7 - diagnosis and treatment of TBI Flashcards
treatment for the neurotoxic cascade
there is no drug treatment
however cooling slows processes down
why is cooling an effective treatment for neurotoxicity
blood is temperature sensitive
cooling slows processes down
e.g. lack of O2 and glutamate transmission
able to restore some function
use of x-ray to diagnose TBI
only useful to show bone fractures in the skull
use of CT-scan to diagnose TBI
shows bleeding within the skull area
use of MRI scan
shows build up of fluid
imaging methods for TBI
x-ray CT scan MRI EEG PET DTI
which imaging method shows whether there is damage within the brain
DTI
Diffusion Tensor Imaging
features of DTI
- separates axon tracks
- able to show location of injury and what part of the brain it will affect (where the tracks are headed in relation to the functional areas of the brain)
why is it important to see axons in imaging when diagnosing TBI
(axons are shown to be missing in TBI patients)
disadvantage of DTI
expensive
cognitive reserve after recovery from acute effects of TBI
cognitive recovers to almost original magnitude but not quite
means you are more likely to reach the dementia threshold later on
examples of 4 types of animal model
blast injury
fluid percussion injury
weight drop
controlled cortical impact (CCI) injury
blast injury model
mimics impact from explosions on soldiers
fluid percussion injury model
mimics subdural haemorrhage
fluid injected
behavioural models carried out
2 types of weight drop model
Marmarou’s for generalised/diffuse/widespread concussion
Shohami’s for specific area of concussion and localised/focal effects e.g. on occipital lobe
controlled cortical impact (CCI) injury model
controlled slow impact on exposed dura of animal to induce TBI
mimics blood brain barrier disruption
measure brain
what does latest TBI research look for
changes in microglial or astrocyte activity in animals after impact
optical coherence tomography
new technology to detect TBI
look into retina (where glial progenitors are found)
look for early changes due to concussive injuries
benefits of optical coherence tomography
most non-invasive method
clearer than CTs or X-rays
which animal models would you use to model a compressed or fractured skull
penetrating injury so weight drop or blast injury model
which animal models would you use to model subdural haematomas or stroke
use fluid percussion model
3 locations of microglia
cortex
corpus callosum
hippocampus
features of cortical microglia
ramified
star-like projections
freedom and flexibility for movement
are microglia in corpus callosum ramified
no
not much room to develop outward ramifications
activated microglia in chronic/long-term disease
enter rod-like state
lay down layers of individual rods for further protection
can inter-loop between amoeboid or hyper-ramified state
activated microglia in acute disease
enter amoeboid-like state
pass through hyper-ramified state
phagocytose and mop up damaged cells
which cells activate microglia into M1 polarisation state
IL-1B
TNF-A
IFN-Y
Th1 cells
effect of M1 microglia
inflammation
neuronal cell death
which cells activate microglia into M2 polarisation state
IL-4
Il-13
Th2 and Treg cells involved
effect of M2 microglia
release TGF-B
neuroprotective
anti-inflammatory
subtypes of M2 polarisation state
M2a, M2b, M2c –> secrete cytokines for generalised anti-inflammatory response
M2d –> secretes VEGF for angiogenesis
cytokines secreted by M2 subtypes
M2a: Il-4
M2b - IgG
M2c - IL-10
M0 polarisation state
resting state
secretes BDNF and IGF-1
what does DAM stand for
disease associated microglia
what are disease associated microglia
new protective microglia
commonly identified in people with ALS
CX3CR1 receptor
function of DAM
makes area surrounding insult (plaque deposition) secrete anti-inflammatory cytokines to prevent further damage
microgliosis/astrogliosis overview
over reactiveness of glia after resting state
what characterises TBI neuro-inflammation
reactive gliosis
drug to change polarisation state from M1 to M2
bexarotene
enhances APOE protein
enhances IL-4 and IL-10
inhibits ROS and TNF-a
TSPO
radio-ligand that gives indication of microglia activity in vivo using PET imaging
benefits of TSPO
very specific marker for microglia
microglia express the protein in membrane
GFAP
marker in imaging for astrocytes
astrocytes express the protein- so it is stained
examples of therapeutics targeting M1/M2 subtypes
minocycline
lipid lowering drugs
HDAC inhibitors
HDAC inhibitors mechanism of action
prevent removal of acetyl group on histones
histone wrapping is relaxed/less condensed
gene transcription is activated
lipid lowering drugs function
important for immunomodulation
minocycline
target microglia and inhibit their activation to suppress innate immune response
also down-regulate release of pro-inflammatory cytokines (e.g. TNF-a)
genetic biomarkers for prediction of vulnerability for TBI
APOE
TREM2
BDNF
BDNF
growth factor actively secreted by microglia
benefits of CCI model
different parameters of injury (depth, velocity of impact) can be controlled to change the severity of the TBI induced
no rebound concussive events –> results are reliable
mimics concussion, axonal damage and BBB disruption
disadvantage of CCI model
craniotomy (surgical opening into the
skull) is needed –> requires technical expertise
invasive
method of Marmarou’s weight drop model
- animal’s skull exposed by midline incision so a steel disc can be fixed on (to prevent bone fracture)
- rats placed onto deep foam bed
- a column of brass weights falls from a designated height through a tube onto the steel disc
method ofl:
animal is anesthetized
midline incision is made exposing skull
stainless steel disc is attached in a central location
animals are then placed on a foam bed
impact is generated by free-falling weights
weight drop is delivered to one side of the unprotected skull
injury produced by Shohami’s weight drop mode
reproduces neuronal and axonal pathology that is scattered throughout the cerebrum and brainstem. Depending on the severity of the injury, the induced brain injury results in hemorrhages, neuronal cell death, astrogliosis, diffuse axonal injury, and cytotoxic brain edema.
advantages of weight drop model
cheap
easy to set up
good replicability
severity of the injury can be manipulated based on changing pre-impact parameters such as varying the weights and weight height
limitations of weight drop model
control of parameters is less than CCI
more accidental deaths of rodents
aim of fluid percussion model
to mimic non-fracture TBIs
how is TBI induced using fluid percussion model
a pressure pulse is targeted at the intact dura via a craniotomy the pulse (or “percussion”) is generated when a pendulum strikes the piston of a reservoir of fluid
injury induced can cause contra-lateral or unilateral damage
limitations of fluid percussion injury model
use of fluid means less control over strength of parameters
high incident of accidental death of rodents
altered ionic homeostasis (increase in Ca2+)
EEG depression, motor and cognitive deficits induced
aim of blast injury model
to investigate how military blast waves affect the brain by inducing mainly diffuse injuries
military personnel often suffer from TBI without any external injuries
consequences of injuries from blast waves
often lead to motor coordination, spatial memory and social recognition impairments
what is the acute function of activated microglia in TBI
to remove cellular and molecular debris to restore normal neuronal environment
DAMPs
damage associated molecular patterns
stimuli released by damaged cells which can stimulate pro-inflammatory events –> further tissue damage
phenotype shift of microglia in chronic TBI
microglia polarisation phenotype shifts from M2 to M1 in chronic TBi
noxious stimuli released from activated microglia
ROS
pro-inflammatory cytokines
nitrogen species
excitatory neurotransmitters (e.g. glutamate) –> neurotoxicity
development of assistive technology for TBI patients
talking clock/calendar –> announces date and time at push of a button
large print calendar or checklist to help with daily routine and activities or appointment reminders
ultra key seeker to help locate lost keys
shake awake –> vibrating alarm clock
pill alert –> alarm feature for taking medication
importance of HLA subtype
HLA subtype can affect vulnerability of developing autoimmune diseases (TBI has autoimmune effects)
use of diuretics to treat TBI
reduce the amount of fluid in tissues and increase urine output
Diuretics given intravenously help reduce pressure inside the brain.
vorinostat
ahistone deacetylase (HDAC) inhibitor.
inducing iNOS/Nrf2/ARE pathway reduces the amount of oxidative stress and therefore has neuroprotective effects.
anti-seizure drugs
seizures common for TBI patients during the first week after their injury.
drugs may be given during the first week to avoid any additional brain damage that might be caused by a seizure.
coma-inducing drugs
a brain in a temporary coma needs less oxygen to function
why might putting a patient with TBI into a coma be useful
blood vessels are often compressed by increased pressure in the brain
therefore are unable to supply brain cells with required amounts of nutrients and oxygen
what is PU.1
transcription factor expressed by microglia in the brain
controls microglia development and function
glasgow coma scale
Measures a persons functioning:
Ability to speak
Ability to open eyes
Ability to move
identifying features of severe TBI
person unconscious for more than 24 hours
memory loss lasts more than a week
identifying features of moderate TBI
person unconscious from 30 minute up to 24 hours
memory loss lasts between 24 hours and 1 week
identifying features of mild TBI
person not unconscious or for less than 30 minutes
memory loss lasts less than 24hours
advantage of x-ray
small radiation dose
method of ct scan
Computerised tomography
Scan takes X-rays from many angles to create a complete 3D picture
pros/cons of ct scan
+
Can quickly show bleeding in the brain,
bruised brain tissue and other damage
-
Radiation dose exposure higher than
xray
Still lacks some detail
disadvantage of MRI
takes too long
however good detail
what is an EEG
electroencephalogram (measures electrical activity using electrodes)
pros/cons of EEG
Non invasive and no radiation
higher sensitivity
Doesn’t give such a good image of where the damage is and to what extent it has reached
problems which require surgical treatment
Haematoma –> bleeding puts further pressure on the brain, damaging tissue (remove haematoma)
skull fracture –> removal of pieces of
skull in the brain
Bleeding in the brain –> surgery in order to stop it
pressure inside skull –> relieved by draining accumulated
CSF or making a window
supportive care methods for CTE as there is no cure or treatment
Calming environment –> Reducing clutter and distracting noise makes it easier for patients to focus and function, reducing confusion and frustration.
Reassuring responses –> Avoid correcting or quizzing the patient. Reassurance and validate their concerns.
Modify tasks –> Break tasks into easier steps and
concentrate on success, not failure. Create structure &
routine in their day to reduce confusion.
Regular exercise –> Promotes sleep, motor skills, lessens
depression, creates calming effect.
Games and thinking activities –>Helps slow cognitive
decline
Night-time rituals –> Establish calming bedtime rituals as behaviour is often worse at night. Leave night light on to prevent disorientation
