L15 - Traumatic Brain Injury

Question 1

Why is TBI a problem?

Answer 1

common cause of death and morbidity worldwide

Increased incidence of other neurodegenerative conditions

currently no effective pharmacological treatment

poor understanding of complex pathophysiology

Question 2

What happens in TBI?

in particular name some primary and secondary in jury mechanisms

Answer 2

Primary Injury mechanisms (ireversible):

• mechanical tissue disruption
• necrotic cell death
• axonal shearing
• BBB damage

Secondary Injuiry mechanisms

• Neuroinflammation
• H-Tau
• ROS
  etc. ..

Main point: very complex and things aren’t independent of each other

Question 3

What kind of patient studies can we do and are they rigourous?

Answer 3

neurophysiological/psychologuical tests

Neuroimagine

Microdialysis/CSF

Post-mortem

Due to technical, methodological, ethical , financial and temporal limitations we cannot rigourously study TBI solely in patients

Question 4

Animal models of TBI allow for…

Answer 4

the rigourous examination of causal factors and underlying mechanisms involved in TBI

Question 5

Describe the Fluid Percussion injury?

Answer 5

controlled cortical impact: gives a focal impact and diffuse injury to mouse

fluid pulse passed onto brain

pendulum can be adjusted

Question 6

true or false

Weight drop can be a small or large, focal or diffuse impact on mouse brain

Answer 6

true

Question 7

Blast injjury is relevant for…

Answer 7

military inferences

Question 8

What are the scientific methods of analysing animal models?

Answer 8

Everything as for patients and more

extensive neuroimaging

behaviour

physiology

molecular

whenever you want with advanced techniques

Question 9

what are the advantages of animal models?

Answer 9

1. Investigate causal pathophysiological factors/mechanisms - allow tight control of parameters
2. Assessment of experimental intervention
3. Avoid temporal and other confounding factors
4. study chronic condition in months versus years/decades
5. cheap!

Question 10

What are the limitations of animal models?

Answer 10

1. interspecies physiological difference
2. There is no perfect model
3. Haven’t been used effectively

Question 11

What are inter-species physiological differences relevant for TBI animal research?

Answer 11

different ratios of grey and white matter

metabolic differences

immune system not identical

Question 12

What is a concussion?

Answer 12

subset of mild TBI

complex pathophysiological process induced by mechanical forces to the brain

Question 13

true or false

Repetitive mTBI may have cumulative and chronic neurological effects

Answer 13

true

Question 14

True or false

concussion increases incidence of numerous neurodegenerative diseases

• Alzheimers
• MND
• Chronic Traumatic Encephalopathy (neurodegenerative condition with severe cognitive, emotional and motor symptoms)

Answer 14

true

plus risk factor of depression

Question 15

A translational research approach to TBi involves..

Answer 15

a bidirectional approach to patients studies and animal models

looking a treatments, biomarkers and effects/mechanisms

Question 16

For NRL players long term studies have indentified…

Answer 16

neurophycholigcal outcomes- memory, recall

but these aren’t resulting in a deficit or abnormality

so you cannot conlcude that mild brain traumas CAUSE long term neurological deficits and neurodegeneration from it.

Question 17

when you give repetitive injuries you still see significant effect with one but the conditions are ____ with multiple injuries

Answer 17

when you give repetitive injuries you still see significant effect with one but the conditions are worse with multiple injuries

Question 18

true or false

repetitive mTBIs may have long-term neuro effects and may be dure to 2nd mTBI during vulnerable period which means it is important to DIAGNOSE WITH OBJECTIVE BIOMARKERS

Answer 18

true

Question 19

What are 2 non-invasive measures of changes after concussion?

Answer 19

MRI and blood sample

Question 20

Name some behaviour, MRI and blood biomarkers in mice

Answer 20

behaviour

• water maze = cognitive
• Elevated plus = anxiety
• forced swim = depession

MRI
- weighted MRI= structural damage

Blood

• cell death = NSE
• axonla injury = NF-H

Question 21

cognitive deficits in rats with a mFPI (fluid percussion injury) have cognitive deficits recover by day _

Answer 21

5

no overt brain damage on structural MRI

Question 22

In rat studies of mTBI following mFPI what were the study findings?

Answer 22

MRI, blood and behaviour changes post mFBI
- consistnet with human studies

2nd injury after behavioural recovery = exacerbated outcomes

patient studies began in 2015 but remaining hurdles include feasibility, biological relevance

Question 23

true or false

sodium selenate (PP2A tau dephyophylation catalyst) was beneficial after a single severe TBI in rats

Answer 23

true

Question 24

What effect does mTBI have on PP2A?

Answer 24

it decreases

therefore mTBI increases phyosphorylated tau

Question 25

By selenate post TBI increasing PP2A and reducing phyosphorylated tau what is effected?

Answer 25

atrophy, behavioural impairments and axonal injury is reduced

Question 26

Does selenate reprsent a translatable treatment approach?

Answer 26

YES!

but more complimentary approaches are neccessary

Question 27

IN EXAM

What is the awake, closed head model?

Answer 27

A new neuro-model that addresses the confounding craniotomy and anesthetic factors that are present in other mTBI models

Rats are awake when they have their injury