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!