The Relationship Between Cerebral Blood Flow and Neuropsychological Outcomes in Veterans with History of Mild Traumatic Brain Injury

Author(s): Clark, Alexandra Leigh | Advisor(s): Delano-Wood, Lisa M. | Abstract: Rationale. Though the short and long-term consequences of neurotrauma are only beginning to be appreciated, those with history of mild traumatic brain injury (TBI) show increased rates of psychiatric disorders, decreased quality of life, and cognitive deficits relative to those with no history of mTBI. Potentially important, though vastly understudied, is the role of the cerebrovascular system in cognitive outcomes after mild TBI. Primary injury to the cerebrovasculature (i.e., stretching and shearing of vessels) coupled with secondary pathophysiological processes (e.g., ischemia, neuroinflammation, vascular remodeling) may alter cerebral blood flow (CBF) post-injury. Such CBF changes may negatively affect the brain’s process of post-traumatic repair and contribute to poor long-term outcomes. However, the contribution of CBF to cognitive dysfunction post-injury remains incompletely characterized, and no known human studies have investigated how important genetic and environmental risk factors (i.e., cumulative number of sub-concussive blasts, history of multiple TBIs, time since injury, apolipoprotein E [APOE]-e4 genotype) may moderate CBF and cognitive associations. Design. The current study utilized multi-phase pseudo-continuous arterial spin labeling neuroimaging methods to (1) evaluate whether resting CBF differences occur in those with history of TBI, (2) investigate the relationship between resting CBF and neuropsychological function, and (3) in exploratory analyses, examine possible moderators of resting CBF and cognition in those with history of mTBI. We recruited and enlisted 54 OEF/OIF/OND service members between the ages of 18 and 50 for this study. Study groups include those with history of mild or moderate TBI (n = 31) and military controls with no history of TBI (n = 23). Analyses of covariance controlling for age and symptoms of posttraumatic stress and depression were used to explore group differences in resting CBF of the whole brain as well as bilateral frontal and temporal regions of interest. Multiple regression analyses were performed within the TBI group to assess whether resting CBF in bilateral frontal and temporal ROIs was predictive of performance on measures of executive functioning and memory; whether regional CBF measures were associated with genetic and environmental risk factors; and whether these risk factors moderated regional CBF and cognitive associations. Results. ANCOVAs indicated that, independent of age and symptoms of posttraumatic stress and depression, TBI Veterans demonstrated significantly higher resting CBF in several frontal and temporal regions of interest. No significant group differences in whole brain resting CBF were observed. Multiple regression analyses revealed that, independent of age, higher resting CBF in frontal regions was significantly associated with better performance on measures of executive functions within the mTBI group. However, resting CBF in temporal regions was not significantly associated with performance on memory measures. Further analyses identified number of mTBIs as the only significant risk factor associated with resting CBF of frontal regions. However, several significant risk factor x resting CBF interactions on cognition were observed. Results revealed that resting CBF and cognitive associations were generally more pronounced in those with lower versus high risk factor burden such that higher resting CBF of frontal and temporal regions was associated with better executive functioning and memory performance in those with fewer injuries as well as in those who were closer in time to their injury; and those who were APOE-e4 non-carriers. Conclusions. Findings suggest that, independent of age and psychiatric symptoms, history of TBI is associated with increased resting CBF. Importantly, increased resting CBF was associated with better cognitive performance in APOE-e4 non-carriers as well as those who were closer in time to their TBI event(s). Results suggest that elevated resting CBF may represent a critical compensatory mechanism that allows for better cognitive performance in certain Veterans with TBI. These findings align with the “compensation related utilization of neural circuit hypothesis of aging,” which suggests that increases in brain activation allow for task demands to be met, though the effectiveness of these increases appear to plateau within the context of greater injury. Information gleaned from these findings has the potential to improve diagnosis and possibly provide a useful biomarker of both impairment and recovery in a vulnerable population for which persistent behavioral dysfunction remains poorly understood.