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PATH30001 > lecture 24 > Flashcards

lecture 24 Flashcards

1
Q

What cell types are going to react to injury in the brain?

A
  • neurons
  • oligodendrocytes
  • astrocytes
  • microglia
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2
Q

What happens during acute neuronal injury?

A
  • ‘red neurons’
  • healthy cell –> damaging event e.g. hypoxia/ischaemia, acute insult –> nuclear pyknosis, shrinkage of cell body, loss of Nissl substance (rER), disappearance of nucleolus, eosinophilia of cytoplasm –> dissolution of cell, phagocytosis of debris

problem is that once that neuron is gone it can’t be replaced
generally we think of neurons as permanent tissue - not dividing tissue

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3
Q

What happens during subacute and chronic neuronal injury (degeneration)?

A
  • cell loss
  • often with selective targeting of related systems of neurons
  • reactive gliosis
  • apoptosis
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4
Q

What is transynaptic degeneration?

A
  • damaging event interrupts afferent input
  • i.e. effect of eye enucleation on cells of lateral genticulate neurons
  • if neurons aren’t receiving stimulation from local neurons they will die as well
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5
Q

What is the axonal reaction?

A
  • morphological change in cell body following damage to axon
  • associated with regeneration of axon (protein synthesis and axonal sprouting)
  • enlargement and rounding of cell body
  • displacement of nucleolus
  • dispersion of Nissl substance (chromatolysis)
  • response to injury but injury is not irreversible
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6
Q

What are neuronal inclusions?

A
  • ageing (complex lipids; lipofuscin, proteins and carbohydrates)
  • viral infection
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7
Q

What are intracytoplasmic inclusions?

A
  • neurofibrillary tangles (Alzheimer’s disease)
  • Lewy bodies (Parkinson’s disease)
  • more specifically pathological (generally)
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8
Q

What happens to astrocytes when injured?

A
  • when directly injured as a result of ischaemia, toxicity or acute inflammation cytoplasmic swelling occurs as a result of failure of cellular and organelle membrane pumps
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9
Q

How do astrocytes respond to injury?

A
  • astrocytes respond to any type of injury in the CNS

gliosis

  • hypertrophy and hyperplasia
  • up-regulation of GFAP synthesis
  • extension of processes
  • stimulated by TNF-alpha, IL-beta, IL-6 from activated microglia
  • release of by-products of increased biological activity (nitric oxide, glutamate): toxic to the environment
  • may contribute to further injury

rosenthal fibre

  • observed in regions of chronic gliosis
  • cytoplasmic inclusions of heat shock proteins and ubiquitin
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10
Q

What does a rosenthal fibre indicate?

A

that the injury is chronic

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11
Q

What is the most important histological indicator of CNS injury?

A

gliosis

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12
Q

What is hypertrophy and hyperplasia of astrocytes?

A

gliosis

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13
Q

How is gliosis detected?

A

GFAP

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14
Q

Where are rosenthal fibres typically found?

A

in regions of long standing gliosis

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15
Q

How do rosenthal fibres stain?

A
  • contain brightly eosinophilic inclusions

- detected by H and E stain

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16
Q

How do oligodendrocytes respond to injury?

A
  • do not respond to injury but can be injured
  • high potential for repair (relatively)
    • myelin damage ≠ oligodendrocyte loss
  • if myelin is damaged, it can be replaced provided that oligodendrocytes survive
    • remyelination: thinner than normal, shorter internodes
  • if oligodendrocytes are lost, they can be replaced from the pool of oligodendrocyte progenitors; however this pool will eventually be depleted
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17
Q

How do microglia respond to injury?

A
  • ameboid microglia - during development and perinatal period
  • ramified, under normal conditions - in mature CNS
  • reactive, non-phagocytic microglia - sublethal injury
  • phagocytic microglia - neuronal death
    • trauma
    • inflammation
    • neuronal necrosis
    • viral/bacterial infections
    • in response to gliomas (malignant astrocyte tumours)
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18
Q

When are microglia activated?

A
  • activated in response to injury
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19
Q

What is the nature of the microglial response?

A
  • rapid and graded

- - the more severe the injury, the greater the activation

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20
Q

What do microglia do in response to damage but not death of neurons

A
    • microglia activated by not phagocytic
    • proliferate
    • express CD4, MHC I and II antigens, cell adhesion molecules
    • produce cytokines e.g. IL-6, TGF-beta
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21
Q

What do microglia do when neuronal dEATH occurs?

A
  • activated microglia become rounded phagocytic cells
  • destructive (Th1: IFN-gamma, TNF-alpha, IL-2, IL-12) and
  • repair promoting (Th2: IL-4, 5, 6, 10, 13)
22
Q

What are causes of injury?

A
  • trauma
  • cerebrovascular disease
  • infection
  • demyelinating diseases
  • degenerative disorders
  • metabolic abnormality (may be congenital)
  • toxic and acquired metabolic diseases
  • tumours
23
Q

What is trauma?

A
  • loss of function caused by an external force
  • trauma can cause:
    • skull fractures (does the bone stay in place or protrude?)
    • parenchymal injuries
  • – concussion
  • – contusions and lacerations
  • – diffuse axonal injury
    • vascular injuries
  • – epidural and subdural hematoma (accumulation of blood)
24
Q

What are consequences of CNS trauma?

A
  • clinically silent
  • severely disabling (or maybe less severe e.g. damage to olfactory bulb)
  • fatal

depends on location of lesion

25
Q

What is cerebrovascular disease?

A

stroke

  • thrombosis
  • embolism
  • hemorrhage

hypoxia, ischaemia, infarction
- impairment of blood supply and oxygenation of CNS

hemorrhage from rupture of CNS vessels

26
Q

What is global focal ischaemia? How do you still get certain cells more or less affected during this?

A
  • generalised loss of cerebral perfusion
  • cardiac arrest, shock, severe hypotension

selective vulnerability

  • neurons (oligodendrocytes, astrocytes)
  • subpopulations of neurons
    • cerebral blood supply (closer or further from arteries)
    • metabolic requirements (higher metabolically active cells will die first)
  • pyramidal cells CA I region of hippocampus
  • purkinje cells of cerebellum
  • cortical pyramidal cells
27
Q

What is focal cerebral ischaemia?

A
  • cerebral artery occlusion

- selective vulnerability and adequacy of collateral flow

28
Q

What is intracranial haemorrhage?

A
  • spontaneous (non-traumatic) haemorrhage
  • hypertension leading to weakening of vessel wall through atherosclerosis and hyaline arteriolosclerosis
  • cerebral amyloid angiopathy resulting in deposition of amyloidogenic peptides that weaken the vessel wall
29
Q

With what is subarachnoid haemorrhage most frequently associated?

A
  • sacular (berry) aneurysms
  • thin walled outpouching at an arterial branch point along the circle of Willis or major vessel
  • depending on when you catch it either severe or not
30
Q

How does infection cause damage?

A
  • direct-contact or entry
  • indirect - microbial toxins
  • inflammatory or immune response (in many cases, this is what causes more damage to the brain than the infection itself)
31
Q

Through what does infection occur?

A
  • haematogenous spread
  • directly (trauma or malformation)
  • local extensions (air sinuses, infected tooth)
  • peripheral nervous system
32
Q

What can cause brain infection?

A
  • bacteria
  • virus
  • fungus (usually in immunocompromised individual)
33
Q

What is inflammation of the meninges?

A
  • meningitis
  • inflammation of leptomeninges and CSF
  • pyogenic meningitis (pus forming bacterial infection)
34
Q

What encephalitis?

A
  • inflammation of brain parenchyma

- brain abcess

35
Q

What is inflammation of both meninges and parenchyma?

A

meningoencephalitis

36
Q

What are demyelinating diseases?

A
  • acquired condition characterised by preferential damage of myelin, with relative preservation of axons
  • clinical presentation due to loss of transmission of electrical impulses
    • immunological (MS: body hasn’t necessarily learnt that myelin is a self antigen due to it being an immune privileged site, presentation will depend on which axons are attacked, not a set pattern of disease)
    • infection (JC infection oligodendrocytes, dysfunction and death of these cells and hence myelin)
    • inherited (leukodystrophies, aberrant production of myelin, less well myelinated axons)
37
Q

What are degenerative disorders?

A
  • diseases of grey matter
  • progressive loss of neurons (2º white matter change)
  • selective targeting of neuronal groups
  • commonly associated with protein aggregates
  • symptomatic/anatomic – based on the region affected and associated symptoms
    • alzheimer’s disease
    • parkinson’s disease
    • pick disease (dementia type)
  • pathologic - based on the type of inclusion
    • e.g. tauopathies
  • limited capacity for repair

one of the biggest challenges with NGD disorders is that clinical symptoms arise long after significant cell loss

38
Q

What are genetic metabolic diseases that affect the CNS?

A
  • genetic defect that results in abnormal protein formation or reduced gene product
  • protein = enzyme
    • reduced activity
    • reduced amount
  • accumulation of the substrate
  • metabolic block and decreased end-product
  • failure inactive a tissue damaging substrate
  • effects organs where
    • tissue to be degraded is found
    • location where degradation occurs

neuronal storage disease

  • deficiency of enzyme involved in catabolism of sphingolipids, mucopolysaccharides and mucolipids
  • accumulation of substrate within lysosomes causes neuronal death

leukodystrophies

  • myelin abnormalities (synthesis or turnover)
  • diffuse involvement of white matter
39
Q

What are toxic and acquired metabolic diseases?

A

the toxicity of chemicals is affected by the age, genetic predisposition and sensitivity of the exposed tissue to injury

  • vitamin deficiencies
  • metabolic disturbances
    • hyperglycemia in the setting of uncontrolled diabetes
  • toxic disorders
    • carbon dioxide, methanol/ethanol, radiation
    • idiopathic Parkinson’s disease caused by toxic exposure to MPTP

even if other cells are affected neurons can’t regenerate - so damage to neurons more damaging

40
Q

What is MPTP induced parkinsonism?

A
  • four people developed marked parkinsonism after using an illicit drug (synthetic heroin) intravenously
  • analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP, a by product of drug synthesis)
  • selective damage of cells in the substantia nigra
41
Q

What are tumours of the CNS?

A

consequences unique to tumours of CNS

  • confined
  • location
    • benign or malignant

gliomas

  • astrocytomas
  • oligodendrogliomas
  • ependymomas

neuronal tumours
metastatic tumours

42
Q

What questions should be considered when looking CNS injury?

A

what are the consequences of CNS trauma?

how does the structure/function of the brain protect from injury?

does the structure/function of the brain contribute to the injury?

43
Q

What is traumatic brain injury?

A

an alteration in brain function, or other evidence of brain pathology, caused by an external force

  • head striking or being struck by an object
  • rapid acceleration or deceleration of brain
  • penetration of the brain by a foreign object
  • exposure to forces associated with blasts

not acquired brain injuries due to cerebrovascular, neoplastic, or neurodegenerative conditions

not a head injury, which might be limited to damage to the face or scalp

44
Q

What is the primary injury?

A

mechanical damage

protection by:

  • skull
    • external force will make contact with skull which protects the brain from mechanical stress
  • CSF
    • shock-absorbing

a blow to the surface of the brain resulting in lesion at

  • point of contact
  • diametrically opposed
  • both

a blow to surface of the brain that causes shearing, tearing or stretching

45
Q

What is primary mechanical injury?

A
  • crest of mechanical injury are most vulnerable to direct injury
  • acute neuronal injury
  • axonal swelling close to or distant from site of damage
  • haemorrhage
46
Q

What is secondary injury?

A
  • secondary injury mechanisms include a wide variety of processes including initiation of inflammatory and immune processes
  • pro-inflammatory molecules such as nitric oxide, prostaglandins, reactive oxygen and nitrogen species, proinflammatory cytokines
  • these can lead to lipid peroxidation, BBB disruption or the development of oedema
  • the associated increase in intracranial pressure ICP can contribute to local hypoxia and ischaemia, secondary haemorrhage and herniation and additional neuronal cell death via necrosis or apoptosis
47
Q

What is inflammation in the brain?

A

following injury

  • activation of endothelial cells and associated cells (astrocytes)
  • reduced tight junction integrity
  • formation of transendothelial channels
  • migration of leukocytes
48
Q

What causes raised intracranial pressure?

A
  • brain and spinal cord are protected by rigid compartment
  • injury may increase the volume of the brain
    • brain oedema
    • increased CSF volume (hydrocephalus)
    • focally expanding lesion (tumour or haemorrhage)
  • absence of lymphatic drainage
  • volume initially compensated by compression of veins and displacement of CSF
  • raised intracranial pressure
  • herniation
49
Q

What is herniation due to intracranial pressure?

A
  • the cranial vault is rigid (skull) and divided by rigid dural folds (meninges)
  • brain may be displaced by localised expansion (herniation)
  • tonsillar (downward cerebellar)
    • life threatening
    • brain stem compression
    • compromises respiratory and cardiac centres
50
Q

What is the potential for brain repair?

A

Adult neural stem cell (NSC)

  • capable of self-renewal by cell-division
  • capable of differentiation
  • subventricular zone (SVZ) and subgranular zone (SGZ)
  • in vitro
    • stem cell potential
    • self renewing neurospheres
    • neurons, astrocytes, oligodendrocytes
  • in vivo
    • low frequency of division
    • generate neurons

NG2 glia

  • dispersed throughout the adult brain parenchyma
  • generate differentiated myelinating oligodendrocytes
51
Q

What was NSC treatment of MPTP lesion?

A
  • hNSCs implanted into the striatum showed a remarkable migratory ability and were found in the substantia nigra, where a small number appeared to differentiate into dopamine neurons

PATH30001 (34 decks)

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