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Overview of lecture Causes of brain damage Cerebral Stroke General - Definition/prevalence/symptoms/risk
factors Pathology Treatments - current and in research
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Brain damage
‘leads to the death or degeneration of neurones’
Unpredictable Various causes
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Causes of brain damage
Genetics Trauma Tumour Alterations in blood flow
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Traumatic Brain Injury
Physical Trauma Males : Females (4:1) Car accidents, sports injuries, falls,
violence, industrial accidents
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Mechanism of impact Neuronal shearing, stretching and
tearing Retrograde degeneration Anterograde degeneration
1. Penetrating head injuryPenetrating mechanism
2. Closed head injuriesBlow to the head but no penetration of skull
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1. Penetrating head injury
Effects cortical integrity of brain;1. Location of injury
2. Complications – infection and hemorrhaging
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2. Closed head injury= Acceleration and/or deceleration Acceleration
Significant physical force, propels brain quickly from stationary to moving
Deceleration Brain is already in motion – stops abruptly
Impact injury – or at its opposite pole
Shear, tear and rupture nerves, blood vessels and the covering of the brain
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Head Injury - Consequences
Glasgow Coma Scale (GCS) Edema, Intracranial bleeding, Skull fractures Post-traumatic epilepsy/seizures
Symptoms;Difficulties with
Memory, concentration, attention, Alterations in mood
Hugely variable
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Brain Tumours
5% of all cancers
Tumours = morbid enlargement of new growth/tissue in which cell multiplication is uncontrolled and progressive
Growth = disorganised, often at expense of surrounding, intact tissue
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Brain Tumours - Classification
1. Infiltrative infiltrate neighbouring areas2. Non-infiltrative
Encapsulated, differentiated, compress
MalignantInfiltrative, spread (metastatic)
2. BenignNon-infiltrative, fibrous capsule, do not spread
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Brain Tumours
Diagnosisheadache, nausea, vomiting ??CT Scan, MRI
Cognitive effectsDepends on size, location and gradeNeuropsychological evaluations (surgery)
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Cerebral Stroke
Blockage/interruption of cerebral artery → death of cells
Symptoms – depend on location
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Cerebral stroke
CT Scan Angiogram
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Prevalence
In the Western World 250-400 strokes per 100 000 people 3rd cause of death 1st cause of disability (in adults)
NHS Social services Carers Family members
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Outcomes
Death (20%) Varying degrees of disability (60%) Achieve ~neurological recovery (20%)
2nd stroke
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Types of stroke
Ischemic (80%) Haemorrhagic (20%)
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Risk factors
Too many!For example: hypertension, diabetes, cardiac
disease, hyperlipidaemia, smoking, family history of stroke, obesity, diet, oral contraceptive pill, previous stroke…
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Clinical symptoms Sudden or gradual onset One-sided limb weakness/paralysis Confusion, loss of speech/vision Headache Loss of consciousness
= results in dysfunctional cognitive and motor behaviour
… determined by size and location of cell loss
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Cognitive impairment
Amnesia Inattention Confusion Depression Mood and behaviour changes
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Depression
Common after stroke Not simply a consequence of physical effects Patients with PSD often differ from those with
primary depression in that they have more cognitive impairment (memory and concentration problems), irritability, more psychomotor slowing, and more mood liability.
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Pathology of stroke1. Massive cell death What causes death of neurones following
interruption of their blood supply? Are cells simply starving to death because they
lose their supply of glucose and oxygen?
No - primary cause of cell death is excessive amounts of glutamate
ischemic lesion = excitotoxic lesion
2. Cascade of complex eventscell death, inflammation, reperfusion
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Glutamate Receptors
Ionotropic Metabotropic
NMDA AMPA Kainate Many subtypes
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Events following stroke
1. Excitotoxicity
2. Cell death
3. Inflammation
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Events following stroke 1. Excitotoxicity
NMDAR
inflammation
Cell Death
blood flow
Ion homeostasis ATP
Mitochondrial dysfunction
free radical
production
gene activation
disruption
glu
glu
gluglu
glu
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+Ca2+
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Calcium
Second messenger
Activate enzymes Damage cell structures
e.g. Phospholipases
Endonucleases
Proteases
e.g. components of cytoskeleton, membrane
and DNA
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Core and penumbra
*
* = sub-optimal blood flow (potentially salvageable)# = blood flow below critical, cell death
#
HoursMinutes Days and weeks
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Pathology of stroke
2. Cell death Core - rapid Penumbra -slower
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Events following stroke 2. Cell death
Apoptosis
Cells fragment into vesicles
= triggering of the death programme
Phagocytosis by neighbouring cells
Intracellular signalling(caspases)
Necrosis
Cellular swelling and membrane break down
Depleted ATP
↓ oxygen
HoursMinutes Days/weeks
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Events following stroke 2. Cell death - apoptosis
Intracellular signals
Caspases formed
Several pathways –NFB, P53, Bcl
DNA breaking enzymese.g. endonucleases
Caspase 3
DNA breakdown
Energy consuming DNA repairenzymes e.g. PARP
Extracellular signals
Cell death
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Events following stroke 3. Inflammation
Excessive glutamate = excessive amounts of sodium and calcium in cells
High levels of sodium – cells absorb water and swell (edema)
Inflammation
Resident – microglia
BBB breakdown
Infiltrating – neutrophils, macrophages, T- and B-lymphocytes
Phagocytosis (cell-eating)
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Current treatments
Tissue Plasminogen Activator (t-PA) Thrombolytic Licensed for stroke 3 hours CT scan
>49 neuroprotective agents studied in >114 stroke trials
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Why no effective treatment? Pathology indicates obvious choices?
NMDA receptor antagonists e.g. MK-801Anti-inflammatory agentsCaspase inhibitors
BUT… Pathology is complex Animal studies often poorly designed
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Current research
NXY-059: free radical scavenger Developed by Astra Zeneca Currently undergoing Phase III clinical trials
Stem cells Replacement of dead neurones with new ones Realistic?
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Summary With the help of this lecture and further
reading you should be able to:
Describe types and symptoms of stroke Understand the underlying pathology of
stroke Describe rationale for developing therapies Discuss current and future therapies
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Remember
Understand basic principles first (probably from text book or review paper)
… then progress on to further reading
All references mentioned in lecture on handout/module website
Thank you!
