1 biological basis of brain damage dr claire l gibson cg95@le.ac.uk

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Biological Basis of Brain Damage

Dr Claire L Gibson

cg95@le.ac.uk

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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!