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Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA.

ABSTRACT: Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [(11)C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[(18)F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([(18)F]-FEPPA) to evaluate whether there is increased neuroinflammation in patients with SCZ. A cross-sectional study was performed using [(18)F]-FEPPA and a high-resolution research tomograph (HRRT). Eighteen patients with SCZ with ongoing psychotic symptoms and 27 healthy volunteers (HV) were recruited from a tertiary psychiatric clinical setting and the community, respectively. All participants underwent [(18)F]-FEPPA PET and magnetic resonance imaging, and PET data were analyzed to obtain [(18)F]-FEPPA total volume of distribution (VT) using a 2-tissue compartment model with an arterial plasma input function, as previously validated. All subjects were classified as high-, medium- or low-affinity [(18)F]-FEPPA binders on the basis of rs6971 polymorphism, and genotype information was incorporated into the analyses of imaging outcomes. No significant differences in neuroinflammation indexed as [(18)F]-FEPPA VT were observed between groups in either gray (F(1,39) = 0.179, P = .674) or white matter regions (F(1,38) = 0.597, P = .445). The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and HV suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment.

SUBMITTER: Kenk M

PROVIDER: S-EPMC4266311 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA.

Kenk Miran M Selvanathan Thiviya T Rao Naren N Suridjan Ivonne I Rusjan Pablo P Remington Gary G Meyer Jeffrey H JH Wilson Alan A AA Houle Sylvain S Mizrahi Romina R

Schizophrenia bulletin 20141109 1

Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [(11)C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[(18)F]fluoroethoxybe ...[more]

PMID: 25385788

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Project description: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,

Project description:Prior postmortem studies have shown gray matter (GM) microstructural abnormalities in schizophrenia. However, few studies to date have examined GM microstructural integrity in schizophrenia in vivo. Here, we employed diffusion kurtosis imaging (DKI) to test for differences in GM microstructure in eighteen schizophrenia (SZ) patients versus nineteen healthy controls (HC). GM microstructure was characterized in each participant using DKI-derived metrics of mean kurtosis (MK) and mean diffusivity (MD). Individual T1-weighted images were used to create subject-specific cortically-labelled regions of interest (ROIs) of the four cortical lobes and sixty-eight cortical GM regions delineated by the Desikan-Killiany atlas, and to derive the associated cortical thickness and area measures. The derived ROIs were also registered to the diffusion space of each subject and used to generate region-specific mean MK and MD values. We additionally administered the Wisconsin Card Sorting Test (WCST), Stroop test, and Trail Making Test part B (Trails-B) to test the relationship between GM metrics and executive function in SZ. We found significantly increased MK and MD in SZ compared to HC participants in the temporal lobe, sub-lobar temporal cortical regions (fusiform, inferior temporal, middle temporal and temporal pole), and posterior cingulate cortex after correcting for multiple comparisons. Correlational analyses revealed significant associations of MK and MD with executive function scores derived from the WCST, Stroop, and Trails-B tests, along with an inverse relationship between MK and MD and cortical thickness and area. A hierarchical multiple linear regression analysis showed that up to 85% of the inter-subject variability in cognitive function in schizophrenia measured by the WCST could be explained by MK in combination with either GM thickness or area. MK and MD appear to be sensitive to GM microstructural pathology in schizophrenia and may provide useful biomarkers of abnormal cortical microstructure in this disorder.

Dataset Information

Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA.

Publications

Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA.

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