Neuroimaging and Clinical Findings in Healthy Middle-Aged Adults With Mild Traumatic Brain Injury in the PREVENT Dementia Study

Abstract

Importance: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI.

Objective: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals.

Design, setting, and participants: This cross-sectional analysis used baseline data from the PREVENT Dementia program collected across 5 sites in the UK and Ireland between 2014 and 2020. Eligible participants were cognitively healthy midlife adults aged between 40 and 59 years. Data were analyzed between January 2023 and April 2024.

Exposure: Lifetime TBI history was assessed using the Brain Injury Screening Questionnaire.

Main outcomes and measures: Cerebral microbleeds and other markers of cerebral small vessel disease (white matter hyperintensities [WMH], lacunes, perivascular spaces) were assessed on 3T magnetic resonance imaging. Clinical measures were cognition, sleep, depression, gait, and cardiovascular disease (CVD) risk, assessed using Computerized Assessment of Information Processing (COGNITO), Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, clinical interviews, and the Framingham Risk Score, respectively.

Results: Of 617 participants (median [IQR] age, 52 [47-56] years; 380 female [61.6%]), 223 (36.1%) had a history of TBI. TBI was associated with higher microbleed count (β = 0.10; 95% CI, 0.01-0.18; P = .03), with a dose-response association observed with increasing number of TBI events (β = 0.05; 95% CI, 0.01-0.09; P = .03). Conversely, TBI was not associated with other measures of small vessel disease, including WMH. Furthermore, TBI moderated microbleed associations with vascular risk factors and clinical outcomes, such that associations were present only in the absence of TBI. Importantly, observations held when analyses were restricted to individuals reporting only mild TBI.

Conclusions and relevance: In this cross-sectional study of healthy middle-aged adults, detectable changes in brain imaging and clinical features were associated with remote, even mild, TBI in the general population. The potential contribution of vascular injury to TBI-related neurodegeneration presents promising avenues to identify potential targets, with findings highlighting the need to reduce TBI through early intervention and prevention in both clinical care and policymaking.

Figure 1.. Cerebral Microbleeds Associated With Modifiable Vascular Risk Factors in the Absence of TBI History

Interaction analyses were conducted using general linear regression models fitted to each variable of interest in separate models, adjusting for sex, age, education, and study site. In panel A, dots indicate Framingham Risk Score results for individual participants. APOE4 indicates apolipoprotein E ε4; CMB, cerebral microbleeds; CVD, cardiovascular disease risk; TBI, traumatic brain injury. ^aP < .05.

Figure 2.. Cerebral Microbleeds Associated With Poorer Clinical Outcomes in the Absence of TBI History

Interaction analyses were conducted using linear regression models fitted to each variable of interest in separate models, adjusting for sex, age, education, and study site. In panels A and B, dots represent individual measures of clinical outcomes. CMB indicates cerebral microbleeds; TBI, traumatic brain injury. ^aP < .05.

Figure 3.. Relative Contribution of Risk Factors on Clinical Outcome Measures

Bar heights represent standardized general dominance statistics, which may be interpreted as the relative weight of contribution to R². BP indicates blood pressure; HDL, high-density lipoprotein; TBI, traumatic brain injury.