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Smith, Doug H. - handout Document Transcript

  • 1. 7/26/11
 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) 1

  • 2. 7/26/11
 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
 2

  • 3. 7/26/11
 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+
 3

  • 4. 7/26/11
 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
 4

  • 5. 7/26/11
 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 DecreasedSham 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
 5

  • 6. 7/26/11
 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
 6

  • 7. 7/26/11
 Acknowledgements•  Victoria
Johnson,
Kevin
Browne,
Xiao‐Han
Chen,
Willie
Stewart,
David
 Graham,
John
Trojanowski
•  Funding:
NIH
(P01
NS056202,
R01
NS38104,
T32
NS043126)
 7