a blockage in blood flow to the brain. Ischemic occlusions contribute to around 85% of casualties in stroke patients. A hemorrhagic stroke leads to bleeding into and around the brain. Transient strokes or transient ischemic attack (TIA) occur when blood flow to the brain is briefly blocked.
Stroke is the second leading cause of death and a major contributor to disability worldwide. Symptoms include vomiting, dizziness, change in consciousness along with headache, numbness or weakness in the face, arm, or leg, especially on one side of the body, vision problems, and slurred speech. Even though stroke symptoms may come on suddenly, there are warning signs including a severe headache and TIA. Depending on the region of brain damage caused by the stroke, patients may also have problems with memory, perception, emotions, urination, and bowel movements.
Ischemic Stroke
The blood flow to the brain is managed by two internal carotids anteriorly and two vertebral arteries posteriorly (the circle of Willis). In an ischemic stroke, clots form in the brain blood vessels clog arteries, and interrupt blood flow, causing sudden damage to brain cells due to a lack of oxygen. Unless the blood flow is resumed within six hours, the brain cells can die.
Atherosclerosis is a major risk factor for an ischemic stroke. In atherosclerosis, the brain blood flow is affected by the narrowing of brain blood vessels and constriction of the vascular chamber due to the build-up of plaque. Sometimes, the build-up of plaque in the cerebral artery breaks triggering clot formation. If the clot is large, the blood flow in the brain can become reduced or blocked and stroke occurs. Such ischemic stroke is called thrombotic stroke.
Sometimes a rupture and a blood clot occur outside the brain. That wandering clot, an embolus, is circulating in the bloodstream. When it lodges, blocking blood flow in an artery leading to or in the brain, it results in ischemic attack. This type of ischemic stroke is called embolic stroke. Most embolic strokes are from blood clots that form and then enter the bloodstream due to atrial fibrillation.
Inflammation of the brain blood vessels plays a key role in the development of a stroke. A malfunctioning liver can cause increased response to stress hormones such as cortisol and epinephrine with over production of proinflammatory chemokines by the liver Kupffer cell. When proinflammatory chemokines reach the brain, they trigger microglia activation producing brain inflammatory chemokines causing brain inflammation and cerebral blood vessel inflammation which narrows the blood vessel lumen. Inflammation can also cause tightening or constriction of vascular smooth muscle further narrowing the blood vessel lumen. In addition, blood vessel inflammation destabilizes the atherosclerosis plaque and increases the risk of plaque rupturing and blood clot formation. Chronic activated microglia also release cytotoxic agents including reactive oxygen intermediates, proteinases and complement proteins damaging the lining of the blood vessels, causing blood clot formation leading to a stroke.
Transient Ischemic Attack (TIA)
A transient ischemic attack (TIA) is a temporary symptom similar to a regular stroke. Symptoms include numbness or weakness in the face, arm, or leg, especially on one side of the body, vision problems, and slurred speech. These symptoms are transient and will disappear within 24 hours. TIA is caused by the temporary blockage of the blood flow to the brain due to a blood clot that subsequently dissolves.
Similar to an ischemic stroke, the temporary blood vessel blockage in TIAs can be caused by pieces of fatty deposits, or atherosclerosis plaque that triggers formation of a blood clot in the cerebral artery or one of the branches that supply blood to the brain. The blood clot can also be formed elsewhere and travelled to the arteries supplying the brain. In most cases, the clot comes from the heart or the aorta due to atrial fibrillation. Inflammation of the brain and the brain blood vessels can also result in blood vessel narrowing, reducing or blocking blood flow, leading to TIA. Although TIA doesn’t cause lasting symptoms, it is a serious warning sign of an impending stroke. About 40 percent of people who have had TIAs go on to have an actual stroke.
TIAs can also occur due to narrowing and closure of small blood vessels deep inside the brain. These vessels are frequently damaged by high blood pressure or diabetes if left untreated throughout a person's lifetime. Such small blood vessel blockage in the brain can be easily ignored. However, patients can develop symptoms such as depression, headache or forgetfulness, which may not be helped even with the use of antidepressants because of the restricted blood supply.
Ischemic Stroke and Aging
Strokes primarily affect the elderly population, and mortality after therapies is associated with advanced age. Atherosclerosis, the major risk factor of ischemic stroke is a disease of aging. Increasing age is an independent risk factor for the development of atherosclerosis. Systemic, chronic low-grade inflammation occurs during the aging process, termed as “inflammaging”, aggravates stroke pathology. The human body generates over 150 billion deceased cells in a day. As people aged, their immune system can’t clear them promptly. The accumulated deceased cells stimulate the innate immune system and drive the body towards a pro-inflammatory state. Aged cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP) which promote chronic inflammation. Persistently elevated inflammation levels destabilize the atherosclerosis plaque and aggravates the plaque rupture and blood clot formation, increasing risk of stroke.
Age also accounts for a dismal outcome of ischemic stroke. Increased post-stroke brain injury occurs in aged patient’s due to age-related changes of immune response. Animal studies have shown that aged mice had increased neutrophil flux to the brain microvascular system following an ischemic stroke. Aged mice have an enhanced granulopoietic response to stroke which triggers rapid release of immature atypical neutrophil (CD62Llo) from the bone marrow which migrate quickly to sites of injury. The accumulation of such neutrophils increases oxidative stress, phagocytosis and procoagulant features causing elevated blood viscosity, increased vascular resistance, and extended circulating time. Although blood circulation is resumed in the artery following acute attack, the microcirculation is still blocked with no-re-flow. The senescent neutrophils can aggravate thrombo-inflammation causing secondary injury in ischemic brain leading to increased mortality.7,8
Hemorrhagic Strokes
Hemorrhagic stroke happens when a blood vessel in the brain ruptures. It causes bleeding inside the brain, intracerebral hemorrhage (ICH) or into the subarachnoid space (between the brain and its outer covering) subarachnoid hemorrhage (SAH). The accumulated blood, a hematoma, puts pressure on the surrounding area, disrupting blood circulation and causing severe brain damage. A hematoma bigger than 3 cm3 requires surgical removal as soon as possible. If the pressure is too high for too long, those brain cells can be permanently destroyed. This kind of stroke is life-threatening because it can worsen quickly.
A hematoma also induces neuroinflammation, oxidative brain damage, and blood-brain barrier damage causing post-stroke injury. Secondary injury can persist for an extended period and result in long-term neurological deficits. The volume of the initial hematoma correlates with morbidity and mortality, and hematoma expansion was associated with poor patient prognosis. Necrosis is followed with the disruption of the plasma membrane, organelle swelling and leaking of cellular contents into the extracellular space. The dying brain tissue and resulting inflammation can cause scar tissue, known as a glial scar. The parts of the brain that become damaged can also be liquified. Brain liquefaction is toxic and can leak and damage healthy brain tissue in the surrounding area.6
Hemorrhagic stroke has a 40% to 50% mortality rate within 30 days, 2-fold that of ischemic stroke. High blood pressure is the most common cause of a hemorrhagic stroke, especially when a person’s blood pressure stays high for a long period of time causing damage to the blood vessel. Other risk factors include cerebral amyloid angiopathy, advanced age, cigarette smoking, diabetes, alcohol abuse, drug abuse, Asian ethnicity, genetic factors, menopause, and oral anticoagulant treatment. Inflammation of the blood vessel also plays a key role as inflammation causes the blood vessel wall to weaken, stretch, thicken, and swell with scarring, which narrows the vessel and slows or completely stops the blood flow. The weakened vessel can burst and bleed into surrounding tissues leading to hemorrhagic stroke.
Hemorrhagic Stroke and Aging
Advanced age is an important factor for the development of hemorrhagic stroke and the higher death rate. As a person gets older, the risk of developing intracerebral hemorrhage increases. Elderly individuals have a fivefold higher risk as opposed to their younger counterparts. The chance of having high blood pressure increases as people get older, especially isolated systolic hypertension causing damage to the blood vessels. Age-related chronic brain blood vessel inflammation, the “inflammaging” causes weakening and scarring of the blood vessel walls which can burst and bleed leading to a hemorrhagic stroke.
Microglia and brain infiltrating macrophages regulate hematoma resolution and brain recovery due to their ability to phagocytose accumulated cellular debris after a brain injury. Timely removal of dying cells prevent the release of intracellular inflammatory agents. Microglial or macrophage mediated phagocytosis is important for recovery after intracerebral hemorrhage. Aged microglia exhibited reduced expression of genes associated with phagocytosis. TGFβ-induced phagocytosis was abolished in aged microglia compared to their younger counterparts. Age-related parenchymal degeneration and subsequent reduction in the structural integrity of the brain tissue is unable to restrict hematoma growth causing hematoma expansion with poor outcomes in elderly who had larger volume hematoma.
Post-Stroke
The types and degrees of disability following a stroke depend upon the area of the brain being damaged. Generally, a stroke can cause five types of disabilities including paralysis and motor control issues, sensory disturbances, aphasia (problem understanding language), problems with thinking and memory, and emotional disturbances. These can lead to symptoms of weakness, lack of coordination, problems walking, loss of sensation, problems with hand grasp, visual loss, or trouble speaking or understanding. Stroke can also lead to depression and dementia.
