Cerebrovascular Disease Flashcards
What is the epidemiology of a Stoke?
= 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)
What are some different stroke types / aetiologies?
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
What are some risk factors for stroke?
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
How do risk factors increase the propensity to stroke?
= 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
How do risk factors affect cerebral blood vessels?
= 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)
What are stroke triggers?
= 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
What is the ischaemic core and penumbra?
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
What happens in the Penumbra?
= 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)
What is excitotoxicity?
= 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
What is the ischaemic cascade?
= 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
How does BBB breakdown and vasogenic oedema occur?
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)
How does stroke / cerebrovascular disease relate to Dementia?
= (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
How does white matter damage lead to vacular cognitive impairement?
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
Stroke and Dementia Risk?
= 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
What is inflammation
= 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
What are cytokines?
= polypeptides associated with inflammation, immune activation, cell differentiation and death
= macrophages, monocytes, lymphocytes, endothelial cells, fibroblasts, platelets
= activated microglia
= self-regulating network
How does inflammation in the brain occur?
= 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
How does the intravascular initiation of inflammatory response occur?
= 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)
What is the peripheral immune response to stroke?
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
What are the innate immune cells involved in stroke?
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)
What are the adaptive immune cells involved in stroke?
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
Where does evidence for role of inflammation in stroke derive from?
Experimental
Epidermiology
Pathology
Imaging
Clinical trials
What is an example of an epidemiological study of link of inflammation to stroke?
= 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)
How does imaging inflammation in carotid atherosclerosis wor?
= 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)
