A model of repetitive mild brain injury without symptoms – risk for Parkinson’s disease with aging?

Kulkarni, P.; Morrison, T. R.; Cai, X.; Iriah, S.; Lange, M. S.; Kennedy, L.; Sabrick, J.; Neuroth, L.; Hoffman, G. E.; Ferris, C. F.; Praveen Kulkanri, Thomas R Morrison, Xuezhu Cai, Sade Iriah, Mary S Lange, Laprosha Kennedy, Julia S,

doi:10.1101/390856

bioRxiv · 10.1101/390856

A model of repetitive mild brain injury without symptoms – risk for Parkinson’s disease with aging?

Kulkarni, P.·Morrison, T. R.·Cai, X.·Iriah, S.·Lange, M. S.·Kennedy, L.·Sabrick, J.·Neuroth, L.·Hoffman, G. E.·Ferris, C. F.·Praveen Kulkanri, Thomas R Morrison, Xuezhu Cai, Sade Iriah, Mary S Lange, Laprosha Kennedy, Julia S,

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Abstract

Objectives: To test the hypothesis that repetitive mild traumatic brain injury in early life may be a potential risk factor for Parkinson's disease. Methods: A closed-head momentum exchange model was used to produce one or three mild concussions in young adult male rats as compare to non-injured, age and weight-matched controls. Six-seven weeks post-injury, rats were studied for deficits in cognitive and motor function Changes in brain anatomy and function were evaluated through analysis of resting state functional connectivity, diffusion weighted imaging with quantitative anisotropy and immunohistochemistry for neuroinflammation. Results: Head injuries occurred without skull fracture or signs of intracranial bleeding or contusion. There were no significant differences in cognitive or motors behaviors between experimental groups. Rats concussed three times showed altered diffusivity in white matter tracts, basal ganglia, central amygdala, brainstem, and cerebellum. With a single concussion, the affected areas were limited to the caudate/putamen and central amygdala. Disruption of functional connectivity was most pronounced with three concussions as the midbrain dopamine system, hippocampus and brainstem/cerebellum showed hypoconnectivity. The suprachiasmatic nucleus was isolated from all functional connections. Interestingly, rats exposed to one concussion showed enhanced functional connectivity (or hyperconnectivity) across brain sites, particularly between the olfactory system and the cerebellum. Immunostaining for microglia activation showed inflammation in striatum and substantia nigra with three concussions but not with one. Interpretation: Neuroradiological and immunohistochemical evidence of altered brain structure and function, particularly in striatal and midbrain dopaminergic areas, persists long after mild repetitive head injury. These changes may be long lasting and serve as early biomarkers of neurodegeneration and risk for Parkinson's disease with aging.

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Kulkarni, P., Morrison, T. R., Cai, X., Iriah, S., Lange, M. S., Kennedy, L., Sabrick, J., Neuroth, L., Hoffman, G. E., Ferris, C. F., Praveen Kulkanri, Thomas R Morrison, Xuezhu Cai, Sade Iriah, Mary S Lange, Laprosha Kennedy, Julia S,. 2018-08-13. A model of repetitive mild brain injury without symptoms – risk for Parkinson’s disease with aging?. https://doi.org/10.1101/390856

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