1. 1 Biological Basis of Brain Damage Dr Claire L Gibson cg95@le.ac.uk

2. 2 Overview of lecture Causes of brain damage Cerebral Stroke General - Definition/prevalence/symptoms/risk factors Pathology Treatments - current and in research

3. 3 Brain damage ‘ leads to the death or degeneration of neurones’ Unpredictable Various causes

4. 4 Causes of brain damage Genetics Trauma Tumour Alterations in blood flow

5. 5 Traumatic Brain Injury Physical Trauma Males : Females (4:1) Car accidents, sports injuries, falls, violence, industrial accidents

6. 6 Mechanism of impact Neuronal shearing, stretching and tearing Retrograde degeneration Anterograde degeneration 1. Penetrating head injury Penetrating mechanism 2. Closed head injuries Blow to the head but no penetration of skull

7. 7 1. Penetrating head injury Effects cortical integrity of brain; 1. Location of injury 2. Complications – infection and hemorrhaging

8. 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. 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. 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. 11 Brain Tumours - Classification 1. Infiltrative infiltrate neighbouring areas 2. Non-infiltrative Encapsulated, differentiated, compress Malignant Infiltrative, spread (metastatic) 2. Benign Non-infiltrative, fibrous capsule, do not spread

12. 12 Brain Tumours Diagnosis  headache, nausea, vomiting ??  CT Scan, MRI Cognitive effects  Depends on size, location and grade  Neuropsychological evaluations (surgery)

13. 13 Cerebral Stroke Blockage/interruption of cerebral artery → death of cells Symptoms – depend on location

14. 14 Cerebral stroke CT ScanAngiogram

15. 15 Prevalence In the Western World  250-400 strokes per 100 000 people  3 rd cause of death  1 st cause of disability (in adults) NHS Social services Carers Family members

16. 16 Outcomes Death (20%) Varying degrees of disability (60%) Achieve ~neurological recovery (20%) 2 nd stroke

17. 17 Types of stroke Ischemic (80%) Haemorrhagic (20%)

18. 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. 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. 20 Cognitive impairment Amnesia Inattention Confusion Depression Mood and behaviour changes

21. 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. 22 Pathology of stroke 1. 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 events cell death, inflammation, reperfusion

23. 23 Glutamate Receptors Ionotropic Metabotropic NMDA AMPA Kainate Many subtypes

24. 24 Events following stroke 1. Excitotoxicity 2. Cell death 3. Inflammation

25. 25 Events following stroke 1. Excitotoxicity NMDAR inflammation Cell Death  blood flow Ion homeostasis  ATP Mitochondrial dysfunction free radical production gene activation disruption glu Ca 2+

26. 26 Calcium Second messenger Activate enzymes Damage cell structures e.g. Phospholipases Endonucleases Proteases e.g. components of cytoskeleton, membrane and DNA

27. 27 Core and penumbra * * = sub-optimal blood flow (potentially salvageable) # = blood flow below critical, cell death # Hours MinutesDays and weeks

28. 28 Pathology of stroke 2. Cell death  Core - rapid  Penumbra -slower

29. 29 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 Hours MinutesDays/weeks

30. 30 Events following stroke 2. Cell death - apoptosis Intracellular signals Caspases formed Several pathways – NF  B, P53, Bcl DNA breaking enzymes e.g. endonucleases Caspase 3 DNA breakdown Energy consuming DNA repair enzymes e.g. PARP Extracellular signals Cell death

31. 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. 32 Current treatments Tissue Plasminogen Activator (t-PA) Thrombolytic Licensed for stroke 3 hours CT scan >49 neuroprotective agents studied in >114 stroke trials

33. 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. 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. 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. 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!