1
Q
What cells in the CNS respond to injury?
A
- Neurons
- Oligodendrocytes
- Astrocytes
- Microglial
2
Q
What is neuronal injury?
A
- Neurons are terminally differentiated so the brain has limited capacity to replace them
- Neurons may suffer acute injury they require glucose and oxygen to meet the metabolic demand
- Neurons may suffer chronic injury; they are maintained for the lifetime of the individual
3
Q
What happens during acute neuronal injury?
A
o Red neurons: ‘dying neurons’ neurons that have undergone irreversible injury due to an insufficient supply of oxygen and glucose
Red neurons typically exhibit shrinkage of the cytoplasm, a loss of Nissl substance, and clumping of the chromatin in the nucleus. They are a hallmark of acute neuronal injury and are often seen in conditions such as cerebral ischemia, hypoxia, and traumatic brain injury.
o Ischemic event
Nuclear pyknosis, shrinkage of cell body, loss of Nissi substance, disappearance of nucleolus and eosinophilia of cytoplasm occurs first.
Lastly, dissolution of the cell and phagocytosis of debris occurs
4
Q
What occurs during subacute and chronic neuronal injury?
A
Degeneration
Loss associated with a particular groups of neurons - often by apoptosis
Reactive gliosis
Inflammation
Exotoxicity
Oxidative stress
5
Q
What occurs during trans-synaptic/trans-neuronal degeneration?
A
A process in which neurons and their synapses degenerate as a result of damage or injury to other neurons with which they are connected through neural circuits. This process is a secondary consequence of an initial injury or disease process that affects a subset of neurons within a neural circuit.
Damaging event that interrupts the afferent input e.g., the effect of eye enucleation on cells of lateral genticulate neurons
6
Q
What occurs during an axonal reaction?
A
o Morphologic change in cell body following damage to the axon
o Associated with the regeneration of the axon (through protein synthesis and axonal sprouting)
Enlargement and rounding the cell body
Displacement of the nucleolus
Dispersion of Nissl substance (chromatolysis)
7
Q
What occurs during neuronal inclusions?
A
o Ageing (complex lipids, lipofuscin, proteins and carbohydrates)
o Viral infection
Neuronal inclusions are abnormal accumulations of proteins or other molecules within the cytoplasm or nuclei of neurons.
8
Q
What occurs during intracytoplasmic inclusions?
A
o Neurofibrillary tangles (Alzheimer disease)
o Lewy bodies (Parkinson disease)
Intracytoplasmic inclusions are abnormal accumulations of substances within the cytoplasm of cells, including neurons.
9
Q
How are oligodendrocytes affected by injury?
A
- Does not respond to injury but can be injured
- High potential for repair
o Pool of oligodendrocyte progenitors can replace the lost oligodendrocytes - Myelin damage DOES NOT mean oligodendrocyte loss
o Myelin can be replaced if damaged as long as oligodendrocytes survive
o Remyelination thinner than normal, shorter internodes
10
Q
How are astrocytes affected by injury?
A
- When directly injured as a result of ischaemia, toxicity or acute inflammation cytoplasmic swelling occurs as result of failure of cellular and organelle pumps
- Reactive astrogliosis
o It is a conserved defence mechanism that regulates neuroinflammation, limits the site of damage by forming a perilesional barrier and compact glial scar with fibro meningeal and other glia cells and promotes post-injury neuronal function recovery - Most important histological indicator of CNS injury
- Hypertrophy and hyperplasia
o Up-regulation of GFAP synthesis
o Extension of processes
o Stimulated by cytokines produced by activated microglia
o Release by-products of increased biological activity (nitric oxide, glutamate); toxic to the environment
o May contribute to further injury
11
Q
What are the phenotypes of astrocytes in response to injury?
A
- A1 astrocytes:
o Contributes to injury
o Loss of function
o Neuroinflammation - A2 astrocytes:
o Promote healing after ischemic injury
12
Q
How are microglia affected by injury?
A
- Morphological phenotype is used to indicate distinct microglial functional states
- Phagocytic microglia-neuronal death
o Trauma
o Inflammation
o Neuronal necrosis
o Viral and bacterial infections
o In response to gliomas (malignant astrocyte tumour) - Activated in response to injury
- Rapid and graded
o The more severe the injury – the greater the activation - Microglia activated but not phagocytic:
o Damage but not death of neurons
o Proliferate
o Expresses CD4, MHC 1 AND 2 antigens, cell adhesion molecules
o Produces cytokines - Activated microglia become rounded phagocytic cells
o ONLY when neuronal death occurs
o Can be destructive or reparative
13
Q
What are the major causes of CNS injury?
A
- Trauma brain injury
- Cerebrovascular disease
- Infection
- Demyelinating disease
- Degenerative disorders
- Metabolic abnormality
- Toxic and acquired metabolic diseases
- Tumours
14
Q
What is traumatic brain injury (TBI)?
A
- An external force that exceeds the protective capacity of the brain
- Mechanical injury: compression, shearing, tearing, stretching
- Affecting neurons, axons, glia cells and blood vessels
- Trauma can cause:
o Skull fractures
o Parenchymal injuries
o Vascular injuries (e.g., haematoma)
15
Q
What is parenchymal injury?
A
- Contusions (bruising) and lacerations (penetration or tear)
- Crest of gyri are most vulnerable
- Evidence of acute brain injury:
o Haemorrhage
o Axonal swelling close to or distant from the site of damage
o Inflammatory response
o Oedema - A blow to the surface of the brain resulting in lesion at
o Point of contact
o Diametrically opposed
o Both
16
Q
What is vascular injury in the brain?
A
- Direct disruption of the blood vessel wall leading to haemorrhage
- Epidural = rapid
o Epidural hematoma is the collection of blood in the epidural space, which is the space between the dura mater and inner surface of the skull - Subdural = delayed
o Subdural hematoma is the collection of blood in the subdural space, meaning between the dura mater and the arachnoid mater. - Subarachnoid space
- Intraparenchymal
o Direct due to trauma
o Consequence of underlying condition
17
Q
What are the outcomes of TBI?
A
- Temporary days, weeks, lifetime
- Location of lesion
- Capacity of brain for repair
- Consequences of CNS trauma
o Clinically silent
o Severely disabling
o Fatal
18
Q
What is cerebrovascular disease?
A
- Consequence of altered blood flow
- STROKE
o Hypoxia, ischemia, infarction
Impairment of blood supply and oxygenation of CNS
Cardiac arrest/hypotension
Thrombosis/embolism
o Haemorrhage
Rupture of CNS blood vessels - Hypertension
- Aneurysm
- Global cerebral ischemia
o Generalised loss of cerebral perfusion
o Cardiac arrest, shock, severe, hypotension - Selective vulnerability
o Neurons»_space;> oligodendrocytes and astrocytes
o Subpopulations of neurons
Cerebral blood supply
Metabolic requirements
o Pyramidal cells CA I region of hippocampus
o Purkinje cells of cerebellum
o Cortical pyramid cells - Focal cerebral ischemia
o Cerebral artery occlusion
o Outcomes determined by the duration of ischaemia, selective vulnerability and adequacy of collateral flow
o Embolism
o Thrombosis – atherosclerosis - Intraparenchymal haemorrhage
o Consequence of underlying disease
o Extravasation of blood and compression of adjacent parenchyma
19
Q
How does infection cause CNS injury?
A
- Infection causes damage by:
o Direct contact or entry
o Indirect – microbial toxins
o Inflammatory or immune response - Infection occurs through:
o Haematogenous spread
o Directly (trauma or malformation)
o Local extensions (air sinuses, infected tooth)
o PNS - Meningitis - inflammation of leptomeninges and CSF
- Encephalitis – inflammation of brain parenchyma
20
Q
What is meningitis and its effect on the CNS?
A
- • Etiology: Neisseria meningitis
- Inflammation of the brain and spinal cord typically due to bacterial infection
- Headache, fever, neck stiffness, altered mental status
- Evasion of host defence systems/invasion and pathogenesis in CNS
o Tropism: Binds epithelial cells of nasopharynx
o Penetrates mucosa and gains access to blood stream – avoiding recognition and destruction
o Crosses the BBB - Proinflammatory mediators in the subarachnoid space leads to:
o Inflammatory response in CNS
o Increased permeability of the BBB
o Central oedema
o Increased intracranial pressure
21
Q
What is encephalitis-viral infection of microglial and its effect on the CNS?
A
- HIV encephalitis
- Chronic inflammatory reaction with widely distributed infiltrates of microglial nodules, tissue necrosis and reactive gliosis
- Caused by transmission of HIV into the brain by infected monocytes (only cells of the CNS with receptors for HIV infection)
- Neuropathological changes associated with:
o Viral products and soluble factors produced by infected microglia
o Inflammatory cytokines - Blood brain barrier
o Limits anti-viral immune response and efficacy of anti-viral therapy
22
Q
What are demyelinating diseases?
A
- Acquired condition characterised by preferential damage of myelin, with relative preservation of axons
- Clinical presentation due to the loss of transmission of electrical impulses along the axon
- Immunological (Multiple sclerosis)
- Infection (JC polyomavirus infection oligodendrocytes)
- Inherited (Leukodystrophies)
23
Q
What is multiple sclerosis and its effect on the CNS ? (Demyelinating disease)
A
- Autoimmune response to the myelin sheath
- Distinct episodes of neurologic deficit
- Associated with white matter lesions
o Areas of abnormal myelination in the brain - Genetic and environmental factors
- Self-reactive T cells
o CD4+ TH1 and TH17 cells react to self myelin antigen
o TH1 cell secretes IFN-gamma which activates macrophages and TH17 and causes leukocyte recruitment - Both healthy and MS patients have T-lymphocytes against myelin sheath (tolerance/immune privilege)
- Breach in integrity of blood brain barrier (of genetically predisposed) which allows the infiltration of T-lymphocytes that recognise myelin, causing acute inflammatory demyelinating lesions
24
Q
What are genetic metabolic diseases?
A
- A genetic defect that results in abnormal protein formation or reduced gene product
- Protein = enzyme
o Reduced activity
o Reduced amount - Accumulation of the substrate
- Metabolic block and decreased end product
- Failure to inactivate a tissue-damaging substrate
- Effects organs where:
o Tissue to be degraded is found
o Location where degradation occurs
25
What are the different genetic metabolic diseases and their effects on the CNS?
Genetic metabolic diseases: Neuronal storage disease
* Deficiency of enzyme involved in catabolism of sphingolipids, mucopolysaccharides and mucolipids
* Accumulation of substrate within lysosomes causes neuronal death
Genetic metabolic diseases: Leukodystrophies
* Myelin abnormalities (synthesis or turnover)
* Diffuse involvement of white matter
Genetic metabolic disease: Lysosomal storage disease
* Tay-Sachs Disease
o Hexosaminidase A deficiency
o GM2 ganglioside accumulates in many tissues (heart, liver, spleen and brain)
o GMS gangliosides
Lipid essential for neuronal function
Neurological defects predominant clinical feature
26
What are the types of tumours that can affect the CNS and their effect?
* Consequences unique to tumours of CNS
o Confined
o Location
o Benign or malignant
* Gliomas
o Astrocytoma
o Oligodendrogliomas
o Ependymomas
* Neuronal tumours
o Less common, generally seen in younger adults
* Metastatic tumours
o Arising from primary tumours in lung, breast, skin, GIT, kidney
o Account for up to half or intra-cranial tumours
27
What are degenerative disorders?
* Diseases of grey matter
* Progressive loss of neurons (secondary white matter change)
* Selective targeting of neuronal groups
o Defined clinical symptoms
* Symptomatic/anatomic
o Alzheimer’s disease
o Parkinson’s disease
o Pick’s disease
* Pathologic
o Tauopathies
o Prion diseases
* Commonly associated with protein aggregates
* Familial, sporadic (and acquired aetiologies)
* Imbalance between protein synthesis and clearance
* Accumulation of protein in and around neurons
* Toxic gain of function or loss of function
28
What is Parkinson's disease and its effect on the CNS ? (Degenerative disorder)
* Characterised by motor dysfunction typical of disturbance of nigrostriatal dopaminergic system
o Tremor, rigidity, bradykinesia
* Typified by the loss of pigmented catecholaminergic neurons of the substantia nigra and presence of Lewy bodies in neurons – accumulation of alpha-synuclein which correlated with symptoms
* Progressive disease that beings in the brain stem and spreads to the cerebral cortex eventually leading to cognitive impairment
* Evidence supports prion-like spread of protein misfolding
* Mutations in alpha-synuclein and genes associated with mitochondrial function
29
What are the toxic and acquired metabolic diseases?
* Vitamin deficiencies
* Metabolic disturbances
o Hyperglycaemia in the setting of uncontrolled diabetes
* Toxic disorders
o Carbon dioxide, methanol/ethanol, radiation
o Idiopathic Parkinson’s disease caused by toxic exposure to MPTP
30
What are red neurons
Neurons that have undergone acute injury
31
What is eosinophilia?
Increased acidity
32
What is gliosis?
Astrocyte reaction to any type of injury in the CNS
Features:
* Hypertrophy and hyperplasia of astrocytes
* Upregulation of GFAP synthesis
* Extension of processes
33
What are Rosenthal fibres?
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
34
Do oligodendrocytes respond to injury?
NO - but they can be injured
35
What happens if myelin is damaged?
Myelin can be replaced provided that oligodendrocytes have survived
36
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
37
What is the normal form of microglia found in the mature CNS when there is no pathology?
Ramified
38
When do microglia become activated?
Characterise this activation
In response to injury
Activation is graded:
→ The greater the injury, the greater the activation
39
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
40
What are the various causes of stroke?
Thrombosis
Embolism
Haemorrhage
41
Where are NG2 glia located?
NG2 glia, also known as oligodendrocyte precursor cells (OPCs), are a type of glial cell that are primarily located in the central nervous system (CNS).
Specifically, NG2 glia are found in the gray and white matter of the CNS
42
Why is the absence of lymphatic drainage in the CNS significant?
In the CNS, there are no lymphatic vessels or nodes, which means that immune cells and other substances must be removed through alternative pathways. Instead, the brain relies on a specialized system of cells called microglia, which act as the brain's primary immune defense.
While the absence of lymphatic drainage in the CNS may make it more difficult for the immune system to remove waste and immune cells from the brain, this unique immune system architecture also helps to protect the brain from excessive inflammation and immune activity, which can be damaging to the delicate neural tissue.
PATH30001
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