• Rebekah Mannix, William P Meehan, Joseph Mandeville, Patricia E Grant, Tory Gray, Jacqueline Berglass, Jimmy Zhang, John Bryant, Shervin Rezaie, Joon Yong Chung, Nicholas V Peters, Christopher Lee, Lee W Tien, David L Kaplan, Mel Feany, and Michael Whalen.
• Division of Emergency Medicine, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
• Ann. Neurol. 2013 Jul 1; 74 (1): 65-75.

ObjectiveAlthough 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.MethodsA 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).ResultsMice 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.InterpretationWithin 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.Copyright © 2013 American Neurological Association.

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