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As a FA complex, myelin causes the white matter
to appear white
Penn Center for Brain Injury and Repair
If someone calls you a fathead, reply;
TBI and demyelina2on:
What is Chewing the Fat? “yes, you’re right,
and a good thing too”
Douglas H. Smith, MD
Department of Neurosurgery and
Penn’s Center for Brain Injury and Repair
University of Pennsylvania
Mul2ple Sclerosis:
An Immune or
Neurodegenera2ve Disorder?
Bruce D. Trapp1 and Klaus‐Armin Nave2
Annu. Rev. Neurosci. 2008. 31:247–69
Demyelina2on is a
major feature
of many CNS
disorders and injuries.
Why has it not been
extensively
examined in TBI?
"How long has THAT been there?"
Regina Armstrong;
“although not yet studied in TBI,
mul2ple sclerosis studies indicate that
demyelinated axons can remain viable for
prolonged periods , but may be more vulnerable to Contact Loading Iner2al Loading
further damage from repeated insults.”
1o BLAST? Diffuse Axonal Injury (DAI)
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What is DAI?
Can the
progression from
axonal swelling
to disconnection
be stopped?
What is the role
of myelin?
Are swollen axons the predominant pathology of DAI?
TUNEL + Oligodendrocytes observed acutely and
up to weeks / months following TBI in humans
.
TUNEL‐posi5ve staining in white and grey ma;er a<er fatal head injury in man.
Shaw K, MacKinnon MA, Raghupathi R, Saatman KE, McIntosh TK, Graham DI.
Clin Neuropathol. 2001 May-Jun;20(3):106-12
Con5nued In Situ DNA Fragmenta5on of
Microglia/Macrophages in White Ma;er
Weeks and Months a<er Trauma5c Brain
Injury
Wilson S, Raghupathi R, Saatman KE,
Mackinnon MA, McIntosh TK, Graham DI
J Neurotrauma. (2004) 21;3;239‐50
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Iner2al Brain Injury in the Pig
Pre‐Accelera2on Accelera2on Decelera2on
Long‐term axonal pathology
hrs‐days months‐yrs
Chen X‐H, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Chen X‐H, Johnson VE, Uryu K, Trojanowski JQ,
Smith DH. Am J Pathol 165(2): 357‐371, 2004. Smith DH:. Brain Pathol 19(2): 214‐223, 2009.
TUNEL+ TUNEL+
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TUNEL+ TUNEL+
6‐8hrs 1d 3d
TUNEL+
TUNEL+
7d 6mo
Evolu2on of oligo death following TBI in the pig
Apopto5c Oligodendrocytes Acutely Following
Rota5onal Accelera5on Injury in Swine
Annexin V Oligodendrocytes Merge
3d
7d
7d 6mo
3d 7d 6mo
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Quan5ta5ve structural changes in white and gray ma;er
Macrophages chewing the fat (MBP) and 1 year following trauma5c brain injury in rats
loss myelin aher TBI in humans Helen M. Bramlei, W. Dalton Dietrich
Acta Neuropathol (2002) 103:607-14
1 Year Post-Injury Sham
LFB Staining:
Demyelination at 1
hrs‐days post‐injury year post-injury in
corpus callosum?
MBP
Atrophy in white
matter structures
months‐yrs post‐injury
MBP Chen X‐H, Johnson VE, Uryu K, Trojanowski JQ,
Smith DH:. Brain Pathol 19(2): 214‐223, 2009.
Neuroscience Letters 499 (2011) 143–148
Decreased
Sham oligodendrocytes
acutely post-injury
3d
Increased caspase-3 activation
in oligodendrocytes acutely
post-injury
EFFECT OF BLAST EXPOSURE ON THE BRAIN
STRUCTURE AND COGNITION IN THE MACACA FASCICULARIS
Jia LU et al., J. Neurotrauma, in press
No DAI reported, but apparent demyelina2on, disorganized myelin, vaculoes
and loss of structure
Oligos – darken and shrunken
or necro2c
MBP
EM
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Corpus Callosum Anterior & Posterior Internal Capsules Frontal & Temporal Lobes Combined ROIs for OI (left)
Myelin Sheath Ionic Gradients?
Could DTI in TBI elucidate changes
in myelin vs. axonal pathology?
Myelin plays a key role in axonal ionic homeostasis
Stys and Lipton, TIPS 28(11), 2007
Does dysfunc2onal myelin promote axonal degenera2on?
Do dysfunc2onal axons promote demyelina2on?
Are axonal channelopathies in TBI similar to channelopathies in MS?
What is needed
More study
AFTER TBI:
Beier probes to show demyelina2on
Knowns: Unknowns:
Long‐term degenera2on of axons A causa2ve link between
any of the knowns
Long‐term death of oligodendrocytes
Whether there is an ac2ve process
Loss of myelin at play or if simply epiphenomenon
Role of calpains and capases in the above
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Acknowledgements
• Victoria Johnson, Kevin Browne, Xiao‐Han Chen, Willie Stewart, David
Graham, John Trojanowski
• Funding: NIH (P01 NS056202, R01 NS38104, T32 NS043126)
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