Lecture 5: Mild TBI, How the Brain Breaks Flashcards
Why is mild TBI/concussion not so mild?
1) Induces axon disconnection: permanent!
2) Causes sodium channelopathy on axons, which leads to dysfunction
3. Induces long-term neurodegeneration AND atrophy
4. Triggers the early formation of AMYLOID-BETA plaques and NEUROFIBRILLARY TANGLES
5. Increases the risk of developing AD
How many cases of mild TBI in US each year?
1.3 million
What is the percentage of mTBI patients have persisting cognitive dysfunction?
15-20%
What is a synonym for mTBI?
Concussion
What are the biochemical mechanisms of concussion?
Contact load leads to inertial loading leads to DAI
OR
Primary blast leads to DAI
What is contact loading?
Hitting your head with a bat…is not THE MOA of mTBI…instead this motherfucker leads to inertial loading
What is inertial loading?
The direct cause of DAI
This is due to the angular acceleration of the brain
The rigid falx cerebri keeps on side of the brain in place while the other bangs against the other side of the cranium
-this leads to DAI and stretching of axons
What is the significance of Viscoelacticity?
Brain stretches like silly puddy
But a fast enough rate of injury can caused
The elasticity to break
What is the neuropathology of mTBI?
Swelling of the white matter
Disconnection of axons
Varicose vein formation (bulbs)
What are the delineating histological features of mTBI?
Axonal Bulbs (bulbous structures forming on axon) Axonal swelling (axon goes from thin line to bigger jaggedy line)
What is cause of the “bulb” we see neuropathologically?
Swelling due to the accumulation of shit that the microtubules were trying to transport?
Example: Amyloid precursor proteins, enzymes that cleave APP, etc.
What is the takehome point with mTBI?
It is FIRST a BIOCHEMICAL effect Breakage of the microtubules Fucks with axonal transport obviously Takes place at MULTIPLE areas at MULTIPLE axons After mechanical damage, there is a Secondary CHEMICAL effect of Microtubule depolymerization
What is Tau?
Tau = microtubule associated protein
What is the significance of tau?
It is the bungee cord or elastic band between microtubules
Holds Microtubules together
-allows microtubules to slide among each other…but if there is too much stress, then you are fucked
What happens to microtubules after DAI? Cross-sectional image?
Both breakage of the microtubules and progressive degeneration
(depolymerization) of microtubules
What is the gold standard protein that is used to diagnose DAI after death?
Amyloid precursor protein
What is Amyloid precursor protein? Significance
Protein that accumulates at the bulbs of axons that have undergone DAI
Gold standard diagnostic tool for DAI postmortem
Parent protein of amyloid beta plaques
What is taxol? Significance?
Taxol is a microtubule STABILIZER
Stops the secondary chemical damage
Inhibits relaxation of axonal undulations post-injury to stabilize microtubules
Significance: no relaxation = NO LOSS of the microtubules or degenerations
What is the biomechanical pathway of traumatic axonal injury (TAI)?
- primary mechanical breakage of microtubules
- Broken microtubules imped/ relaxation = undulations
- Secondary microtubule chemical “catastrophe” begins at break sites
- Relaxation of undulations but disrupted transport
- Swelling and disconnection
- Axon degeneration
What are the CHEMICAL effects on the ENTIRE axon during DAI from mTBI?
There is an influx in calcium
-calcium activates proteins
The more time that passes, the more calcium that comes in
What is the significance of calcium?
Enough calcium in the cell causes proteinolysis of cell from inside out
What causes the influx of calcium?
The dysregulation of the SODIUM channel by PROTEOLYSIS (Calpain proteolyzing inactivation gate)
Inactivation gate of sodium is damaged
Unremitting influx of sodium into the cell
-sodium causes swelling
Too much sodium causes a REVERSAL of the Na-Ca exchanger and activation of the voltage sensitive calcium channel
Final result: influx of calcium!
What is calpain?
The proteinase that eats up inactivation gate of sodium channel
(this is mechanism of diffuse axonal injury and mTBI)
-activated by calcium influx
What is the period of vulnerability?
Window where another mild injury is thought to trigger a greatly exaggerated response
Nobody knows!
What is the mechanism of the period of vulnerability?
Posttraumatic increase in NaCh density
(as kids we have more NaCh than adults…so adults to get the “lights back on” would be to add more sodium channels after mTBI)
This leads to increased sodium channelopathy (more calcium influx due to the Na-Ca exchanger, etc.)
What is sodium channelopathy?
When as an adult, you are adding more sodium channels to the axons to compensate for mTBI
Leads to axon dysfunction
What is the relationship between the amount of angular acceleration of the brain and mass?
Amount of angular acceleration of brain is PROPORTIONAL to the MASS of the brain
Bigger brains = experience more angular acceleration…so animal models need to have big brains to simulate human mTBI
Use of gyrencephalic animal (pigs)…brains with gyri insead of smooth shit
What is the source of immediate loss of consciousness (LOC) and coma following brain trauma?
DAI
Consciousness does NOT equal lack of pathology
Do you need to see loss of consciousness to be worried about DAI?
No, you don’t need LOC for DAI
What do people with double concussions present with?
Increased precursor amyloid protein (period of vulnerability)
How do you detect DAI in vivo?
A STEALTH pathology
Difficult to detect, difficult to model
-can only be seen postmortem
What is the hottest technology right now being used to try and diagnose DAI?
- Diffusion Tensor Imaging
- shows water protons that migrate alone pathway of axons
- this can show if water protons change in direction (change in anisotropy of axons) - Susceptibility Weighted Imaging
- demonstrates edema and small hemorrhage - Serum biomarker detection of mTBI
The white matter of our brain is anisotropic, which means
Anistropic = property of being directionally dependent
Axon flow is path dependent
What is the link between TBI and AD?
- TBI is the HIGHEST epigenetic risk factor for developing AD-like dementia
- The hallmark pathologies of amyloid-beta plaques and neurofibrillary tangles are also found in Chronic Traumatic Encephalopathy (CTE)
What is the predominant pathology in dementia pugilistica/CTE?
Neurofibrillary tangles (NFTs)
Where is CTE found?
Moderate to severe single TBI
OR
Repetitive mTBI
So what can be seen after TBI?
Extracellular accumulations of amyloid beta protein
Can be Neuritic vs. Diffuse plaques
Hallmark of AD
Seen immediately after TBI (hours after a young person’s injury)
What is the mechanism of amyloid beta plaques?
The fact that there is an accumulation of amyloid precursor proteins, which then gets cleaved to form amyloid beta in white matter
-amyloid precursor protein travels with the necessary enzymes need to cleave APP to amyloid beta plaques
-accumulation of multiple proteins (APP and enzymes) necessary for alpha beta
When you have the bulbs, it will swell and break, thereby releasing the APP + enzymes that leas to amyloid beta
TBI is an injury that
keeps on taking
-ongoing axonal pathology
Decades after injury, you never stop making amyloid beta and losing axons
What is the hallmark neuropathological feature of AD?
Amyloid beta plaques Neurofibrillary tangles (tauopathy)
What are neurofibrillary tangles? Significance?
Abnormal HYPERPHOSPHORYLATED intra-neuronal accumulation of TAU
What is supposedly the marker of CTE and dementia pugilistica
-phoshorylation and isoform ration of tau indistinguishable from AD neurofibrillary tangles
-present in single TBI
What is the significance of chronic inflammation in TBI/CTE?
There is presence of microgliosis after a single TBI
Can lead to post TBI microgliosis and ATROPHY of corpus callosum
