lecture 24

Question 1

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

Answer 1

• neurons
• oligodendrocytes
• astrocytes
• microglia

Question 2

What happens during acute neuronal injury?

Answer 2

• ‘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

Question 3

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

Answer 3

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

Question 4

What is transynaptic degeneration?

Answer 4

• 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

Question 5

What is the axonal reaction?

Answer 5

• 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

Question 6

What are neuronal inclusions?

Answer 6

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

Question 7

What are intracytoplasmic inclusions?

Answer 7

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

Question 8

What happens to astrocytes when injured?

Answer 8

• 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

Question 9

How do astrocytes respond to injury?

Answer 9

• 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

Question 10

What does a rosenthal fibre indicate?

Answer 10

that the injury is chronic

Question 11

What is the most important histological indicator of CNS injury?

Answer 11

gliosis

Question 12

What is hypertrophy and hyperplasia of astrocytes?

Answer 12

gliosis

Question 13

How is gliosis detected?

Answer 13

GFAP

Question 14

Where are rosenthal fibres typically found?

Answer 14

in regions of long standing gliosis

Question 15

How do rosenthal fibres stain?

Answer 15

• contain brightly eosinophilic inclusions

- detected by H and E stain

Question 16

How do oligodendrocytes respond to injury?

Answer 16

• 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

Question 17

How do microglia respond to injury?

Answer 17

• 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)

Question 18

When are microglia activated?

Answer 18

• activated in response to injury

Question 19

What is the nature of the microglial response?

Answer 19

• rapid and graded

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

Question 20

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

Answer 20

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

Question 21

What do microglia do when neuronal dEATH occurs?

Answer 21

• 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)

Question 22

What are causes of injury?

Answer 22

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

Question 23

What is trauma?

Answer 23

• 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)

Question 24

What are consequences of CNS trauma?

Answer 24

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

depends on location of lesion

Question 25

What is cerebrovascular disease?

Answer 25

stroke - thrombosis - embolism - hemorrhage hypoxia, ischaemia, infarction - impairment of blood supply and oxygenation of CNS hemorrhage from rupture of CNS vessels

Question 26

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

Answer 26

- 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

Question 27

What is focal cerebral ischaemia?

Answer 27

- cerebral artery occlusion | - selective vulnerability and adequacy of collateral flow

Question 28

What is intracranial haemorrhage?

Answer 28

- 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

Question 29

With what is subarachnoid haemorrhage most frequently associated?

Answer 29

- 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

Question 30

How does infection cause damage?

Answer 30

- 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)

Question 31

Through what does infection occur?

Answer 31

- haematogenous spread - directly (trauma or malformation) - local extensions (air sinuses, infected tooth) - peripheral nervous system

Question 32

What can cause brain infection?

Answer 32

- bacteria - virus - fungus (usually in immunocompromised individual)

Question 33

What is inflammation of the meninges?

Answer 33

- meningitis - inflammation of leptomeninges and CSF - pyogenic meningitis (pus forming bacterial infection)

Question 34

What encephalitis?

Answer 34

- inflammation of brain parenchyma | - brain abcess

Question 35

What is inflammation of both meninges and parenchyma?

Answer 35

meningoencephalitis

Question 36

What are demyelinating diseases?

Answer 36

- 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)

Question 37

What are degenerative disorders?

Answer 37

- 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

Question 38

What are genetic metabolic diseases that affect the CNS?

Answer 38

- 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

Question 39

What are toxic and acquired metabolic diseases?

Answer 39

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

Question 40

What is MPTP induced parkinsonism?

Answer 40

- 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

Question 41

What are tumours of the CNS?

Answer 41

consequences unique to tumours of CNS - confined - location - - benign or malignant gliomas - astrocytomas - oligodendrogliomas - ependymomas neuronal tumours metastatic tumours

Question 42

What questions should be considered when looking CNS injury?

Answer 42

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?

Question 43

What is traumatic brain injury?

Answer 43

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

Question 44

What is the primary injury?

Answer 44

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

Question 45

What is primary mechanical injury?

Answer 45

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

Question 46

What is secondary injury?

Answer 46

- 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

Question 47

What is inflammation in the brain?

Answer 47

following injury - activation of endothelial cells and associated cells (astrocytes) - reduced tight junction integrity - formation of transendothelial channels - migration of leukocytes

Question 48

What causes raised intracranial pressure?

Answer 48

- 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

Question 49

What is herniation due to intracranial pressure?

Answer 49

- 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

Question 50

What is the potential for brain repair?

Answer 50

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

Question 51

What was NSC treatment of MPTP lesion?

Answer 51

- 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