7 - traumatic brain injury and neuroinflammation Flashcards
what does TBI stand for
traumatic brain injury
define TBI
injury to the brain caused by trauma to the head
not of degenerative or congenital nature
commonly requires external force
effects when frontal cortex affected by TBI
lack of focus/concentration
irritability
speech/language difficulty
effects when parietal lobe affected by TBI
difficulty with reading
spatial misperception
loss of sense of touch/pain/temperature
effects when occipital lobe affected by TBI
blind spots and blurred vision
effects when temporal lobe affected by TBI
problems with long and short term memory
hearing difficulties
if TBI causes difficulty walking, lack of balance and slurred speech which area has been affected
cerebellum
if TBI causes changes in breathing patterns and difficulty swallowing, which area has been affected?
brainstem
2 categories of traumatic head injury
open head injury
closed head injury
features of open head injury
penetration into the skull
–> dura mater (outer meninges layer) is breached
severity dependent on areas affected
–> fatal if brainstem, both hemispheres, ventricles or multiple lobes are damaged
example of open head injury
gun shot wound
knife stab
features of closed head injury
hit with a blunt object
local impact onto skull
(skull/dura mater remain intact)
skull impacts nerve tissue
coup injury
injury occurs under first impact point
contrecoup injury
injury occurs on the side opposite the area that was hit
can lead to subdural haematomas
motor-action caused by closed head injury
back and forth/rotational motion within the skull
bleeding, tearing and sheering in the brain
subdural haematoma
collection of blood outside the brain
bleeding under the dura mater (between cortex and axons)
causes increased pressure on the brain
white matter injury
axonal damage
secondary damage caused by closed head ijnury
leakage of neurotransmitters lack of glucose to the brain changes in blood flow and oxygen levels --> excitotoxic events --> inflammation
examples of closed heady injury
hitting head when falling over
–> causes concussion or can lead to stroke
neurotransmitters involved in neurotoxic cascade
glutamate
Cl-
K+
Na+
changes in the brain due to CTE
large ventricles affected
loss of matter
gyri become chunkier and more prominent
common name for dementia pugilistica
boxing dementia
punch drunk syndrome
features of dementia pugilistica
progressive symptoms
slurred speech
memory impairment
similar to CTE
chronic traumatic encephalopathy (CTE)
progressive condition
caused by repeated hits to the head
involves memory loss and lack of concentration
subtype of CTE
dementia puglistica
secondary impact syndrome (SIS)
rare
life-threatening
caused by consecutive concussion
leads to loss of auto-regulation of the blood supply
why does SIS cause lack of blood supply control
damage to blood vessels is exacerbated at second impact
rapid brain stem failure
vascular engorgement
increased intracranial pressure
proteins underlying risk of developing CTE
Tau protein is excessively hyperphosphorylated
Apolipoprotein E
why did the american footballer die of SIS
he had two head impacts in quick succession (knee to the head then impact to his chin)
he then collapsed as his cells didnt have time to repair and left permanent damage
pathological effects of the neurotoxic cascade after secondary TBI
Blood brain barrier disruption cell death cascade excitotoxicity energy failure --> lack of glucose ischemia --> lack of oxygen cerebral oedema
features of the BBB
tight junctions formed between endothelial cells
only allows water, oxygen and lipid soluble proteins to move through
–> restricts immune cell migration
surrounded by pericytes and glial cells
importance of pericytes for BBB maintenance
monitor nutrient load across membrane
role of glial cells for BBB maintenance
surround and support complex
(astrocytes and microglia)
help make CSF
help prevent immune cell migration
role of glia in CNS
responsible for monitoring metabolsim and maintenance
make up 70%
which glia are in CNS
ependymal cells
astrocytes
oligodendrocytes
microglia
which glia are in PNS
schwann cells
satellite cells
what is the gliovascular complex
made up of the BBB and the astrocytes surrounding it and their receptors
interface between brain vessels and astrocytes
ensures sufficient blood supply to brain regions
effect of TBI on endothelial tight junctions
tight junctions become sheered apart
brain exposed to other neurotransmitters
astrogliosis
response to CNS insult
astrocytes become “reactive” after injury
abnormal increase in number of astrocytes due to destruction of nearby neurons
overall effects of astrogliosis
increased proliferation and migration of astrocytes towards point of injury
secretion of cytokines and cytotoxins
glial scar formation
immune cells of the brain
microglia
monocytes
role of monocytes in acute brain injury
get through BBB and become active
overall functions of microglia polarisation states
M1: neurotoxic and pro-inflammatory
M2: neuroprotective
microgliosis
the process of microglia becoming “reactive”
excessive production of microglia
microglia receptor enhanced in inflammatory states
TREM2
why do microglia need to remain active for quite a while
ratio of M1/M2 important for brain homeostasis
enhanced inflammatory response within the brain to cope with neurotoxic cascade
how do microglia remain active
secrete more cytokines and interleukins
overall effects of neuroinflammation
microglia activated
glial scar formation
immunotoxicity
when is TBI acquired
after birth
symptoms of concussion
sadness
balance problems
sleeping more/less than usual
memory loss
axonal injury
white matter injury
caused by tearing and shearing
result of acceleration and rotation of the brain
how does axonal injury result in neuronal death of grey matter
cells are engulfed by cytotoxins released by tearing
symptoms of CTE
memory loss depression suicidal thoughts explosive or aggressive behaviour trouble walking or speaking
which groups of people commonly suffer from CTE
athletes in contact sports (boxing, american football)
military veterans
victims of domestic abuse
role of Tau in CTE
protein becomes tangled and accumulates
Tau collects around blood vessels and deep into the sulci of brain cortex
what is a NG2 glia cell
oligodendrocyte precursor cell
function of NG2 glia
actively secrete proteoglycans and form synaptic contacts
inhibit further development of axons
prevent axon regeneration
what is a glial scar
structural formation of reactive glia around an area of severe tissue damage
hallmarks of astrocyte reactivity
increased homeostatic and trophic functions secretory activity proliferation migration glial scar formation BBB repair
extracellular hallmark of glial scar formation and BBB repair
variety of different cell types line up around damaged area
intracellular hallmark of glial scar formation and BBB repair
NF-kB signalling
dictates M1 or M2 polarisation depending on cytokines secreted by astrocytes
3 main events occuring in glial scar development
- BBB leakage
- increase in numbers of microglia
- neurogenesis
importance in rebuilding of blood vessels after injury
allows healing of vascular leakage of the meninges
definition of BBB
semipermeable membrane separating blood from the CSF
prevents harmful substances reaching brain while still allowing passage of nutrients
what features of the CNS environment make it unique
- different ionic composition for neuronal function
- specialized neurotransmitter pool
- low protein concentration, to minimizecell proliferation
- low exposure to systemic toxins, to minimize neuronal damage
- reduced traffic ofinflammatory cellsand molecules, to
minimize local inflammation.
effect of cytokines on BBB
cytokines are secreted by cells of the CNS (e.g. BBB endothelium) in response to trauma or inflammation
increase its permeability by re-organising actin cytoskeleton
act as chemotactic agents recruiting more immune cells which increases inflammation
why are adhesion molecules important
for adherence of leukocytes to the brain endothelium
cytokines can increase production of adhesion molecules
what is connexin 43 (cx43)
immuno-regulating factor
- a gap junction protein highly expressed by astrocytes at the BBB interface
absence of astroglial cx43
endothelial activation and immune cell recruitment
morphological changes to astrocytes after injury
extend their processes to form a dense web to fill the empty space left by dead neurons (astrogliosis)
produce more GFAP
molecules secreted during astrocyte proliferation
lamins
proteoglycans
microglia expression of molecules dependent on location
the closer the microglia are to the site of injury, the more they express the biologically active molecules
role of microglia in immune function
sensitive to stimuli due to K+ channels
survey CNS for plaques, damaged neurons and pathogens
initial responders and initiate inflammation
remove damaged cells by phagocytosis
microglia state under healthy/normal conditions
maintained in immunosuppressed ‘resting’ state due to inhibitory signalling from cell-surface and soluble ligands from surrounding neurons
contribute to brain homeostasis by remodelling synapses, monitoring neural firing and surveillance of the environment for pathogens
microglia activation upon brain insult
detect PAMPs such as LPS or IFN-y from a bacterial cell wall which activate PRRs
- inhibitory signalling is removed
- microglia retract their processes and transform into an amoeboid shape
- recognised and engulf pathogens and present antigens
(antibodies are too big to cross BBB)
- adopt one of their two possible phenotypes
- secrete cytokines, bioactive lipids, coagulation factors, ROS and neurotrophic factors
- try to break down plaque build-up of proteins
- contribute to glial scar formation
why is glial scar formation important
for repair of the BBB and revascularisation the blood capillaries
microglia plasticity
ability to change phenotype depending on local conditions or environment –> necessary to
perform the large variety of functions
acute neuroinflammation
Characterised by rapid activation of microglia
No peripheral immune damage/response
chronic neuroinflammation
Microglia continually activated by pro-inflammatory stimuli
Continuous production of pro-inflammatory cytokines and ROS
–> ROS recruit peripheral cells to contribute to immune response
Neuronal death
–>Degradation of tissue and BBB
effects of volume loss of brain matter
Damage to neurons restricts communication within and between different brain
areas
- Most abilities result from the cooperative action of multiple brain regions
role of oligodendrocytes
support nerves and axons
produce myelin sheath for axon insulation
