Clinical correlates in an experimental model of repetitive mild brain injury.
OBJECTIVE
Although there is growing awareness of the long-term cognitive effects of repetitive mild traumatic brain injury (rmTBI; eg, sports concussions), whether repeated concussions cause long-term cognitive deficits remains controversial. Moreover, whether cognitive deficits depend on increased amyloid β deposition and tau phosphorylation or are worsened by the apolipoprotein E4 allele remains unknown. Here, we use an experimental model of rmTBI to address these clinical controversies.


METHODS
A weight drop rmTBI model was used that results in cognitive deficits without loss of consciousness, seizures, or gross or microscopic evidence of brain damage. Cognitive function was assessed using a Morris water maze (MWM) paradigm. Immunostaining and enzyme-linked immunosorbent assay (ELISA) were used to assess amyloid β deposition and tau hyperphosphorylation. Brain volume and white matter integrity were assessed by magnetic resonance imaging (MRI).


RESULTS
Mice subjected to rmTBI daily or weekly but not biweekly or monthly had persistent cognitive deficits as long as 1 year after injuries. Long-term cognitive deficits were associated with increased astrocytosis but not tau phosphorylation or amyloid β (by ELISA); plaques or tangles (by immunohistochemistry); or brain volume loss or changes in white matter integrity (by MRI). APOE4 was not associated with worse MWM performance after rmTBI.


CONCLUSIONS
Within the vulnerable time period between injuries, rmTBI produces long-term cognitive deficits independent of increased amyloid β or tau phosphorylation. In this model, cognitive outcome is not influenced by APOE4 status. The data have implications for the long-term mental health of athletes who suffer multiple concussions.
Division of Emergency Medicine, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
Rebekah
R
Mannix
William P
WP
Meehan
Joseph
J
Mandeville
Patricia E
PE
Grant
Tory
T
Gray
Jacqueline
J
Berglass
Jimmy
J
Zhang
John
J
Bryant
Shervin
S
Rezaie
Joon Yong
JY
Chung
Nicholas V
NV
Peters
Christopher
C
Lee
Lee W
LW
Tien
David L
DL
Kaplan
Mel
M
Feany
Michael
M
Whalen
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001369:Axons / Q000473:pathology; D001921:Brain / Q000378:metabolism*; D001924:Brain Concussion / Q000150:complications*; D001930:Brain Injuries / Q000150:complications / Q000209:etiology* / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning; D051379:Mice; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D011897:Random Allocation; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D016875:tau Proteins