Degeneration of Nervous system Flashcards
Neurodegeneration
‘Progressive damage or death of neurons leading to a gradual deterioration of the bodily functions controlled by the affected part of the nervous system.’
Acute neurodegeneration
Stroke
Chronic neurodegeneration
Alzheimers, Parkinsons, Huntington’s Chorea
Cerebral stroke
Blockage/interruption of cerebral artery
Death of cells
Symptoms – depend on location
Prevalence of strokes
- In the UK
250-400 strokes per 100 000 people
3rd cause of death
1st cause of disability (in adults)
Ischemic stroke (80%)
Occur when blockage within blood vessel - stops flow or reduces flow to area of the brain
Haemorrhagic (20%)
Individual experiences area of bleeding as blood vessel bursts
High blood pressure
Cerebral arteries under pressure
Haemorrhagic stroke
May experience anuerism
Risk of stroke
At all stages of lifespan
Important factor but can occur at any stage
1 in 4 working age adults
Risk Factors
Age
Medical conditions (high blood pressure, diabetes, high cholesterol etc.)
Lifestyle (smoking, drinking, diet, exercise)
Family history and ethnicity (Likely related to incidence of other risk factors (e.g diabetes, high cholesterol)
Specific for women (pregnancy, contraceptive pill)
Clinical symptoms
symptoms depend on where the stroke is occurring
Sudden or gradual onset
One sided limb weakness/paralysis
Confusion, loss of speech or vision
Headache
Loss of consciousness
= results in dysfunctional cognitive and motor behaviour… determined by size and location of cell loss
Cognitive impairment
Amnesia
Inattention
Confusion
Depression
Mood and behavioural changes
Depression
Common after stroke
Often differ from those with primary depression, they have more cognitive impairment, irritability, more psychomotor slowing and more mood liability
Transient Ischemic Attach (TIA)
Transient episode of neurological dysfunction without acute tissue death
- Disruption of CBF
- Mini-strokes
- Risk factor for subsequent stroke
* 10% strokes within 90 days of TIA
- Silent strokes
* No visible symptoms
Cerebral Stroke pathology
Massive cell death - caused by excessive amounts of glutamate
Inflammation, cell death, reperfusion - trying to re-establish blood flow
Inflammation
Inflammation
- Sodium ions – water, swell, inflammation
Microglia – become phagocytic
Phagocytosis = ‘cell-eating’
Blood-brain barrier breakdown – influx of blood-borne immune cells (neutrophils, macrophages)
Oedema formation, adhesion molecules, cytokines (brain swelling, stroke0
Mechanisms of cell death
Necrosis and Apoptosis
Necrosis
decrease in oxygen
depleted ATP
Cellular swelling and membrane break down
Apoptosis
= triggering of the death programme
Intracellular signalling
Cells fragment into vesicles
Phagocytosis
Hyperperfusion
A major increase in CBF, well above metabolic demands of the CNS tissue
Intracranial haemorrhage/edema
Mortality 36-63%
80% patients significant morbidity
Excitatory neurotransmitters
glutamate and aspartate
Inhibitory neurotransmitters
GABA and glycine
Closely related neurotransmitters
GABA and Glutamate
Lucas and Newhouse 1957
glutamate caused retinal damage
Olney 1969
glutamate produced brain damage in neonatal mice
Ultrastructural studies
amino acid treatment = postsynaptic (but not presynaptic) alterations
Excitotoxic hypothesis
Excess amino acids results in prolonged depolarization of receptive neurones which in some way* leads to their eventual damage or death
GABA system
functions in opposite to glutamate
during ischemia - GABA accumulates in extracellular space
Increase activation in GABA override excessive excitation of glutamate
Stroke treatments
Pharmacological
Thrombolysis (break down clots)
Aspirin
Modifiable risk factors
Physiotherapy
Drugs and receptors
Effect after synaptic function
Agonist - increase NT
Antagonist - decrease NT
direct= attaches to NT binding site
indirect = drug binds to alternative binding site
Non-competitive binding = does not compete with NT
Pharmacological treatments
Neuroprotection - aims to protect neurones from injury (limited by time window and effectiveness)
NMDA receptor antagonists - obvious choice for treating stroke
NMDA receptor antagonists
- Proved to be the most successful compounds ever generated to protect against cell death in vitro and in vivo (models)
- Various compounds developed
ALL clinical trials have failed, why?
Lack of efficacy
Toxic side effects
Aspirin
- Antiplatelet agents (and anticoagulant)
- Prevention of recurring strokes
- Reduction of severity of stroke
Inhibit production of thromboxane (decrease natural levels of blood clotting)
Physiotherapy
- Weakness/paralysis
- Improve motility/avoid injury
- Re-gain everyday activities
- Promote Independent living
- Exercise, manipulation, massage, skills training, electrical treatment
