Lecture 24 - CNS 2 Flashcards
What are ‘red neurons’?
Neurons that have undergone acute injury
What changes are observed in the cell body after acute insult to neurons?
What happens from there?
1. Acute insult • Nuclear pyknosis • Loss of Nissl substance • Cell body shrinkage • Eosinophilia of cytoplasm
- Later on
• Dissolution of cell due to loss of membrane integrity
• Phagocytosis of the debris
What is eosinophilia?
Increased acidity **
What is transynaptic degeneration?
One neurone is lost
The neurons that were receiving signals from this neurons undergo degeneration, because they are no longer receiving stimulation
What is the axonal reaction?
→ Axonal damage
• Regeneration of axon; axonal sprouting
• Enlarged and rounded cell body
• Dispersion of Nissl substance
What are neuronal inclusions?
When are they observed?
Accumulation of various lipids
Observed in ageing neurons, since they can not be replaced
Give some examples of ‘intracytoplasmic inclusions’
- Neurofibrillary tangles
* Lewy bodies
Describe what happens after acute insult to astrocytes
Why does this happen?
→ Ischemia, toxicity, acute inflammation
• Cytoplasmic swelling
due to failure of cellular/ organelle membrane pumps
• Gliosis
• Rosenthal fibres
What is gliosis?
List the features
Astrocyte reaction to any type of injury in the CNS
Features:
• Hypertrophy and hyperplasia of astrocytes
• Upregulation of GFAP synthesis
• Extension of processes
What is GFAP?
Glial fibrillary acidic protein
What are Rosenthal fibres?
When are they observed?
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
How are Rosenthal fibres detected?
Brightly eosinophilic inclusions under the H&E stain
Do oligodendrocytes respond to injury?
No
However, they can be injured
What is the potential for repair of oligodendrocytes?
High potential for repair
What happens if myelin is damaged?
Myelin can be replaced provided that oligodendrocytes have survived
What happens to myelin if the oligodendrocyte is lost?
The oligodendrocyte can be replaced from a pool of oligodendrocyte progenitors
However the pool will eventually be exhausted
What is the normal form of microglia found in the mature CNS when there is no pathology?
Ramified
Which microglia are present in sublethal injury, i.e. there is no neuronal death?
Reactive microglia
non-phagocytic
Which microglia are present when there is neuronal death?
Which sorts of injury will they be activated?
Describe the actions of these cells
Phagocytic microglia
Insults: • Necrosis of neurons • Infection • Trauma • Response to gliomas
- Phagocytosis
- Destruction (through cytokines)
- Promotion of repair through cytokines
When do microglia become activated?
Characterise this activation
In response to injury
Activation is graded:
→ The greater the injury, the greater the activation
Describe the actions of reactive microglia
In response to sublethal injury (neurons are damaged but not dead)
- No phagocytosis
- Proliferation
- Increased antigen presentation
- Production of cytokines
List some causes of injury in the CNS
- Trauma
- Cerebrovascular disease
- Infection
- Demyelinating diseases
- Degenerative disorders
- Metabolic abnormality
- Toxic and acquired metabolic diseases
- Tumours
What can trauma to the CNS cause?
- Skull fracture
- Vascular injuries → haematoma (sub- and epidural)
- Concussion
- Contusions
- Lacerations
- Diffuse axonal injury
What are vascular injuries in the CNS?
Haematoma:
• Epidural: dura peeled away from skull
• Subdural: dura intact
What are the various consequences of CNS trauma?
- Clinically silent
- Severely disabling
- Fatal
What is cerebrovascular disease?
“Stroke”
What are the various causes of stroke?
- Thrombosis
- Embolism
- Haemorrhage
What are the various causes of impairment of blood supply to CNS?
- Hypoxia
- Ischemia
- Infarction
What is ‘global focal ischemia’?
Generalised loss of cerebral perfusion
Whole brain affected
However, there are still focal regions of injury, due to selective vulnerability
What are some potential causes of global focal ischemia?
- Cardiac arrest
- Shock
- Severe hypotension
Describe selective vulnerability of cells to cerebrovascular disease
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
What is focal cerebral ischemia?
What gives rise to the selective vulnerability?
Cerebral artery occlusion
Selective vulnerability due to presence of collateral flow
What is intracranial haemorrhage?
How does it come about?
Spontaneous haemorrhage, not in response to trauma
Causes:
• Hypertension
• Cerebral amyloid angiopathy
Pathogenesis:
- Hypertension → atherosclerosis → weakening of vessel wall → haemorrhage
- Depsition of amyloidogenic peptides in vessel walls → weakening of vessel wall → haemorrhage
What are saccular (berry) aneurysms?
Where do they normally occur?
Thin walled out-pouching
Location:
• branch point along the circle of Willis
• or branch point of major vessel
How does infection in the brain cause damage?
- Contact / Entry (direct)
- Toxin (indirect)
- Inflammatory / immune response
How do infections spread to the brain?
- Haematogenous (disseminated from the blood)
- Direct (through trauma)
- Local extension from air sinuses or infected tooth
- from PNS
Which pathogenic agents cause infection in the brain?
- Bacteria
- Viruses
- Fungi
What is the name for inflammation of leptomeninges and CSF?
Meningitis
What is the name for inflammation of brain parenchyma?
Encephalitis
Compare encephalitis and meningitis
Encephalitis: inflammation of brain parenchyma
Meningitis: inflammation of leptomeninges and CSF
What is meningoencephalitis?
Inflammation of both brain parenchyma and meninges
What are demyelinating diseases?
What is the clinical presentation due to?
List some examples
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)
What happens to the axons in demyelinating diseases?
Relative preservation of axons
Which tissue in the brain is affected in degenerative disorders?
Grey matter
Characterise degenerative disorders
Progressive loss of neurons
Commonly associated with protein aggregates
What are the clinical presentations of neurodegenerative disorders due to?
The region of the brain affected
Describe genetic metabolic diseases
Why are they affect the brain in particular
Give some examples
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
Describe what happens to enzymes in genetic metabolic diseases
- Reduced activity
- Reduced amount
Result:
• Accumulation of substrate
• Decreased end-product formation
Describe neuronal storage disease
Neuronal storage disease
• Deficiency of enzyme involved in catabolism of sphingolipids, mucopolysaccharides and mucolipids
• Accumulation of the substrate within lysosomes
→ Neuronal death
What are leukodystrophies?
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
What does the toxicity of chemicals in the brain depend on?
- Age
- Genetic predisposition
- Sensitivity of the tissue to injury
What are some examples of toxic and acquired metabolic diseases?
- Vitamin deficiencies
- Metabolic disturbances (e.g. hyperglycaemia in uncontrolled DM)
- Toxic disorders (CO2, methanol, radiation-
Describe MPTP induced parkinsonism
→ 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
What are the unique features of tumours in the CNS
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
What types of tumours can occur in the CNS?
Gliomas:
• Astrocytomas
• Oligodendrogliomas
• Ependymomas
Neuronal tumours
Metastatic tumours
What sorts of trauma affect the CNS?
- Head stuck with an object
- Rapid acceleration / deceleration
- Penetration of head with foreign object
- Blasts
What is the difference between head injury and brain injury?
Head injury: face / scalp
Brain: CNS
What is primary injury to the CNS?
Mechanical damage Blow to surface causing: • Shearing • Tearing • Stretching
What protection does the CNS have?
Skull (mechanical stress)
CSF (shock absorption)
Which part of the brain is most vulnerable to direct injury?
What happens to the cells in this area?
Crest of gyri
Undergo:
• Acute neuronal injury
• Axonal swelling
• Haemorrhage
What is secondary injury to the CNS?
Inflammatory and immune processes that occur secondary to primary injury (mechanical trauma)
Describe pathogenesis of secondary injury to the CNS
(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
What causes increased ICP?
What things can it lead to?
Why is this?
(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
Describe the effect of injury on the BBB
- 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
What does loss of the Nissl substance mean for neurons?
No longer able to produce proteins
Describe the changes to neurons in subacute injury
Insult: ? often neurodegenerative disorder
Features:
• Cell loss (apoptosis or necrosis)
• Reactive gliosis
What features do we see in ageing neurons?
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
By what mechanism do the cell bodies of astrocytes swell in response to injury?
Failure of cellular and organelle membrane pumps
When is increased staining of GFAP seen?
In gliosis
When astrocytes are reacting to injury
As well as being injured, astrocytes can …
react to injury
What are the features of demyelination?
The myelin is:
• Thinner
• Internodes are shorter
With continual damage, there will be less effective conduction along the axon
Describe the pathogenesis of MS
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
In a blow to the head, where is injury seen?
Point of contact
Or, diametrically opposed
(or both)
Distant to point of contact:
• Crest of gyri
Describe the capacity of the brain for repair
Some stem cells present:
- Adult neural stem cells (NSC)
• Capable of self renewal and differentiation
• Generate neurons, however, in vivo, low frequency of division - NG2 glia
• Generate myelinating oligodendrocytes
Compare NSC in vitro and in vivo
In vitro:
• Generation of neurons, astrocytes and oligodendrocytes
In vivo:
• Generation of neurons
• Low frequency of division
Where are NSC located?
SVZ: sub ventricular zone
SGZ: sub granular zone
Where are NG2 glia located?
Dispersed throughout adult brain parenchyma
Describe an example of NSC use as treatment
- MPTP induced lesion in SN
- hNSCs implanted into striatum
- Found in SN
- Small number differentiated into dopamine neurons
What is the term for increased CSF volume?
Hydrocephalus
Why is the absence of lymphatic drainage in the CNS significant?
Difficult to drain excess fluid when there is increased ICP
Describe herniation secondary to increased ICP
Give a specific example, including consequences
Herniation: displacement of tissue
Tonsillar herniation: • Cerebellum herniates downwards • Life-threatening • Compression of the brain stem • Compromise of respiratory and cardiac centres
