Outcome after Repetitive Mild Traumatic Brain Injury Is Temporally Related to Glucose Uptake Profile at Time of Second Injury

Abstract

Repeated mild traumatic brain injury (rmTBI) results in worsened outcomes, compared with a single injury, but the mechanism of this phenomenon is unclear. We have previously shown that mild TBI in a rat lateral fluid percussion model results in globally depressed glucose uptake, with a peak depression at 24 h that resolves by 16 days post-injury. The current study investigated the outcomes of a repeat injury conducted at various times during this period of depressed glucose uptake. Adult male rats were therefore subjected to rmTBI with a latency of 24 h, 5 days, or 15 days between injuries, followed by assessment of motor function, histopathology, and glucose uptake using positron emission tomography (PET). Rats that received a 24 h rmTBI showed significant deficits in motor function tasks, as well as significant increases in lesion volume and neuronal damage. The level of microglial and astrocytic activation also was associated with the timing of the second impact. Finally, rmTBI with latencies of 24 h and 5 days showed significant alterations in [(18)F]fluorodeoxyglucose uptake, compared with baseline scans. Therefore, we conclude that the state of the metabolic environment, as indicated by FDG-PET at the time of the repeat injury, significantly influences neurological outcomes.

Temporal Changes in Cortical and Hippocampal Expression of Genes Important for Brain Glucose Metabolism Following Controlled Cortical Impact Injury in Mice

“…Changes in hippocampal gene expression were both delayed and prolonged, when compared with those in the cortex. This finding agrees with clinical observations that the hippocampus exhibits prolonged impairments in glucose metabolism when compared with other brain regions, as detected by positron emission tomography ( 11 ). For all three key glucose metabolism-related enzymes tested in the current study, their mRNA alterations returned to or toward normal shortly after injury in the cortex.…”

Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

“…The 1-day interval choice was supported from our recent findings that glucose uptake is decreased at 24 h post-TBI 30 and a second injury at 24 h worsens outcome. 53 This r-mTBI model is anterior, but otherwise similar, to several other more posterior repetitive mTBI models, 54–57 suggesting that paradigms of at least three to five mild impacts with 1- to 3-day intervals are effective and practical. Our expectation was that the impact used in the r-mTBI model would result in relatively mild initial damage in the corpus callosum whereas repetition may promote progression toward chronic white matter pathology, including neuroinflammation.…”

Repeated Closed Head Injury in Mice Results in Sustained Motor and Memory Deficits and Chronic Cellular Changes

“…Motor dysfunction is not a prominent feature of mild TBI, but difficulties in motor coordination are a common symptom associated with CTE. A number of repeated mild TBI models result in tissue damage in the motor cortex without concomitant motor impairment as assessed by beam crossing [ 42 ], rotarod [ 21 , 30 , 32 , 40 , 43 , 59 – 61 ], or gait analysis [ 40 ]. Others have described transient motor impairment that resolves within a week after injury [ 16 , 41 , 61 ] or between 1wk and 6mo [ 30 , 43 ].…”