Elm 18/19 Strokes

Question 1

Q: What are the differences between acute and chronic neuronal damage or death?

Answer 1

A: Acute neuronal damage or death occurs suddenly, while chronic damage develops gradually over time.

Question 2

Q: What is stroke, and what causes it?

Answer 2

A: Stroke is a medical condition characterized by reduced blood flow and oxygen to the brain. It is caused by brain artery blocks or bleeds, which can result from factors such as poor circulation, heart failure, drowning, or low oxygen at birth.

Question 3

Q: What are the consequences of stroke?

Answer 3

A: Stroke is the third greatest killer in the UK and the second globally, leading to neurological disability. It results in decreased blood flow and oxygen delivery to the brain, which can lead to neuronal damage or death.

Question 4

Q: Why is the brain vulnerable to stroke?

Answer 4

A: The brain is highly metabolically active, accounting for 2-3% of body weight but consuming 20% of all oxygen and 25% of all glucose. It is critically dependent on a continuous blood supply for nutrients and oxygen.

Question 5

Q: What are the risk factors for stroke?

Answer 5

A: Risk factors for stroke include atherosclerosis, age, diabetes, ethnicity, alcohol consumption, family history, heart disease, high blood pressure/cholesterol, obesity, and smoking.

Question 6

Q: What are some common symptoms of stroke?

Answer 6

A: Common symptoms include sudden, severe headache (in the case of a bleed), dizziness, falls, difficulty speaking or understanding speech, dimness or loss of vision, and weakness or numbness in the face, arm, or leg, typically on one side of the body.

Question 7

Q: What damage does a stroke cause to the brain?

Answer 7

A: A stroke, often referred to as a “brain attack,” leads to the loss of millions of brain cells and billions of connections, causing destruction of brain wiring. The damage occurs rapidly, with approximately 2 million brain cells lost every minute.

Question 8

Q: What are the main causes of stroke, and what are the two main types?

Answer 8

A: The main causes of stroke include athero-thrombo-embolism affecting cerebral arterial supply, embolism from the heart, intracranial small vessel disease, and rare causes. The two main types of stroke are ischemic stroke, where a blood vessel is blocked (most common), and hemorrhagic stroke, where a blood vessel bursts.

Question 9

Q: What treatment is used for stroke, and how does it work?

Answer 9

A: Tissue plasminogen activator (TPA) is used to treat stroke, particularly ischemic stroke. TPA helps dissolve blood clots and restore blood flow to the affected area of the brain. It must be administered quickly, ideally within a few minutes of symptom onset, to be effective.

Question 10

Q: What functional consequences can result from stroke, and how do they depend on the location of the stroke?

Answer 10

A: The functional consequences of stroke depend on the location of the stroke in the brain. Many individuals can retain some functions, such as trouble speaking but being able to sing. Artistic functions are often retained despite other impairments.

Question 11

Q: What is the development of ischemic damage in the brain following a stroke?

Answer 11

A: Cells in the immediate area of a stroke die within minutes to hours, beyond rescue. Surrounding regions have compromised blood supply but are not completely cut off, making them under threat but potentially rescuable if treatment is started early. The core dead tissue releases toxins, affecting the penumbra, or vulnerable tissue.

Question 12

Q: What are some of the killers in the brain following a stroke?

Answer 12

A: Neurotransmitters like glutamate, ions such as calcium (Ca) and sodium (Na), and free radicals, which are abnormal oxygen molecules, contribute to the cascade of events leading to damage after a stroke.

Question 13

Q: What is excitotoxicity, and how does it contribute to ischemic damage?

Answer 13

A: Excitotoxicity occurs when energy failure due to arterial occlusion leads to the release of glutamate, causing an influx of calcium and sodium ions. This influx triggers proteolysis and membrane/cytoskeletal breakdown, contributing to neuronal damage.

Question 14

Q: What is reperfusion injury, and how does it occur?

Answer 14

A: Reperfusion injury happens when blood flow is restored to an area of the brain previously deprived of oxygen due to thrombotic blockade of an artery. It can result in inflammation and oxidative stress, caused by the release of free radicals during reperfusion.

Question 15

Q: What cells are involved in strokes, besides neurons?

Answer 15

A: In addition to neurons, capillary cells (involved in blood transport), astrocytes (which take up glutamate but rely on pumps), microglia (immune cells), and oligodendrocytes (responsible for myelin sheath) are also affected by strokes.

Question 16

Q: What are some common disabilities that can occur after a stroke?

Answer 16

A: Post-stroke disabilities may include paralysis or loss of motor control, sensory disturbances, language issues (aphasia), memory impairment, and mental health issues such as depression or anxiety.

Question 17

Q: What are some reparative mechanisms that can occur after a stroke?

Answer 17

A: Reparative mechanisms in the brain following a stroke include plasticity, neurogenesis (the formation of new neurons), and angiogenesis (the formation of new blood vessels).

Question 18

Q: What is therapeutic hypothermia, and how does it work in the context of stroke treatment?

Answer 18

A: Therapeutic hypothermia involves lowering the brain’s temperature to reduce neuronal death, as cooling decreases oxygen demand. Studies in animal models have shown that cooling to 32 degrees Celsius can provide substantial benefits and be tolerated for long periods.

Question 19

Q: What are the mechanisms behind therapeutic hypothermia’s effects on stroke pathology?

Answer 19

A: Therapeutic hypothermia has diverse effects on stroke pathology. In the early stages of stroke, it reduces excitotoxicity and decreases brain oxygen demands. Later stages involve reducing apoptosis, inflammation, and disruption of the blood-brain barrier.

Question 20

Q: What are the limitations of therapeutic hypothermia as a treatment for stroke?

Answer 20

A: Some limitations include the difficulty of translating animal experiments to humans, challenges in precise temperature control, and risks of serious complications such as pneumonia. Selective brain cooling and managing shivering using opioids are approaches to address these limitations.

Question 21

Q: What are the outcomes of studies on therapeutic hypothermia for stroke treatment?

Answer 21

A: The translation of therapeutic hypothermia’s promise into clinical benefits has not been proven conclusively. While some trials showed benefits over control groups, many showed no significant differences. Recent studies, including the Polar study, have shown disappointing results, leading to cautionary recommendations from organizations like NICE.

Question 22

Q: What is an important aspect of treating stroke patients admitted to an acute stroke unit?

Answer 22

A: An important aspect of treating stroke patients is managing the effects of the stroke, which can involve addressing symptoms and preventing complications.

Question 23

Q: What is the status of pharmaceutical treatments for stroke based on preclinical and clinical studies?

Answer 23

A: Over 1000 agents have been tested in experimental models, and over 100 have made it to clinical trials. However, there is still no widely effective pharmaceutical treatment for stroke in the clinic.

Question 24

Q: What are the current treatments for stroke?

Answer 24

A: The main treatment for ischemic stroke caused by a clot is tissue plasminogen activator (TPA), which dissolves the clot. Mechanical approaches for clot removal are also used but carry the risk of breaking the clot into smaller pieces. For hemorrhagic strokes caused by bleeding, surgical intervention may be necessary to repair or remove the burst vessel, though deep hemorrhages are more difficult to treat.

Question 25

Q: What are some factors contributing to the lack of success in developing new approaches to stroke treatment?

Answer 25

A: Factors contributing to the lack of success include a focus on the brain and post-stroke processes rather than treating stroke as a vascular disease, failure to differentiate between normal and disease processes, and overlooking co-morbidities. Issues with clinical recruitment and trial design may also play a role.

Question 26

Q: What is inflammation, and how has it been historically defined?

Answer 26

A: Inflammation is the response of the immune system to infection or injury. It was first defined by Cornelius Celsus around AD 25. Inflammation is characterized by heat, redness, swelling, pain, and loss of function.

Question 27

Q: What are some characteristics and mediators of inflammation in the context of stroke?

Answer 27

A: Inflammation involves various mediators, including glial cell activation, edema, systemic acute phase response, expression of adhesion molecules, invasion of immune cells, and synthesis of inflammatory mediators such as cytokines, free radicals, and prostaglandins. Edema, or swelling in the brain, can lead to increased pressure within the skull, causing further damage.

Question 28

Q: How quickly does inflammation occur following a stroke?

Answer 28

A: Inflammation occurs very rapidly, within a few hours following a stroke, and plays a significant role in the progression of tissue damage and functional impairment.

Question 29

Q: What are cytokines, and what are some examples of them?

Answer 29

A: Cytokines are small proteins involved in all forms of disease and injury. Examples include interleukins, interferons, tumor necrosis factors, growth factors, and chemokines. They are produced by damaged cells and act as communication molecules between cells.

Question 30

Q: What effects do cytokines have on the brain?

Answer 30

A: Cytokines have various effects on the brain, including hormonal regulation, fever induction, weight loss, appetite modulation, immune system activation, promotion of sleepiness, and activation of the sympathetic nervous system.

Question 31

Q: How are cytokines involved in stroke?

Answer 31

A: In stroke, cytokines are rapidly produced in the brain, with microglia being the main source. Interleukin-1 (IL-1) is particularly important in this context.

Question 32

Q: How was interleukin-1 (IL-1) discovered?

Answer 32

A: IL-1 was discovered when a convent of nuns simultaneously contracted the flu. Researchers collected and purified urine from these nuns, identifying IL-1 as a key inflammatory mediator.

Question 33

Q: What are some characteristics of interleukin-1 (IL-1)?

Answer 33

A: IL-1 is considered a master cytokine and a major disease target. It is produced rapidly in the brain after injury or stroke. Additionally, there is a naturally occurring and highly selective antagonist of IL-1, known as IL-1Ra (interleukin-1 receptor antagonist).

Question 34

Q: How is the middle cerebral artery occlusion (MCAO) model used in stroke research?

Answer 34

A: The middle cerebral artery occlusion (MCAO) model is commonly used to mimic stroke in research settings. It has shown that interleukin-1 (IL-1) is rapidly produced after stroke, and increasing amounts of IL-1 worsen stroke outcomes.

Question 35

Q: What evidence suggests the role of interleukin-1 (IL-1) in stroke damage?

Answer 35

A: Studies have demonstrated that inhibiting the amount of IL-1 reduces stroke damage. The rapid upregulation of IL-1 and IL-1Ra (interleukin-1 receptor antagonist) after stroke is consistent with their contribution to injury. IL-1Ra has shown promise in reducing stroke damage and is currently being tested in patients.

Question 36

Q: How does aging affect inflammation and stroke risk?

Answer 36

A: Aging is associated with increased inflammation, and stroke is more common in older individuals. Serious lung infections in older people can triple the risk of stroke.

Question 37

Q: What are some effects of inhibiting interleukin-1 (IL-1) beyond stroke?

Answer 37

A: Inhibition of IL-1 has been shown to reduce damage in various conditions, including focal, global, and permanent ischemia, traumatic injury, excitotoxic damage, clinical symptoms of experimental autoimmune encephalomyelitis (EAE), heat stroke damage, and epileptic seizures.

Question 38

Q: What are the cellular targets of interleukin-1 (IL-1), and how does it act in the brain and outside the brain?

Answer 38

A: IL-1 acts on neurons, glia, and endothelial cells. It has effects both within the brain and outside the brain, contributing to systemic inflammation.

Question 39

Q: How does interleukin-1 (IL-1) cause damage in the context of stroke?

Answer 39

A: IL-1 induces CNS responses when expressed peripherally, leading to rapid production in the brain after acute insults. Higher IL-1 levels are associated with increased damage, as it activates glia to release toxins, affects neurons (both beneficially and detrimentally), induces cerebrovascular actions, contributes to extracellular matrix breakdown, and elicits physiological responses such as fever.

Question 40

Q: What are some beneficial effects of interleukin-1 (IL-1) in stroke?

Answer 40

A: IL-1 acts on astrocytes to produce growth factors, which can be helpful in the repair process following stroke.

Question 41

Q: How do stroke risk factors relate to interleukin-1 (IL-1) activation in the brain?

Answer 41

A: Patients with stroke risk factors show higher activation of microglia, as observed in PET scans, indicating the involvement of IL-1 in the inflammatory response.

Question 42

Q: What is the potential of IL-1Ra as a therapy for stroke?

Answer 42

A: IL-1Ra (interleukin-1 receptor antagonist) shows promise as a therapy for stroke. However, further research is needed to assess its pharmacokinetics, safety, and efficacy in targeting IL-1-mediated damage in stroke.

Question 43

Q: How was the presence of interleukin-1 (IL-1) in the brain demonstrated in patient studies?

Answer 43

A: In patients with raised intracranial pressure, IL-1 concentration was found to increase within one hour, suggesting that IL-1 can penetrate the brain.

Question 44

Q: What were the findings of the first clinical trial of interleukin-1 receptor antagonist (IL-1Ra) in stroke patients?

Answer 44

A: The small phase 2 study, which was double-blinded, placebo-controlled, and randomized, focused on safety and feasibility as primary outcomes. It found no increase in infections in patients receiving IL-1Ra over three days. Additionally, IL-1 blockade reduced defense response biomarkers in the circulation. Clinical outcomes showed that patients who received IL-1Ra had less impairment and fewer deaths.

Question 45

Q: What were the results of the larger study involving IL-1Ra in stroke patients, and why was there no clinical benefit observed?

Answer 45

A: The larger study met the primary endpoint of reduced inflammatory markers but did not show clinical benefit, and there was even a slight detriment. This discrepancy was attributed to the interaction between tissue plasminogen activator (TPA) and the IL-1Ra. Patients who did not receive TPA showed better outcomes.

Question 46

Q: What are some considerations regarding increased IL-1 in the brain in various conditions, and its role in causing damage?

Answer 46

A: Increased IL-1 levels in the brain have been observed in other conditions, but it is unclear whether this increase is a response to damage or a cause of it.

Question 47

Q: What is hibernation, and how does it benefit animals like ground squirrels?

Answer 47

A: Hibernation is a physiological method of conserving energy during periods of food scarcity, characterized by a dramatic drop in body temperature, heart rate, and metabolic rates. Ground squirrels, for example, hibernate for about 7 months each year, during which their core body temperature drops to around -3 degrees Celsius, and their brain temperature drops to 0 degrees Celsius. Their heart rate decreases significantly, beating only once per minute.

Question 48

Q: What are reperfusion injuries, and how are they related to hibernation and stroke?

Answer 48

A: Reperfusion injuries occur when oxygen is restored to an area of ischemic brain tissue, leading to inflammatory and oxidative stress. Hibernation involves the brain operating at very low oxygen levels, so animals like ground squirrels have evolved mechanisms to avoid reperfusion injuries.

Question 49

Q: How can the study of ground squirrel hibernation contribute to stroke treatment?

Answer 49

A: Understanding the physiology of the mechanisms that ground squirrels use to avoid reperfusion injuries during hibernation may provide insights for developing therapies for stroke victims. It is thought that the opioid peptide system, particularly the delta opioid receptor, plays a role in triggering hibernation and may be important for protecting the brain during periods of low oxygen levels.

Question 50

Q: What was observed in a study where strokes were induced in mice by blocking middle cerebral arteries?

Answer 50

A: Mice given groundhog serum or a delta opioid receptor agonist suffered significantly less brain damage compared to the control group given saline.

Question 51

Q: What might be the mechanism behind the protective effect of groundhog serum or delta opioid receptor agonist in stroke-induced mice?

Answer 51

A: The exact mechanism is unknown, but it may involve a decrease in nitric oxide (NO) production.

Question 52

Q: What recent studies suggest about biochemical changes during hibernation?

Answer 52

A: Recent studies suggest that sumoylation, a process involving the addition of a tag called SUMO to proteins, is upregulated during hibernation.

Question 53

Q: How do inhibitors of the enzyme SENP2 affect cells during hypoxia?

Answer 53

A: SENP2 inhibitors increase the rate of SUMOylation in cells and protect them from hypoxia.

Question 54

Q: How might ground squirrels serve as a model for Alzheimer’s disease (AD)?

Answer 54

A: Ground squirrels undergo dendritic die-back during hibernation, accompanied by the buildup of tau, a protein implicated in AD in humans.

Question 55

Q: What occurs when ground squirrels emerge from hibernation in relation to dendritic die-back and tau buildup?

Answer 55

A: Dendrites rapidly grow back to re-establish lost synapses, and tau is simultaneously removed from the brain, suggesting implications for stroke victims and dementia sufferers.