The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review
Authors: Kelly N Roberts
Grant K Nation
Josh M Morganti
Scott J Webster
David K Powell
Danielle S Goulding
Adam D Bachstetter
Emma K Higgins
Henry Snider
Moriel Vandsburger
Linda J Van Eldik
Shelby E Meier
Colleen N Bodnar
Jose F Abisambra
Matthew Hamm
Journal: Experimental Neurology (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: CTE; Concussion; Neurodegeneration; Rodent behavior; TBI
Affiliations: Spinal Cord & Brain Injury Research Center, University of Kentucky, Lexington, KY, United States of America; Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States of America. Electronic address: ., Spinal Cord & Brain Injury Research Center, University of Kentucky, Lexington, KY, United States of America; Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States of America., Spinal Cord & Brain Injury Research Center, University of Kentucky, Lexington, KY, United States of America; Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America., Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States of America., Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America; Department of Physiology, University of Kentucky, Lexington, KY, United States of America., Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States of America., Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, United States of America., Department of Bioengineering, University of California Berkeley, Berkeley, CA, United States of America., Department of Physiology, University of Kentucky, Lexington, KY, United States of America; Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States of America. Electronic address: .

Abstract:  In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established. 

Retracted: No

PubPeer comments:
 Something doesn t add up with Figure 3-D,E on Manganese Enhanced Magnetic Resonance Imaging (meMRI). There are common references in text as having an effect;  The results of MEMRI revealed an attenuated increase of 52% in cortex R1 rates following MnCl2 infusion in the rTg4510 mice following 2u00d7CHI compared to sham treated mice (Fig. 3D-E),  Using MEMRI, while an indirect measure of brain health, we found that the 2u00d7 CHI does have a greater effect than a 1u00d7 CH,  Interestingly, 2u00d7 CHI, but not 1u00d7 CHI decreased an indirect measure of neuronal activity in the form of MEMRI, but **no statistical test is reported** in the Figure. The low n (3? why not 4 considering Figure 3C had n = 4 and these were presumably the same mice??) and small effect size means the test likely did not produce a significant p 0.05 value. Did the authors just simply forget to include the stats?? ,