From Trauma To Neurodegeneration: A One-Year Time Progression Of Functional Impairments And Its Associated Neuropathological Link Following Varied Severity Of Experimental Diffuse Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is seen as more than just a static insult but an injury with a disease like progression, in which it is deemed as a risk factor for neurodegenerative diseases later in life. Clinical studies have shown a severity dependent relationship between TBI and neurodegenerative diseases. However, there is still a lack of understanding on the timely progression of experimental diffuse TBI into long-term impairments as well as the brain mechanism accounting for these deficits. Furthermore, many preclinical studies have not investigated this progression in relation to the severity of the initiating insult. Therefore, this study investigated the timely change in functional outcomes through a behavioral battery assessing general motor activity, anxiety, depression and cognition as well as its associated neuropathology up to 12 months post injury following varied TBI severities. To investigate this aim, this study first use male Sprague Dawley rats (10-12 weeks) which were subjected to either sham surgery or Marmarou’s impact acceleration model of moderate to severe diffuse TBI, in determining the functional and neuropathological changes at early sub-chronic stages (1 and 3 months) post injury. Since the moderate to severe TBI animals in this study showed persistent depressive-like impairments up to 3 months coupled with subtle cognitive flexibility deficits (supported by prefrontal cortex neuropathology), the study continued in determining the progression of these functional impairments at later chronic stage (12 months) post injury while concurrently determine if injury severity (single mild, repetitive mild (3 mild diffuse injury at 5 day intervals) and moderate to severe TBI) may be a factor influencing them. Moderate to severe TBI continue to display significant cognitive flexibility impairments at 12 months that were not present in other severity groups when compared to shams. However, no other functional deficits were present at 12 months post injury regardless of injury severity. Thus, to explore further the cognitive deficits, the study delved deeper into determining the injury severity effect on the evolution of executive function using the touchscreen cognitive paradigm up to 12 months post injury. The effect of age, but not injury severity on executive dysfunction was revealed. Lastly, this study sought out to determine the associated neuropathology to the functional impairments seen at 12 months post injury through molecular analysis of neurodegenerative disease related brain areas and spinal cord regions after different severities of TBI. Cytoplasmic mis-localization of TDP-43 proteins in the cervical spinal region with abnormal changes in NeuN and phosphorylated-TDP-43 levels were found in motor cortex and spinal regions of the single and repetitive mild TBI animals only at 12 months post injury. No other neuropathology was seen in the other brain regions regardless of injury severity. Thus, overall this thesis suggest that injury severity and age play as important factors in predicting long term functional outcomes post injury, with cognitive impairments in moderate to severe TBI suggesting implication towards later dementia development, while mild diffuse TBI may have higher implications towards motor neurone diseases based on the neuropathological evidence. This thesis advocates the significance of understanding the temporal profile of functional deficits and accompanying neuropathological changes that occur in the months and years following TBI which is critical for improving the predictability of neurodegenerative disease risk following TBI.