Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer’s disease

Abstract

Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post-traumatic stress disorder diagnoses. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance in individuals at genetic risk for Alzheimer's disease, with the caveat that the order of causal effects cannot be inferred from cross-sectional studies. These results underscore the importance of documenting head injuries even within the mild range as they may interact with genetic risk to produce negative long-term health consequences such as neurodegenerative disease.

Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology

“…However, we used multiple comparison correction in our initial analyses of DMN connectivity and polygenic risk to reduce the likelihood of this increase in error. Moreover, these analyses were comparable to previously published work with similar sample sizes investigating genetics, clinical disorders, and neuroimaging measures (Costafreda et al., ; Hayes et al., ; Miller et al., ; Miller et al., ; Whitwell et al., ). Nonetheless, it will be important for other studies with larger sample sizes to replicate these findings.…”

“…These findings should be considered in light of several limitations. (Costafreda et al, 2013;Hayes et al, 2017;Miller et al, 2016;Miller et al, 2015;Whitwell et al, 2012). Nonetheless, it will be important for other studies with larger sample sizes to replicate these findings.…”

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…The pathophysiology of TBI Traumatic brain injury is characterized by instant damage to mechanical force and delayed damage to the subsequent pathophysiological processes [21]. The mechanical force directly leads to neuronal or diffuse axonal damage and vascular disruption, followed by secondary injury mediated by extensive neuroinflammation, dysfunction of the BBB, oxidative stress, and apoptosis [22][23][24][25][26]. While the immediate primary injury is considered untreatable, the delayed secondary injury gives a window for intervention and has, therefore, attracted a lot of attention [27].…”

BDNF genotype is associated with hippocampal volume in mild traumatic brain injury

“…Although most of the evidence comes from studies of moderate and severe head injury, there is growing indication that mild TBI (mTBI), or concussion, when combined with additional vulnerability factors such as advanced age, repetitive injury and genetic risk, is also a risk factor for neurodegeneration (Hayes et al . ; McKee et al . ).…”

“…Increasing evidence suggests that TBI heightens the risk for neurodegenerative diseases such as Alzheimer's disease (AD; Fleminger et al 2003;Mortimer et al 1991) and chronic traumatic encephalopathy (McKee et al 2013). Although most of the evidence comes from studies of moderate and severe head injury, there is growing indication that mild TBI (mTBI), or concussion, when combined with additional vulnerability factors such as advanced age, repetitive injury and genetic risk, is also a risk factor for neurodegeneration (Hayes et al 2017b;McKee et al 2013). As mTBI represents the majority of all head injuries (∼75%; Bergman & Bay 2010), studying the factors linking mTBI to brain atrophy and dementia is worthy of greater attention.…”