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week 9 part 2 Flashcards

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1
Q

What is TBI?

A

Heterogenous condition

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2
Q

What is TBI also called?

A

CranioCerebral Injury

Any injury to the skull and brain

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3
Q

What happens as a consequence of TBI?

A

skin, bone, and dura are no longer intact

The brain is exposed to the external environment

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4
Q

What is a open head injury?

A

A head injury in which the dura mater, the outer layer of meninges, is breached

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5
Q

What can penetrating injury be caused by?

A

High-velocity projectiles or objects of lower velocity such as knifes or bone fragments from a skull fracture that are driven into the brain

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6
Q

What is a penetrating head injury?

A

Involves a wound in which an object breaches the cranium but does not exit it

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7
Q

What are examples of penetrating object?

A
  1. Knife
  2. Needle
  3. Nail
  4. Shrapnel
  5. Bullet
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8
Q

What is an example of blunt object?

A
  1. Tree branch

2. Baseball bat

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9
Q

What can pieces of bone do?

A

Compress the brain

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10
Q

What is a direct violent shock?

A

Piece of skin will puncture the skull and reveal the fracture inside the brain

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11
Q

What is a closed head injury?

A

Skull and dura mater remain intact
Nothing directly touches the brain
Injury comes from the brain rattling in the skull

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12
Q

What happens if the head is hit with sufficient force (closed head injury)?

A

The brain may even be bruised by the skull itself

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13
Q

What can a crash impact do?

A

Shake the brain so violently that axonal fibres are torn

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14
Q

Closed Head Injury

A

The brain does NOT get exposed to the external environment

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15
Q

What are axons going to be?

A

very susceptible to minor forms of injury

  1. Forces applied directly to the brain and tearing the axons
  2. Twisting axons
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16
Q

What is a concussion injury?

A

Sudden but short-lived loss of mental function that occurs after a blow or other injury to the head

most common but lead serious type of brain injury

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17
Q

What are the symptoms of concussion?

A
  1. Loss of consciousness after the head injury
  2. Periods of memory loss
  3. Disturbances in vision, such as ‘‘seeing stars’’ or blurry vision
  4. A period of confusion, a blank expression, or a delay in answering questions immediately after the head injury
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18
Q

What is cortical contusion injury?

A

A bruising of the brain’s surface ( A bruise of the brain tissue)

Haemorrhagic and necrotic lesion

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19
Q

When does bruising occur?

A

When the small veins and capillaries under the skin break and the contusion foci may be multiple and bilateral

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20
Q

What is Hematoma

A

A collection of blood outside of blood vessels

Injury to the wall of a blood vessel - prompting blood to seep out of the blood vessel into the surrounding tissues

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21
Q

What can be present in Hematoma?

A
  1. Epidural, subdural, or intracerebral collection of blood

2. Fractures and/or swelling

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22
Q

What is subdural hematoma?

A

A hematoma between brain tissue and inside lining of the brain

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23
Q

What is coup-contrecoup injury?

A

Coup Injury - under the site of impact with an object

Contrecoup injury - on the side opposite the area that was hit

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24
Q

What is coup-contecoup brain injury?

A

A contact effect

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25
Q

What is a contact effect?

A
  1. the head strikes an obstacle or is hit by an object

2. Blow puts the brain in motion - get a countercoup

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26
Q

What is an Inertia effect?

A
  1. Brain is not following the skull as you move - has its own independence
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27
Q

What are the symptoms of mild TBI?

A
  1. confused
  2. Disorientated
  3. might lose consciousness for a few sec/min
  4. headache
  5. show motor signs with loss of balance
  6. Drowsiness
  7. Fatigue
  8. Nausea
  9. Vomitting
  10. Trouble sleeping/sleeping more than usual
  11. Ringing in the ears
  12. Blurred vision
  13. Changes in the sense of smell and mood swings
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28
Q

What are the symptoms for moderate-severe TBI?

A
  1. loss of consciousness
  2. Headaches that persist and get worse
  3. Extreme confusion
  4. Dilation of one pupil
  5. Presence of seizures
  6. Spinal fluid can be seen coming out of ears/nose
  7. Motor signs - very strong loss of coordination
  8. Numbness
  9. Weakness in fingers/toes
  10. Inability to wake up from sleep
  11. Slurred speech
  12. Go into coma
  13. Show very unusual behaviour including anxiety agitation
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29
Q

What can TBI result in?

A

Development of complex neurological deficits and is caused by both primary and secondary injury mechanism

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30
Q

What does primary injury event encompass?

A

The mechanical damage that occurs at the time of trauma to neurons, axons, glia and blood vessels as a result of shearing, tearing or stretching

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31
Q

What does secondary injury involve?

A

Evolves over minutes to days and even months after the initial traumatic insult and results from delayed biochemical, metabolic and cellular changes that are initiated by the primary event

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32
Q

What are secondary injury cascade thought to account for?

A

Development of many of the neurological deficits observed after TBI

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33
Q

What does secondary injury mechanisms include?

A

A wide variety of processes:

  1. Depolarisation
  2. Disturbances of ionic homeostasis
  3. Release of neurotransmitters (excitatory amino acid)
  4. Lipid degradation
  5. Mitochondrial dysfunction
  6. Initiation of inflammatory and immune processes
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34
Q

What does the associated increase in intracranial pressure contribe to?

A
  1. Local hypoxia and ischaemia
  2. Secondary hemorrage
  3. herniation and additional neuronal cell death via necrosis or apoptosis
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35
Q

What does lipid peroxidation lead to?

A
  1. Disruption of the membrane
  2. Abnormal depolarisation
  3. Excessive glutamate and GABA release - excitoxicity by increasing glutamate, NMDA activation, entry of ca2+

Damaging to the functioning of mitochondria with an increase in PARP-1 activation

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36
Q

What does PARP-1 activation have a role in?

A

Repairing single stranded DNA breaks

  1. Increasing calpin activation and other lytic enzymes
  2. Increase in permeability pore
  3. Mitochondrial swelling
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37
Q

What happens after TBI?

A
  1. There is AB deposition/oxidative stress
  2. Activity is induced by hypoxia and PS1
  3. Increase in gamma secretase activity
  4. Persistant neuroinflammation
  5. Hyperphosphorylation of microtubule associated protein Tau
  6. Neurite pathology and degeneration/synapse loss
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38
Q

When are axons very susceptible to TBI?

A
  1. Neurite pathology and degeneration

2. synapse loss

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39
Q

What does APOE place people at?

A

Higher risk on the outcome of TBI compared to other variants

40
Q

What used to be a major cause of TBI?

A

vehicle traffic accidents

41
Q

What is leading cause of TBI?

A

Falls

Falling from height

42
Q

What are falls linked to ?

A

Aging

43
Q

What is TBI?

A

Traumatic brain injury (TBI) is a significant public health problem associated with both acute and long-term disabilities, which are mediated by multiple, not entirely understood, molecular cascades

44
Q

What can initiate long-term neurodegeneration processes leading to pathological features that have similarities with Alzheimer’s disease (AD)?

A

debilitating acute effects, severe TBI, and especially repeated mild TBI

45
Q

What is the consequence of TBI through vascular shear stress that can induce acute BBB disruption?

A

Contribute to both ischemic damage and AB accumulation

46
Q

What may contribute to AB deposition after TBI?

A
  1. Hypoperfusion
  2. Vascular dysfunction
  3. Ischemia
47
Q

What can traumatic induced brain heat/cooling alterations modulate?

A

brain metabolism

48
Q

What can metabolic acidosis after TBI potentially contribute to?

A

AB accumulation

49
Q

What plays a role in secondary injury cascade, including cerebrovascular damage, oxidative stress, mitochondrial damage and endothelial cell dysfunction/death?

A

he formation Aβ aggregates in the perivascular spaces induced by these acute events after TBI

50
Q

What is a strong epigenetic risk factor for AD?

A

TBI

51
Q

What are many pathological feature common to both acute brain injury and AD?

A
  1. AB deposition
  2. Tau phosphorylation
  3. Neurite degeneration
  4. Synapse loss
  5. Microgliosis
52
Q

What does TBI deregulate?

A

The expression patterns of alpha-synuclein

  1. APP
  2. BACE1
  3. Tau
  4. ApoE4 genes
53
Q

What do these genes and their cleaved products implicated in?

A
  1. Neurodegenerative disorders
  2. Axonal pathology
  3. Apoptosis
54
Q

What does TBI also induce?

A

Caspase 3 which in turn is involved in APP processing contributing to AD

55
Q

What accumulates in damaged axons following TBI?

A
  1. APP
  2. BACE1
  3. PS1
56
Q

Is TBI a risk factor for AD?

A
  • Not all studies have made a diagnosis of probable or possible AD using established criteria
  • Probable AD is NOT pathologic confirmation of AD (rarely obtained) – need to look into the brain and have post-mortem
  • These studies are largely inconclusive cos they are incomplete
  • No information available about signs of other dementias that may overlap or coexist in AD (depression, agitation, irritability, parkinsionism)
57
Q

What are the other proteins present after repeat mild TBI?

A
  1. TDP-43

2. Alpha-synuclein

58
Q

TDP-43

A

Neurite, intraneuronal, and glial inclusions in 85% of cases

59
Q

Alpha-synuclein

A

as alpha-synuclein-positive Lewy bodies in 22% of cases

60
Q

Patients 55 and older with moderate to severe TBI

Garner et al

A

1.3 greater risk of developping dementia (AD and FTD)

61
Q

Why couldnt several studies and meta-analyes have not found an association between TBI and risk of dementia?

A
  1. recall bias - self reported diagnosis
  2. possible reverse casuality
  3. possible confusionpostconcussive syndrome due to transient post-TBI cognitive symptoms
  4. possible confounding
62
Q

Patients with a fractured skull and intracranial injury

Wang et al

A

Retrospective cohort study of 147,510 patients

4.13 greater risk of developing FTD

63
Q

Patients with a fractured skull and intracranial injury

Wang et al

A

6- fold greater risk of developing FTD in patients under 65 compared to aged matched controls

retrospective cohort study of 147,510 patients

64
Q

What does TBI increase?

A

φ However TBI increases risk of PD by 44% in one study

φ In another study it was found that the risk was increased by 57%

65
Q

how many people can get dementia?

A

only 1/3 of PD patients

66
Q

What are the conditions that increases risk of you getting different forms of dementia after TBI?

A
  1. Age

2. Susceptibility

67
Q

Who do all neurodegenerative disease have in common?

A
  1. Abnormal aggregation
  2. Misfolding
  3. Accumulation of proteins
68
Q

What is TBI a risk factor for?

A
  1. CTE
69
Q

What are examples of punch-drunk symptoms?

A
  1. Clumsiness
  2. Ataxia
  3. Disorientation

In severe cases: Parkinsonism-type symptoms and dementia

70
Q

Chronic Traumatic Encephalopathy (CTE):

A
  1. Chronic postconcussion symptoms (‘‘punch-drunk’’ symptoms/ ‘‘dementia pugillstica’’
  2. Contact sports (e.g. professional boxers), soldiers, civilians with a history of repeat mild TBI
71
Q

What does Tau protein have?

A

6 isoforms

3- or 4- repeat tau

72
Q

What is the cell origin of Tau?

A

Neuronal

Astrocytic

73
Q

What are the neuronal domain of Tau?

A
  1. Cell body
  2. Dendrite
  3. Axon
74
Q

Wha tis Tau protein?

A
  1. Phosphoprotein (P-tau)

2. phosphorylated on around 30 sites in the longest normal tau isoform

75
Q

What is found in CTE and not in AD?

A

Prominent astrocytic tangles

Irregular and patchy cortical distribution

76
Q

Alzheimer’s disease

A

NFTs and pre-tangles

Astrocytic tangles not present

77
Q

CTE

A

NFT and pre-tangles

prominent astrocytic tangles

78
Q

Alzheimers disease

A

Axons: Sparse

79
Q

CTE

A

Axons: Prominent

80
Q

Where does CTE have prominent NFTs and astrocytic tangles in?

A
  1. Perivascular
  2. Foci at depths of cerebral sulci
  3. Irregular, patchy cortical distibution (prominent)
  4. Subpial astrocytic tangles (prominent)
81
Q

What is present in CTE?

A

Periventricular astrocytic tangles

82
Q

Where are NFT found?

A

mainly in the superficial cortical layers as opposed to deeper layers

83
Q

What is CTE?

A

Tauopathy

84
Q

Research being done on mouse models long before?

A
  1. Other forms of P-tau appear
  2. Oligomers, aggregation,NFT
  3. Brain atrophy
85
Q

What is cis P-tau?

A

P tau with phosphorylated Thr231 - pro motif in cis form instead of trans

86
Q

What may be an early driver of disease after TBI?

A

Cistauosis

87
Q

What is Cistauosis?

A
  1. Spreading of protein
  2. This form of tau can jump/spread to another neuron or another axon
  3. Apoptosis coming from cis p-tau
88
Q

What is the process of Cistauosis which lead to Apoptosis?

A
  1. TBI
  2. Neuronal stress
  3. Induction of cis P-tau
  4. Disruption of axonal MT and organelle transport
  5. Transneuronal spreading
  6. Apoptosis
89
Q

When do you get no cistauosis ?

A

Mild TBI

Transient expression of cis P -tau

90
Q

Cistauosis

A
  1. LTP defect
  2. Neuron death
  3. Behaviour defect
  4. Disease spread
  5. Brain atrophy
91
Q

Where does cis P tau accumulate?

A

Excusively in degenerated neurons

92
Q

Where does Cis P tau localize?

A

dystrophic neurites during Alzheimer’s progression

93
Q

Where is trans P tau almost exclusively located?

A

Neuronal bodies

94
Q

What factors influence AB pathology after TBI?

A

After acute TBI:
• APP and Aß increase in tissue and CSF
• Rapid formation of diffuse Aß plaques in the cortex

95
Q

What was the evidence for this?

A

In a cohort of 68 CTE athletes and military veterans (McKee et al., 2013):
deposition of diffuse plaques in 44% of subjects (10% met the criteria for clinical AD )
In another cohort of 104 CTE athletes and military veterans (Stein et al., 2015):
diffuse or neuritic plaques in 52% of subjects

96
Q

Aß deposition in deceased athletes and military veterans:

A

occurred at an accelerated rate in CTE compared to the normal aging population
• was significantly associated with the presence of the APOE ε4 allele
• was associated with older age at symptom onsetwas associated with older age at death
• was associated with increased tauopathy, co-morbid Lewy body disease, and dementia

97
Q

Aß deposition:

A

• is altered and accelerated in a cohort of CTE
subjects
• is associated with both pathological and clinical
progression of CTE, independent of age

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