Neuron Death

Question 1

clinical background

Answer 1

• Traumatic brain injury is common in children and
  young adults
• Vascular (ischemic and hemorrhagic) brain injury
  occurs in infants (e.g. premature birth) and is
  common in older adults
• Degenerative disease is common in the elderly
• It is important to understand the pathogenesis of
  brain cell damage, because:
• NEURONS CANNOT BE REPLACED

*clinical conditions associated
- stroke
- raised ICP
- intracranial hemorrhage
- dementia
- trauma - brain and spinal cord

Question 2

neuron dysfunction and death

Answer 2

• Neurons and their (often very long) output
  processes, the axons, are:
  – Highly dependent on a constant supply of oxygen and
  glucose, which diffuse from the capillaries
• 4-5 minute deprivation can be fatal to the cell
• Astrocytes have only a small supply of glycogen, which can be
  converted to glucose for use by neurons
• Intermediate injury can be associated with delayed neuron death
  (weeks to months after insult)
  – Highly dependent on a stable microenvironment
• Blood-brain barrier, supporting glial cells
  – Incapable of regenerating in the central nervous system
• Must be protected from injury (metabolic or physical)
• Must last the lifetime of the person

Question 3

vascular injury - definitions:
stroke
ischemic
hemorrhagic
hypoxia

Answer 3

• Stroke: Clinical effect of an acute brain vascular
  disorder, usually manifested by a degree of focal
  or global brain dysfunction.
• Ischemic - occlusion (embolus, thrombus,
  atherosclerotic, mechanical) of a blood vessel
  thereby depriving the brain of blood flow.
• Hemorrhagic - Due to rupture of a blood vessel
  within or on the brain.
• Hypoxia (reduced oxygen) and ischemia
  (reduced blood flow) have essentially the same
  effect

Question 4

anatomical considerations

Answer 4

• Volume of damage depends on size of blood
  vessel obstructed
• Systemic reduction in blood pressure or O2 or
  glucose delivery can affect entire brain
• However, vascular anatomy affects distribution of
  damage, often creating gradients
• Areas further along vascular tree are more
  susceptible to damage: autoregulation allows
  dilatation of arterioles to improve local blood
  flow; blood flow is “stolen” from more distal
  regions
• Same effect occurs locally; superficial cortex can
  “steal” blood flow from deeper cortex

Question 5

obstruction of cerebral blood flow

Answer 5

• can be atherosclerotic disease, local or distal
• get atherosclerotic plaque, then thrombus, then embolus, or occlusive thrombus
• flow is turbulent in carotids due to anatomy
• wall has propensity for damage - leads to plaque buildup
• predisposes to blood clot
• thrombi can break off and clot vessels in the brain

Question 6

interarterial boundary zone damage

Answer 6

(“watershed” infarct) occurs at the distal end of
the arterial branches in global insult situations (e.g.
cardiac arrest). Nutrients / blood flow are diverted
to more proximal sites by vasodilatation.

Question 7

effect of increasing insult severity

Answer 7

• Selective neuron death (end stage - slightly
  atrophic tissue with reactive microglial
  changes) vs.
• Infarct - all cell types destroyed (by necrosis,
  with liquefaction, inflammation, and
  macrophage activity) (end stage - cavity in
  brain)
• The two can co-exist; selective neuron death
  occurs at the edge (penumbra) of an infarct
  or hematoma; in this region nutrient delivery
  is reduced therefore neurons can survive or
  die depending on restoration of blood flow,
  oxygen supplementation, etc.

Question 8

selective neuron death

Answer 8

• Hypoxia, ischemia, and
  hypoglycemia cause similar (but
  not identical) changes.
• <6 hours to ~1 week – dead
  neurons are eosinophilic (pink
  staining) and pyknotic
  (shrunken)
• 1 week to ~3 weeks – microglia
  surround and consume the
  dead neurons (neuronophagia)

Question 9

infarct

Answer 9

severe insult - all cell components destroyed
- dead cells are removed by macrophages
- old or healed infarcts are characterized by cavities surrounded by reactive astrocytes at the edges and along viable vessels - may bridge the cavities
*large infarct - microglia aren’t enough and monocytes come in and become macrophages

Question 10

small vessel occlusion

Answer 10

• can cause thousands of microinfarcts
• thrombotic thrombocytopenic purpura (TTP) is spontaneous aggregation of platelets and activation of coagulation in small blood vessels
  *clinical manifestations are different than one large stroke - more global brain dysfunction

Question 11

venous obstruction

Answer 11

ex. thrombosis of superior sagittal sinus (dehydration, hypercoagulation or local tumour obstruction)
- prevents outflow of blood and causes
hemorrhagic infarction in
non-arterial distribution
- hemorrhagic changes crosses arterial boundary zones

Question 12

hemorrhagic conversion of cerebral infarct

Answer 12

• if blood vessels are damaged and blood flow is restored - bleeding can occur into the infarcted tissue
• usually 1-3 days later
• venous obstruction can cause similar appearance although the affected regions differ

Question 13

subarachnoid hemorrhage

Answer 13

ex. from basilar artery aneurysm
- distribution of blood varies with aneurysm site
- bleeding in subarachnoid compartment - large arteries on surface of brain around subarachnoid space
- ballooning of tissue with aneurysm - can rupture and bleed on brain surface
- can lead to vasospasm - blood is irritating outside vessels
- bleeding will continue to equilibration of pressure = increased ICP

Question 14

microvascular changes dt chronic arterial HTN

Answer 14

• arteriolosclerosis
• arteriolar reduplication
• patchy white matter axon/myelin reduction on MRI
• perivascular space enlargement (lacunes)
• with HTN - brain wants to protect, capillaries become fragile, smooth muscle will proliferate and thickening of small vessels entering the brain
  = markers of HTN
• vessels are more pulsatile than should be
• gradually eroding brain around perivascular space
• seen on MRI as abnormal signal in white matter
• subtle decreases in number of axons and myelination in area

Question 15

hypertensive intracerebral hemorrhage

Answer 15

• chronic arterial HTN weakens vessel walls
• intraparenchymal hypertensive hemorrhage occurs most often in basal nuclei (+/- intraventricular extension)
• other sites include thalamus, pons and cerebellum
• primary hemorrhage in cortex can be associated with amyloid angiopathy, a vascular disease that occurs in conjunction with Alzheimer’s dementia
• can lead to catastrophic hemorrhage - ballooning of small vessels in brain (deep parts of brain)

Question 16

summary of hemorrhagic lesions

Answer 16

• Location of bleeding within brain or on surface of
  brain depends on source
• Size and site are prognostic indicators;
  intraventricular hemorrhage (IVH) is bad
• Plasma enzymes (especially thrombin) and
  blood breakdown products are toxic to brain
  cells
• Secondary ischemia:
  – Blood collection can distort / compress adjacent
  tissue
  – Blood can cause spasm of adjacent blood vessels
  – Blood flow beyond damaged vessel might not be
  possible

Question 17

vascular lesions in the immature (perinatal) brain

Answer 17

• Vascular lesions in the immature brain have different
  etiology (blood vessel maturity and integrity) and
  pathogenesis (differing neurochemistry) than mature brain
• Premature birth (<32 weeks) is often complicated by
  hemorrhage or hypoxic / ischemic damage in deep brain
  tissue
• Problems at full-term delivery (e.g. related to umbilical cord
  or placenta) can lead to diffuse hypoxic damage to neurons
• If children survive, they may have cognitive delay, epilepsy,
  cerebral palsy, learning disabilities, etc.
  *small premature vessels that can rupture easily
  *lungs are immature and O2 delivery is suboptimal

Question 18

germinal matrix hemorrhage

Answer 18

• Germinal matrix (next
  to the lateral ventricles)
  generates brain cells
  until ~34 weeks
  gestation.
• In premature infants,
  bleeding arises from
  blood vessels that
  cannot tolerate
  deformation during
  birth and blood
  pressure fluctuations
  after birth
  *germinal matrix = cell proliferation generating diff cell types around ventricles
• fragile with not much holding together
• lots of blood flow and big veins
• vessel rupture can lead to local ischemic damage and post hemorrhage hydrocephalus
• can lead to cerebral palsy and developmental disorders
  *germinal tissues cannot come back

Question 19

Periventricular Leukomalacia
(“white matter softening”)

Answer 19

Pre-myelinating oligodendrocytes (26-32 weeks
gestation) and axons in white matter surrounding
ventricles are very susceptible to hypoxia and ischemia
- focal necrosis can result
- see discolouration and cavity formation in white matter
(axons and oligodendrocytes)

Question 20

traumatic injury

Answer 20

• Physical / mechanical injury to the nervous
  system
  – Direct disruption of neurons / axons
• and / or
  – Indirect damage to neurons / axons secondary
  to disruption of blood vessels
• Consider the mechanism, contact location,
  force direction, velocity / acceleration,
  anatomy, associated injury, age of person
• Differential mechanical strength of cellular
  components (e.g. axon < capillary < artery)

Question 21

concussion

Answer 21

transient disruption of brain function
(e.g. loss of consciousness) following acceleration
of the head

Question 22

contusion

Answer 22

(bruising) - injury to a tissue that causes
damage to cells and small blood vessels but no
break in the surface

Question 23

definitions

Answer 23

• Fracture - breaking of tissue (especially bone)
• Laceration - jagged tearing of tissue
• Hemorrhage (bleeding) – escape of blood from
  vessels
• petechia (pinpoint collection), ecchymosis (small patch)
• hematoma - localized collection of blood that separates
  tissue components

Question 24

anatomic layers of head and types of traumatic injuries

Answer 24

• Scalp (lacerations)
• Skull (fractures) – protects the brain, but the enclosure can itself
  impact the brain or have consequences with respect to pressure
• Dura (epidural / subdural hematomas)
• Arachnoid (subarachnoid hemorrhage; CSF leak)
• Brain
  – contusion (microscopic petechial hemorrhages) ± laceration
  – intracerebral hematoma
  – distortional axonal / vascular “shearing” injury
  – secondary edema / swelling / herniation

Question 25

distortional brain injury

Answer 25

* rapid acceleration / stretch damages axons & blood vessels - multiple hemorrhages in white matter - separation of parts of brain - extreme cases - medulla ripped away from pons (very high speed crash)

Question 26

axon damage

Answer 26

* follows distortional injury of white matter (“diffuse axonal injury”) * can also develop secondary to ischemia * axoplasmic flow ceases before physical separation occurs, proteins accumulate, and the axon swells at the point of physical or metabolic damage

Question 27

infant brain injury

Answer 27

* Pattern of damage differs from adult (“softer” brain, open skull sutures) – Brain swelling / edema – Subdural hemorrhage (thin) – Retina and optic nerve sheath hemorrhage * Mechanisms – Crushing, deceleration, fall from height (limit unknown), child abuse (“Shaken baby syndrome” postulated, NOT proven)

Question 28

brain edema

Answer 28

* Increased tissue water content * Disruption of blood-brain barrier allows protein-rich fluid to cross into brain (“vasogenic” edema) * Loss of energy causes cells to swell (“cellular” or “cytotoxic” edema)

Question 29

brain edema - consequences

Answer 29

* dysfunction of neurons because extracellular environment is altered (Na/K balance must be maintained or else neurons won't fire properly) * swelling of brain – secondary decrease in cerebral blood flow * if severe, swelling may be fatal due to “herniation” of brain structures (e.g. shift of brain from its normal intracranial position)

Question 30

cellular considerations

Answer 30

* Neurons have high metabolic demand * Susceptible to hypoxia / ischemia / hypoglycemia: – neurons > oligodendrocytes & axons > astrocytes & microglia > blood vessels * Neuron vulnerability varies regionally and by type because of neurochemical variation – e.g. CA1 neurons of hippocampus, medium spiny neurons in striatum, Purkinje neurons in cerebellum (these vulnerabilities are not absolute) * Neurons cannot be replaced

Question 31

chemical / molecular considerations

Answer 31

* Deprivation of O2 or glucose reduces ATP production * Loss of electrical activity precedes membrane pump failure * Lactic acid production è acidosis * Glutamate release and Ca++ influxè proteolytic damage proteins (e.g. calpains) and membranes (e.g. phospholipases) and DNA (e.g. caspases)

Question 32

neuron death

Answer 32

* Neuron death after hypoxia-ischemia has hybrid features of apoptosis and necrosis * Immature neurons (i.e. prior to full term gestation) tend to die by apoptosis

Question 33

excitotoxicity

Answer 33

* Neurons are killed by excessive stimulation by excitatory neurotransmitters released by hypoxic neurons * Glutamate (or aspartate) + glycine bind to the N-methyl-D-aspartate (NMDA) receptor and AMPA receptor allowing high levels of calcium ion (Ca2+) to enter the neuron * Differential expression of NR subunits helps to explain why not all neurons are equally susceptible to hypoxia-ischemia **cytotoxicity - irritated neurons release glutamate and stimulates other neurons persistently and burn out essentially

Question 34

chemical toxins that mimic hypoxia-ischemia

Answer 34

* Carbon monoxide (CO) binds iron-compounds; binding to hemoglobin interferes with O2 delivery; binding to ferritin in globus pallidus contributes to focal necrosis * Cyanide (CN-; and others) interfere with mitochondrial activity by binding cytochrome c oxidase * Domoic acid (produced by algae and accumulate in shellfish) and BOAA (contained in the legume Lathyrus sativus) are glutamate agonists (There is no proof whatsoever for alleged aspartame toxicity)

Question 35

carbon monoxide poisoning

Answer 35

- CO binds hemoglobin strongly creating carboxyhemoglobin. - It also binds to cytochromes in tissues, which retain a bright red color after death - survival after CO poisoning - necrosis of globus pallidus - globus pallidus - very susceptible to CO

Question 36

roles of inflammation

Answer 36

* Processes that aggravate inflammation (e.g. hemorrhage or bacterial infection) – bystander injury * Autoimmune processes – (mis)directed attack on host brain cells * Microglial reaction – mostly secondary (e.g. clean up) but cytokines can modify * Systemic inflammation – cytokines can enter brain and aggravate responses to direct injuries (e.g. hypoxia)

Question 37

aging of the nervous system

Answer 37

* Gradual loss of neurons and atrophy often becomes apparent in 7th decade. * Multifactorial e.g. genetic, lifestyle (ethanol etc.), arteriosclerosis * Cells that must last a lifetime accumulate debris that cannot be metabolized or disposed of (e.g. lipofuscin in neurons, corpora amylacea in astrocytes) *abnormal proteins due to mutations in protein or enzyme, or abnormal processing - can be seen in neurodegenerative disease ex. alzheimers

Question 38

degeneration of the nervous system

Answer 38

* Abnormal proteins (mutated or abnormally processed) can accumulate in neurons with lethal effect (toxic gain of function) * Abnormal protein aggregates can be detected by immunohistochemistry within neurons (inclusion bodies, often bound to ubiquitin) * Neurons are lost gradually - they are rarely observed in the process of dying (contrast with ischemia). The secondary reaction to neuron death can be easier to detect (i.e. activated microglia)

Question 39

Alzheimer's disease

Answer 39

* Most common form of dementia * Dementia is usually determined by coexisting cerebrovascular disease * Cerebral atrophy * Principles of pathogenesis are similar in other common neurodegenerative diseases; e.g. frontotemporal lobar degeneration (FTLD), Parkinson / Lewy body disease, etc.) *neurofibrillary tangles (hyperphosphorylated tau??) *senile/neuritic plaques (beta amyloid core) *surface arteries - beta amyloid (congophilic) angiopathy - risk of hemorrhage

Question 40

amyloid precursor protein (APP)

Answer 40

- at synapses is recycled by gamma and beta secretase cleavage, assisted by presenilin - in alzheimers, cleavage by gamma secretase is abnormal and results in Ab42 (instead of Ab40), which is less soluble and cannot be cleared by perivascular drainage system - presenilin mutations can also result in abnormal cleavage

Question 41

metabolic waste

Answer 41

- washed out of the brain via perivascular fluid (glymphatic) channels - A beta retained = microglia involved in secondary inflammatory response - A beta accumulation is toxic to neurons - likely at synapse - stress leads to abnormal phosphorylation of microtubule associated protein tau - accumulates in neurons - neurons become dysfunctional and eventually die

Question 42

chronic traumatic encephalopathy

Answer 42

* Reported mainly in context of sports with multiple accelerations of the head (e.g. boxing, football, hockey) * Formerly known as “dementia pugilistica” (boxer’s dementia) * Mild neuron loss, neurofibrillary tangles, and protein deposits immunoreactive for tau (microtubule binding protein) around blood vessels and in cortex at depths of sulci * Mechanism unclear (physical + blood brain barrier disruption possible)

Question 43

prevention of neurologic injury

Answer 43

- prevention or mitigation are better than (largely non-existent) cures for neurologic injuries and disease * Head / brain injuries are bad – avoid them; wear helmets and / or seatbelts when appropriate * Cerebrovascular disease is bad – control blood pressure; avoid tobacco * Toxins are bad – minimize alcohol and other drugs; work environments should be well ventilated; ? role of air pollutants * Optimal maternal health during pregnancy is good - reduce chances of preterm birth; minimize adverse changes in developing brain * Physical exercise is good – increased vascular pulsations assist brain “cleansing” through the glymphatic system * Sleep is good – mechanism(s) unclear; “reset” neurotransmitters and synapses; ? enhanced resilience to pathological and behavioral stress