Supplementary Materials s36

Supplementary materials

1- Supplementary Methods

Measures

The following measures were used to examine the psychopathology in CHR: Structured Interview for Psychosis-risk Syndromes, SIPS(Miller et al, 2002); scale of psychosis-risk symptoms (SOPS)(Miller et al, 2002); Calgary Depression Scale, depression scale(Addington et al, 1994); Snaith-Hamilton Pleasure Scale, pleasure scale(Snaith et al, 1995); Apathy Evaluation Scale, apathy scale(Marin et al, 1991); Global Assessment of Functioning, GAF(Jones et al, 1995); state-trait anxiety inventory, STAI(Spielberger, 1989).

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function in CHR. It has been validated in psychotic patients and comprises five subscales: immediate memory, visuospatial ability, language, attention, and delayed memory (Randolph, 1998; Wilk et al, 2004).

MRI data acquisition Proton density-weighted (PD) brain MRI scan (TE = 17, TR = 6000, FOV = 22 cm, matrix = 256 × 256, slice thickness = 2 mm, number of excitations = 2) was obtained for each subject using a 1.5T Signa scanner (General Electric Medical Systems, Milwaukee, WI, USA) for 4 healthy volunteers and 2 CHR. For the remaining 23 CHR and 20 HV, PD MRI images (TE= Min full, TR = 6000, FOV = 22 cm, slice thickness = 2 mm, and number of acquisitions = 1) were acquired using a 3T MR-750 scanner (General Electric Medical Systems). MRI images were used for the anatomical delineation of regions and the quantification of PET images. As we previously reported (Kenk et al, 2015; Suridjan et al, 2015), differences in MRI acquisition parameters and scanner used did not have a significant effect on [18F]FEPPA outcome measures (data not shown).

PET data acquisition

All [18F]FEPPA PET scans were performed using a high-resolution CPS- high resolution research tomograph PET scanner (Siemens Molecular Imaging, Knoxville, TN, USA), which measures radioactivity in 207 1.2-mm thick slices. Dynamic emission data were acquired for 125 minutes (34 time frames: 1 frame of variable length, 5 × 30 s, 1 × 45 s, 2 × 60 s, 1 × 90 s, 1 × 120 s, 1 × 210 s, and 22 × 300 s) following an intravenous bolus injection of 183.74 ± 12.14 (mean ± SD) MBq of [18F]FEPPA. Kinetic parameters of [18F]FEPPA were derived from the time activity curves using two-tissue compartment model and plasma input function to obtain the binding outcome measure total distribution volume (VT) for each region of interest, which has been validated for [18F]FEPPA quantification(Rusjan et al, 2011b). Kinetic analysis of regions of interest incorporated a 5% contribution from the blood in the vascular lumen (Leenders et al, 1990) in the fitting of the two-compartment kinetic model using PMOD software (PMOD Technologies, Zurich, Switzerland).

1 Voxel-based PET image analysis

18 Parametric images of [ F]FEPPA VT were generated using the Logan graphical analysis method, (Logan et al, 1990) A wavelet-based kinetic modeling approach was applied to increase the signal-to-noise ratio while maintaining the resolution. (Turkheimer et al, 2000) To examine voxel-wise group differences of VT, an independent sample T-test was conducted using Statistical Parametric Mapping (SPM8- http://www.fil.ion.ucl.ac.uk/spm/software/spm8). TSPO genotype (rs6971 polymorphism) was included as a covariate. Significant level for the whole brain analysis was thresholded at p<0.05, FWE corrected at the voxel level.

Input function measurement

Arterial blood was collected for the first 22.5 min after radiotracer injection at a rate of 2.5 mL/min and blood radioactivity levels were measured using an automatic blood sampling system (Model PBS-101, Veenstra Instruments, Joure, Netherlands). Additionally, 7 mL blood samples were drawn manually at -5, 2.5, 7, 12, 15, 20, 30, 45, 60, 90, and 120 min following tracer injection. The relative proportion of radiolabeled metabolites was measured using high-performance liquid chromatography (HPLC) and dispersion- and metabolite-corrected plasma input function was generated as previously described (Mizrahi et al, 2012; Rusjan et al, 2011a).

TSPO polymorphism genotyping

Using high salt extraction method, DNA samples were extracted from peripheral white blood cells. (Lahiri et al, 1992)A single-nucleotide polymorphism (rs6971), which is known to affect binding of second-generation TSPO PET radioligands (Kreisl et al, 2013; Mizrahi et al, 2012; Owen et al, 2012; Yoder et al, 2013), was genotyped using a TaqMan assay (Applied Biosystems, Foster City, CA, USA), as previously described(Kenk et al, 2015; Suridjan et al, 2015).

[18F]FEPPA pseudo-reference regions distribution volume ratios (DVR) estimation

For exploratory purposes, we investigated the difference between clinical groups using distribution volume ratio

(DVR) as an outcome measure. DVR is defined as regional VT normalized by VT in the cerebellum, gray matter, or whole brain (DVR = VT_Region /VT_k, where k represents cerebellum, gray matter, or whole brain). This method has previously been used in other TSPO PET studies(Bloomfield et al, 2015; Coughlin et al, 2014) and is suggested to reduce variability in the data (Coughlin et al, 2014).

Statistical analysis

2 Multivariate analysis of variance (MANOVA), with regional DVRs as the dependent variables, group (CHR individuals vs. healthy volunteers) as the independent variable, and the TSPO genotype (rs6971) as a covariate were carried out to test for differences in DVRs between clinical groups. Partial correlations controlling for the effects of TSPO rs6971 polymorphism were used to explore the association between DVRs and clinical and neuropsychological measures. p<0.05 two-tailed considered significant. Bonferroni correction was used to correct for multiple comparisons in regions we set out to test (i.e. dorsolateral prefrontal cortex and hippocampus). For descriptive purposes, we also report differences in medial prefrontal cortex, temporal cortex, total gray matter, and whole brain, with DVR data.

3 Supplementary Results

18 Differences in [ F]FEPPA VT between CHR and healthy volunteers corrected for partial volume effects

18 The lack of group effect on [ F]FEPPA VT was observed after correction for partial volume effects (F(2, 43) = 3.15, p

= .05; Hippocampus: F(1, 44) = 2.90, p =.10, 16.03% higher in healthy volunteers than CHR individuals; DLPFC: F (1,

44) = .33, p =.57, 4.88% higher in healthy volunteers than CHR individuals). After removing an outlier, we found (F (2,

42) = 3.62, p =.035; Hippocampus: F(1, 43) =3.92, p =.054, 18.89% higher in healthy volunteers than CHR individuals;

DLPFC: F(1, 43) = .63, p =.43, 6.77 % higher in healthy volunteers than CHR individuals)

Differences in DVR with cerebellum as denominator (DVRCer) between CHR and healthy volunteers

18 There was no significant group effect on [ F]FEPPA VT in cerebellum, before (F(1, 44) =.39, p = .54) or after correction for partial volume effects (F(1, 44) =.50, p = .48).

We found no significant effect of clinical group on DVRCer (F(2, 43) = 2.43, p = .10). While not statistically significant, healthy volunteers show higher DVR in hippocampus (F(1, 44) = 4.67, p = .04; 10.08% higher in healthy volunteers than CHR) and dorsolateral prefrontal cortex (DLPFC: F(1, 44) =.004 , p = .95; .10% higher in healthy volunteers than CHR). Information on the results after partial volume correction and also other regions of interest is reported in ST2.

Differences in DVR with whole brain as denominator (DVR WB) between CHR and healthy volunteers

18 [ F]FEPPA VT of whole brain did not differ significantly between the two clinical groups before (F(1, 44) =.32, p = .

58) or after correction for partial volume effect (F(1, 44) =.57, p =.46).

No significant differences in DVR WB were observed between the groups (F(2, 43) = 2.14, p =.13). Although not significant, healthy volunteers had higher DVR WB than CHR in hippocampus (F(1, 44) =4.19, p =.05; 10.33% higher in healthy volunteers than CHR) and dorsolateral prefrontal cortex (F(1, 44) =.16, p =.69; .79% higher in healthy volunteers than CHR). Results of analysis after partial volume correction and other regions of interest are reported in ST3.

Differences in DVR gray matter as denominator (DVRGM) between CHR and healthy volunteers

18 We found no significant difference between [ F]FEPPA VT in gray matter between CHR and healthy volunteers before (F(1, 44) =.27, p =.61) and after correction for partial volume effects (F(1, 44) =.44 , p =.51).

No significant difference was observed between groups in DVRGM (F(2, 43) =2.35, p =.11). Although not significant, healthy volunteers showed higher DVRGM than CHR in hippocampus (F(1, 44) = 4.78, p = .03; 10.89% higher in healthy volunteers than CHR) and dorsolateral prefrontal cortex (F(1, 44) =.39, p = .53; 1.23% higher in healthy volunteers than CHR). Results of analysis after partial volume correction and other regions of interest are reported in ST4.

4 2- Supplementary tables

18 Supplementary Table 1: Regional [ F]FEPPA VT between CHR and healthy volunteers. Factorial ANOVA were performed for each region of interest to examine the diagnostic groups effect with genotype added as covariates. % difference was calculated as the

18 difference in [ F]FEPPA VT between the groups (VT CHR – VT healthy volunteers) divided

18 by [ F]FEPPA VT of the healthy volunteers group times 100.

HV (n = 23) CHR (n = 24) Percent Diagnostic Effect Differenc effect size e 2 ROI Adjusted SE Adjuste SE % F (1, 44) P η mean d mean

VT DLPFC 10.99 .64 10.41 .63 -5.27 .41 .52 .009 HC 10.82 .72 9.13 .71 -15.61 2.78 .10 .059 MPFC 10.07 .64 9.88 .63 -1.89 .05 .83 .001 Temporal cortex 11.09 .68 10.54 .66 -4.93 .33 .57 .007 GM 10.43 .61 9.99 .60 -4.26 .27 .61 .006 WB 9.61 .56 9.16 .55 -4.59 .32 .58 .007 Cerebellum 11.21 .68 10.61 .67 -5.32 .39 .54 .009

PVEC VT DLPFC 13.60 .82 12.94 .81 -4.88 .331 .568 .007

HC 11.46 .77 9.63 .75 -16.03 2.895 .096 .062

MPFC 11.05 .72 10.71 .70 -3.09 .115 .736 .003

Temporal cortex 12.53 .78 11.95 .76 -4.61 .280 .599 .006

GM 12.87 .76 12.16 .74 -5.50 .442 .510 .010

WB 13.19 .76 12.39 .74 -6.07 .568 .455 .013

Cerebellum 12.04 .75 11.29 .74 -6.21 .500 .483 .011

Abbreviations: CHR, Clinical high risk; DLPFC, dorsolateral prefrontal cortex; GM, gray matter; HC, hippocampus; HV, healthy volunteer;

MPFC, medial prefrontal cortex; ; SE, standard error; VT, Volume of distribution; WB, whole brain.

5 Supplementary Table 2: Regional distribution volume ratio of cerebellum (DVRCer) 18 between CHR and healthy volunteers. DVRCer was calculated as the ratio [ F]FEPPA VT of 18 region to [ F]FEPPA VT of cerebellum. % difference was calculated as the difference in

DVRCer between the groups (VT CHR – VT healthy volunteers) divided by DVRCer of the healthy volunteers group times a 100.

HV (n = 23) CHR (n = 24) Percent Diagnostic Effect Differenc effect size e 2 ROI Adjuste SE Adjuste SE % F (1, 44) P η d mean d mean .990 .015 .989 .015 -.101 .004 .950 .000 DVRCer DLPFC .962 .032 .865 .031 -10.083 4.669 .036 .096 HC .905 .018 .931 .018 2.873 .995 .324 .022 MPFC Temporal .996 .013 .993 .013 -.301 .024 .877 .001

cortex .939 .012 .946 .011 .745 .192 .663 .004 GM .866 .012 .870 .012 .462 .056 .813 .001 WB DVR Cer 1.139 .022 1.160 .022 1.844 .461 .501 .010 with DLPFC PVEC .950 .032 .859 .031 -9.579 4.127 .048 .086 HC .926 .019 .949 .019 2.484 .757 .389 .017 MPFC Temporal 1.048 .014 1.059 .014 1.050 .371 .546 .008

cortex 1.080 .015 1.086 .015 .556 .086 .771 .002 GM 1.105 .018 1.112 .017 .633 .085 .772 .002 WB

Abbreviations: CHR, Clinical high risk; DLPFC, dorsolateral prefrontal cortex; DVR, distribution volume ratio; GM, gray matter; HC, hippocampus; ; HV, healthy volunteer; MPFC, medial prefrontal cortex; ; ROI, region of interest; SE, standard error; WB, whole brain.

6 Supplementary Table 3: Regional distribution volume ratio of whole brain (DVRWB) 18 between CHR and healthy volunteers. DVRWB was calculated as the ratio [ F]FEPPA VT of 18 region to [ F]FEPPA VT of whole brain. % difference was calculated as the difference in

DVRWB between the groups (VT CHR – VT healthy volunteers) divided by DVRWB of the healthy volunteers group times a 100.

HV (n = 23) CHR (n = 24) Percent Diagnostic Effect Differenc effect Size e 2 ROI Adjuste SE Adjuste SE % F (1, 44) P η d mean d mean 1.15 .02 1.14 .02 -.79 .16 .689 .004 DVRWB DLPFC 1.11 .04 1.00 .04 -10.33 4.19 .047 .087 HC 1.05 .02 1.07 .02 2.29 .90 .349 .020 MPFC Temporal .16 .689 .004 1.15 .02 1.14 .02 -.87 cortex 1.08 .01 1.09 .01 .37 .27 .608 .006 GM 1.16 .02 1.16 .02 -.35 .02 .881 .001 Cerebellum

DVRWB 1.03 .01 1.05 .01 1.46 .50 .486 .011 with DLPFC PVEC .86 .03 .78 .03 -9.22 4.08 .050 .085 HC .84 .02 .86 .02 2.27 .81 .373 .018 MPFC Temporal .95 .01 .96 .01 .84 .24 .630 .005

cortex .98 .01 .98 .01 .20 .05 .832 .001 GM .91 .02 .91 .02 .11 .001 .979 .000 Cerebellum Abbreviations: CHR, Clinical high risk; DLPFC, dorsolateral prefrontal cortex; DVR, distribution volume ratio; GM, gray matter; HC, hippocampus; HV, healthy volunteer; MPFC, medial prefrontal cortex; ; ROI, region of interest; SE, standard error; WB, whole brain.

7 Supplementary Table 4: Regional distribution volume ratio of gray matter (DVRGM) 18 between CHR and healthy volunteers. DVRGM was calculated as the ratio [ F] FEPPA VT 18 of region to [ F] FEPPA VT of gray matter. % Difference was calculated as the difference in DVRGM between the groups (VT CHR – VT healthy volunteers) divided by DVRGM of the healthy volunteers group times a 100.

Percent Diagnostic Effect HV (n = 23) CHR (n = 24) Differen effect size ce 2 Gray Adjuste SE Adjust SE % F (1, 44) P η matter d mean ed ROI mean 1.06 .01 1.04 .01 -1.23 .39 .53 .009 DVRGM DLPFC 1.03 .04 .92 .04 -10.89 4.78 .03 .098 HC .97 .02 .98 .02 1.87 .60 .44 .013 MPFC Temporal 1.06 .01 1.05 .01 -1.32 .49 .49 .011

cortex Cerebellu 1.07 .01 1.06 .01 -.75 .16 .69 .004

m .92 .01 .92 .01 -.33 .20 .66 .004 WB

DVRGM 1.06 .02 1.07 .01 1.23 .40 .53 .009 with DLPFC PVEC .88 .03 .79 .03 -9.46 4.76 .04 .098 HC .86 .01 .87 .01 1.87 .95 .33 .021 MPFC Temporal .97 .01 .98 .01 .62 .26 .61 .006

cortex Cerebellu .93 .01 .93 .01 -.32 .03 .87 .001

m 1.02 .01 1.02 .01 -.10 .003 .96 .000 WB Abbreviations: CHR, Clinical high risk; DLPFC, dorsolateral prefrontal cortex; DVR, distribution volume ratio; GM, gray matter; HC, hippocampus; HV, healthy volunteer; MPFC, medial prefrontal cortex ; ROI, region of interest; SE, standard error; WB, whole brain.

8 18 Supplementary Table 5: Association between [ F]FEPPA VT and SOPS scores in CHR, adjusted for TSPO genotype (rs6971).

VT Positive Negative Disorganization General Total

ROI r p r p R p r p r p DLPFC .04 .85 -.20 .35 -.01 .97 -.30 .17 -.19 38 HC .16 .46 -.09 .69 .26 .23 .004 .99 .05 .81 MPFC .13 .56 -.10 .64 .11 .62 -.14 .52 -.04 .85 Temporal .12 .58 -.19 .40 .10 .64 -.22 .32 -.11 .61 cortex GM .11 .62 -.19 .40 .10 .69 -.20 .35 -.11 .60 WB .11 .62 -.20 .35 .07 .76 -.20 .35 -.13 .55

VT with PVEC r p r p r p r p r p

DLPFC -.04 .85 -.25 .25 -.05 .81 -.31 .15 -.26 .23 HC .11 .62 -.18 .40 .21 .33 -.05 .81 -.04 .85 MPFC .08 .72 -.18 .41 .05 .82 -.18 .42 -.12 .59 Temporal cortex .08 .72 -.22 .32 .07 .75 -.24 .27 -.16 .48 GM .09 .70 -.17 .44 .08 .72 -.21 .33 -.12 .59 WB -.01 .98 -.13 .56 .01 .95 -.26 .23 -.15 .49 Abbreviations: CHR, clinical high risk; DLPFC, dorsolateral prefrontal cortex; GM, gray matter; HC, hippocampus; MPFC, medial prefrontal cortex; SOPS, scale of psychosis-risk symptoms; WB, whole brain.

9 18 Supplementary Table 6: Association between [ F]FEPPA VT and RBANS scores in CHR, adjusted for TSPO genotype (rs6971).

Immediate Delayed Visuospatial Language Attention Total VT memory memory

r p r p r p r p r p r p DLPFC .23 .18 .01 .95 .11 .55 -.01 .95 .04 .81 .10 .59 HC .19 .27 -.19 .29 .08 .65 -.02 .90 -.05 .79 .02 .91 MPFC .23 .18 .01 .97 .04 .83 -.02 .91 .06 .75 .07 .69 Temporal cortex .23 .19 -.03 .88 .09 .63 -.06 .72 .02 .89 .06 .74 GM .27 .12 .02 .89 .13 .45 -.04 .81 .06 .74 .11 .54 WB .28 .11 .03 .89 .15 .39 -.05 .77 .05 .76 .11 .51 VT with PVEC r p r p r p r p r p r p DLPFC .26 .14 .06 .73 .10 .58 .06 .72 .07 .69 .15 .41 HC .21 .24 -.17 .34 .09 .61 -.008 .97 -.04 .82 .04 .83 MPFC .27 .12 .04 .83 .07 .70 .02 .92 .08 .64 .12 .51 Temporal cortex .24 .17 .002 .99 .09 .61 -.03 .87 .05 .80 .09 .63 GM .23 .18 -.001 .10 .07 .70 -.02 .90 .05 .79 .08 .67 WB .21 .24 .01 .94 .10 .56 .01 .98 .02 .90 .09 .61 Abbreviations: CHR, clinical high risk; DLPFC, dorsolateral prefrontal cortex; GM, gray matter; HC, hippocampus; MPFC, medial prefrontal cortex; WB, whole brain.

10 18 Supplementary Table 7: Association between [ F]FEPPA VT and apathy scale, depression scale, pleasure scale, and global functioning scores in CHR, adjusted for TSPO genotype (rs6971).

VT Apathy scale Depression scale Pleasure Scale Global functioning r p r p r p r p DLPFC .55 .008* .17 .46 .32 .14 .21 .35 HC .52 .013* .28 .21 .32 .15 .04 .85 MPFC .51 .015* .29 .20 .45 .04* .11 .63 Temporal cortex .55 .008* .23 .31 .41 .06 .17 .45 GM .57 .006* .20 .38 .33 .13 .18 .44 WB .59 .004* .20 .37 .32 .15 .22 .33

VT with PVEC r p r p r p r p DLPFC .44 .038* .05 .84 .26 .25 .14 .54 HC .50 .019* .19 .40 .25 .27 .83 .83 MPFC .47 .027* .21 .35 .37 .10 .60 .59 Temporal cortex .51 .016* .16 .48 .37 .09 .54 .54 GM .52 .013* .18 .43 .35 .11 .55 .55 WB .55 .008* .12 .61 .31 .16 .53 .53 * p<0.05

Abbreviations: CHR, clinical high risk; DLPFC, dorsolateral prefrontal cortex; GM, gray matter; HC, hippocampus; MPFC, medial prefrontal cortex; WB, whole brain.

11 18 Supplementary Table 8: Association between [ F]FEPPA VT and state and trait sub-scores of state-trait anxiety inventory (STAI) in CHR, adjusted for TSPO genotype (rs6971).

VT STAI state sub-score** STAI trait sub-score** r p r p DLPFC .60 .003* .05 .82 HC .48 .024* .19 .41 MPFC .57 .006* .12 .61 Temporal cortex .54 .010* .09 .70 GM .52 .013* .07 .76 WB .50 .018* .08 .73

VT with PVEC r p r p DLPFC .57 .006* -.03 .91 HC .48 .025* .16 .49 MPFC .53 .012* .09 .71 Temporal cortex .54 .009* .06 .81 GM .54 .009* .05 .83 WB .62 .002* .04 .86 * p<0.05

**STAI scores were not available for one CHR.

Abbreviations: CHR, clinical high risk; DLPFC, dorsolateral prefrontal cortex; GM, gray matter; HC, hippocampus; MPFC, medial prefrontal cortex; WB, whole brain.

12 18 Supplementary Table 9: Regional [ F]FEPPA VT between CHR and healthy volunteers after removing an outlier from CHR. Factorial ANOVA were performed for each region of interest to examine the diagnostic group effect with genotype added as covariates. %

18 difference was calculated as the difference in [ F]FEPPA VT between the groups (VT CHR

18 – VT healthy volunteers) divided by [ F]FEPPA VT of the healthy volunteers group times 100.

HV (n = 23) CHR (n = 23) Percent Diagnostic Effect Differenc effect size e 2 ROI Adjusted SE Adjuste SE % F (1, 43) P η mean d mean

VT DLPFC 10.98 .63 10.19 .63 -7.19 .78 .38 .018 HC 10.81 .71 8.85 .71 -18.13 3.83 .057 .082 MPFC 10.06 .61 9.56 .61 -4.97 .33 .57 .008 Temporal cortex 11.08 .65 10.22 .65 -7.76 .86 .36 .020 GM 10.42 .59 9.72 .59 -6.71 .68 .41 .016 WB 9.6 .54 8.91 .54 -7.19 .79 .38 .018 Cerebellum 11.2 .65 10.26 .65 -8.4 1.03 .32 .023

PVEC VT DLPFC 13.59 .81 12.67 .81 -6.77 .63 .43 .014

HC 11.45 .75 9.36 .75 -18.89 3.92 .054 .084

MPFC 11.04 .68 10.35 .68 -6.25 .51 .48 .012

Temporal cortex 12.52 .75 11.59 .75 -7.43 .75 .39 .017

GM 12.86 .74 11.84 .74 -7.93 .94 .34 .021

WB 13.2 .76 12.23 .76 -7.34 .76 .39 .017

Cerebellum 12.03 .72 10.91 .72 -9.31 1.21 .28 .027

Abbreviations: CHR, Clinical high risk; DLPFC, dorsolateral prefrontal cortex; GM, gray matter; HC, hippocampus; HV, healthy volunteer;

MPFC, medial prefrontal cortex; ; SE, standard error; VT, Volume of distribution; WB, whole brain.

13 Supplementary figure

18 Supplementary figure 1: Total distribution volume of [ F]FEPPA (VT) in CHR and healthy volunteers (HV) across different ROIs (DLPFC, hippocampus, mPFC, Temporal cortex, total gray matter, and whole brain) after partial volume correction (PVEC).

14 Supplementary Figure 2: Average [18F]FEPPA total distribution volume (VT) overlaid on T1-weighted magnetic resonance imaging (MRI) template.

15 18 Supplementary figure 3: Total distribution volume of [ F]FEPPA (VT) in CHR and healthy volunteers (HV) across different ROIs (DLPFC, hippocampus, mPFC, Temporal cortex, total gray matter, and whole brain) after removing an outlier.

16 Supplementary references

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