Biological basis of stroke, ageing and Alzheimer's

Question 1

What is neurodegeneration?

Answer 1

Progressive damage or death of neurons leading to gradual deterioration of bodily functions controlled by affected area

Question 2

What are the 2 main mechanisms of cell death?

Answer 2

Necrosis - e.g. oxidative stress caused by free radicals, toxic metabolites, excitotoxicity (excited to death) or ingested toxins
Apoptosis - routinely programmed cell death, every cell naturally pre-programmed to die at a certain time in absence of pathology

Question 3

What is the main mechanism for necrotic cell death?

Answer 3

Ischaemic damage e.g. in stroke reduces oxygen supply
Oxidative stress disrupts ionic balance of cell by disrupting ion transport across membrane
Cell becomes depolarised, there is calcium influx and glutamate release and further depolarisation
This cycle of calcium and glutamate release leads to overexcitation of cell –> death

Question 4

What is the energy supply of the brain like?

Answer 4

Brain has limited capacity for energy storage, as so specialised for integration and transmission of info so little room for energy apparatus
Relies heavily on good blood supply

Question 5

What are the 2 types of stroke?

Answer 5

Haemorrhagic - 20% of strokes, involving ruptured blood vessel and internal bleeding
Ischaemic - 80%, blockage of a blood vessel to/within brain

Question 6

What is cell death like in stroke?

Answer 6

Extent of immediate/rapid cell death from acute lack of blood depends on volume of tissue starved and time taken to re-perfuse
Region of immediate death is the CORE and this area is unsalvageable, forming in five minutes and unlikely to be amenable to clot busting drugs unless administered VERY quickly
If treatment delayed too long, this area of cell death becomes dangerously large - need to return blood supply as quickly as possible, ideally within 3 hours to minimise spread of penumbra

Question 7

What is the major concern regarding treatment of stroke?

Answer 7

Type of stroke occurred - reperfusing a haemorrhagic stroke using clot-busting drugs could be disastrous (but need to make treatment decision quickly!)

Question 8

What is the penumbra in a stroke?

Answer 8

Area surrounding core, area of DELAYED cell death, severely compromised but recoverable as not yet dead
Oxidative stress and excitotoxicity leading to necrosis and also accelerated apoptosis occurring here, not directly affected by lack of blood supply

Question 9

What are some effective treatments for stroke penumbras?

Answer 9

Anti-oxidants to reduce oxidative stress
Inhibition of glutamate to reduce excitotoxic process
Inhibition of apoptosis
Calcium ions are a theoretical target for drug therapy to recover tissue and prevent further damage

Question 10

What is ageing?

Answer 10

A process of chronic degeneration, most likely involving subtle changes in cognitive capabilities with differences most easily evident in visual perception and constructional tests, memory mostly preserved (visuospatial)

Question 11

What is ageing associated with?

Answer 11

Shrinkage of brain tissue especially in areas such as hippocampus and frontal lobes
There is both a decrease in number of synapses in these areas and decreased cerebral blood flow resulting in reduced metabolism because areas not receiving required nutrients
Ultimately produces SLOWER COGNITIVE PROCESSING

Question 12

What is a critical feature of ageing to highlight?

Answer 12

Minimal change in the actual NUMBER of neurons, simply the connections between them

Question 13

What are some of the key indicators that cell function is compromised in the brain?

Answer 13

Lewy bodies, b-amyloid plaques and neurofibrillary tangles - same ones seen to greater extent in neurodegenerative diseases

Question 14

What is Mild Cognitive Impairment?

Answer 14

Stage reached as progress through ageing, point at which there is some clinical evidence of cognitive impairment but not severe enough to warrant diagnosis of dementia
Kind of an intermittent period between the normal but declining functioning during ageing and full dementia (most never progress to full dementia)

Question 15

What do we see in the ageing brain in addition to synaptic changes?

Answer 15

Changes to NTs, critically dopamine, serotonin, and glutamate
Dopamine - decreased synthesis and fewer receptors esp in basal ganglia and frontal cortex
Serotonin - decreasing serotonin receptors and serotonin transporter
Glutamate - decreased glutamate conc in motor cortex, parietal lobe, frontal lobe and basal ganglia (areas involved in motor function)

Question 16

What is dementia?

Answer 16

Category of brain disorders that share a common feature of lost brain function that is usually progressive and severe - more intense, rapid and earlier onset of normal ageing changes
Alzheimer’s is the most common - progressive memory loss, motor deficits and eventual death

Question 17

What are the early signs of Alzheimer’s?

Answer 17

Clinical symptoms of neurodegeneration
Blunting of emotional responses
Social withdrawal
MCI –> depression, anxiety, agitation, withdrawal, forgetfulness

Question 18

What are advanced signs of Alzheimer’s?

Answer 18

Gross disorientation in time and space
Inability to comprehend/communicate
Little awareness of past or future
Total dependence on carer

Question 19

What are the 3 main symptoms of Alzheimer’s?

Answer 19

Memory impairment - progressive memory loss, initially episodic and declarative but becoming more widespread
Loss of function - memory, insight, judgement, language production and comprehension
Personality changes - Apathy with decreased motivation and indifference, possibly linked to dopamine

Question 20

What is a key aspect of the physical pathology of Alzheimer’s?

Answer 20

Brain atrophy - cortex dramatically shrinks, ventricles enlarge and hippocampus shrinks dramatically

Question 21

What are 2 key histopathological features of Alzheimer’s?

Answer 21

Senile amyloid plaques - b-amyloid is present in healthy brains but in AD the levels increase and accumulate as insoluble plaques
Neurofibrillary tangles - abnormal aggregates of protein derived from the Tau microtubule protein (microtubules are responsible for transport of chemicals down axon from cell body)

Question 22

What are 2 further pathological changes in an AD brain?

Answer 22

Synaptic loss enhanced beyond that of normal ageing

Selective depletion of NT systems - neurones that use ACh or glutamate are particularly affected esp in forebrain

Question 23

What is the cholinergic hypothesis of AD?

Answer 23

Cholinergic neurones involved in memory, learning and aspects of sleep, all states disrupted in AD
Antagonists of ACh have deleterious effects on learning and memory in healthy people
In AD there is degeneration of ACh-containing neurones in the sub-cortical forebrain, and also deficit in ACh-producing enzymes
So at least a partial cause of AD, or maybe downstream effect of true cause, is degeneration of forebrain cholinergic neurones

Question 24

What are 2 risk factors for alzheimers aside from ageing?

Answer 24

Pre-morbid cognitive capacity - also known as cognitive reserve, if an individual begins their age-related deterioration from a higher level they take longer to reach clinical problems
Brain injury - for example TIAs, in which damage done is small and no obvious acute or chronic changes to behaviour but damage remains and areas can accumulate and lead to changes like cortical shrinking seen in AD

Question 25

What are the 2 main classes of drugs for treating AD?

Answer 25

Acetylcholinesterase inhibitors - most drugs are this category, boosting activity at cholinergic synapses by preventing ACh breakdown e.g. Aricept
Glutamate receptor antagonists - more long-term, e.g. memantine, NMDA-receptor antagonists which protect brain cells from excitotoxicity resulting from excess glutamate