117.4 Pet Imaging of Neuroinflammation in Schizophrenia

ABSTRACT: Abstract Background: Epidemiological, genetic and clinical evidence all indicates that inflammation plays a role in schizophrenia. Microglia are the resident immune cells of the CNS and act as major mediators of neuroinflammation. When microglia are activated, they express high levels of the 18-kDa translocator protein (TSPO). TSPO can be measured in vivo with Positron Emission Tomography (PET) radiotracers, such as [11C]PK11195 and [11C]PBR28. In the present investigation we seek to determine whether microglial activity is elevated in patients with schizophrenia and in ultra high risk (UHR) for developing a psychotic disorder using the novel TSPO radioligand [11C]PBR28 while testing if there is a relationship between microglial activity, symptom severity and grey matter volume. Finally, we also aim to estimate the non-displaceable binding component (VND) of [11C]PBR28 in schizophrenia patients. Methods: A total of 56 subjects completed the study. 14 subjects meet UHR criteria and were matched with 14 healthy volunteers (HV), while 14 subjects with schizophrenia were matched with 14 HV. We used [11C]PBR28 PET to image microglial activity with the main outcome measure being total grey matter [11C]PBR28 binding ratio. All subjects were genotyped for the rs6971 polymorphism, and all patients were homozygote high-affinity binders (HABs) or mixed-affinity binders (HABs). A subgroup of 7 schizophrenia patients were invited for a follow-up PET scan. In this visit patients received a selective TSPO blocker (90mg of XBD173) followed 2 hours later by a repeat [11C]PBR28 scan. Results: UHR subjects and schizophrenia patients showed greater PET TSPO binding, indicating microglia activity, relative to controls, in total gray matter, fronta,l and temporal cortices, with large effect sizes (0.9–1.8). Moreover, we found that microglia activity was positively correlated with greater prodromal symptom severity. In schizophrenia patients, the gray matter microglia activity could be predicted by the volumes of several gray matter regions, indicating a positive correlation between volume deficits and neuroinflammation. Following blockade with XBD173 schizophrenia patients showed a significant reduction in TSPO specific binding across different brain regions. Regional VT data for individual subjects were fitted to an occupancy plot. By constraining the VND to be equal for all patients, the population VND was estimated to be 1.99. Conclusion: Our main finding is that [11C]PBR28 binding ratio is elevated in people at UHR as well as in schizophrenia patients, relative to HV. This data implicates microglial activation in the pathophysiology and severity of schizophrenia and potentially account for the brain structural changes seen in schizophrenia. Moreover, a substantial component of [11C]PBR28 VT represents specific binding,

SUBMITTER: Marques T 

PROVIDER: S-EPMC5475629 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature