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Cellular & Molecular Pathology > Molecular pathology of brain injury > Flashcards

Molecular pathology of brain injury Flashcards

1
Q

give 4 examples of 4 chronic neurodegenerative conditions

A

alzheimers disease
parkinsons disease
multiple sclerosis
prion disease

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2
Q

give 4 examples of acute neurodegenerative conditions

A

traumatic brain injury
stroke
transient ischaemic attack (TIA)(mini stroke)
intracranial haemorrhage

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3
Q

what are the two main differences between chronic and acute neurodegeneration?

A

chronic: slow onset, progressive
acute: sudden onset, secondary progression

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4
Q

who fraction of stroke sufferers survive?

A

two thirds

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5
Q

how many strokes happen every year?

how many are first strokes

A

152,000 strokes every year
(100,000 are first strokes)

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6
Q

how many strokes happen every year?

how many are first strokes

A

152,000 strokes every year
(100,000 are first strokes)

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7
Q

how many people in the uk are stroke survivors?

A

1 in 53
(1.2 million people)

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8
Q

what percentage of those who have strokes need caring for themselves, have speech impediments, or have to be institutionalised?

A

31% need help caring from themselves
71% have speech impediments
16% have to be institutionalised

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9
Q

what is the 4th most common cause of death in the UK?

A

stroke

5% men, 8% women

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10
Q

incidence of first stroke __ every __ after __

A

incidence of stroke double every decade after 55

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11
Q

which ethinic group has the lowest risk of stroke

A

caucasian

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12
Q

what reasons underly the reduction of mortality from stroke?

A

improved clinical pathways
wider access to specialist stroke wards
increased public and professional awareness (eg FAST campaign)

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13
Q

give four risk factors of stroke

A

hypertension
diabetes (type 2)
hypercholestrolaemia
previous stroke or transient ischaemic attack

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14
Q

what are the two major types of stroke

share of all and approx mortality

A

Ischaemic stroke: 85% of all strokes, 30% mortality

Haemorrhagic stroke: 15% of all stroke, 70% mortality

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15
Q

what is ischaemia

A

loss of blood supply to areas downstream of the clot

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16
Q

neurological deficit of a stroke is determined by what

A

location of the clot

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17
Q

what is the most common vessel affected in strokes?

A

Middle cerebral artery (>50% of strokes)

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18
Q

breifly describe the mechanims of neurodegeneration following descreased blood supply

A
  1. a decrease in blood supply results in a descrease in oxygen and glucose levels which leads to energy failure
  2. energy failure leads to loss of protein synthesis resulting in a decrease in protective protein, failure of Na/K ATPase cause depolarisation and anaerobic metabolism leading to decrease in pH (acidic environment due to lactate).
  3. depolarisation leads to release of neurotransmitter (glutamate) as well as increase in calcium levels. the acidic environment also causes release of calcium.
  4. these increased calcium levels lead to oedema, activated proteases and free radicals which all cause cell death
  5. in addition, reperfusion results in aerobic metabolism and inflammatory response with both add to the free radicals that lead to cell death
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19
Q

what is reperfusion?

A

the restoration of blood flow to an organ or tissue after having been blocked

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20
Q

what are the four types of glutamate receptors?

A

NMDA
AMPA
Kainate
metabotropic

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21
Q

blockage of postsynaptic glutamate receptors is __

glutamate antagonists are __

A

neuroprotective

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22
Q

direct application of low concentrations of AMPA/NMDA is highly __

A

neurotoxic

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23
Q

why isnt direct application of glutamte not neurotoxic?

A

because glutamate is an endogenous neurotransmitter and the brain already has mechanisms in place to get rid of it

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24
Q

under what conditions do physiological concentrations of glutamate become hghly toxic

A

hypoxic conditions

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25
Q

In ischaemia why does loss of ATP result in depolarisation and normalisation of transmembrane ionic gradients

A

loss of ATP means that the sodium potassium ATPase no longer functions, meaning the sodium gradient is no longer present
this means that the cotransport of glutamine with sodium no longer occurs

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26
Q

free radicals are natural by products of what parts of cellular metabolism

A
  • oxidative metabolism
  • enzyme reactions
  • inflammatory cells
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27
Q

what regulate free radicals

A

superoxide dismutases (Cu/ZnSOD, MnSOD)
glutathione peroxidase

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28
Q

why are free radicals so reactive

A

due to an unpaired electron

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29
Q

what three things lead to reactive oxygen species in ischaemia

A

substrate limitation leads to nitric oxide synthase uncoupling
Ca overload leads to mitochondrial depolarisation and NOX/p22
preotease activation leads to xanthine dehydrogenase conversion to xanthine oxidase

30
Q

what are the four types of nitric oxide synthase (NOS)

A

endothelial eNOS
neuronal nNOS
inducible iNOS
mitochondrial mtNOS

31
Q

nitric oxide formation is mediated by what

what is the equation

A

arginine -> NO + citrulline + H2O

mediated by nitric oxide synthase

32
Q

what happens to Nitric oxide when it enters the mitochondria

A

preferentially reacts with superoxide to form peroxynitrite which is highly toxic

NO + O2- -> ONOO-

33
Q

what is the drug currently used to treat stroke

A

Tissue plasminogen activator (tPA)

34
Q

why are there so many regulations for who can be given tPA

what are they

A

Because of the risk of hemorrhage is thought to outweigh any potential benefits, patients with any absolute contraindication should not be given tPA.
because 6.4% of those who received tPA had an intracerebral haemorrhage within 36 hours

  • requires absolute certainty that there is no intracranial bleeding
  • very limited time window of efficacy: within 4.5 hours of onset

ageed between 18-79

  • very small percentage (12-20%) of patients actually receive r-tPA
35
Q

excitotoxicity and free radical production onset occurs and ends within what period after onset of ischaemia

A

3-4 hours

36
Q

describe the progressionof degeneration

A
37
Q

Expression of what groups of genes are increased following ischaemia

A

Immediate early genes
Heat shock proteins
Cytokines
Growth factors
Adhesion molecules
Protease inhibitors
Remodelling factors

38
Q

compare the peripheral and CNA inflammatory response

A
  • Perioheral inflammatory response
    o Expression of adhesion molecules
    o Recruitment and activation of pahgocytes
    o Increase vascular permeability
    o All driven by cytokines
  • In CNS
    o Rapid and sustained upregulation of cytokines
    o Inflammatory response delayed by hours-days
    o Local activation of microglia
    o Differential sensitivity of parenchyma and menige
39
Q

what is the predominant form of Interleukin 1 in the brain

A

Interleukin 1 beta

40
Q

how is interleukin beta fromed

A

by activation of IL-1 converting enzyme (caspase-1)

41
Q

how is interleukin beta fromed

A

by activation of IL-1 converting enzyme (caspase-1)

42
Q

what is the selective endogenous antagonist of interleukin 1

A

Interleukin 1ra

43
Q

what are the effects of interleukin 1 beta in the CNS?

A

In endothelium - increase in permeability, upregulation of ICAM-1
In glia - astrogliosis, proliferation of microglia, release of neurotoxins
In neurons/other cells - COX-2 induction, NO production, induction of TNFalpha

44
Q

name the contradictory effects of interleukin 1

A

elevated IL-1 after injury is linked to neurodegeneration
however IL-1 has also been shown to: increase glial activation and proliferation, induce synthesis of nerve growth factor, enhance neuronal sprouting, promote neovascularisation, decrease calcium entry into neurons, enhance GABA activity all of which may be neuroprotective

45
Q

in clinical trials with IL1ra (for strike) what occurred and why didn’t they follow through further with it

A

the proportion of patients in the upper group of the independence scales significantly increased with IL-1ta treatment
however it had no effect at all on the that were more severely affected by their stroke(even increasing the worst outcomes)

46
Q

in clinical trials with IL1ra (for strike) what occurred and why didn’t they follow through further with it

A

the proportion of patients in the upper group of the independence scales significantly increased with IL-1ta treatment
however it had no effect at all on the that were more severely affected by their stroke(even increasing the worst outcomes)

47
Q

why cant the neuroprotective effects of TNFalpha be utilised clinically

A

because the mechanism that contributes to the neuroprotective effects is needed to be triggered before ischaemia sets in
TNF activation leads to superoxide poduction which increases the superoxide dismutase produced
pretreatment allows time for production of dismutases to deal with the effects of free radicals

If there is a delay after a period of ischaemia, TNF actually contributes to more cell death

48
Q

give two examples of independence scales used to monitor patients after brain injury

A

Barthel index
Modified rankin scale

49
Q

what are the three main cytokines upregulated after head injury

A

IL-1beta
IL-6
TNF alpha

50
Q

what is the largest cause of death and long term disability in the under 35s in the developed world

A

traumatic brain injury

51
Q

there is correlation between cytokine production and outcome of traumatic brian injury between only 1 of the cytokines, which is it?

A

IL-6

52
Q

What is the ischaemic penumbra

A

an area of constrained blood flow with partially preserved energy metabolisM

53
Q

why is glutamate uptake reduced in stroke

A

GLutamate uptake is driven by the sodium concentration gradient. If no sodium gradeitns then nothing is driving glutamate uptake so it stays in synapse and builds up moving to the next synapse. killing cells quickly

54
Q

why is glutamate uptake reduced in stroke

A

GLutamate uptake is driven by the sodium concentration gradient. If no sodium gradeitns then nothing is driving glutamate uptake so it stays in synapse and builds up moving to the next synapse. killing cells quickly

55
Q

Under hypoxic conditions, physiological concentrations of glutamate become highly toxic… WHY

A

During hypoxia-ischemia, as cellular energy reserves and Na+ gradients fall, increased release and impaired uptake of glutamate mediate a toxic buildup of extracellular glutamate, leading to overstimulation of glutamate receptors and consequent neuronal cell death

56
Q

Under physiological conditions large quantities of ATP required to maintain resting potential, how do they do this?

A

It mediates activity of the SOdium potassium ATPase pump
channelling 3 sodiums out of the cell and 2 potassiums into it to create a sodium gradient and membrane potential of -60mV

57
Q

how does calcium overload affect mitochondria?

A

Can drive production of ROS and effect breakdown of other things in the cells like Xanthine
causing over production of ROS

58
Q

how do reactive oxygen species cause cell death?

A

Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis

59
Q

how do reactive oxygen species cause cell death?

A

Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis

60
Q

how do cell protect against reactive oxygen species

A

cells possess a variety of defenses including cell-cycle delay (9–11), the induction of enzymes such as catalases, peroxidases, and superoxide dismutases, and the synthesis of antioxidants such as glutathione, vitamins C and E, and ubiquinol

61
Q

what is nitrosative stress?

A

Nitrosative stress refers to the joint biochemical reactions of nitric oxide (NO) and superoxide (O2–) when an oxygen metabolism disorder occurs in the body

62
Q

what are the neurotoxic effects of iNOS activation?

A

the production of NO induced by iNOS leads to brain damage during ischemia reperfusion.
The overexpression of iNOS can promote the secretion of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and subsequently induce secondary inflammatory reaction and the generation of oxygen free radicals.

63
Q

which NOS are have neurotoxic activity and which are neuroprotective?

A

No plays a dual role in ischemic stroke,
The production of NO in the early stage of transient cerebral ischemia has a positive effect on the neuroprotection of stroke, but nNOS and iNOS play a negative role in the later stage.
eNOS plays a key role in the protection of neurovascular system

64
Q

describe the role of eNOS in stroke

A

NO derived from eNOS often plays a neuroprotective role in ischemic stroke.
eNOS generates a small amount of NO,
it plays a critical role in the regulation of cerebral microvascular tone, the protection of the blood-brain barrier, the reduction of oxidative stress and the alleviation of procoagulant stimulation.
The NO released can scavenge oxygen free radicals, inhibit the expression of adhesion molecules, and promote the aggregation of platelet and the adhesion of lymphocyte

65
Q

what is the effect of nNOS in stroke?

A

The synthesis of NO through nNOS is mainly related to calcium overload induced by glutamate in ischemic neurons

66
Q

what happens to the NO levels in ischeamic stroke

A

In ischemic stroke, the concentration of NO decreases rapidly due to blocked blood flow.
Once the blood flow is restored, the production of NO will increase, which is mainly mediated by nNOS

67
Q

what are the absolute contraindication for using tissue plasminogen activator (tPA)

A

Significant head trauma or prior stroke in the previous 3 months.
Symptoms suggest subarachnoid hemorrhage.
Arterial puncture at a noncompressible site in previous 7 days.
History of previous intracranial hemorrhage.
Intracranial neoplasm, AVM, or an aneurysm.
Recent intracranial or intraspinal surgery.
active internal bleeding
abnormal blood glucose

68
Q

how does tPA work to improve the outcome of stroke

A
69
Q

how does tPA work to improve the outcome of stroke

A

tPA attaches to the fibrin on the clot surface. It activates the fibrin-bound plasminogen. Plasmin is subsequently cleaved from the plasminogen affiliated with the fibrin. The plasmin breaks up the molecules of fibrin, and the clot dissolves
tPA helps to restore blood flow to brain regions affected by a stroke, thereby limiting the risk of damage and functional impairment.

70
Q

give one reason why there was a strong correlation between amount of IL6 produced and good outcome in stroke patients

A

IL-6 stimulates the production of IL-1 receptor antagonist, which is an anti-inflammatory mediator. IL-6 therefore can have a protective effect.

Cellular & Molecular Pathology (12 decks)

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