Replicating predictive serum correlates of greater translocator protein distribution volume in brain

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Abstract

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO VT, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF), and tumor necrosis factor alpha (TNFα)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO VT were measured in 3 cohorts: prefrontal cortex TSPO VT of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO VT of 20 subjects with obsessive-compulsive disorder. Ln(PGE2/CRP) and ln(TNFα/CRP) consistently correlated with TSPO VT (R2 = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO VT, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R2 = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO VT. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.

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Acknowledgements

AN, LN, and CC worked as study PET technicians. AK, NK, AS, and RM provided medical coverage for the PET scans. JP, AG, and Michael Harkness of Research Imaging Centre, served as PET chemistry staff. AR, GED, and HB, worked as study MRI technicians. All other contributors are paid employees of the Centre for Addiction and Mental Health.

Author information

Study concept and design: JHM, ES, AAW, SH. Acquisition, analysis, or interpretation of data: SA, ES, PMR, LM, CX, CH, SK, JHM. Drafting of the manuscript: SA, JHM. Critical revision of the manuscript for important intellectual content: SA, Setiawan, Wilson, PMR, LM, CX, CH, MIH, SK, NV, SH, JHM. Statistical analysis: SA, JHM. Obtained funding: SA, JHM, ES, AAW, SH. Administrative, technical, or material support: AAW, PMR, LM, SK, NV, SH, JHM. Study supervision: JHM.

Correspondence to Jeffrey H. Meyer.

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Supplementary information

Supplementary Information Section

Figure S1. Correlation of Ln(PGF2α/CRP) with Dorsal Caudate Translocator Protein Distribution Volume in Obsessive Compulsive Disorder

Figure S2. Negative Ln(CRP) Serum Marker Significantly Correlated with Translocator Protein Distribution Volume in Collective Depressed (MDE and TRD) Cohorts

Figure S3. Receiver Operating Characteristic Curve Analysis of Ln(CRP) Serum Marker in Collective Depressed (MDE and TRD) Cohorts

Figure S4. Relationship of Positive Predictive Value of Ln(CRP) Serum Marker and Proportion of Participants Retained in Collective Depressed (MDE and TRD) Cohorts

Figure S5. Linear Combination of Ln(CRP) and Body Mass Index Significantly Predictive of Translocator Protein Distribution Volume in Collective Depressed (MDE and TRD) Cohorts

Figure S6. Receiver Operating Characteristic Curve Analysis of Linear Combination of Ln(CRP) and Body Mass Index in Collective Depressed (MDE and TRD) Cohorts

Figure S7. Relationship of Positive Predictive Value of Linear Combination of Ln(CRP) and Body Mass Index and Proportion of Participants Retained in Collective Depressed (MDE and TRD) Cohorts

Figure S8. Receiver Operating Characteristic Curve Analyses in Entire Sample

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Attwells, S., Setiawan, E., Wilson, A.A. et al. Replicating predictive serum correlates of greater translocator protein distribution volume in brain. Neuropsychopharmacol. (2019) doi:10.1038/s41386-019-0561-y

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