Progressive Neurodegeneration Across Chronic Stages of Severe Traumatic Brain Injury

Abstract

Objective: To examine the trajectory of structural gray matter changes across 2 chronic periods of recovery in individuals who have sustained severe traumatic brain injury (TBI), adding to the growing literature indicating that neurodegenerative processes occur in the months to years postinjury. Participants: Patients who experienced posttraumatic amnesia of 1 hour or more, and/or scored 12 or less on the Glasgow Coma Scale at the emergency department or the scene of the accident, and/or had positive brain imaging findings were recruited while receiving inpatient care, resulting in 51 patients with severe TBI. Methods: Secondary analyses of gray matter changes across approximately 5 months, 1 year, and 2.5 years postinjury were undertaken, using an automated segmentation protocol with improved accuracy in populations with morphological anomalies. We compared patients and matched controls on regions implicated in poorer long-term clinical outcome (accumbens, amygdala, brainstem, hippocampus, thalamus). To model brain-wide patterns of change, we then conducted an exploratory principal component analysis (PCA) on the linear slopes of all regional volumes across the 3 time points. Finally, we assessed nonlinear trends across earlier (5 months-1 year) versus later (1-2.5 years) time-windows with PCA to compare degeneration rates across time. Chronic degeneration was predicted cortically and subcortically brain-wide, and within specific regions of interest. Results: (1) From 5 months to 1 year, patients showed significant degeneration in the accumbens, and marginal degeneration in the amygdala, brainstem, thalamus, and the left hippocampus when examined unilaterally, compared with controls. ( 2) PCA components representing subcortical and temporal regions, and regions from the basal ganglia, significantly differed from controls in the first time-window. (3) Progression occurred at the same rate across both time-windows, suggesting neither escalation nor attenuation of degeneration across time. Conclusion: Localized yet progressive decline emphasizes the necessity of developing interventions to offset degeneration and improve long-term functioning.

Effect of traumatic brain injury on mild behavioral impairment domains prior to all‐cause dementia diagnosis and throughout disease progression

“… 19 , 46 After moderate–severe TBI, hippocampal volumetric decrements have been observed and may continue to progress for years after the injury event. 47 , 48 In the context of dementia, TBI may introduce vulnerabilities to hippocampal neurodegeneration, such as vascular dysfunction, 49 thereby increasing risk of these NPS by similar mechanisms as have been proposed outside the context of dementia (see Bray et al. 19 and Grace 46 ).…”

“…19,46 After moderate-severe TBI, hippocampal volumetric decrements have been observed and may continue to progress for years after the injury event. 47,48 In the context of dementia, TBI may introduce vulnerabilities to hippocampal neurodegeneration, such as vascular dysfunction, 49 thereby increasing risk of these NPS by similar mechanisms as have been proposed outside the context of dementia (see Bray et al 19 and Grace 46 ). The present study found that risk of this MBI domain was increased solely in the more severe group and that increased risk appeared to be more pronounced later in dementia progression; while these are in line with this possible explanation, evidence in support of this proposed mechanism is preliminary and further study is required.…”

“…Interestingly, emerging literature has suggested that, in the chronic stages of moderate–severe TBI, progressive hippocampal atrophy may dysregulate amplitude of dopaminergic firing in mesolimbic circuits, increasing risk of positive psychotic symptoms in the years post‐injury 19,46 . After moderate–severe TBI, hippocampal volumetric decrements have been observed and may continue to progress for years after the injury event 47,48 . In the context of dementia, TBI may introduce vulnerabilities to hippocampal neurodegeneration, such as vascular dysfunction, 49 thereby increasing risk of these NPS by similar mechanisms as have been proposed outside the context of dementia (see Bray et al 19 .…”

Patterns of change in cortical morphometry following traumatic brain injury in adults

“…The study samples' data were obtained from a longitudinal, prospective study investigating TBI recovery (The Toronto TBI Recovery Study) (Adnan et al, 2013;Belchev et al, 2021;Greenberg, Mikulis, Ng, DeSouza, & Green, 2008;Miller, Colella, Mikulis, Maller, & Green, 2013;Ng et al, 2008;Terpstra, Girard, Colella, & Green, 2017;Till, Colella, Verwegen, & Green, 2008). A total of 105 participants with clinically confirmed TBI were recruited, and after quality control, 67 participants were included in the present study.…”

“…Previous studies, including ones that have examined the cohort assessed here, have described ongoing losses in brain volume, including subcortical structures, white matter, and the cortex over the months and years following moderate-severe TBI (Belchev et al, 2021;Bendlin et al, 2008;Brezova et al, 2014;Cole et al, 2018;Gooijers et al, 2016;O'Phelan, Otoshi, Ernst, & Chang, 2018;Sidaros et al, 2009). While these studies provide substantial evidence for volumetric changes in both grey and white matter following moderate-severe TBI, no longitudinal studies in adults have investigated changes to the two cortical surface-based morphometry measures that contribute to volume: cortical thickness (CT) and cortical surface area (CSA).…”