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PATH30001 - Mechanisms of Disease > Lecture 24 - CNS 2 > Flashcards

Lecture 24 - CNS 2 Flashcards

1
Q

What are ‘red neurons’?

A

Neurons that have undergone acute injury

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2
Q

What changes are observed in the cell body after acute insult to neurons?

What happens from there?

A 
1. Acute insult
 • Nuclear pyknosis
 • Loss of Nissl substance
 • Cell body shrinkage
 • Eosinophilia of cytoplasm
  1. Later on
    • Dissolution of cell due to loss of membrane integrity
    • Phagocytosis of the debris
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3
Q

What is eosinophilia?

A

Increased acidity **

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4
Q

What is transynaptic degeneration?

A

One neurone is lost

The neurons that were receiving signals from this neurons undergo degeneration, because they are no longer receiving stimulation

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5
Q

What is the axonal reaction?

A

→ Axonal damage
• Regeneration of axon; axonal sprouting
• Enlarged and rounded cell body
• Dispersion of Nissl substance

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6
Q

What are neuronal inclusions?

When are they observed?

A

Accumulation of various lipids

Observed in ageing neurons, since they can not be replaced

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7
Q

Give some examples of ‘intracytoplasmic inclusions’

A
  • Neurofibrillary tangles

* Lewy bodies

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8
Q

Describe what happens after acute insult to astrocytes

Why does this happen?

A

→ Ischemia, toxicity, acute inflammation

• Cytoplasmic swelling
due to failure of cellular/ organelle membrane pumps
• Gliosis
• Rosenthal fibres

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9
Q

What is gliosis?

List the features

A

Astrocyte reaction to any type of injury in the CNS

Features:
• Hypertrophy and hyperplasia of astrocytes
• Upregulation of GFAP synthesis
• Extension of processes

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10
Q

What is GFAP?

A

Glial fibrillary acidic protein

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11
Q

What are Rosenthal fibres?

When are they observed?

A

Observed in regions of chronic gliosis

When the source of the injury is not removed → chronic stimulation of astrocytes

It is cytoplasmic inclusions of heat shock proteins and ubiquitin

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12
Q

How are Rosenthal fibres detected?

A

Brightly eosinophilic inclusions under the H&E stain

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13
Q

Do oligodendrocytes respond to injury?

A

No

However, they can be injured

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14
Q

What is the potential for repair of oligodendrocytes?

A

High potential for repair

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15
Q

What happens if myelin is damaged?

A

Myelin can be replaced provided that oligodendrocytes have survived

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16
Q

What happens to myelin if the oligodendrocyte is lost?

A

The oligodendrocyte can be replaced from a pool of oligodendrocyte progenitors

However the pool will eventually be exhausted

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17
Q

What is the normal form of microglia found in the mature CNS when there is no pathology?

A

Ramified

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18
Q

Which microglia are present in sublethal injury, i.e. there is no neuronal death?

A

Reactive microglia

non-phagocytic

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19
Q

Which microglia are present when there is neuronal death?

Which sorts of injury will they be activated?

Describe the actions of these cells

A

Phagocytic microglia

Insults:
 • Necrosis of neurons
 • Infection
 • Trauma
 • Response to gliomas
  • Phagocytosis
  • Destruction (through cytokines)
  • Promotion of repair through cytokines
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20
Q

When do microglia become activated?

Characterise this activation

A

In response to injury

Activation is graded:
→ The greater the injury, the greater the activation

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21
Q

Describe the actions of reactive microglia

A

In response to sublethal injury (neurons are damaged but not dead)

  • No phagocytosis
  • Proliferation
  • Increased antigen presentation
  • Production of cytokines
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22
Q

List some causes of injury in the CNS

A
  • Trauma
  • Cerebrovascular disease
  • Infection
  • Demyelinating diseases
  • Degenerative disorders
  • Metabolic abnormality
  • Toxic and acquired metabolic diseases
  • Tumours
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23
Q

What can trauma to the CNS cause?

A
  • Skull fracture
  • Vascular injuries → haematoma (sub- and epidural)
  • Concussion
  • Contusions
  • Lacerations
  • Diffuse axonal injury
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24
Q

What are vascular injuries in the CNS?

A

Haematoma:
• Epidural: dura peeled away from skull
• Subdural: dura intact

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25
Q

What are the various consequences of CNS trauma?

A
  • Clinically silent
  • Severely disabling
  • Fatal
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26
Q

What is cerebrovascular disease?

A

“Stroke”

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27
Q

What are the various causes of stroke?

A
  • Thrombosis
  • Embolism
  • Haemorrhage
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28
Q

What are the various causes of impairment of blood supply to CNS?

A
  • Hypoxia
  • Ischemia
  • Infarction
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29
Q

What is ‘global focal ischemia’?

A

Generalised loss of cerebral perfusion
Whole brain affected

However, there are still focal regions of injury, due to selective vulnerability

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30
Q

What are some potential causes of global focal ischemia?

A
  • Cardiac arrest
  • Shock
  • Severe hypotension
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31
Q

Describe selective vulnerability of cells to cerebrovascular disease

A

Within the brain, some neurons are more susceptible to injury than others

Most to least vulnerable:
• Neurons
• Astroytes and oligodendryocytes

Within the neuronal population, there are some neurons that are more vulnerable than others: (most to least vulnerable)
• Pyramidal cells
• Purkinje cells
• Cortical pyramidal cells
The deeper neurons are most at risk because they are furthest from the blood supply

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32
Q

What is focal cerebral ischemia?

What gives rise to the selective vulnerability?

A

Cerebral artery occlusion

Selective vulnerability due to presence of collateral flow

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33
Q

What is intracranial haemorrhage?

How does it come about?

A

Spontaneous haemorrhage, not in response to trauma

Causes:
• Hypertension
• Cerebral amyloid angiopathy

Pathogenesis:

  1. Hypertension → atherosclerosis → weakening of vessel wall → haemorrhage
  2. Depsition of amyloidogenic peptides in vessel walls → weakening of vessel wall → haemorrhage
34
Q

What are saccular (berry) aneurysms?

Where do they normally occur?

A

Thin walled out-pouching

Location:
• branch point along the circle of Willis
• or branch point of major vessel

35
Q

How does infection in the brain cause damage?

A
  • Contact / Entry (direct)
  • Toxin (indirect)
  • Inflammatory / immune response
36
Q

How do infections spread to the brain?

A
  • Haematogenous (disseminated from the blood)
  • Direct (through trauma)
  • Local extension from air sinuses or infected tooth
  • from PNS
37
Q

Which pathogenic agents cause infection in the brain?

A
  • Bacteria
  • Viruses
  • Fungi
38
Q

What is the name for inflammation of leptomeninges and CSF?

A

Meningitis

39
Q

What is the name for inflammation of brain parenchyma?

A

Encephalitis

40
Q

Compare encephalitis and meningitis

A

Encephalitis: inflammation of brain parenchyma

Meningitis: inflammation of leptomeninges and CSF

41
Q

What is meningoencephalitis?

A

Inflammation of both brain parenchyma and meninges

42
Q

What are demyelinating diseases?

What is the clinical presentation due to?

List some examples

A

Condition characterised by preferential damage of myelin

Clinical presentation due to:
• Loss of transmission of electrical impulses along axon

Examples:
• MS (immunological)
• JC virus infection of oligodendrocytes
• Leukodystrophies (inherited)

43
Q

What happens to the axons in demyelinating diseases?

A

Relative preservation of axons

44
Q

Which tissue in the brain is affected in degenerative disorders?

A

Grey matter

45
Q

Characterise degenerative disorders

A

Progressive loss of neurons

Commonly associated with protein aggregates

46
Q

What are the clinical presentations of neurodegenerative disorders due to?

A

The region of the brain affected

47
Q

Describe genetic metabolic diseases

Why are they affect the brain in particular

Give some examples

A

Genetic defect that results in abnormal protein formation or reduced gene product

In the rest of the body, there is wiggle room and space for dysfunction. This isn’t an option in the brain

Examples:
• Neuronal storage disease
• Leukodystrophies

48
Q

Describe what happens to enzymes in genetic metabolic diseases

A
  • Reduced activity
  • Reduced amount

Result:
• Accumulation of substrate
• Decreased end-product formation

49
Q

Describe neuronal storage disease

A

Neuronal storage disease
• Deficiency of enzyme involved in catabolism of sphingolipids, mucopolysaccharides and mucolipids
• Accumulation of the substrate within lysosomes
→ Neuronal death

50
Q

What are leukodystrophies?

A

Myelin abnormalities: synthesis or turnover
Diffuse involvement of white matter

Enzymes involved in production / turn over of myelin
If these enzymes are absent, the myelin does not function properly

51
Q

What does the toxicity of chemicals in the brain depend on?

A
  • Age
  • Genetic predisposition
  • Sensitivity of the tissue to injury
52
Q

What are some examples of toxic and acquired metabolic diseases?

A
  • Vitamin deficiencies
  • Metabolic disturbances (e.g. hyperglycaemia in uncontrolled DM)
  • Toxic disorders (CO2, methanol, radiation-
53
Q

Describe MPTP induced parkinsonism

A

→ Synthetic heroin use intravenously
• Selective damage of cells in SN
• Development of parkinsonism

MPTP is now used as a research tool for PD in mice models

54
Q

What are the unique features of tumours in the CNS

A

Confined
Location: the brain is such a special place:
• Even if it is benign, it can be fatal (it may be pressing on a certain part)
• Surgical removal is not as easy as in other areas in the body

55
Q

What types of tumours can occur in the CNS?

A

Gliomas:
• Astrocytomas
• Oligodendrogliomas
• Ependymomas

Neuronal tumours

Metastatic tumours

56
Q

What sorts of trauma affect the CNS?

A
  • Head stuck with an object
  • Rapid acceleration / deceleration
  • Penetration of head with foreign object
  • Blasts
57
Q

What is the difference between head injury and brain injury?

A

Head injury: face / scalp

Brain: CNS

58
Q

What is primary injury to the CNS?

A 
Mechanical damage
Blow to surface causing:
 • Shearing
 • Tearing
 • Stretching
59
Q

What protection does the CNS have?

A

Skull (mechanical stress)

CSF (shock absorption)

60
Q

Which part of the brain is most vulnerable to direct injury?

What happens to the cells in this area?

A

Crest of gyri

Undergo:
• Acute neuronal injury
• Axonal swelling
• Haemorrhage

61
Q

What is secondary injury to the CNS?

A

Inflammatory and immune processes that occur secondary to primary injury (mechanical trauma)

62
Q

Describe pathogenesis of secondary injury to the CNS

A

(Secondary to the primary injury)

1. Presence of pro-inflammatory molecules:
 • Pro-inflammatory cytokines
 • NO
 • ROS
 • Prostaglandins
2. Lipid peroxidation
3. BBB disruption
4. Oedema → increase in ICP
63
Q

What causes increased ICP?

What things can it lead to?

Why is this?

A

(Intracranial pressure)

Causes:
 • Oedema
 • Hydrocephalus
 • Tumours
 • Haemorrhage
Leads to:
 • Herniation
 • Compression of veins
 • Local hypoxia and ischemia
 • Secondary haemorrhage
 • Neuronal cell death

The brain sits in a limited space. When there is swelling, there is the potential of increased pressure and the brain will be compressed

64
Q

Describe the effect of injury on the BBB

A
  • Activation of endothelial cells and astrocytes
  • Reduced tight junction integrity
  • Formation of channels through the endothelium
  • Migration of leukocytes into the brain through the leaky BBB
65
Q

What does loss of the Nissl substance mean for neurons?

A

No longer able to produce proteins

66
Q

Describe the changes to neurons in subacute injury

A

Insult: ? often neurodegenerative disorder

Features:
• Cell loss (apoptosis or necrosis)
• Reactive gliosis

67
Q

What features do we see in ageing neurons?

A

Neuronal inclusions
• Lipids
• Proteins
• Carbohydrates

These inclusions just stay there, because the neurons aren’t being turned over
In the periphery, these cells would be removed. However, in the CNS neurons can not be replaced

68
Q

By what mechanism do the cell bodies of astrocytes swell in response to injury?

A

Failure of cellular and organelle membrane pumps

69
Q

When is increased staining of GFAP seen?

A

In gliosis

When astrocytes are reacting to injury

70
Q

As well as being injured, astrocytes can …

A

react to injury

71
Q

What are the features of demyelination?

A

The myelin is:
• Thinner
• Internodes are shorter

With continual damage, there will be less effective conduction along the axon

72
Q

Describe the pathogenesis of MS

A

Immunologically determined

The brain is an immune privileged organ
The immune system isn’t necessarily tolerant of myelin
Specific destruction of myelin by the immune system

73
Q

In a blow to the head, where is injury seen?

A

Point of contact
Or, diametrically opposed
(or both)

Distant to point of contact:
• Crest of gyri

74
Q

Describe the capacity of the brain for repair

A

Some stem cells present:

  1. Adult neural stem cells (NSC)
    • Capable of self renewal and differentiation
    • Generate neurons, however, in vivo, low frequency of division
  2. NG2 glia
    • Generate myelinating oligodendrocytes
75
Q

Compare NSC in vitro and in vivo

A

In vitro:
• Generation of neurons, astrocytes and oligodendrocytes

In vivo:
• Generation of neurons
• Low frequency of division

76
Q

Where are NSC located?

A

SVZ: sub ventricular zone

SGZ: sub granular zone

77
Q

Where are NG2 glia located?

A

Dispersed throughout adult brain parenchyma

78
Q

Describe an example of NSC use as treatment

A
  • MPTP induced lesion in SN
  • hNSCs implanted into striatum
  • Found in SN
  • Small number differentiated into dopamine neurons
79
Q

What is the term for increased CSF volume?

A

Hydrocephalus

80
Q

Why is the absence of lymphatic drainage in the CNS significant?

A

Difficult to drain excess fluid when there is increased ICP

81
Q

Describe herniation secondary to increased ICP

Give a specific example, including consequences

A

Herniation: displacement of tissue

Tonsillar herniation:
 • Cerebellum herniates downwards
 • Life-threatening
 • Compression of the brain stem
 • Compromise of respiratory and cardiac centres

PATH30001 - Mechanisms of Disease (34 decks)

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