ABSTRACT
OBJECTIVE: To image ß-amyloid (Aß) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aß are correlated, and compare the spatial distribution of Aß to Alzheimer disease (AD). METHODS: Patients 11 months to 17 years after moderate-severe TBI underwent (11)C-Pittsburgh compound B ((11)C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of (11)C-PiB, which index Aß plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with (11)C-PiB BPND. RESULTS: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased (11)C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. CONCLUSIONS: Increased Aß burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.
Subject(s)
Amyloid Neuropathies/diagnosis , Amyloid Neuropathies/etiology , Amyloid beta-Peptides/metabolism , Axons/pathology , Brain Injuries/complications , Brain Injuries/diagnosis , Adult , Amyloid Neuropathies/metabolism , Biomarkers/metabolism , Brain Injuries/metabolism , Diffusion Tensor Imaging/methods , Female , Humans , Longitudinal Studies , Male , Middle Aged , Multimodal Imaging/methods , Positron-Emission Tomography/methods , Reproducibility of Results , Sensitivity and Specificity , Tissue DistributionABSTRACT
BACKGROUND: Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo. FINDINGS: Using [(11)C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage. CONCLUSIONS: These findings support a link between axonal damage and persistent inflammation after brain injury.
Subject(s)
Brain Injuries/metabolism , Cerebral Cortex/metabolism , Thalamus/metabolism , White Matter/metabolism , Adult , Brain Injuries/diagnostic imaging , Cerebral Cortex/diagnostic imaging , Female , Humans , Inflammation/diagnostic imaging , Inflammation/metabolism , Male , Middle Aged , Neural Pathways/diagnostic imaging , Neural Pathways/metabolism , Radionuclide Imaging , Thalamus/diagnostic imaging , White Matter/diagnostic imagingABSTRACT
OBJECTIVE: Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. METHODS: Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. RESULTS: PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. INTERPRETATION: We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed.
