TBI Flashcards
(65 cards)
What is traumatic brain injury (TBI)?
Traumatic brain injury (TBI) is an injury to the brain caused by an external
force:
* Bump, blow, or jolt to the head, or
* Penetrating injury (such as a gunshot) to the head
What are the three components to determine a patients consciousness level on the Glasgow coma scale (GCS)?
- Eye opening
- Verbal response
- Motor response
What are considered mild, moderate and severe scores on the GCS
- Mild (score: 13-15)
- Moderate (score: 9-12)
- Severe (score: <9)
Why is TBI such a complex disease to treat?
Major Challenges:
* TBI Heterogeneity (Concussion/mTBI ⟶ Repeated mTBI ⟶ Severe
TBI)
* Huge variability in Clinical Care and Outcomes
Describe the current treatments used to treat TBI?
Emergency treatments:
o Focuses on stabilising &
keeping the patient alive
(oxygen to brain,
controlling blood & brain
pressure)
o Sometimes surgery is
needed to: remove
blood clot, repair skull
fractures, relieve
pressure inside the skull
(intracranial pressure)
or
Medications :
Used to treat symptoms of
TBI & lower the risk of
associated conditions:
o Anti-anxiety medications
o Anticoagulants
o Anticonvulsants
o Antidepressants
o Diuretics
o Muscle relaxants
o Stimulants
or
Rehabilitation Therapies:
Rehabilitation therapy may
include the following:
o Physical therapy
o Occupational therapy
o Speech therapy
o Psychological counselling
o Vocational counselling
o Cognitive therapy
What are the 3 phases of in the pathophysiology of TBI?
Primary injury, Secondary injury and neurological deficits
What are the 3 key regulatory points in the timeline of TBI inflammation?
- Limit the acute pro-inflammatory response to the level needed for clearance
- Promote an anti-inflammatory and pro-regenerative immune phenotype
- Prevent the development of chronic neuroinflammation and return to normal function.
Describe what happens in each of the pathophysiological steps of TBI
Primary mechanical injury to the CNS may cause cell membrane disruption, vascular rupture, and BBB damage
secondary reactions involving ionic imbalance, release of excitatory amino acids, calcium overload, and mitochondrial dysfunction - ultimately culminating in cell death pathways.
Primary and secondary injury lead to release of DAMPs, cytokines, chemokines, activation of microglia and astrocytes, and recruitment of circulating immune cells. These immune responses largely overlap temporally. The inflammatory response is crucial to clearance of debris, repair, and regeneration after TBI. However, dysregulated inflammation can lead to additional acute and chronic brain injury.
What are the role of microglia in the CNS?
- Primary immunosurveillance cell in the
CNS - Multiple activation phenotypes:
Pro-inflammatory ‘M1’ – classical:
neurotoxicity
Anti-inflammatory ‘M2’ – alternative:
neuroresotration
Others (DAM, homeostatic, interferon-
related)
What can a blockade in molecules such as TNF-alpha or iNOS cause in mice subjected to TBI
TNFα−/− mice had impaired motor function and larger lesions at 4 weeks after injury, despite showing early neuroprotection.
Genetic or chemical iNOS blockade resulted in significantly worsened spatial memory 2–3 weeks after injury
Describe the role of co-ordinated inflammatory responses in TBI?
Wound healing after injury
Firstly this activates through an initial Pro-inflammatory phase to clear debris
Secondly, an anti-inflammatory phase activates to function in wound healing and resolution of M1.
What biomarker is used to track TBI neuroinflammation?
- Translocator protein 18 kDa (TSPO) is dramatically up-
regulated in microglia during neuroinflammation. - TSPO PET ligand = [11C]PK11195
What neurodegenerative diseases does TBI cause an increased risk in?
- TBI is associated with an
increased risk of
neurodegenerative disease
including: - Alzheimer’s disease,
- Parkinson’s disease and,
- Chronic traumatic encephalopathy
- Estimated that around 5% of all
dementia cases worldwide may
be attributable to TBI
What does increased [11C]DPA-713 binding indicate in a study done on NFL players?
Results suggest that localized brain injury and repair, indicated by increased [11C]DPA-713 binding to TSPO, may be linked to history of NFL play. Leading to brain atrophy.
Describe 2 Pre-clinical models used to examine TBI in mice
Fluid Percussion Injury (FPI)
* Diffuse injury (DAI), minor focal contusion
* Bilateral cortical damage
* Craniotomy required
* High mortality at moderate-severe level
* mild TBI (concussion) model
Controlled Cortical Impact (CCI)
* Unilateral focal contusion
* Cortical tissue loss, subdural
hematoma, BBB disruption
* Craniotomy required
* Highly reproducible
* Low mortality
What does sterological analysis confirm in patients with TBI?
confirms progressive
lesion expansion and demonstrates ongoing
hippocampal neurodegeneration up to 1
year post-injury.
With lesions having the highest volume 52 weeks post injury (1 year)
Is there an increase or decrease in resting (ramified) microglial activation after brain insult
Decrease
Is there an increase or decrease in activated (hypertrophic) microglial activation after brain insult
Increase, they stay chronically activated 1 year after brain insult
What type of signalling triggers microglial proliferation/survival?
CSF1/CSF-1R signalling
In a trial, what did the CSF1R inhibitor PLX5622 cause?
The CSFR1 inhibiting action of PLX5622 improved motor and cognitive recovery in TBI patients by decreasing microglial induced neurodegeneration and neurological decline
Give 4 reasons why their has been clinical translation problems from bench to bedside in TBI?
- Heterogeneity of TBI
- Lack of comparisons across preclinical
models - Appropriate therapeutic window
- poor experimental design
- focus on male only
- Brain centric treatments
- Drug pharmacokinetics
Describe how TBI can negatively impact systemic organs?
In turn, functional changes in
the periphery can affect the
response to subsequent insult
or disease.
TBI-induced peripheral changes
can drive secondary
neuroinflammatory responses
and subsequent
neurodegeneration and
neurological decline
How does TBI affect colon morphology
It increases mucosal hyperplasia, mucosa and thickness of smooth muscle
How does TBI affect immune cells in the colon
Moderate-level TBI results in
increases in colonic glial GFAP &
SOX10 expression
