In vivo imaging correlates of long-term behavioural outcome following different brain insults
8 May 2018
UAntwerp, Campus Drie Eiken, Building O, Auditorium O.7 - Universiteitsplein 1 - 2610 Wilrijk (route: UAntwerpen, Campus Drie Eiken
Prof S. Dedeurwaerdere & Prof M. Verhoye
PhD defence Stephan Missault - Faculty of Medicine and Health Sciences
In this PhD thesis we set out to identify in vivo imaging correlates of long-term behavioural outcome following different brain insults, which could pave the way towards the identification of novel prognostic and predictive biomarkers.
First of all, we investigated extracellular matrix proteases as possible biomarkers of epileptogenesis following brain insults. A SPECT radiotracer with high affinity for active uPA and KLK8 was implemented in an in vitro autoradiography study of two animal models of acquired epilepsy. A decreased activity of the extracellular proteases uPA/KLK8 was observed in relevant brain regions following both kainic acid-induced status epilepticus (SE) and controlled cortical impact (CCI)-induced traumatic brain injury (TBI) during young adulthood. The chronically decreased uPA/KLK8 activity in hippocampus following SE correlated with the epileptic seizure burden in this animal model of temporal lobe epilepsy.
Secondly, we investigated the prognostic value of changes in brain inflammation and microstructure during the subacute phase for the long-term outcome following CCI-injury during young adulthood. Neuroinflammation was assessed by PET imaging with a radioligand for translocator protein (TSPO), a marker of brain inflammation. Alterations in brain microstructure were assessed with diffusion tensor imaging (DTI). Subacute changes in brain inflammation and DTI metrics were able to predict different chronic TBI sequelae, including disinhibition, increased seizure susceptibility and impaired visuospatial learning/memory. In addition, we studied the impact of maternal immune activation (MIA), a risk factor for schizophrenia, on the offspring’s brain and behaviour. We investigated whether adult MIA offspring had alterations in functional connectivity, brain microstructure and NMDA receptor function using respectively resting-state functional MRI, DTI and pharmacological MRI with an NMDA receptor antagonist. Increased functional connectivity was observed in the default mode-like network of adult MIA offspring of dams that lost weight following the immune challenge during pregnancy. No changes in brain microstructure were observed.
An attenuated response to the NMDA receptor antagonist was observed in MIA offspring and was most pronounced in offspring of dams that gained weight following the immune stimulus. Functional connectivity in the default mode-like network correlated with behaviour in the MIA offspring, as has been observed in schizophrenia patients. Future studies are warranted to investigate whether functional connectivity in the default mode-like network is a predictive biomarker in this neurodevelopmental animal model with relevance for schizophrenia.
Taken together, we have identified several relevant imaging correlates of chronic outcome following different brain insults.
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