Blood Supply to the Brain and Cerebral Ischaemia

What is the leading cause of neurological disability?

- stroke

(2nd leading cause of death worldwide)

What is stroke?

(and where does it occur?)

- damage to the brain due to interruption of its blood supply

(via a clot or bleed in either the brain parenchyma or subarachnoid space)

What % of the following does the brain account for:

- body weight

- cardiac output

- O2

- glucose

- 2-3% of body weight (~1.4kg)

- 15% of cardiac output

- 20% of all O2

- 25% of all glucose

What is the brain critically dependent on?

- constant blood supply

(as it is very metabolically demanding)

Which pairs of arteries supply blood to the brain? (2)

Which pair provides anterior circulation and which pair provides posterior circulation?

- internal carotid arteries (anterior circulation)

- vertebral arteries

(posterior circulation)

What are the internal carotid arteries branches of?

- branches of the common carotid artery

Where do the vertebral arteries traverse and how? (3)

1). the vertebral arteries pass adjacent to the spinal cord in the vertebrae (in the cervical transverse foramina)

2). they then unite in the base of the brain to form the basilar artery

3). the basilar artery runs along the pons and medulla in the brain stem

What are the branches of the internal carotid artery? (3)

(which are the smallest and largest branches?)

- anterior cerebral artery (smallest branch)

- middle cerebral artery (largest branch)

- posterior cerebral artery

What is the Circle of Willis?

a circulatory anastomosis/connection of arteries that supplies blood to the brain and surrounding structures

What are some of the important branches of the anterior cerebral artery? (2)

(What can be said of the size of each of these branches?)

- anterior communicating artery (small branch)

- medial striate artery (large branch)

What can occlusion of the anterior cerebral artery result in? (2)

- paralysis and/or sensory loss in the contralateral leg and perineum

What is the role of the anterior communicating artery?

- connects the left and right anterior cerebral arteries

Which is the major artery affected in stroke?

- middle cerebral artery

What is the course of the (branches of the) middle cerebral artery? (2)

1). passes through lateral sulcus

2). and then travels along the lateral surface of the frontal and parietal lobes

What can occlusion of the middle cerebral artery result in? (3)

- contralateral paralysis (mostly in lower face and in arm)

- general somatosensory defects

- speech defects (aphasia) - if the dominant hemisphere (usually the left) is affected

Which arteries supply the basal ganglia?

- lenticulostriate arteries

What are the segments of the middle cerebral artery? (3)

What does each segment supply?

(and which is the horizontal branch?)

- M1: horizontal segment that supplies the end arteries

- M2: supplies the lateral sulcus/sylvian fissure

- M3: cortical branches

Where does the basilar artery run?

(and in what direction?)

- runs forward in midline on the ventral surface if the pons

What are the branches of the basilar artery? (3)

- anterior inferior cerebellar

- pontine

- superior cerebellar

Where does the basilar artery divide, and what branches does it give rise to?

- divides at the rostral end of the midbrain - into the posterior cerebral arteries

What is the role of the posterior communicating artery?

- connects the two posterior cerebral arteries

What can occlusion of the basilar artery lead to?

- coma - followed by death due to respiratory failure

(as the basilar artery supplies brainstem areas - essential for resp function)

What is the course of the posterior cerebral artery? (2)

1). curves around the midbrain

2). and reaches the medial surface of the cerebral hemisphere

What are the important branches of the posterior cerebral artery? (3)

- cortical branches

- posterior choroidal

- posterior communicating

What do the cortical branches of the posterior cerebral artery supply?

- supply visual cortex

What does occlusion of the posterior cerebral artery result in?

- blindness

Where is the Circle of Willis located?

- (ring of arteries at) base of the brain

What is the benefit/purpose of the circle of willis?

- provides a 'safety mechanism' - if one of the arteries gets blocked the "circle" will still provide the brain with blood

In the elderly, why is the anastomoses function of the circle of willis more variable?

- due to narrowing of large vessels and communicating arteries - due to vascular disease

(less collateral flow)

Which artery provides the majority of blood supply to the lateral aspect of the brain?

- middle cerebral artery

Which artery provides the majority of blood supply to the medial aspect of the brain?

- anterior cerebral artery

What does the anterior cerebral artery supply?

- medial frontal and parietal lobes

What does the middle cerebral artery supply?

- lateral surface of cerebral hemispheres

- inferior aspect of temporal lobe (medially)

What does the posterior cerebral artery supply? (3)

- occipital lobe and lower part of temporal lobe

- visual cortex (medially)

What do symptoms of stroke depend on?

- location of stroke

(which part of brain is affected)

What are general symptoms of stroke? (3)

(and which artery causes them?)

due to middle cerebral artery:

- weakness on one side of face

- weakness in arms

- impaired/slurred speech

What is the basic acute pathophysiology of acute stroke? (8)

1). reduction in blood supply to the brain leads to energy failure

2). due to reduced oxygen and glucose supply to the brain

3). so ATP can't be generated - causing changes in different systems in the brain

4). leading to depolarisation of cell membranes

5). leading to glutamate release - which causes oxidative stress and CELL DEATH

6). this cell death triggers a cascade of events - leading to infarcts - and a necrotic CORE infarct

7). the spread of depolarisations throughout brain cells lead to calcium overload - leading to mitochondrial damage and release of reactive oxygen species

8). which triggers INFLAMMATION and downstream programmed cell death - and eventual tissue death

of areas surrounding the necrotic core)

(with SOME repair and remodelling in the brain)

What is an infarct?

- area of dead tissue after a lack of blood supply

What is haemorrhage?

- rupture of blood vessel

What is the basic acute pathophysiology of ICH? (6)

1). blood leakage into the brain causes tissue disruption/displacement

2). as the skull is closed, this displaced tissue causes an increase in intracranial pressure

3). which reduces blood flow (secondary ischaemia to the haemorrhage)

4). this secondary ischaemia leads to blood-brain barrier break down, as well as triggering inflammation - contributing to cell death

5). blood within the brain tissue releases blood products such as thrombin, and RBC's lyse to release Hb - which generates reactive oxygen species and toxic substances

6). and in severe cases midline shift and herniation can occur - leading to DEATH

What % of strokes are ischemic?

- 80%

How long can the effects of ischaemic stroke take to develop?

- from immediately upon presentation, to mins, hours, days , weeks & months following presentation

At what point following stroke does an infarct tend to present on CT?

How does an infarct present on a CT scan?

- within a day after presentation

(dense region on scan)

How can infarcted tissue be recovered?

- through re-perfusion of that brain tissue

What is neuroprotection?

What is its main purpose in stroke?

- prevention of neuronal cell death by intervening and inhibiting the pathogenetic process that causes neuronal dysfunction and death

- acts to prevent non-infarcted tissue from becoming infarcted/dead following stroke

What is the core in stroke?

- the primary region of damage to the brain in the immediate area - caused by stroke

(where the blood supply is reduced to very low levels -

What happens to the cells in the core in stroke?

(and at what rate?)

- the cells will die quite quickly (within mins-hours)

- cells are beyond rescue - dead tissue

What is the penumbral region in stroke?

- surrounding regions to the core with reduced blood flow, but not cut off as much as in the core

(20-50% normal flow) - so neurones receive SOME supply and are functionally active, just not at full capacity

vulnerable tissue

What happens to the cells in the penumbral region in stroke?

- cells are under threat, but not dead - so can potentially be rescued if treatment is started early

If the penumbral region isn't immediately treated, what can happen?

Why?

- it becomes core tissue (core expands)

- dead cells in the core release various factors/toxins that are detrimental to neighbouring cells

(cascade effect)

What are some examples of cells that neurones work alongside in the brain? (3)

What do these cells do?

- microglial cells

(macrophages - remove damaged neurones)

- oligodendrocytes (axon myelination)

- astrocytes

(provide close coupling between blood vessel and neurone)

etc

How can the onset of stroke be described?

- acute

(onset happens instantly)

Which factors affect the pathophysiology and outcome of stroke? (3)

- age

(elderly - diminished brain protection)

- size of stroke

(bigger = worse)

- location of stroke

What are some of the molecular pathophysiological mechanisms that occur in stroke? (4)

- oxidative stress

- post-ischaemic inflammation

- excitotoxicity

- thrombo-inflammation

What are the first molecular events to occur in stroke?

- excitotoxicity

What is glutamate?

Where does it bind?

- the major excitatory neurotransmitter in the brain

- binds to surface membrane receptors - causing downstream effects

Which receptor does glutamate act at?

What kind of receptor is this?

Where is this receptor located?

- NDMA receptor

(N-methyl D-aspartate)

- ligand-gated ion channel

- located in the post-synaptic membrane

What is excitotoxicity?

What does it result in?

- pathological process by which nerve cells are damaged and killed by excessive stimulation by excitatory neurotransmitters like glutamate

- over-excitation of receptors (e.g. NMDA) by excess glutamate overwhelms the synapse and leads to Ca influx into cells - activating dangerous enzymes which damage the cell

How is glutamate usually removed from the synapse? (2)

- re-uptaken back into the pre-synaptic terminal

- by glial cells

(for glutamate metabolism)

How does excitotoxicity occur in stroke? 3

1). the synapse may be overwhelmed in stroke due to loss of energy

2). causing glutamate to build-up in the synaptic cleft

3). glutamate then spills out of the synaptic cleft and activates other subtypes of glutamate receptor - which triggers downstream mechanisms that lead to cell death

What is oxidative stress?

- disturbance in the balance between production of reactive oxygen species (free radicals) and antioxidant defenses

How is oxidative stress generated? (3)

(briefly)

1). loss of energy in stroke

2). causing a collapse in membrane potential

3). leading to oxidative stress generation

What drives oxidative stress?

- collapse of mitochondria membranes

How does mitochondrial collapse drive oxidative stress?

1). mitochondrial collapse causes release of reactive oxygen species

2). which are then acted upon by free radicals

What are reactive oxygen species?

What is a key example of a reactive oxygen species?

- highly reactive forms of oxygen

- e.g. hydrogen peroxide

What are free radicals?

What is an example of a free radical?

- unstable, toxic oxygen-containing molecules that can cause cell damage and death through oxidation of proteins, peroxidation of lipids

- e.g. superoxide dismisutase

Which process does oxidative stress drive?

- inflammation

How does post-ischaemic inflammation occur in stroke?

- when blood can re-enter the tissue (re-perfusion injury) there are changes in vasculature which cause activation and migration of inflammatory cells into the brain - and triggering of immune events which are triggered by resident brain immune cells too

How can cytokines cause cell damage/death following stroke?

- by activating different membrane proteases which affect of different proteins

What are some examples of inflammatory events that may be triggered by immune cells following stroke? (2)

- (cytokines) activation of different membrane proteases which affect breakdown of different proteins

- degeneration of free radicals

(leading to cell membrane damage, changes in intra-cellular processes & cell death)

What is thromboinflammation?

What does it cause? (2)

loss of the normal anti-thrombotic and anti-inflammatory functions of endothelial cells - which causes thrombosis with associated inflammation

What does thrombo-inflammation refer to the interaction between?

- interaction between coagulation cascades and inflammatory processes involved in stroke

How does thrombo-inflammation occur in stroke? (4)

1). clot formation or vessel damage in stroke leads to breakdown of the tight junctions of the brain - leading to exposure of the underlying basement membrane

2). this leads to the release of vWF - which binds platelets

3). these platelets will then bind fibrin , RBC's, neutrophils etc - leading to clot formation within the vessel and disruption of the blood-brain barrier

4). disruption to the blood-brain barrier causes movement of water into tissue - causing oedema, as well as infiltration into the tissue causing cytokine release, activation of resident brain microglia, migration of neutrophils & other immune cells to the tissue - releasing their pro-inflammatory contents and damaging the tissue

What is the key feature of thrombo-inflammation?

- the ability of immune cells to bind and migrate across into the brain tissue

What are the stages of the 'patient journey' in inflammation and ischaemic stroke? (9)

1). risk factors

2). which change the vasculature of the brain and cause endothelial dysfunction and vascular injury

(inflammatory process)

3). atherosclerosis - formation and build-up of lipid deposits in artery followed by macrophage invasion

(inflammatory event)

4). plaque rupture and thromboembolism

5). vessel occlusion in the brain - ishcaemic infarction

(e.g. interactions between leukocytes and platelets; neutrophils)

6). acute damage cascade

(ie activation of resident inflammation cells - microglial cells as well as invading monocytes)

7). subacute pathways

(post-stroke infection/pneumonia - immunosuppression, body can't fight infections)

8). chronic phase

9). chronic inflammation and adaptive immunity

What is the mortality rate for ischaemic stroke?

- 12%

(has reduced from ~28% 20yrs ago)

What are some examples of post-stroke complications that may occur? (6)

- motor impairment

- complete hemiplegia (impairment down one side)

- aphasia (speech problems)

- problems with comprehension of language

- visual problems

- cognitive problems

(e.g. post-stroke dementia, anxiety depression)

What are some risk factors for stroke? (7)

- infections

- high CRP

(C reactive protein: increased when there is inflammation in body)

- hypertension

- smoking

- obesity

- stress

- sedentary

Which type of immune response mediates inflammation in the first few hours of a stroke?

- innate

Which type of immune response mediates inflammation from days of stroke?

- adaptive

What happens to neurones that are initially damaged during stroke due to reduced blood supply?

- the damaged neurones release DAMPs

(damage associated molecular patterns) - which cause cell damage and death

What are some examples of DAMPs? (5)

- ATP

- UTP

- HMGB1

- HSPs (heat shock proteins)

- ROS (reactive oxygen species)

What happens to DAMPs following release from damaged neurones immediately following stroke? (2)

(innate response)

1). following release from damaged neurones, DAMPs are recognised by receptors on the resident brain microglia as well as infiltrating monocytes

2). this leads to up-regulation of receptors on the cell surface - followed by chemokine and cytokine release

(inflammatory mediators associated with inflammatory events) - causing bystander inflammation (as there is no pathogen to kill) and tissue damage

What is sterile inflammation?

what is an example of something that transmits sterile information?

- inflammation triggered in the absence of a pathogen

- ie DAMPs

What happens in the adaptive immune response to inflammation after having had stroke for a number of days?

- delayed entry of b and t cells

(with pro and anti-inflammatory lymphocytes)

When does the recovery/resolution stage of inflammation during stroke occur?

- after weeks of the stroke

What are some examples of resolving anti-inflammation measures occur in the brain after weeks of stroke? (4)

- neurogenesis

- angiogenesis

- re-myelination from damaged oligodendrocytes

- release of various growth and nerve growth factors - which drive these recovery processes

What is IL-1?

- pro-inflammatory cytokine

When is IL-1 released?

(and by what?)

- released by different brain cells in response to INJURY

What kind of drug are IL-1 antagonists?

- anti-inflammatories

How can IL-1 antagonists reduce the inflammation response? (2)

1). naturally occurring IL-1 antagonist (called anakinra) binds to the receptor and prevents the accessory protein from binding

2). so prevents signalling from IL-1 - and reduces inflammation response

What are the stages of treating stroke, and what do each of these stages entail? (4)

1). primary prevention (reducing stroke risk in patients who have never had stroke)

2). acute treatment

(early intervention to alter the clinical course of stroke in patients with stroke - re-perfusion or drugs such as anakinra to provide neuro and vascular protection)

3). rehabilitation

(to restore functionality)

4). secondary prevention

(reduce stroke risk in people who have had stroke before)

What is the front-line treatment for ischaemic stroke?

- thrombectomy (tPA)

What are some examples of secondary prevention strategies used to prevent further strokes? (2)

- anti-platelet drugs

- anticoagulants

What are some examples of rehabilitation strategies used following stroke? (3)

- physiotherapy

- speech therapy

- occupational therapy

What is a thrombectomy?

What can it be coupled with as a treatment therapy?

- surgical removal of a clot via a retrieval stent into the artery to the brain to pull the clot out

- could be coupled with intravascular therapy - delivering a drug directly & quickly into the tissue alongside the retrieval stent

By which processes can the brain produce new cells following stroke? (2)

- neurogenesis (forming new neurones)

- angiogenesis

(forming new blood vessels)

How can the brain recover following stroke if infarcts result in loss of function in certain areas of the brain?

- neuroplasticity; brain areas can take over functions

Why may inflammation play a significant role in repair processes of the brain following stroke?

- as stem cells release inflammatory substances

(which may be important in brain recovery following stroke)

What is cell therapy?

At what stage of stroke would it be optimal to implement this in and why?

- placing new, healthy cells into the body to replace diseased or damaged ones - to modulate function

- could be useful days-weeks- months following stroke; if the patient has persistent deficit/injury - to drive new tissue formation