There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naïve). CCI-injured (n = 18) and sham-operated rats (n = 6) underwent positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (≤3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated, and naïve rats (n = 8) underwent behavioral testing in the chronic phase (5.5–10 months post-injury): open field and sucrose preference tests, two one-week video-electroencephalogram (vEEG) monitoring periods, pentylenetetrazole (PTZ) seizure susceptibility tests, and a Morris water maze (MWM) test. In vivo imaging revealed pronounced neuroinflammation, decreased fractional anisotropy, and increased diffusivity in perilesional cortex and ipsilesional hippocampus of CCI-injured rats. Behavioral analysis revealed disinhibition, anhedonia, increased seizure susceptibility, and impaired learning in CCI-injured rats. Subacute TSPO expression and changes in DTI metrics significantly correlated with several chronic deficits (Pearson's |r| = 0.50–0.90). Certain specific PET and DTI parameters had good sensitivity and specificity (area under the receiver operator characteristic [ROC] curve = 0.85–1.00) to distinguish between TBI animals with and without particular behavioral deficits. Depending on the investigated behavioral deficit, PET or DTI data alone, or the combination, could very well predict the variability in functional outcome data (adjusted R2 = 0.54–1.00). Taken together, both TSPO PET and DTI seem promising prognostic biomarkers to predict different chronic TBI sequelae.
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References
1.
RoozenbeekB., MaasA.I., and MenonD.K. (2013). Changing patterns in the epidemiology of traumatic brain injury. Nat. Rev. Neurol. 9, 231–236.
2.
BramlettH.M., and DietrichW.D. (2015). Long-term consequences of traumatic brain injury: current status of potential mechanisms of injury and neurological outcomes. J. Neurotrauma, 32, 1834–1848.
3.
MRC CRASH Trial Collaborators, PerelP., ArangoM., ClaytonT., EdwardsP., KomolafeE., PoccockS., RobertsI., ShakurH., SteyerbergE., and YutthakasemsuntS. (2008). Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ, 336, 425–429.
4.
SteyerbergE.W., MushkudianiN., PerelP., ButcherI., LuJ., McHughG.S., MurrayG.D., MarmarouA., RobertsI., HabbemaJ.D., and MaasA.I. (2008). Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med, 5, e165; discussion e165.
5.
MaasA.I., MarmarouA., MurrayG.D., TeasdaleS.G., and SteyerbergE.W. (2007). Prognosis and clinical trial design in traumatic brain injury: the IMPACT study. J. Neurotrauma, 24, 232–238.
6.
YoungN.H., and AndrewsP.J. (2008). Developing a prognostic model for traumatic brain injury—a missed opportunity?. PLoS Med, 5, e168.
7.
WebsterK.M., SunM., CrackP., O'BrienT.J., ShultzS.R., and SempleB.D. (2017). Inflammation in epileptogenesis after traumatic brain injury. J. Neuroinflammation, 14, 10.
8.
RussoM.V., and McGavernD.B. (2016). Inflammatory neuroprotection following traumatic brain injury. Science, 353, 783–785.
9.
JamesM.L., WangH., CantillanaV., LeiB., KernagisD.N., DawsonH.N., KlamanL.D., and LaskowitzD.T. (2012). TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice. Anesthesiology, 116, 1299–1311.
10.
ClausenF., HanellA., BjorkM., HilleredL., MirA.K., GramH., and MarklundN. (2009). Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur. J. Neurosci. 30, 385–396.
11.
LloydE., Somera-MolinaK., Van EldikL.J., WattersonD.M., and WainwrightM.S. (2008). Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury. J. Neuroinflammation, 5, 28.
12.
JuengstS.B., KumarR.G., FaillaM.D., GoyalA., and WagnerA.K. (2015). Acute inflammatory biomarker profiles predict depression risk following moderate to severe traumatic brain injury. J. Head Trauma Rehabil. 30, 207–218.
13.
WitcherK.G., EifermanD.S., and GodboutJ.P. (2015). Priming the inflammatory pump of the CNS after traumatic brain injury. Trends Neurosci. 38, 609–620.
14.
FennA.M., GenselJ.C., HuangY., PopovichP.G., LifshitzJ., and GodboutJ.P. (2014). Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol. Psychiatry, 76, 575–584.
15.
BertoglioD., VerhaegheJ., SantermansE., AmhaoulH., JonckersE., WyffelsL., Van Der LindenA., HensN., StaelensS., and DedeurwaerdereS. (2017). Non-invasive PET imaging of brain inflammation at disease onset predicts spontaneous recurrent seizures and reflects comorbidities. Brain Behav. Immun. 61, 69–79.
16.
WangY., YueX., KiesewetterD.O., NiuG., TengG., and ChenX. (2014). PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714. Eur. J. Nucl. Med. Mol. Imaging, 41, 1440–1449.
17.
YuI., InajiM., MaedaJ., OkauchiT., NariaiT., OhnoK., HiguchiM., and SuharaT. (2010). Glial cell-mediated deterioration and repair of the nervous system after traumatic brain injury in a rat model as assessed by positron emission tomography. J. Neurotrauma, 27, 1463–1475.
18.
RoncaroliF., SuZ., HerholzK., GerhardA., and TurkheimerF.E. (2016). TSPO expression in brain tumours: is TSPO a target for brain tumour imaging?. Clin. Transl. Imaging, 4, 145–156.
19.
DonatC.K., GaberK., MeixensbergerJ., BrustP., PinborgL.H., HansenH.H., and MikkelsenJ.D. (2016). Changes in binding of [(123)I]CLINDE, a high-affinity translocator protein 18 kDa (TSPO) selective radioligand in a rat model of traumatic brain injury. Neuromolecular Med. 18, 158–169.
20.
IrimiaA., WangB., AylwardS.R., PrastawaM.W., PaceD.F., GerigG., HovdaD.A., KikinisR., VespaP.M., and Van HornJ.D. (2012). Neuroimaging of structural pathology and connectomics in traumatic brain injury: Toward personalized outcome prediction. Neuroimage Clin. 1, 1–17.
21.
KoerteI.K., HufschmidtJ., MuehlmannM., LinA.P., and ShentonM.E. (2016). Advanced neuroimaging of mild traumatic brain injury, in: Translational Research in Traumatic Brain Injury. LaskowitzD., and GrantG. (eds). Boca Raton (FL).
22.
WrightD.K., JohnstonL.A., KershawJ., OrdidgeR., O'BrienT.J., and ShultzS.R. (2017). Changes in apparent fiber density and track-weighted imaging metrics in white matter following experimental traumatic brain injury. J. Neurotrauma, 34, 2109–2118.
23.
WrightD.K., TreziseJ., KamnakshA., BekdashR., JohnstonL.A., OrdidgeR., SempleB.D., GardnerA.J., StanwellP., O'BrienT.J., AgostonD.V., and ShultzS.R. (2016). Behavioral, blood, and magnetic resonance imaging biomarkers of experimental mild traumatic brain injury. Sci. Rep. 6, 28713.
24.
KharatishviliI., ImmonenR., GrohnO., and PitkanenA. (2007). Quantitative diffusion MRI of hippocampus as a surrogate marker for post-traumatic epileptogenesis. Brain, 130, 3155–3168.
25.
ImmonenR., KharatishviliI., GrohnO., and PitkanenA. (2013). MRI biomarkers for post-traumatic epileptogenesis. J. Neurotrauma, 30, 1305–1309.
26.
ImmonenR.J., KharatishviliI., GrohnH., PitkanenA., and GrohnO.H. (2009). Quantitative MRI predicts long-term structural and functional outcome after experimental traumatic brain injury. Neuroimage, 45, 1–9.
27.
FreyL., LepkinA., SchickedanzA., HuberK., BrownM.S., and SerkovaN. (2014). ADC mapping and T1-weighted signal changes on post-injury MRI predict seizure susceptibility after experimental traumatic brain injury. Neurol. Res. 36, 26–37.
28.
ChastainC.A., OyoyoU.E., ZippermanM., JooE., AshwalS., ShutterL.A., and TongK.A. (2009). Predicting outcomes of traumatic brain injury by imaging modality and injury distribution. J. Neurotrauma, 26, 1183–1196.
29.
MissaultS., PeetersL., AmhaoulH., ThomaeD., Van EetveldtA., FavierB., ThakurA., Van SoomJ., PitkanenA., AugustynsK., JoossensJ., StaelensS., and DedeurwaerdereS. (2017). Decreased levels of active uPA and KLK8 assessed by [111 In]MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy. Epilepsia, 58, 1615–1625.
30.
ColeJ.T., YarnellA., KeanW.S., GoldE., LewisB., RenM., McMullenD.C., JacobowitzD.M., PollardH.B., O'NeillJ.T., GrunbergN.E., DalgardC.L., FrankJ.A., and WatsonW.D. (2011). Craniotomy: true sham for traumatic brain injury, or a sham of a sham?. J. Neurotrauma, 28, 359–369.
31.
BourdierT., PhamT.Q., HendersonD., JacksonT., LamP., IzardM., and KatsifisA. (2012). Automated radiosynthesis of [18F]PBR111 and [18F]PBR102 using the Tracerlab FXFN and Tracerlab MXFDG module for imaging the peripheral benzodiazepine receptor with PET. Appl. Radiat. Isot. 70, 176–183.
32.
KatsifisA., Loc'hC., HendersonD., BourdierT., PhamT., GreguricI., LamP., CallaghanP., MattnerF., EberlS., and FulhamM. (2011). A rapid solid-phase extraction method for measurement of non-metabolised peripheral benzodiazepine receptor ligands, [(18)F]PBR102 and [(18)F]PBR111, in rat and primate plasma. Nucl. Med. Biol. 38, 137–148.
33.
HudsonH.M., and LarkinR.S. (1994). Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans. Med. Imaging, 13, 601–609.
34.
DefriseM., KinahanP.E., TownsendD.W., MichelC., SibomanaM., and NewportD.F. (1997). Exact and approximate rebinning algorithms for 3-D PET data. IEEE Trans. Med. Imaging, 16, 145–158.
35.
TuT.W., TurtzoL.C., WilliamsR.A., LescherJ.D., DeanD.D., and FrankJ.A. (2014). Imaging of spontaneous ventriculomegaly and vascular malformations in Wistar rats: implications for preclinical research. J. Neuropathol. Exp. Neurol. 73, 1152–1165.
36.
MissaultS., Van den EyndeK., Vanden BergheW., FransenE., WeerenA., TimmermansJ.P., Kumar-SinghS., and DedeurwaerdereS. (2014). The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model. Brain Behav. Immun. 42, 138–146.
37.
AmhaoulH., HamaideJ., BertoglioD., ReichelS.N., VerhaegheJ., GeertsE., Van DamD., De DeynP.P., Kumar-SinghS., KatsifisA., Van Der LindenA., StaelensS., and DedeurwaerdereS. (2015). Brain inflammation in a chronic epilepsy model: evolving pattern of the translocator protein during epileptogenesis. Neurobiol. Dis. 82, 526–539.
38.
AmhaoulH., AliI., MolaM., Van EetveldtA., SzewczykK., MissaultS., BielenK., Kumar-SinghS., RechJ., LordB., CeustersM., BhattacharyaA., and DedeurwaerdereS. (2016). P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy. Neuropharmacology, 105, 175–185.
HuuskoN., RomerC., Ndode-EkaneX.E., LukasiukK., and PitkanenA. (2015). Loss of hippocampal interneurons and epileptogenesis: a comparison of two animal models of acquired epilepsy. Brain Struct. Funct. 220, 153–191.
41.
van der WerfI.M., Van DamD., MissaultS., YalcinB., De DeynP.P., VandeweyerG., and KooyR.F. (2017). Behavioural characterization of AnkyrinG deficient mice, a model for ANK3 related disorders. Behav. Brain Res. 328, 218–226.
42.
Van den EyndeK., MissaultS., FransenE., RaeymaekersL., WillemsR., DrinkenburgW., TimmermansJ.P., Kumar-SinghS., and DedeurwaerdereS. (2014). Hypolocomotive behaviour associated with increased microglia in a prenatal immune activation model with relevance to schizophrenia. Behav. Brain Res. 258, 179–186.
43.
MizrahiR., RusjanP.M., KennedyJ., PollockB., MulsantB., SuridjanI., De LucaV., WilsonA.A., and HouleS. (2012). Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA. J. Cereb. Blood Flow Metab. 32, 968–972.
44.
OwenD.R., YeoA.J., GunnR.N., SongK., WadsworthG., LewisA., RhodesC., PulfordD.J., BennacefI., ParkerC.A., StJeanP.L., CardonL.R., MooserV.E., MatthewsP.M., RabinerE.A., and RubioJ.P. (2012). An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J. Cereb. Blood Flow Metab. 32, 1–5.
45.
AlbrechtD.S., GranzieraC., HookerJ.M., and LoggiaM.L. (2016). In vivo imaging of human neuroinflammation. ACS Chem. Neurosci. 7, 470–483.
46.
LyooC.H., IkawaM., LiowJ.S., ZoghbiS.S., MorseC.L., PikeV.W., FujitaM., InnisR.B., and KreislW.C. (2015). Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. J. Nucl. Med. 56, 701–706.
47.
HutchinsonE.B., SchwerinS.C., AvramA.V., JulianoS.L., and PierpaoliC. (2017). Diffusion MRI and the detection of alterations following traumatic brain injury. J. Neurosci. Res. 96, 612–625.
48.
JohnstoneV.P., WrightD.K., WongK., O'BrienT.J., RajanR., and ShultzS.R. (2015). Experimental traumatic brain injury results in long-term recovery of functional responsiveness in sensory cortex but persisting structural changes and sensorimotor, cognitive, and emotional deficits. J. Neurotrauma, 32, 1333–1346.
49.
BuddeM.D., JanesL., GoldE., TurtzoL.C., and FrankJ.A. (2011). The contribution of gliosis to diffusion tensor anisotropy and tractography following traumatic brain injury: validation in the rat using Fourier analysis of stained tissue sections. Brain, 134, 2248–2260.
50.
ImmonenR.J., KharatishviliI., NiskanenJ.P., GrohnH., PitkanenA., and GrohnO.H. (2009). Distinct MRI pattern in lesional and perilesional area after traumatic brain injury in rat–11 months follow-up. Exp. Neurol. 215, 29–40.
51.
KockaA., and GagnonJ. (2014). Definition of impulsivity and related terms following traumatic brain injury: a review of the different concepts and measures used to assess impulsivity, disinhibition and other related concepts. Behav. Sci. (Basel) 4, 352–370.
52.
Vonder HaarC., MartensK.M., RiparipL.K., RosiS., WellingtonC.L., and WinstanleyC.A. (2017). Frontal Traumatic Brain Injury Increases Impulsive Decision Making in Rats: A Potential Role for the Inflammatory Cytokine Interleukin-12. J Neurotrauma, 34, 2790–2800.
53.
TuckerL.B., BurkeJ.F., FuA.H., and McCabeJ.T. (2017). Neuropsychiatric symptom modeling in male and female C57BL/6J mice after experimental traumatic brain injury. J. Neurotrauma, 34, 890–905.
54.
JonesN.C., CardamoneL., WilliamsJ.P., SalzbergM.R., MyersD., and O'BrienT.J. (2008). Experimental traumatic brain injury induces a pervasive hyperanxious phenotype in rats. J. Neurotrauma, 25, 1367–1374.
55.
KimH., YuT., Cam-EtozB., van GroenT., HubbardW.J., and ChaudryI.H. (2017). Treatment of traumatic brain injury with 17alpha-ethinylestradiol-3-sulfate in a rat model. J. Neurosurg. 127, 23–31.
56.
McNamaraK.C., LisembeeA.M., and LifshitzJ. (2010). The whisker nuisance task identifies a late-onset, persistent sensory sensitivity in diffuse brain-injured rats. J. Neurotrauma, 27, 695–706.
57.
RoweR.K., ZiebellJ.M., HarrisonJ.L., LawL.M., AdelsonP.D., and LifshitzJ. (2016). Aging with traumatic brain injury: effects of age at injury on behavioral outcome following diffuse brain injury in rats. Dev. Neurosci. 38, 195–205.
58.
KellyK.M. (2004). Spike-wave discharges: absence or not, a common finding in common laboratory rats. Epilepsy Curr. 4, 176–177.
59.
PearceP.S., FriedmanD., LafrancoisJ.J., IyengarS.S., FentonA.A., MacluskyN.J., and ScharfmanH.E. (2014). Spike-wave discharges in adult Sprague-Dawley rats and their implications for animal models of temporal lobe epilepsy. Epilepsy Behav. 32, 121–131.
60.
ShawF.Z. (2004). Is spontaneous high-voltage rhythmic spike discharge in Long Evans rats an absence-like seizure activity?. J. Neurophysiol. 91, 63–77.
61.
RodgersK.M., DudekF.E., and BarthD.S. (2015). Progressive, Seizure-like, spike-wave discharges are common in both injured and uninjured Sprague-Dawley Rats: implications for the fluid percussion injury model of post-traumatic epilepsy. J. Neurosci. 35, 9194–9204.
62.
SickT., WassermanJ., BregyA., SickJ., DietrichW.D., and BramlettH.M. (2017). Increased expression of epileptiform spike/wave discharges one year after mild, moderate, or severe fluid percussion brain injury in rats. J. Neurotrauma, 34, 2467–2474.
63.
KellyK.M., MillerE.R., LepsveridzeE., KharlamovE.A., and McHedlishviliZ. (2015). Posttraumatic seizures and epilepsy in adult rats after controlled cortical impact. Epilepsy Res. 117, 104–116.
64.
BolkvadzeT., and PitkanenA. (2012). Development of post-traumatic epilepsy after controlled cortical impact and lateral fluid-percussion-induced brain injury in the mouse. J. Neurotrauma, 29, 789–812.
65.
HuntR.F., ScheffS.W., and SmithB.N. (2009). Posttraumatic epilepsy after controlled cortical impact injury in mice. Exp. Neurol. 215, 243–252.
66.
HuntR.F., ScheffS.W., and SmithB.N. (2010). Regionally localized recurrent excitation in the dentate gyrus of a cortical contusion model of posttraumatic epilepsy. J. Neurophysiol. 103, 1490–1500.
67.
NissinenJ., AndradeP., NatunenT., HiltunenM., MalmT., KanninenK., SoaresJ.I., ShatilloO., SallinenJ., Ndode-EkaneX.E., and PitkanenA. (2017). Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy. Epilepsy Res. 136, 18–34.
68.
HammR.J., DixonC.E., GbadeboD.M., SinghaA.K., JenkinsL.W., LyethB.G., and HayesR.L. (1992). Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J. Neurotrauma, 9, 11–20.
69.
ScheffS.W., BaldwinS.A., BrownR.W., and KraemerP.J. (1997). Morris water maze deficits in rats following traumatic brain injury: lateral controlled cortical impact. J. Neurotrauma, 14, 615–627.
70.
SmithD.H., OkiyamaK., ThomasM.J., ClaussenB., and McIntoshT.K. (1991). Evaluation of memory dysfunction following experimental brain injury using the Morris water maze. J. Neurotrauma, 8, 259–269.
71.
WhitingM.D., BaranovaA.I., and HammR.J. (2006). Cognitive impairment following traumatic brain injury, in: Animal Models of Cognitive Impairment. LevinE.D., and BuccafuscoJ.J. (eds). Boca Raton (FL).
72.
LiL., WangW., ZhangL.M., JiangX.Y., SunS.Z., SunL.J., GuoY., GongJ., ZhangY.Z., WangH.L., and LiY.F. (2017). Overexpression of the 18 kDa translocator protein (TSPO) in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects. Neuropharmacology, 125, 117–128.
73.
WangS., ChoppM., Nazem-ZadehM.R., DingG., Nejad-DavaraniS.P., QuC., LuM., LiL., Davoodi-BojdE., HuJ., LiQ., MahmoodA., and JiangQ. (2013). Comparison of neurite density measured by MRI and histology after TBI. PLoS One, 8, e63511.
74.
SaveE., and MoghaddamM. (1996). Effects of lesions of the associative parietal cortex on the acquisition and use of spatial memory in egocentric and allocentric navigation tasks in the rat. Behav. Neurosci. 110, 74–85.
75.
IkegayaY., NishiyamaN., and MatsukiN. (2000). L-type Ca(2+) channel blocker inhibits mossy fiber sprouting and cognitive deficits following pilocarpine seizures in immature mice. Neuroscience, 98, 647–659.
76.
ShultzS.R., CardamoneL., LiuY.R., HoganR.E., MaccottaL., WrightD.K., ZhengP., KoeA., GregoireM.C., WilliamsJ.P., HicksR.J., JonesN.C., MyersD.E., O'BrienT.J., and BouilleretV. (2013). Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?. Epilepsia, 54, 1240–1250.
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