RESEARCH ARTICLE Inflammation after Trauma: Microglial Activation and Traumatic Brain Injury Anil F. Ramlackhansingh, MRCP, 1 David J. Brooks, MD, DSc, 1 Richard J. Greenwood, FRCP, 2 Subrata K. Bose, PhD, 3 Federico E. Turkheimer, PhD, 1 Kirsi M. Kinnunen, PhD, 4 Steve Gentleman, PhD, 1 Rolf A. Heckemann, PhD, 1,5 Karen Gunanayagam, BSc, 1 Giorgio Gelosa, MD, 1 and David J. Sharp, MRCP, PhD 1 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. ANN NEUROL 2011;00:000–000 T he underlying pathophysiology of traumatic brain injury (TBI) remains poorly understood. 1 Patient out- comes are highly variable, 2 for reasons that are often unclear. Although TBI is usually thought to involve a static pathological insult from a single event, new clinical effects can emerge many years after the injury. Patients often clini- cally improve or deteriorate long after TBI 2 and may develop unexpected consequences such as post-traumatic epilepsy 3 or late cognitive decline including Alzheimer dis- ease. 4 These observations suggest the presence of a dynamic element to the underlying pathophysiology of TBI. An important factor is likely to be the inflamma- tory response produced by TBI. 5–7 The initial insult results in neuronal injury and can disrupt the blood– brain barrier. Microglial cells resident in the central nerv- ous system react to this injury within minutes, and become chronically activated. 8,9 Once transformed, microglia become indistinguishable from peripheral mac- rophages, secreting cytokines and acting as antigen- presenting cells. 10 In animal models, the initial inflamma- tory process has been shown to persist for at least a year, particularly within the thalamus. 5,7,11 In humans, post- mortem studies have shown microglial activation many years after TBI. 12 Sites of activation often coincide with those of neuronal degeneration and axonal abnormality, and include disconnected nuclei such as the thalamus. 6,13 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22455 Received Jan 5, 2011, and in revised form Apr 1, 2011. Accepted for publication Apr 8, 2011. Address correspondence to Dr Sharp, Computational, Cognitive, and Clinical Neuroimaging Laboratory, 3rd Floor, Burlington Danes Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, United Kingdom. E-mail: david.sharp@imperial.ac.uk From the 1 Centre for Neuroscience, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK; 2 Institute of Neurology, University College London, London, UK; 3 MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London, UK; 4 Goldsmiths, University of London, London, UK; and 5 Neurodis Foundation AQ1 , CERMEP Imagerie du Vivant, Lyon, France. Additional supporting information can be found in the online version of this article. J_ID: ZAY Customer A_ID: 11-0023.R2 Cadmus Art: ANA22455 Date: 27-April-11 Stage: Page: 1 ID: jaishankarn I Black Lining: [ON] I Time: 13:00 I Path: N:/3b2/ANA#/Vol00000/110112/APPFile/JW-ANA#110112 V C 2011 American Neurological Association 1