Clinical correlates in an experimental model of repetitive mild brain injury

Ann Neurol. 2013 Jul;74(1):65-75. doi: 10.1002/ana.23858. Epub 2013 Aug 6.


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.

Interpretation: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apolipoproteins E / genetics
  • Axons / pathology
  • Brain / metabolism*
  • Brain Concussion / complications*
  • Brain Injuries / complications
  • Brain Injuries / etiology*
  • Brain Injuries / pathology*
  • Cognition Disorders / etiology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Magnetic Resonance Imaging
  • Male
  • Maze Learning
  • Mice
  • Neuroglia / pathology
  • Neurons / pathology
  • Random Allocation
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • tau Proteins