TBI

Question 1

Definition of TBI

Answer 1

Alteration in brain function, or other evidence of pathology, caused by an external force (NINDS)
Caused by external forces, either direct impact (colliding object), non-impact (acceleration-related like in a car-crash) or penetrating injury (bullet wound)

Question 2

Primary causes of TBI

Answer 2

traffic accidents, falls and sport-related causes

Question 3

Prevalence of severity levels

Answer 3

light (70-95%), moderate /severe (5-30%)

Question 4

The 3 age peaks of TBI

Answer 4

children (0-5 yr), young (15-25 yr), old (75+ yr)

Question 5

Gender ratio of TBI

Answer 5

2:1 male:female (for children/young adults, not for elder)

Question 6

TBI is a risk factor for?

Answer 6

Dementia & neuropsychiatric disease

Question 7

In the sheared brain we see?

Answer 7

Microbleeding

Question 8

In the bruised brain we see?

Answer 8

Eontusions

Question 9

In the pressured brain we see?

Answer 9

Epidural haematomas

Question 10

In the disconnected brain we see?

Answer 10

Progressive late white matter loss

Question 11

What are the two mechanisms leading to heterogeneity of TBI?

Answer 11

Insult spread: it’s hard to predict where secondary damage will be worst
Focal damage
Tissue elasticity: not all tissue damages in the same way. Depending on what is damaged, the pathomechanisms will be different

Question 12

Rodent model: controlled cortical impact (CCI)

Answer 12

Craniotomy is done and a piston is hammered on to the dura. The dura doesn’t break
Focal damage

Pros: adjust severity of injury be change pressures of pistol - it’s reproducible
Cons: long anesthesia, no immediate neural scoring, craniotomy

Question 13

Rodent model: A penetration ballistic injury (PBLI)

Answer 13

The piston is hammered through the dura

Focal damage

Question 14

Rodent model: cryogenic injury

Answer 14

Intact skull, exposure of skull to cold is causing focal necrosis
Focal damage

Pro: severity can be adjusted, highly reproducible and quantifiable
Cons: doesn’t mimic all we see in human TBI studies

Question 15

Rodent model: weight-drop injury (mixed focal and diffuse)

Answer 15

A weight is falling on the skull

Pros: the most clinically relevant and closest to humans - severe can be adjusted based on drop height. It can be induced in brief anesthesia and neuro-scoring can be done shortly after lesions
Cons: high mortality due to apnea and skull fractures. One has to use many animals as the injury patterns are not reproducible

Question 16

Rodent model: fluid percussion (FP) injury

Answer 16

Craniotomy, fluid is driven onto the exposed dura causing focal contusion and defuse neuronal injury
Mixed focal and diffuse

Pros: severity can be adjusted, it’s reproducible
Cons: requires craniotomy, which compensates for brain edema. We have high mortality

Question 17

Rodent model: weight-drop (diffuse)

Answer 17

The weight dropping has a plate on it to level the impact out a bit

Question 18

Rodent model: blast TBI

Answer 18

Pressure wave mimic an explosion in war

Diffuse injury

Question 19

primary damage of TBI

Answer 19

Primary is the mechanical, immediate damage (irreversible)

Question 20

Secondary damage of TBI

Answer 20

Secondary is the expanding injury (excitotoxicity, ion disturbances, mitochondria damage, free radicals, altered gene expression)

Question 21

Organic brain damage of TBI

Answer 21

Cause by secondary damage. Includes damage to the BBB, brain edema, increased inter-cranial pressure, inflammation, apoptosis/necrosis, ischemia, metabolic failure, axonal injury
This leads to functional deficits and brain injury

Question 22

Explain the components of excitotoxicity

Answer 22

In excitotoxicity we have increased glutamate release
Metabolic failure –> opening of voltage gated Ca2+ channels –> Increase in intracellular Ca2+ leading to excessive glutamate release. The glutamate uptake is reversed (how)?. The reversal of glutamate uptake in the astrocytes and the opening of astrocytic ion and water channels leads to astrocytic swelling and cytotoxic edema. NMDAR open –> Ca2+ in –> repeat
Cell death is caused by Ca2+ overload

Question 23

What causes excitotoxicity?

Answer 23

Energy decrease, extreme glutamate release and too much Ca2+ in the cell

Question 24

Why is it not a good idea to block NMDARs to stop excitotoxicity?

Answer 24

Synaptic NMDAR signaling can lead to neuroprotective factors

Question 25

What's the difference between synaptic and extrasynaptic NMDAR signalling in terms of neuroprotection?

Answer 25

Enhancing synaptic activity can lead to many neuronal protection factors. Increasing extra synaptic NMDAR activity can lead to cell death

Question 26

In the study presented, what was found about NMDA signalling in mouse models of TBI?

Answer 26

TBI: after 15 min of TBI, glutamate binds more than normally, but after 8 hours it's decreased more than normal. Decreased binding were not useful. Having NMDAR activity increased neuronal improvement and is important for functional recovery

Question 27

Is inflammation good or bad in TBI?

Answer 27

Both. Early stages of inflammation leads to clearing of debris, but later stages leads to neuronal degeneration

Question 28

M1 microglia

Answer 28

Pro-inflammatory - the ones we don't like

Question 29

M2 microglia

Answer 29

Anti-inflammatory - the ones we like

Question 30

Microglia for severe TBI

Answer 30

is up-regulated

Question 31

Microglia in former NFL players

Answer 31

up-regulated - microglia correlated with loss of cognitive abilities

Question 32

Damage to the BB can lead to?

Answer 32

brain swelling

Question 33

How it be BBB set up?

Answer 33

Layers (from closest to the vessel to furthest away) 1. thigh junctions created by endothelia cells 2. Pericytes creating the basal lamina 3. Astrocytic end-feet

Question 34

What component is responsible for the leak of the BBB after TBI?

Answer 34

Prekallikrein (in the kallikrein system). Blocking it 1) led to less blue dye entering the brain (less leakage) 2) prevented brain swelling by measuring brain water content 3) prevented down regulation of claudin-5 protein (a tight-junction protein)

Question 35

2 types of BBB-related edema

Answer 35

cytotoxic brain edema: intracellular acidosis and ion shifts leads to cell-swelling but not brain swelling vasogenic brain edema: Breakdown of the BBB leads to more water in the extracellular space --> leads to brain swelling, but not cell edema

Question 36

Relationship between axonal damage at tau

Answer 36

Tau usually stables axons, but during axonal damage it becomes hyper-phosphorized and aggregated into neurofibrillary tangles and neuropil threads

Question 37

What is CTE

Answer 37

Chronic Traumatic Encephalopathy (CTE) CTE is due to multiple TBIs leading to dementia, progressive neuropsychiatric symptoms, cognitive deficits, changes in personality

Question 38

How do we diagnose CTE?

Answer 38

Diagnosis only in post-mortem neuopathology

Question 39

When was the term CTE coined?

Answer 39

1949 by Critchley to desribe "punch-drunk" better (term from 1928)

Question 40

When did Omalu first describe CTE in a NFL player?

Answer 40

In 2005

Question 41

When was the criteria and stages for CTE created?

Answer 41

2013

Question 42

Neuropathology of CTE

Answer 42

``` Most important: tau Others: amyloid b transactive response (TAR) binding protein 43 (TDP-43) axonal degeneration white matter degradation neuronal loss persistent neuroinflammation ```

Question 43

Stage 1 of CTE

Answer 43

headache, inability to concentrate, higher depression (no major brain atrophy)

Question 44

Stage 2 of CTE

Answer 44

increased suicidality, aggression, memory loss, mood changes (more tau on the cortical areas, also stats showing in hippocampus and amygdala, but no major cross pathology)

Question 45

Stage 3 of CTE

Answer 45

strong cognitive and executive dysfunction, depression, dementia, suicided (phosphor tau in hippocampus, amygdala, entorhinal cortex, temporal lobe). We start to see dilated vesicles

Question 46

Stage 4 of CTE

Answer 46

brain is extremely atrophied and covered with tau deposits

Question 47

CTE and microphages

Answer 47

The chronic TBI is related to immune responses (microglia remains active). Astrogliosis is also typical along with cell death and a permanent BBB dysfunction (allowing entry of the wrong microphages, which contributes to the neuronal degeneration)

Question 48

Therapy for TBI

Answer 48

None, only prevention