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

- neurons
- oligodendrocytes
- astrocytes
- microglia


What happens during acute neuronal injury?

- '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


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

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


What is transynaptic degeneration?

- 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


What is the axonal reaction?

- 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


What are neuronal inclusions?

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


What are intracytoplasmic inclusions?

- neurofibrillary tangles (Alzheimer's disease)
- Lewy bodies (Parkinson's disease)
- more specifically pathological (generally)


What happens to astrocytes when injured?

- 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


How do astrocytes respond to injury?

- astrocytes respond to any type of injury in the CNS

- 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


What does a rosenthal fibre indicate?

that the injury is chronic


What is the most important histological indicator of CNS injury?



What is hypertrophy and hyperplasia of astrocytes?



How is gliosis detected?



Where are rosenthal fibres typically found?

in regions of long standing gliosis


How do rosenthal fibres stain?

- contain brightly eosinophilic inclusions
- detected by H and E stain


How do oligodendrocytes respond to injury?

- 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


How do microglia respond to injury?

- 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)


When are microglia activated?

- activated in response to injury


What is the nature of the microglial response?

- rapid and graded
-- the more severe the injury, the greater the activation


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

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


What do microglia do when neuronal dEATH occurs?

- 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)


What are causes of injury?

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


What is trauma?

- 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)


What are consequences of CNS trauma?

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

depends on location of lesion


What is cerebrovascular disease?

- thrombosis
- embolism
- hemorrhage

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

hemorrhage from rupture of CNS vessels


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

- 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


What is focal cerebral ischaemia?

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


What is intracranial haemorrhage?

- 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


With what is subarachnoid haemorrhage most frequently associated?

- 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


How does infection cause damage?

- 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)


Through what does infection occur?

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


What can cause brain infection?

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


What is inflammation of the meninges?

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


What encephalitis?

- inflammation of brain parenchyma
- brain abcess


What is inflammation of both meninges and parenchyma?



What are demyelinating diseases?

- 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)


What are degenerative disorders?

- 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


What are genetic metabolic diseases that affect the CNS?

- 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

- myelin abnormalities (synthesis or turnover)
- diffuse involvement of white matter


What are toxic and acquired metabolic diseases?

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


What is MPTP induced parkinsonism?

- 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


What are tumours of the CNS?

consequences unique to tumours of CNS
- confined
- location
-- benign or malignant

- astrocytomas
- oligodendrogliomas
- ependymomas

neuronal tumours
metastatic tumours


What questions should be considered when looking CNS injury?

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?


What is traumatic brain injury?

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


What is the primary injury?

mechanical damage

protection by:
- skull
-- external force will make contact with skull which protects the brain from mechanical stress
-- 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


What is primary mechanical injury?

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


What is secondary injury?

- 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


What is inflammation in the brain?

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


What causes raised intracranial pressure?

- 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


What is herniation due to intracranial pressure?

- 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


What is the potential for brain repair?

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


What was NSC treatment of MPTP lesion?

- 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