Biological Basis of Brain Damage

1
Biological Basis of Brain Damage

• Dr Claire L Gibson
• cg95_at_le.ac.uk

2
Overview of lecture

• Causes of brain damage
• Cerebral Stroke
• General - Definition/prevalence/symptoms/risk
  factors
• Pathology
• Treatments - current and in research

3
Brain damage

• leads to the death or degeneration of neurones
• Unpredictable
• Various causes

4
Causes of brain damage

• Genetics
• Trauma
• Tumour
• Alterations in blood flow

5
Traumatic Brain Injury

• Physical Trauma
• Males Females (41)
• Car accidents, sports injuries, falls, violence,
  industrial accidents

6
Mechanism of impact

• Neuronal shearing, stretching and tearing
• Retrograde degeneration
• Anterograde degeneration
• Penetrating head injury
• Penetrating mechanism
• Closed head injuries
• Blow to the head but no penetration of skull

7
1. Penetrating head injury

• Effects cortical integrity of brain
• Location of injury
• Complications infection and hemorrhaging

8
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

9
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

10
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

11
Brain Tumours - Classification

• Infiltrative
• infiltrate neighbouring areas
• Non-infiltrative
• Encapsulated, differentiated, compress
• Malignant
• Infiltrative, spread (metastatic)
• Benign
• Non-infiltrative, fibrous capsule, do not spread

12
Brain Tumours

• Diagnosis
• headache, nausea, vomiting ??
• CT Scan, MRI
• Cognitive effects
• Depends on size, location and grade
• Neuropsychological evaluations (surgery)

13
Cerebral Stroke

• Blockage/interruption of cerebral artery ? death
  of cells
• Symptoms depend on location

14
Cerebral stroke
CT Scan
Angiogram
15
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

16
Outcomes

• Death (20)
• Varying degrees of disability (60)
• Achieve neurological recovery (20)
• 2nd stroke

17
Types of stroke
Haemorrhagic (20)
Ischemic (80)
18
Risk factors

• Too many!
• For example hypertension, diabetes, cardiac
  disease, hyperlipidaemia, smoking, family history
  of stroke, obesity, diet, oral contraceptive
  pill, previous stroke

19
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

20
Cognitive impairment

• Amnesia
• Inattention
• Confusion
• Depression
• Mood and behaviour changes

21
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.

22
Pathology of stroke

• 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
• Cascade of complex events
• cell death, inflammation, reperfusion

23
Glutamate Receptors
Ionotropic
Metabotropic
Kainate
NMDA
AMPA
Many subtypes
24
Events following stroke

• Excitotoxicity
• Cell death
• Inflammation

25
Events following stroke

• 1. Excitotoxicity

? blood flow
Mitochondrial dysfunction
disruption
Ion homeostasis
? ATP
glu
glu
glu
gene activation
glu
glu
Ca2
Ca2
Ca2
Cell Death
Ca2
NMDAR
Ca2
Ca2
inflammation
free radical production
Ca2
Ca2
26
Calcium

• Second messenger

Damage cell structures

• Activate enzymes

• e.g. Phospholipases
• Endonucleases
• Proteases

e.g. components of cytoskeleton, membrane and DNA
27
Core and penumbra


sub-optimal blood flow (potentially
salvageable) blood flow below critical, cell
death
28
Pathology of stroke

• Cell death
• Core - rapid
• Penumbra -slower

29
Events following stroke

• 2. Cell death

30
Events following stroke

• 2. Cell death - apoptosis

Intracellular signals
Extracellular signals
Several pathways NFkB, P53, Bcl
Caspases formed
Caspase 3
DNA breaking enzymes e.g. endonucleases
Energy consuming DNA repair enzymes e.g. PARP
DNA breakdown
Cell death
31
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)

32
Current treatments

• Tissue Plasminogen Activator (t-PA)
• Thrombolytic
• Licensed for stroke
• 3 hours
• CT scan
• gt49 neuroprotective agents studied in gt114 stroke
  trials

33
Why no effective treatment?

• Pathology indicates obvious choices?
• NMDA receptor antagonists e.g. MK-801
• Anti-inflammatory agents
• Caspase inhibitors
• BUT
• Pathology is complex
• Animal studies often poorly designed

34
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?

35
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

36
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!