Neurobiology of Ageing (A*) Flashcards
In short, why is the central nervous system irreparable?
The irreparability of the central nervous system is a byproduct for its complexity.
Give an overview of the process of long-term potentiation.
Long-term potentiation:
- Long-term potentiation is the strengthening of synaptic connectivity between two neurones that undergo frequent communications with each other - ‘fire together, wire together’.
- This is a form of synaptic plasticity.
- Synaptic activity between two neurones results in the synthesis and secretion of neurotrophins. This results in changes to:
1 - Postsynaptic responsiveness.
2 - Presynaptic neurotransmitter release.
3 - Synaptic morphology.
4 - Membrane excitability.
Which factors influence the synaptic plasticity of the brain?
1 - Synaptic plasticity varies topographically.
- Regions of the brain that are involved in integration, such as the limbic system (esp. hippocampus), are the most plastic.
- Regions of the brain that have descriptive and executive functions, such as the primary sensory and motor areas, are the least plastic.
2 - Synaptic plasticity varies with age; younger brains are more plastic.
3 - Synaptic plasticity varies with phylogeny; phylogenetically newer regions of the brain are more plastic.
List 3 examples of structural changes that occur with normal ageing.
During normal ageing:
1 - Grey matter volume decreases.
- This is particularly noticeable with the hippocampus because more plastic structures are more vulnerable to loss with ageing.
2 - White matter volume decreases.
3 - CSF volume increases (because the ventricles have more space to expand).
How does the haemodynamic response of the brain change with normal ageing?
How does this affect brain function?
- During normal ageing, the ability of different brain regions to increase perfusion simultaneously decreases.
- This has a negative impact on performing tasks which require cooperative functioning of different brain regions because the brain has no energy stores of its own and is highly metabolically active, and therefore needs a functionally reactive blood supply.
Why do more plastic regions of the brain decay more quickly with age?
Plastic regions of the brain decay more quickly with age because:
- Plastic neurones have a high degree of synaptic remodelling, increasing the risk of missignalling and cell cycle errors, resulting in cell death.
- Plastic neurones express ROS and RNS, which are signaling molecules used in LTP. This causes oxidative stress, resulting in:
1 - Mitochondrial dysfunction.
2 - Impairment of DNA repair.
3 - Low ATP production.
4 - Accentuation of the inflammatory response, which can cause further damage by inducing reactive microgliosis.
- By these mechanisms, ROS and RNS are thought to be involved in the pathogenesis of Parkinson’s disease and Alzheimer’s disease (and other diseases not related to synaptic plasticity such as ischaemic stroke).
- Damage by these mechanisms occurs in both neurones and glia.
What is the function of the ATM protein?
How does the function of ATM change with age?
- ATM is a kinase that is recruited and activated by DNA double-strand breaks.
- It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis.
- The ATM damage response reduces with age.
What is the difference between global ischaemia and focal ischemia?
List 5 causes of global ischemia and 4 causes of focal ischaemia.
- Global ischemia involves wide areas of brain tissue. It is caused by:
1 - Cardiac arrest.
2 - Hypoxia, e.g. due to CO poisoning.
3 - Hypoglycaemia.
4 - Severe anaemia.
5 - Generalised seizures.
- Focal ischemia is ischaemic damage confined to a specific region of the brain. It is caused by:
1 - Ageing.
2 - Hypertension.
3 - Diabetes.
4 - Cerebral amyloid angiopathy.
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5 - Hyperhomocysteinemia.
6 - Hypercholesterolaemia.
Describe the process by which ischaemia leads to cell death.
What changes occur following ischaemic damage?
Which disease might arise if this process becomes uncontrolled?
1 - Ischaemia leads to a depletion in ATP.
2 - The decrease in ATP changes the structure of the cell membrane, affecting permeability.
- The change in permeability leads to water entry into the neurones, resulting in cell swelling and, eventually, cytotoxic oedema.
- The change in permeability also affects the movement of ions, resulting in depolarisation.
- Depolarisation results in the activation of cytotoxic enzymes, both directly by neurotransmitters and indirectly by Ca2+.
3 - The buildup of free radicals also causes membrane lipid peroxidation, resulting in cell damage directly and indirectly by triggering an inflammatory response.
- 1-2 days after ischaemic damage, neurones become visibly swollen.
- 2 weeks after ischaemic damage, tissue necrosis occurs and angiogenesis occurs.
- 2 months after ischaemic damage, a glial scar (gliosis) forms.
- With healthy ageing, focal ischaemia occurs, resulting in lots of small infarcts known as lacunae, which build up over time, contributing to cognitive impairment and other behavioural changes.
- If this process is uncontrolled, vascular dementia (multi-infarct dementia) occurs.
How do amyloid and tau proteins affect the cell cycle?
How does this relate to ageing?
- Amyloid beta and tau prevent continuation of the cell cycle from G2 into M, resulting in cell death.
- Amyloid beta and tau load increases with healthy ageing, causing cell death.
List 3 hormones that can contribute to age-related changes in the brain.
Hormonal changes that contribute to age-related changes in the brain include:
1 - Decreasing oestrogen.
2 - Decreasing thyroid hormone.
3 - Increasing cortisol (can result in damage to the hippocampus by reducing glucose metabolism).
List 4 ways of protecting the brain against age-related changes.
Age-related changes in the brain can be protected against by:
1 - Staying intellectually engaged.
2 - Maintaining cardiovascular activity.
3 - Minimising chronic stressors (cortisol!).
4 - Maintaining a healthy diet - A* examples:
1 - Avoiding excessive alcohol.
- However, moderate alcohol consumption is thought to be protective against cerebrovascular risk.
2 - Maintaining a low energy, high antioxidant diet.
- That said, evidence for common antioxidant supplements such as Piracetam and ginkgo biloba extract is unclear (Peters, 2006).
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At what rate does the volume of the brain decline?
List the brain areas that are more severely affected by age-related changes in volume.
List any sex differences.
At what age does the volume of the brain start to decline?
- The volume of the brain declines at a rate of 5% every 10 years.
At study by Scahill et al. (2003) measured changed in volume of different brain regions over time (in men and women), and identified that the brain regions most susceptible to age-related changes in volume are (from most severe to least):
1 - Prefrontal cortex.
2 - Corpus striatum.
3 - Temporal lobe.
4 - Cerebellum.
5 - Hippocampus.
- The occipital lobe was identified as the brain region that is least susceptible to age-related changes in volume.
- There are also sex differences. The most severely affected regions were the temporal and frontal lobes in men, and the parietal lobes and hippocampuses in women.
- Reductions in brain volume begins approximately at the age of 40.
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Which function is most severely affected with ageing?
- The brain function most severely affected by ageing is memory.
- Semantic and episodic memory are more vulnerable than procedural and working memory.
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What is HAROLD?
- HAROLD is hemispheric asymmetry reduction in older adults.
- It refers to the phenomenon in which the capacity for the brain to carry out asymmetrical activation decreases with age.
- This leads to impairment of what is known as ‘inter-hemispheric independence. This is a hypothesis that suggests that brain functions were lateralised during evolution in response to the expanding volume, allowing the brain to bypass delays associated with inter-hemispheric conduction.
- Studied have identified HAROLD in older patients in the prefrontal cortex (Cabeza, 2001), which might explain age-related changes in episodic memory, which is mediated primarily by the prefrontal cortex.
