Cerebrovascular Disease

Question 1

What is the epidemiology of a Stoke?

Answer 1

= most prevalent neurological disorder under 85 years

Stoke associated with:
= increased long-term mortality
= physical, cognitive and behavioural impairements
= recurrent stroke
= increased risk of other vascular events
(e.g. myocardial infarction)

Question 2

What are some different stroke types / aetiologies?

Answer 2

5% = subarachnoid haemorrhage

15% = primary intracerebral haemorrhage

80% = ischaemic stoke
= of which 5% = rare causes
= 25% cardiac source of embolism
= 25% intracranial small-vessel disease
= 50% atherothromboembolism

Question 3

What are some risk factors for stroke?

Answer 3

Non-modifiable
= e.g. family history, age, gender, race

Modifiable
= e.g. hypertension, diabetes, smoking

Risk factors can co-exist
= increase propensity to stroke
= account for 60-80% of stroke risk in general population
= variety of effects on blood vessels

Question 4

How do risk factors increase the propensity to stroke?

Answer 4

= effects on structure and function of blood vessels on the interface with circulating blood

= promotion of atherosclerosis and stiffening of arteries
(inducing narrowing, thickening, tortuosity of arterioles and capillaries)

= in the brain = leads to reduced resting cerebral blood flow (CBF) and alterations in CBF regulation

= ability of endothelium to regulate microvascular flow is compromised

= while increase in blood flow evoked by neural activity is suppressed

= results in mismatch between brain’s energy supply and demand

Question 5

How do risk factors affect cerebral blood vessels?

Answer 5

= increased production of ROS and promotion of inflammation in systemic and cerebral blood vessels

= oxidative stress is related to biological inactivation of nitric oxide
(by the free radical superoxide, which reduces NO bioavailability and prevents its beneficial effects)

= loss of vasoregulatory effects including microvasculature

= loss of anti-aggregant, anti-proliferative and anti-cell adhesion effects
(promotes vascular inflammation)

Question 6

What are stroke triggers?

Answer 6

= precipitating factors
(e.g. atherosclerotic plaque rupture, thrombosis)

= in most cases, factors precipitating ischaemic cannot be established

= some examples:
= systemic infection
= pregnancy and puerperium
= illicit drugs

Question 7

What is the ischaemic core and penumbra?

Answer 7

Icschaemic core zone vs “ischaemic penumbra
= term generally used to define ischaemic but still viable cerebral tissue

Core zone
= area of severe ischemia (blood flow below 10-25%)
= loss of oxygen and glucose results in rapid depletion of energy stores

Severe ischaemia
= results in rapid neuronal death (mins-hrs)
= and supporting cellular elements (glial cells)

Energy deficit results in
= intracellular ionic imbalance
= mitochondrial failure
= activation of intracellular proteases, lipases and ribonucleases
= leading to fast breakdown of cellular structural elements and loss of cell integrity

Brain cells within penumbra may remain viable for several hours
= due to blood being supplied from collateral arteries
= BUT these cells will die is reperfusion is not established during early hours
(since collateral circulation is inadequate to maintain the neuronal demand for oxygen and glucose indefinitely

It may be possible to salvage cells with severely ischaemic core zone
= BUT penumbra is where pharmacologic interventions are most likely to be effective

Question 8

What happens in the Penumbra?

Answer 8

= outside the ischaemic core = brain tissue is still partially perfused
(although at a reduced rate)

= penumbral neurons are functionally compromised
(BUT are salvageable if blood flow is restores)

= even if blood flow restores, neurons in penumbra face major challenged to survival
(e.g. excitotoxicity and inflammation)

Question 9

What is excitotoxicity?

Answer 9

= happens as a result of the uncontrolled release of glutamate from depolarising or dying neurons

= glutamate-mediated activation of NMDA and AMPA receptors

= leads to uncontrolled extracellular calcium influx + dysregulation of intracellular calcium homeostasis

results in:
= generation of ROS and nitrogen species
= mitochondrial dysfunction
= activation of apoptotic cascade
= poly (adenosine diphosphate-ribose) polymerase activation

Question 10

What is the ischaemic cascade?

Answer 10

= sequence of biochemical and physiological events that occur int he brain during an ischaemic stroke

2 phases: early and late

Early phase
= minutes to hours after onset of ischemia
= characterised by depletion of energy stores (e.g. ATP)
= accumulation of harmful substances (e.g. lactic acid, free radicals)
= leads to ion pump failure, membrane depolarisation, release of glutamate = which triggers calcium iflux into neurons = damage

Late phase
= hours to days after onset of ischaemia
= characterised by inflammation and cell death
= release of inflammatory mediators: cytokines and chemokines
= lead to activation of microglia and astrocytes
= release more inflammtory mediators and free radicals
= further damage to neurons and BBB

Question 11

How does BBB breakdown and vasogenic oedema occur?

Answer 11

BBB breakdown after acute ischaemic stroke
= may lead to oedema (first 24-48 hrs)
= and haemorrhagic transformation (bleeding into infarcted area)

BBB breakdown driven by:
= cascade of mediating factors
(E.g. inflammatory processes, formation of ROS, activation of MMP-9)

= associated with poorer clinical outcomes through exacerbation of brain injury

= BBB breakdown evolves with time
(little is known about magnitude and temporal evolution of the damage)

Question 12

How does stroke / cerebrovascular disease relate to Dementia?

Answer 12

= (apart from stoke) there are other presentations of cerebrovascular disease

= include overlap with neurodegenerative disorders (e.g. Alzheimer’s disease - AD)

= AD characterised by deposation of Aβ in brain perenchyma (amyloid plaques) and blood vessels (amyloid angiopathy) and by neurofibrillary tangles

= cerebrovascular disease can lead to cognitive impairement (VCI)

= single stoke - ‘strategic infarct dementia’

= multiple strokes causing stepwise deterioration - ‘multi-infarct dementia’

= most often, small white matter lesions (leukoaraiosis) interrupt neural pathways involved in cognition

= AD and CVD co-exist in up to 60% of cases

Question 13

How does white matter damage lead to vacular cognitive impairement?

Answer 13

Mechanisms of white matter damage unclear
= but there are established family history
(e.g. hypertension, diabetes, chronic smoking)

= White matter lesions (WMLs) compromise demyelination, axonal loss, enlarged perivascular spaces, astrogliosis, microglial activation

= Arteriolar wall thickened by accumulation of hyaline material (lipohyalinosis) or completely disrupted (fibrinoid necrosis)
= microhaemorrhages

= capillary density, resting CBF, cerebrovascular reactivity reduced in normal and affected white matter

Disruption of arteriolar wall by amyloid also associated with WMLs
(as seen in genetic/sporadic forms of cerebral amyloid angiopathy / in AD)

= risk factors for dementia may increase WM susceptibility (ageing)

= disruption of BBB = perivascular oedema, microohaemorrhages, inflammation

= endothelial dysfunction

Question 14

Stroke and Dementia Risk?

Answer 14

= stroke doubles risk of developing dementi
(location, size, number of ischaemic lesions, leukoaraiosis)

= stroke also increases risk for AD

= Alzheimer pathology facilitates development of dementia in patients with ischaemic injury and vice versa

= interaction between amyloid pathology and ischaemic injury previously unrecognised

Aβ has power cerebrovascular effects
= constricts cerebral vessels
= suppresses vascular reactivity
= impairs autoregulation

Ischeamia and hyoxia can induce Aβ accumulation
= promotion of cleavage from APP (amyloid precursor protein)
= downregulation of lipoprotein-related receptor protein-1, critical receptor for vascular clearance of Aβ

Question 15

What is inflammation

Answer 15

= rubor, tumor, calor, dolor

= adherence / invasion of leucocytes into injured or infected tissues

= closely linked to activation of immune system

= kinins, prostanoids, substance P, cytokines

= fever, behavioural changes, endocrine changes
(e.g. hypothaamic-pituitary-adrenal axis activation, acute phase response)

= acute phase response is group of physiological processing occuring soon after onset of infection, trauma, inflammation

= induces a dramatic increase of acute phase proteins in the serum (especially C-reactive protein- CRP)

= host defence responses, including inflammation, generally beneficial
(limit invading pathogens, promote tissue survival, repair, recovery)

= prolonged / unregulated inflammation detrimental

= pro-inflammatory pathways highly regulated by extensive anti-inflammatory processes

Question 16

What are cytokines?

Answer 16

= polypeptides associated with inflammation, immune activation, cell differentiation and death

= macrophages, monocytes, lymphocytes, endothelial cells, fibroblasts, platelets

= activated microglia

= self-regulating network

Question 17

How does inflammation in the brain occur?

Answer 17

= immune privileges

= brain responds to peripheral inflammatory stimuli via neural and humoral afferents

= integrates / regulates many aspects of acute phase response

= exhibits many local inflammatory responses contributing to acute and chronic CNS disease

Question 18

How does the intravascular initiation of inflammatory response occur?

Answer 18

= inflammatory cascade activated immediately after vessel occlusion

= stagnant blood flow and altered rheology induce shear stress on vascular endothelium and platelets

= P-selectin released within minutes
(slows down and attracts circulating leukocytes to endothelial surface)

= leukocyte cluster formation and clogging exacerbates ischaemic injury

= other adhesion molecules promote leukocyte recruitment, adhesion and transmigration
(e.g. E-selectin, ICAM-1, VCAM-1)

= activation of coagulation cascades also enhances inflammation

= complement system activation and associated pathways (converging on C3 activation) associated with unfavourable outcome

= intravascular inflammation sets stage for blood-brain barrier breakdown and leukocytes invasion of ischaemic tissue

= inflammation also initiated in brain parenchyma
(e.g. DAMPs from injures / dying neurons)

Question 19

What is the peripheral immune response to stroke?

Answer 19

DAMPs
= e.g. HMGB1, heat shock proteins

Cytokines
= e.g. microglial activation leading to inflammasome mediated IL-1β release, TNFα production

= both gain access to systemic circulation via disrupted BBB or CSF drainage system

= once in circulation they induce primary and secondary lymphoid organ immune response

= resulting in systemic inflammatory response

= early activation of immune system superseded by state of systemic immunodepression that predisposes to post-stroke infections

= disruption of BBB and brain-CSF barrier releases novel CNS antigens
(e.g. myelin basic protein-derived peptides, neuron-specific enolase)

= exposing them to systemic immune system

= induces T cell responses including damaging Th1 / Th2

Question 20

What are the innate immune cells involved in stroke?

Answer 20

Microglia, monocyte-derived macrophages and dendritic cells
= microglia and monocyte-derived macrophages have largely protective functions in ischaemic brain injury
= initially infiltrating monocytes are of ‘inflammatory’ subtype
= ‘patrolling’ monocytes prevalent at later time points

Neutrophils
= intravascular adhesion occurs early
= parenchumal accumulation observed later

Mast cells
= brain-resident immune cells in perivascular space
= early activation contributes to BBB breakdown and brain oedema

Innate lymphocytes
= T cells detrimental in early phase of ischaemia
(differs from classical antigen-mediated T cell activation)

Question 21

What are the adaptive immune cells involved in stroke?

Answer 21

T cells
= effector T lymphocytes contribute to focal ischaemic injury
= T regs may have protective effect by downregulating postischaemic inflammation
= IL-10 secretion neuroprotective but intravascular Tregs during reperfusion may exacerbate injury
= overall contribution of antigen specific T cells in long term outcome after stroke is unclear

B cells
= have both detrimental and protective properties
= some evidence for B cell response to stroke within CNS

Question 22

Where does evidence for role of inflammation in stroke derive from?

Answer 22

Experimental

Epidermiology

Pathology

Imaging

Clinical trials

Question 23

What is an example of an epidemiological study of link of inflammation to stroke?

Answer 23

= involves CRP and IL-6

= C-reactive protein measured using high-sensitivity assays
(= one of most investigated markers in cardiovascular research)

= predicts ischemic stroke in some, BUT not all populations

= IL-6 = pro-inflammatory cytokine similarly associated with increased vascular risk

= IL-6 is paradoxically linked to anti-inflammatory molecules
(through complex auto-inhibitory feedback mechanisms)

= low ratios of hsCRP to IL-6 have been seen in statin users and morbidly obese patients after weight loss from gastric bypass surgery

= the decrease may reflect improved immune system homeostasis + reduction in underlying inflammatory state

In multi-ethnic cohort
= when hsCRP quartile was higher than IL-6 quartile
(= IS risk increased)

= when the other way around
(= IS risk decreased)

Question 24

How does imaging inflammation in carotid atherosclerosis wor?

Answer 24

= inflammation is component of all forms of atheromatous plaques
(plays key role in destabilisation of vulnerable plaques - with consequent thrombosis and distal thromboembolism)

Studies on carotid endarerectomy samples from symptomatic patients

= shows association between embolic cerebral events and active plaques with a high inflammatory infiltrate

= association seen between macrophage-rich areas within such plaques + microembolic signals detected on transcranial doppler before surgery

= association found between in vivo measures of plaque inflammation detected by FDG PET and presence of transcranial doppler MES

= this strengthens the notion that emobolic events distal to carotid stenoses are related to plaque inflammation
(and that FDG PET may be useful to investigate the carotid lesions involved)

Question 25

What is the risk score?

Answer 25

= based on carotid plaque inflammation and stenosis severity

= it improved identification of recurrent stroke

In randomised trials of symptomatic carotid endarterectomy
= only modest benefit occurred in patients with moderate stenosis and important subgroups experienced no benefit

= carotid plaque FDG uptake on PET (refelecting inflammation) = independently predicts recurrent stroke

= SCAIL score includes FDG standardised uptake values and stenosis
(symptomatic carotis atheroma inflammation lumen-setnosis)

= SCAIL score improved the identification of early recurrent stroke

Question 26

What is Interleukin-1 (IL-1)?

Answer 26

= first cytokine identified to act on brain

= ‘endogenous pyrogen’

Induces:
= fever
= appetite suppression
= weight loss
= sleep modulation
= alterations in endocrine
= immune / nervous system functions
= behavioural changes
= synaptic plasticity
= neuronal transmission
= epilepsy
= neuronal cell death

Question 27

What is the IL-1 receptor antagonist?

Answer 27

= first naturally occurring specific receptor antagonist of any cytokine

= balance between IL-1 and IL-1ra important in determining response to infection and inflammation

= IL-1ra reduces lesion volume in experimental stroke

= intravenous IL-1ra is safe in clinical stroke
(no significant differences in stroke severity or impairement)

= intravenous IL-1ra reduces peripheral markers of inflammation

= subcutaneous IL-1ra also reduces peripheral IL-6
(via upstream action on IL-1)
(BUT has adverse effects)

= IL-1ra could be candidate therapy for IS

Question 28

What are the roles of inflammatory mechanisms and infection in IS?

Answer 28

= inflammation fundamental feature of host immune response to infection

= occurrence of infection before and after AIS well recognised

= research focus on how infection can trigger stroke and influence outcome

= evidence for post-stroke immunodepression

= there is a complex interaction between conventional stroke risk factors and systemic inflammation and chronic infections

= there is seasonal variations in stroke incidence
(winter - excess = suggests environmental factors)

= data exists for link between peripheral infection and stoke risk
(especially bacterial infection)

= infection in week preceding stroke is 10-35%

Question 29

How does acute infection act as a trigger of AIS?

Answer 29

Risk factors that act as acute precipitants of stroke are poorly defined

Systemic infection
= induces transient state of increased stroke susceptibility in the week following infection

= this short window of elevated risk = points to infection (as a potential stroke trigger)

= highest risk period after infection = coincides with high level pro-inflammatory phase of immune response

= potential link with ‘stroke prone’ state

Question 30

What is the link between preceding infection and stroke outcome?

Answer 30

= range of clinical studies support concept that antecedent infection worsens outcome from AIS

= systemic challenge with bacterial endotoxin (LPS) exacerbates ischaemic brain damage in experimental models

= blocked by co-administartion with IL-1ra = similar exacerbation of injury to LPS seen with IL-1β

= LPS resistance in dysfunctional TLR4 signalling

= mechanisms responsible for worsening of ischaemic damage by preceding / concurrent systemic inflammation

Question 31

What is post-stroke infection?

Answer 31

= significant heterogeneity in studies investigating post-stroke infection

= estimated 10% of deaths within 30 days of admission due to pneumonia

= functional outcome also adversely influenced by post-stroke infection

Most consistently reported predictors of post-stoke infection are:
= older age
= greater baseline stroke severity
= total anterior circulation infarction and dysphagia
(BUT pneumonia also common in tube-fed patients, including those ‘nil by mouth’)

Question 32

What is post-stroke immunodepression?

Answer 32

= dysregulation of normally well balances brain-immune interaction after AIS

= spontaneous infections after experimental stroke

= impaired cell-mediated immunity

= reduced peripheral blood lymphocyte counts

= impaired T-cell activity

= links with HPAA-SNS activation

= reduced capacity of LPS to induce cytokine production by blood cells

= strong inverse correlation with early elevated cortisol concentration

Question 33

What are the implications of infection/immunity for clincial practice?

Answer 33

= preceding infection

= vulnerable individuals may have short term increased stroke risk in association with acute systemic infection

= raises prospect of targeting / intensifying stroke prevention strategies at time of acute systemic infection

= statins may protect against endothelial dysfunction related to acute infection / inflammation

= possible statin association with increased post-stroke infection

= vaccination in vulnerable individuals (e.g. influenza)

Question 34

How does COVID-19 relate to stroke?

Answer 34

= SARS-CoV-2 infection associated with many neurological manifestations = including AIS

= various pathophysiological mechanisms associated with peripheral and consequential neural (central) inflammation
= leading to COVID-19 related ischemic stroke

Question 35

What are the inflammatory mediators involved in covid related ischaemic stroke?

Answer 35

Cytokines
= first released by respiratory epithelium
= further released by T cells
= amplification leads to cytokine storm

NLRP3 inflammasomes
(critical components of innate immune system - mediating caspase-1 activation)
= drives production of: cytokines, PAMPs and DAMPs
= may induce plaque instability by overdriving response of cellular mediators
(e.g. macrophages, neutrophils, lymphocytes + vascular smooth muscle cells)

Inflammation-induced plaque vulnerability
= predominance of T cells, macrophages, neutrophils populating atheromatous plaque leading to rupture
= elevation of proteolytic biomarkers (e.g. MMPs)

Oxidised low-density lipoproteins (oxLDL)
= marker of oxidative stress
= covid related disruption of receptor mediated update of oxLDL

Neutrophil extracellular traps (NETs)
= networks of chromatin, proteins, oxidant enzymes protruding from membranes of activated neutrophils, mediate infection containment
= marker of inflammation related thrombosis

Question 36

What is involved in coagulation dysfunction of covid related ischaemic stroke?

Answer 36

D-dimer
= mediates immunologic defence systems resulting in thrombus formation
= increased level is biomarker of fibrinolytic shutdown
(leading to massive fibrin formation and thrombosis)

Natural anticoagulants and antiphospholipid antibodies
= covid-19 induced decrease in physiological anticoagulants
= with increased levels of coagulant factors and antiphospholipid antibodies

Question 37

What is involved in endotheliopathy of covid related ischaemic stroke?

Answer 37

Endothelium-driven activation of extrinisic coagulation system
= imbalance in ACE-2 and angiotensin-II receptors
= leads to upregulation of tissue factor
= tissue factor interacts with factor VII to activate extrinsic coagulation system

Endothelium-driven nitric oxide deficiency
= covid-19 related endothelipathy results in suppression of nitric oxide synthase
= nitric oxide deficiency
= results in loss of vasodilatory effects + promotes adhesion of platelets and leukocytes to vessel wall