week 9 part 2 Flashcards
1
Q
What is TBI?
A
Heterogenous condition
2
Q
What is TBI also called?
A
CranioCerebral Injury
Any injury to the skull and brain
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
4
Q
What is a open head injury?
A
A head injury in which the dura mater, the outer layer of meninges, is breached
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
6
Q
What is a penetrating head injury?
A
Involves a wound in which an object breaches the cranium but does not exit it
7
Q
What are examples of penetrating object?
A
- Knife
- Needle
- Nail
- Shrapnel
- Bullet
8
Q
What is an example of blunt object?
A
- Tree branch
2. Baseball bat
9
Q
What can pieces of bone do?
A
Compress the brain
10
Q
What is a direct violent shock?
A
Piece of skin will puncture the skull and reveal the fracture inside the brain
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
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
13
Q
What can a crash impact do?
A
Shake the brain so violently that axonal fibres are torn
14
Q
Closed Head Injury
A
The brain does NOT get exposed to the external environment
15
Q
What are axons going to be?
A
very susceptible to minor forms of injury
- Forces applied directly to the brain and tearing the axons
- Twisting axons
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
17
Q
What are the symptoms of concussion?
A
- Loss of consciousness after the head injury
- Periods of memory loss
- Disturbances in vision, such as ‘‘seeing stars’’ or blurry vision
- A period of confusion, a blank expression, or a delay in answering questions immediately after the head injury
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
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
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
21
Q
What can be present in Hematoma?
A
- Epidural, subdural, or intracerebral collection of blood
2. Fractures and/or swelling
22
Q
What is subdural hematoma?
A
A hematoma between brain tissue and inside lining of the brain
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
24
Q
What is coup-contecoup brain injury?
A
A contact effect
25
What is a contact effect?
1. the head strikes an obstacle or is hit by an object
| 2. Blow puts the brain in motion - get a countercoup
26
What is an Inertia effect?
1. Brain is not following the skull as you move - has its own independence
27
What are the symptoms of mild TBI?
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
28
What are the symptoms for moderate-severe TBI?
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
29
What can TBI result in?
Development of complex neurological deficits and is caused by both primary and secondary injury mechanism
30
What does primary injury event encompass?
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
31
What does secondary injury involve?
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
32
What are secondary injury cascade thought to account for?
Development of many of the neurological deficits observed after TBI
33
What does secondary injury mechanisms include?
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
34
What does the associated increase in intracranial pressure contribe to?
1. Local hypoxia and ischaemia
2. Secondary hemorrage
3. herniation and additional neuronal cell death via necrosis or apoptosis
35
What does lipid peroxidation lead to?
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
36
What does PARP-1 activation have a role in?
Repairing single stranded DNA breaks
1. Increasing calpin activation and other lytic enzymes
2. Increase in permeability pore
3. Mitochondrial swelling
37
What happens after TBI?
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
38
When are axons very susceptible to TBI?
1. Neurite pathology and degeneration
| 2. synapse loss
39
What does APOE place people at?
Higher risk on the outcome of TBI compared to other variants
40
What used to be a major cause of TBI?
vehicle traffic accidents
41
What is leading cause of TBI?
Falls
Falling from height
42
What are falls linked to ?
Aging
43
What is TBI?
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
What can initiate long-term neurodegeneration processes leading to pathological features that have similarities with Alzheimer's disease (AD)?
debilitating acute effects, severe TBI, and especially repeated mild TBI
45
What is the consequence of TBI through vascular shear stress that can induce acute BBB disruption?
Contribute to both ischemic damage and AB accumulation
46
What may contribute to AB deposition after TBI?
1. Hypoperfusion
2. Vascular dysfunction
3. Ischemia
47
What can traumatic induced brain heat/cooling alterations modulate?
brain metabolism
48
What can metabolic acidosis after TBI potentially contribute to?
AB accumulation
49
What plays a role in secondary injury cascade, including cerebrovascular damage, oxidative stress, mitochondrial damage and endothelial cell dysfunction/death?
he formation Aβ aggregates in the perivascular spaces induced by these acute events after TBI
50
What is a strong epigenetic risk factor for AD?
TBI
51
What are many pathological feature common to both acute brain injury and AD?
1. AB deposition
2. Tau phosphorylation
3. Neurite degeneration
4. Synapse loss
5. Microgliosis
52
What does TBI deregulate?
The expression patterns of alpha-synuclein
1. APP
2. BACE1
3. Tau
4. ApoE4 genes
53
What do these genes and their cleaved products implicated in?
1. Neurodegenerative disorders
2. Axonal pathology
3. Apoptosis
54
What does TBI also induce?
Caspase 3 which in turn is involved in APP processing contributing to AD
55
What accumulates in damaged axons following TBI?
1. APP
2. BACE1
3. PS1
56
Is TBI a risk factor for AD?
* 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
What are the other proteins present after repeat mild TBI?
1. TDP-43
| 2. Alpha-synuclein
58
TDP-43
Neurite, intraneuronal, and glial inclusions in 85% of cases
59
Alpha-synuclein
as alpha-synuclein-positive Lewy bodies in 22% of cases
60
Patients 55 and older with moderate to severe TBI
| Garner et al
1.3 greater risk of developping dementia (AD and FTD)
61
Why couldnt several studies and meta-analyes have not found an association between TBI and risk of dementia?
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
Patients with a fractured skull and intracranial injury
| Wang et al
Retrospective cohort study of 147,510 patients
4.13 greater risk of developing FTD
63
Patients with a fractured skull and intracranial injury
| Wang et al
6- fold greater risk of developing FTD in patients under 65 compared to aged matched controls
retrospective cohort study of 147,510 patients
64
What does TBI increase?
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
how many people can get dementia?
only 1/3 of PD patients
66
What are the conditions that increases risk of you getting different forms of dementia after TBI?
1. Age
| 2. Susceptibility
67
Who do all neurodegenerative disease have in common?
1. Abnormal aggregation
2. Misfolding
3. Accumulation of proteins
68
What is TBI a risk factor for?
1. CTE
69
What are examples of punch-drunk symptoms?
1. Clumsiness
2. Ataxia
3. Disorientation
In severe cases: Parkinsonism-type symptoms and dementia
70
Chronic Traumatic Encephalopathy (CTE):
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
What does Tau protein have?
6 isoforms
| 3- or 4- repeat tau
72
What is the cell origin of Tau?
Neuronal
| Astrocytic
73
What are the neuronal domain of Tau?
1. Cell body
2. Dendrite
3. Axon
74
Wha tis Tau protein?
1. Phosphoprotein (P-tau)
| 2. phosphorylated on around 30 sites in the longest normal tau isoform
75
What is found in CTE and not in AD?
Prominent astrocytic tangles
| Irregular and patchy cortical distribution
76
Alzheimer's disease
NFTs and pre-tangles
| Astrocytic tangles not present
77
CTE
NFT and pre-tangles
| prominent astrocytic tangles
78
Alzheimers disease
Axons: Sparse
79
CTE
Axons: Prominent
80
Where does CTE have prominent NFTs and astrocytic tangles in?
1. Perivascular
2. Foci at depths of cerebral sulci
3. Irregular, patchy cortical distibution (prominent)
4. Subpial astrocytic tangles (prominent)
81
What is present in CTE?
Periventricular astrocytic tangles
82
Where are NFT found?
mainly in the superficial cortical layers as opposed to deeper layers
83
What is CTE?
Tauopathy
84
Research being done on mouse models long before?
1. Other forms of P-tau appear
2. Oligomers, aggregation,NFT
3. Brain atrophy
85
What is cis P-tau?
P tau with phosphorylated Thr231 - pro motif in cis form instead of trans
86
What may be an early driver of disease after TBI?
Cistauosis
87
What is Cistauosis?
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
What is the process of Cistauosis which lead to Apoptosis?
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
When do you get no cistauosis ?
Mild TBI
| Transient expression of cis P -tau
90
Cistauosis
1. LTP defect
2. Neuron death
3. Behaviour defect
4. Disease spread
5. Brain atrophy
91
Where does cis P tau accumulate?
Excusively in degenerated neurons
92
Where does Cis P tau localize?
dystrophic neurites during Alzheimer's progression
93
Where is trans P tau almost exclusively located?
Neuronal bodies
94
What factors influence AB pathology after TBI?
After acute TBI:
• APP and Aß increase in tissue and CSF
• Rapid formation of diffuse Aß plaques in the cortex
95
What was the evidence for this?
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
Aß deposition in deceased athletes and military veterans:
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
Aß deposition:
• is altered and accelerated in a cohort of CTE
subjects
• is associated with both pathological and clinical
progression of CTE, independent of age
