## Abstract

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with 11C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64–68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of 11C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that 11C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between 11C-raclopride BP and cognitive performance. In accordance with previous findings, we show that 11C-raclopride BP was increased in T-homozygotes. Importantly, 11C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest 11C-raclopride BP–cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and 11C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.

## INTRODUCTION

Reduced dopamine (DA) function is a feature of the normal aging process as well as part of the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, attention-deficit hyperactivity disorder, depression, and parkinsonian diseases (Cools & D'Esposito, 2011; Howes & Kapur, 2009; Dunlop & Nemeroff, 2007; Cools, 2006; Solanto, 2002; Arnsten, 1997; Goldman-Rakic, 1997). These states are all characterized by reduced cognitive performance, hence suggesting a causal link between DA and cognition (Bäckman, Nyberg, Lindenberger, Li, & Farde, 2006) and placing the DA system as a target of investigation in several disciplines.

DA receptor availability can be assessed with PET by estimating the binding potential (BP) for a radioligand. BP is a combined measure of receptor density (Bmax) and apparent affinity of the ligand to the receptor (the inverse of the dissociation constant, KD; Mintun, Raichle, Kilbourn, Wooten, & Welch, 1984).
$BP=Bmax⋅1/KD$
The practice of using BP as the primary outcome measure in PET studies, rather than determining receptor density and ligand apparent affinity separately, relates to the laborious nature of the latter task, as it typically involves a minimum of two PET sessions per individual (Holden, Jivan, Ruth, & Doudet, 2002).

11C-raclopride is a commonly used PET ligand in studies assessing DA D2-receptor (D2DR) availability. It has been used to demonstrate neurochemical alterations of the D2DR system and associations to behavioral correlates in aged individuals and in groups with psychiatric and neurological disorders (Rajji et al., 2017; Nyberg et al., 2016; Sawamoto et al., 2008; Lou et al., 2004; Volkow et al., 1998). It is a reversible-binding ligand sensitive to competition from endogenous DA. Research has demonstrated that 11C-raclopride BP changes from drug-induced manipulation of DA levels, with increased BP values observed after DA depletion and vice versa after DA augmentation (Laruelle, 2000). Variations in BP upon changes in DA levels likely result from changed number of available binding sites (Bmax) but, particularly, changed ligand apparent affinity to D2DRs (KD; Doudet & Holden, 2003; Carson, Channing, Der, Herscovitch, & Eckelman, 2002; Ginovart, Farde, Halldin, & Swahn, 1997, 1999). In interindividual comparisons, negative associations have been found between estimations of DA synthesis with 11C-DOPA and 11C-raclopride BP, where the highest 11C-raclopride BP values were observed in young individuals with the lowest DA levels (Ito et al., 2011). The same pattern was found in patients with Parkinson's disease using 11C-raclopride (Ishibashi, Ishii, Oda, Mizusawa, & Ishiwata, 2010; Kaasinen et al., 2000), but not when using a high-affinity D2DR ligand less sensitive to DA competition (Ishibashi et al., 2010). Hence, the sensitivity of 11C-raclopride BP values to DA tone may obscure interpretations of receptor measures in interindividual comparisons as well.

11C-raclopride BP measurements in healthy human populations have revealed substantial interindividual variability in both younger and older age groups (Nevalainen et al., 2015; Pohjalainen, Rinne, Någren, Lehikoinen, et al., 1998; Farde, Hall, Pauli, & Halldin, 1995), which has been suggested to result from differences in D2DR density (Farde et al., 1995). However, interindividual variability in 11C-raclopride apparent affinity has been demonstrated as well (Kuwabara et al., 2012; Hirvonen, Laakso, et al., 2009; Hietala, Någren, Lehikoinen, Ruotsalainen, & Syvälahti, 1999; Pohjalainen, Rinne, Någren, Syvälahti, & Hietala, 1998). Genetic variation can alter functions of proteins regulating DA metabolism and uptake. One single-nucleotide polymorphism (SNP) located in the D2DR gene, C957T, was associated with allelic group differences in KD values (i.e., apparent affinity) in an 11C-raclopride PET study (Hirvonen, Laakso, et al., 2009). Functional effects from C957T were reported for the T-allele, which included reduced messenger RNA stability and translation and altered DA-induced upregulation of D2DR expression (Duan et al., 2003). Hence, the observed allelic group differences in 11C-raclopride apparent affinity may originate from DA system dissimilarities, such as variations in DA tone, and were large enough to yield differences in BP values between allelic groups despite similar values for receptor density (Hirvonen, Laakso, et al., 2009; Hirvonen et al., 2004).

Given this background, this study tested the hypothesis that 11C-raclopride BP values elevated via increased apparent affinity in C957T T-allele carriers may not represent DA system integrity and therefore not predict cognitive performance. Analyses were carried out in a large cohort of healthy older adults (n = 179; 64–68 years old) from the Cognition, Brain, and Aging (COBRA) study (Nevalainen et al., 2015). The sample was stratified according to the D2DR C957T polymorphism, as previous work has shown 11C-raclopride apparent affinity differences for this SNP in the direction of C/C < C/T < T/T (Hirvonen, Laakso, et al., 2009). Participants underwent 11C-raclopride PET, MRI, and tests of episodic memory, working memory, and perceptual speed. More specifically, we tested whether 11C-raclopride BPND–cognition associations were different in groups with low-to-average (C-carriers) versus high (T-homozygotes) affinity. Because of the previously reported gradual increase in 11C-raclopride apparent affinity, BPND–cognition associations and cognitive performance were further compared among C/C, and C/T, and T/T allelic groups. BP is abbreviated BPND in this work and denotes the ratio of specific binding over nondisplaceable binding in a receptor-free reference area (Innis et al., 2007).

## METHODS

### Sample

This work has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Informed consent was obtained from participants before any testing. A detailed description of the COBRA sample and test battery has been published previously (Nevalainen et al., 2015). The original sample consisted of healthy older individuals (age = 64–68 years, n = 181; 100 men) randomly selected from the population registry of Umeå in northern Sweden. Exclusion criteria were factors that affect brain and cognitive functions, such as cognitive impairment, brain pathology, mental and physical disability, and certain medications (e.g., treatment for diabetes and cancer), and MRI-inhibiting factors (e.g., metal implants). Objective measures included a Mini-Mental State Examination (required: 27/30) and radiological evaluation of MR images.

During the first test session, participants underwent half of the cognitive test battery and an MRI session. Two days later, they performed the second part of the cognitive test battery and a 11C-raclopride PET session. Lifestyle data, a medical anamnesis, and blood samples were also collected.

In the present work, two participants were excluded because of observations of atrophy in the left temporal lobe and lack of genetic data, respectively. The remaining sample of 179 persons was subdivided into allelic variants of C957T (C/C: n = 32; C/T: n = 92; T/T: n = 55). The distribution was in Hardy–Weinberg equilibrium (χ2 < 1, p > .1).

### Genotyping

Deoxyribonucleic acid (DNA) extraction and genotyping services were performed by LGC genomics using their in-house products (Hoddesdon). In brief, DNA was extracted from the buffy-coat fraction of blood samples using the Kleargene XL nucleic-acid extraction kits, and genotyping was performed with KASP genotyping assays. When conducting the genotyping analysis of C957T (rs6277), the DNA template was mixed with a KASP master mix (containing KASP Taq polymerase, deoxynucleoside triphosphates, buffers, salts, and two fluorescently labeled reporter cassettes) and an SNP-specific KASP assay mix (containing two allele-specific forward primers and one common reverse primer). Two allele-specific forward primers that differed at one base in the 3′-end (5′-CAT GGT CTC CAC AGC ACT CC T/C-3′) and one common reverse primer (5′-TCT CRG GTT TGG CGG GGC TGT-3′) were constructed. After polymerase chain reaction sessions, allelic variants were determined via detection of either fluorophore for homozygous alleles or both fluorophores for heterozygous alleles.

### Cognitive Assessment

Each ability (episodic memory, working memory, and perceptual speed) was tested using three separate tasks with verbal, numerical, and figural stimuli, respectively. Episodic memory was assessed with word recall, number–word recall, and object-position recall; working memory was tested with letter-string updating, numerical 3-back, and spatial updating; and perceptual speed was evaluated with letter comparison, number comparison, and figure comparison. For each separate test, scores were summarized across the total number of blocks or trials and standardized to form composites (T score: mean = 50, SD = 10). The three composites were then averaged to create one composite score for episodic memory, working memory, and perceptual speed, respectively. Missing values (<1.2% for all variables) were replaced by the average of the available observed scores.

### Imaging Procedures and Analyses

#### Structural MRI

All MRI scans were performed on a 3-T scanner (Discovery MR 750; General Electric). A 3-D fast spoiled gradient-echo sequence was used to obtain high-resolution anatomical T1-weighted images. Imaging parameters were 176 sagittal slices, with a slice thickness of 1 mm, repetition time = 8.2 msec, echo time = 3.2 msec, flip angle = 12°, and field of view = 25 × 25 cm.

##### Volumetric analyses.

Subcortical brain structures were delineated with the Freesurfer 5.3 software (surfer.nmr.mgh.harvard.edu; Fischl et al., 2002), and cortical parcellation was achieved according to the Desikan–Killiany atlas (Desikan et al., 2006). When necessary, Voxel Edit mode in Freeview was used to correct striatal volumes manually. The number of voxels within delineated structures was used to calculate gray matter volumes.

#### PET

A 55-min, 18-frame (9 × 120 sec + 3 × 180 sec + 3 × 260 sec + 3 × 300 sec) dynamic PET scan (Discovery PET/CT 690; General Electric) was acquired during resting-state conditions after an intravenous bolus injection of 250-MBq 11C-raclopride. A CT scan (20 mA, 120 kV, 0.8 sec/revolution) for attenuation correction purposes preceded ligand injection. Attenuation- and decay-corrected images (47 slices, field of view = 25 cm, transaxial images of 256 × 256 pixels, voxel size = 0.977 × 0.977 × 3.27 mm3) were reconstructed with the iterative algorithm VUE Point HD-SharpIR (General Electric; Bettinardi et al., 2011); six iterations, 24 subsets, 3.0-mm postfiltering), yielding an FWHM of 3.2 mm (Wallstén, Axelsson, Sundström, Riklund, & Larsson, 2013). Head movements were minimized with individually fitted thermoplastic masks attached to the bed surface.

PET image data were converted from DICOM to NIfTI format and corrected for head movements. The T1 images were segmented into gray- and white-matter maps, which were used for creating a sample-specific group template with DARTEL (Ashburner, 2007). The PET and T1 images were coregistered, normalized to Montreal Neurological Institute space with DARTEL-created transformation maps, and smoothed using an 8-mm Gaussian filter. All these steps were performed using the SPM software (SPM8). BPND was calculated using time–activity curves for each voxel with orthogonal regression reference Logan analysis (Logan et al., 1996). Logan regression was based on Frames 10–18 (18–55 min). BP was calculated as BPND = distribution volume ratio − 1. Cerebellar gray matter served as the reference area, because of its negligible D2DR expression (Camps, Cortés, Gueye, Probst, & Palacios, 1989; Farde, Hall, Ehrin, & Sedvall, 1986).

11C-raclopride BPND was also determined in extrastriatal ROIs. For BPND in dorsolateral pFC (DLPFC), a mask from the MRIcron atlas (www.mccauslandcenter.sc.edu/mricro/mricron/index.html) was applied to the normalized brain template describe above. Median BPND was extracted for Brodmann's areas (BAs) 46 and 9 for each individual, for which average BPND was entered into the analyses. In determining 11C-raclopride BPND in subcortical ROIs, individual T1-weighted images and PET emission scans were merged (i.e., operating in native space). ROIs consisting of Freesurfer-delineated structures were applied to calculate BPND as described above, from which the median BPND value was used in ROI-based analyses. BPND measures for striatal ROIs were excluded for six individuals, because of imperfect segmentation of MR images or problems with PET/MR coregistration, or for being statistical outliers according to the outlier labeling rule with 2.2 interquartile ranges (Hoaglin & Iglewicz, 1987).

#### Statistical Analyses

Between-group comparisons were made using one- or two-way ANOVAs, independent sample t tests, or chi-square tests. Descriptive data are presented as frequencies or with mean values and standard deviations. Correlations are reported with the Pearson correlation coefficient (r).

First, we checked whether allelic groups differed in striatal 11C-raclopride BPND. Second, the effect of differences in ligand apparent affinity on 11C-raclopride BPND–cognition correlations was assessed in ROI-based analyses. Correlations were compared between groups with low-to-average (C957T C-carriers, n = 124) versus high (T-homozygotes, n = 55) affinity using Fisher's z transformation (statistical threshold of p < .05, two-tailed). ROIs consisted of hippocampus, caudate, and DLPFC, with the latter represented by BAs 46 and 9 (Rajkowska & Goldman-Rakic, 1995; Brodmann, 1909). The region selection was based on previous work by us and others indicating that these areas and their DA constituents are central for cognitive functions including episodic memory, working memory, and perceptual speed (Nyberg, 2017; Nyberg et al., 2016; D'Esposito & Postle, 2015; Eriksson, Vogel, Lansner, Bergström, & Nyberg, 2015; Takahashi, Yamada, & Suhara, 2012; Bäckman et al., 2000). Additional ROIs consisted of select regions where no associations were expected. Gray matter volumes were controlled for to limit partial volume effects on 11C-raclopride BPND.

Next, whole-brain analyses were performed to assess the regional specificity of the ROI-based analyses. Composite cognitive scores were regressed onto a set of whole-brain BPND maps, generating a statistical brain map of the linear relation. Voxels in which linear associations were found between 11C-raclopride BPND and cognitive performance were identified, noting the p value threshold at which they were found (ranging between p < .01 and p < 1 ⋅ 10−5 uncorrected), cluster size (minimum = 10 voxels), and r. An approach of stepwise logarithmic (10-based) increases in the p value threshold, while continuously noting at which threshold new clusters emerged, was performed to fully characterize the whole-brain pattern of BP–cognition associations (i.e., not used for statistical inference). Findings for the whole sample were contrasted with those for C957T C-carriers and T-homozygotes.

Finally, 11C-raclopride BPND–cognition associations were compared among the three allelic groups to assess how the previously demonstrated gradual increase in apparent affinity (C/C < C/T < T/T; Hirvonen, Laakso, et al., 2009) may affect the associations. To complement the correlational analyses, interaction effects between factors Allelic group (C/C, C/T, T/T) and 11C-raclopride BPND measures (low/high) were tested for cognitive performance (with two-way ANOVAs; statistical threshold of p < .05). Low and high BPND measures were defined as less than or equal to or greater than the median BPND, respectively, for the total sample within an ROI.

## RESULTS

### 11C-raclopride BPND–cognition Associations Are Found Exclusively for C957T C-allele Carriers

Cognitive and BPND data were normally distributed within allelic groups (skewness and kurtosis ranged between −1.0 to 1.2 and −0.96 to 1.46 for C/C, −0.39 to 0.48 and −0.56 to 0.43 for C/T, and −0.74 to 0.61 and −0.47 to 0.42 for T/T).

In agreement with previous findings (Hirvonen, Laakso, et al., 2009), T-homozygotes had higher striatal 11C-raclopride BPND values than C-homozygotes (t(83) = 2.17, p = .03, for caudate; t(83) = 1.77, p = .08, for putamen; Table 1). No between-group differences were found in various lifestyle variables, nor when it comes to performance in the main cognitive tasks assessed in COBRA (episodic memory, working memory, and perceptual speed; Table 1).

Table 1.
Lifestyle, Brain, and Cognitive Descriptives across C957T Allelic Groups
C/CC/TT/T
Number of participants 32 92 55
Men/women 15/17 54/38 29/26
Educational attainment (years) 13.2 ± 4.1 13.1 ± 3.4 13.7 ± 3.2
BMI 25.4 ± 3.4 26.4 ± 3.8 26.1 ± 3.2
Nicotine consumption (%) 21.9 17.4 14.5
11C-raclopride BPND
Putamen 3.30 ± 0.24 3.30 ± 0.29 3.39 ± 0.23
Caudate 2.15 ± 0.22 2.20 ± 0.27 2.27 ± 0.25*
Hippocampus 0.25 ± 0.05 0.27 ± 0.05 0.26 ± 0.04
Amygdala 0.40 ± 0.06 0.40 ± 0.06 0.40 ± 0.05
Globus pallidus 1.35 ± 0.18 1.36 ± 0.20 1.39 ± 0.17
DLPFC 0.15 ± 0.04 0.14 ± 0.04 0.14 ± 0.04
Occipital cortex 0.25 ± 0.05 0.24 ± 0.05 0.25 ± 0.05
Ligand injection
Radioactivity dose (MBq) 264.6 ± 16.2 261.1 ± 18.7 266.7 ± 21.1
Raclopride (nM) 3.3 ± 5.5 2.3 ± 3.3 2.2 ± 1.7
Gray matter volume (cm3
Putamen 4.3 ± 0.3 4.5 ± 0.6 4.4 ± 0.6
Caudate 3.6 ± 0.4 3.7 ± 0.6 3.6 ± 0.5
Hippocampus 3.8 ± 0.5 3.9 ± 0.4 3.9 ± 0.5
Amygdala 1.4 ± 0.1 1.4 ± 0.2 1.4 ± 0.2
Globus pallidus 1.4 ± 0.2 1.5 ± 0.2 1.5 ± 0.2
Cortical 436.5 ± 39.7 454.9 ± 53.0 447.9 ± 44.4
White matter volume (cm3579.2 ± 61.0 615.3 ± 72.8 600.6 ± 73.6
Episodic memory 51.3 ± 9.0 49.9 ± 8.2 49.7 ± 6.6
Working memory 51.7 ± 7.6 50.3 ± 7.3 48.8 ± 7.6
Perceptual speed 51.1 ± 8.1 49.6 ± 8.5 49.9 ± 9.3
C/CC/TT/T
Number of participants 32 92 55
Men/women 15/17 54/38 29/26
Educational attainment (years) 13.2 ± 4.1 13.1 ± 3.4 13.7 ± 3.2
BMI 25.4 ± 3.4 26.4 ± 3.8 26.1 ± 3.2
Nicotine consumption (%) 21.9 17.4 14.5
11C-raclopride BPND
Putamen 3.30 ± 0.24 3.30 ± 0.29 3.39 ± 0.23
Caudate 2.15 ± 0.22 2.20 ± 0.27 2.27 ± 0.25*
Hippocampus 0.25 ± 0.05 0.27 ± 0.05 0.26 ± 0.04
Amygdala 0.40 ± 0.06 0.40 ± 0.06 0.40 ± 0.05
Globus pallidus 1.35 ± 0.18 1.36 ± 0.20 1.39 ± 0.17
DLPFC 0.15 ± 0.04 0.14 ± 0.04 0.14 ± 0.04
Occipital cortex 0.25 ± 0.05 0.24 ± 0.05 0.25 ± 0.05
Ligand injection
Radioactivity dose (MBq) 264.6 ± 16.2 261.1 ± 18.7 266.7 ± 21.1
Raclopride (nM) 3.3 ± 5.5 2.3 ± 3.3 2.2 ± 1.7
Gray matter volume (cm3
Putamen 4.3 ± 0.3 4.5 ± 0.6 4.4 ± 0.6
Caudate 3.6 ± 0.4 3.7 ± 0.6 3.6 ± 0.5
Hippocampus 3.8 ± 0.5 3.9 ± 0.4 3.9 ± 0.5
Amygdala 1.4 ± 0.1 1.4 ± 0.2 1.4 ± 0.2
Globus pallidus 1.4 ± 0.2 1.5 ± 0.2 1.5 ± 0.2
Cortical 436.5 ± 39.7 454.9 ± 53.0 447.9 ± 44.4
White matter volume (cm3579.2 ± 61.0 615.3 ± 72.8 600.6 ± 73.6
Episodic memory 51.3 ± 9.0 49.9 ± 8.2 49.7 ± 6.6
Working memory 51.7 ± 7.6 50.3 ± 7.3 48.8 ± 7.6
Perceptual speed 51.1 ± 8.1 49.6 ± 8.5 49.9 ± 9.3

BMI = body mass index. *p < .05 for differences between C- and T-homozygotes.

ROI-based analyses demonstrated significant associations between episodic memory and 11C-raclopride BPND in hippocampus, caudate, and DLPFC in C-carriers, but not in T-homozygotes (Table 2). The correlations in C-carriers were statistically different from those in T-homozygotes for BPND in hippocampus (z = 2.52, p < .05) and DLPFC (z = 2.72, p < .01) but did not reach significance for caudate (z = 0.19, p > .05). No links were found for any of the other regions tested, regardless of genotype, and there were no associations in corresponding analyses of working memory and speed.

Table 2.
11C-raclopride BPND–Cognition Associations in C-carriers (n = 124), T-homozygotes (n = 55), and the Whole Sample (n = 179)
Episodic MemoryWorking MemoryPerceptual Speed
Hippocampus
C-carriers .27**# .07 .01
T/T −.14 .13 .01
Whole sample .19* .09 .01
Caudate
C-carriers .20* −.11 −.07
T/T .17 .07 −.08
Whole sample .19* −.07 −.07
DLPFC
C-carriers .30***## −.03 −.08
T/T −.14 −.16 .21
Whole sample .18* −.07 .01
Putamen
C-carriers .15 −.06 −.01
T/T −.04 −.07 −.15
Whole sample .10 −.07 −.04
Occipital cortex
C-carriers .06 .04 −.12
T/T −.19 −.02 .06
Whole sample −.01 .02 −.06
Amygdala
C-carriers .14 −.01 .10
T/T −.01 .23 −.03
Whole sample .10 .06 .06
Globus pallidus
C-carriers .10 −.18 −.09
T/T −.09 −.04 .19
Whole sample .06 −.14 .01
Episodic MemoryWorking MemoryPerceptual Speed
Hippocampus
C-carriers .27**# .07 .01
T/T −.14 .13 .01
Whole sample .19* .09 .01
Caudate
C-carriers .20* −.11 −.07
T/T .17 .07 −.08
Whole sample .19* −.07 −.07
DLPFC
C-carriers .30***## −.03 −.08
T/T −.14 −.16 .21
Whole sample .18* −.07 .01
Putamen
C-carriers .15 −.06 −.01
T/T −.04 −.07 −.15
Whole sample .10 −.07 −.04
Occipital cortex
C-carriers .06 .04 −.12
T/T −.19 −.02 .06
Whole sample −.01 .02 −.06
Amygdala
C-carriers .14 −.01 .10
T/T −.01 .23 −.03
Whole sample .10 .06 .06
Globus pallidus
C-carriers .10 −.18 −.09
T/T −.09 −.04 .19
Whole sample .06 −.14 .01

Values in bold indicate significant correlations at *p < .05, **p < .01, or ***p < .001. Comparisons of correlations were carried out between C-carries and T-homozygotes (#p < .05 and ##p < .01).

The regional specificity of the ROI-based findings was supported by the whole-brain analysis, which yielded stronger relationships between episodic memory and 11C-raclopride BPND in clusters located in hippocampus, pFC, and striatum in C-carriers compared with the whole sample (Table 3 and Figure 1A and B). In C-carriers, 11C-raclopride BPND–episodic memory associations were observed in a hippocampal cluster already at p < .00001. Relaxing the threshold to p < .0001, the hippocampal cluster increased considerably in size without losing strength of the overall correlation, and prefrontal and striatal clusters emerged as well. As in the ROI-based analyses, no associations were found between 11C-raclopride BPND and episodic memory in T-homozygotes, even at a very liberal threshold (p < .01; Figure 1C). Again, no associations or group differences in associations were found with measures of working memory or perceptual speed.

Table 3.
Results from Whole-brain Analysis of 11C-raclopride BPND–Episodic Memory Associations in the Whole Sample (n = 179) and C957T C-carriers (n = 124)
Threshold (p)RegionPeak (x, y, z)Cluster Sizer
Whole sample
<.001 Hippocampus −18, −10, −18 23 .28
pFC −42, 12, 36 147 .32

<.01 Putamen −28, 8, 4 273 .22
Putamen/caudate 18, 16, 4 13 .20

C-carriers
<.00001 Hippocampus −18, −12, −18 51 .42

<.0001 Hippocampus −18, −12, −18 352 .42
pFC −42, 10, 36 26 .37
Putamen −28, 8, 4 134 .30
Putamen/caudate 20, 16, 4 21 .26
Threshold (p)RegionPeak (x, y, z)Cluster Sizer
Whole sample
<.001 Hippocampus −18, −10, −18 23 .28
pFC −42, 12, 36 147 .32

<.01 Putamen −28, 8, 4 273 .22
Putamen/caudate 18, 16, 4 13 .20

C-carriers
<.00001 Hippocampus −18, −12, −18 51 .42

<.0001 Hippocampus −18, −12, −18 352 .42
pFC −42, 10, 36 26 .37
Putamen −28, 8, 4 134 .30
Putamen/caudate 20, 16, 4 21 .26
Figure 1.

Whole-brain analyses of 11C-raclopride BPND–episodic memory associations in the whole sample (A), C957T C-carriers (B), and T-homozygotes (C). 11C-raclopride BPND–episodic memory associations are shown for hippocampal and striatal clusters. Stronger relationships emerged when removing T-homozygotes from the analysis, and no associations were found for T-homozygotes.

Figure 1.

Whole-brain analyses of 11C-raclopride BPND–episodic memory associations in the whole sample (A), C957T C-carriers (B), and T-homozygotes (C). 11C-raclopride BPND–episodic memory associations are shown for hippocampal and striatal clusters. Stronger relationships emerged when removing T-homozygotes from the analysis, and no associations were found for T-homozygotes.

### The Highest BPND–cognition Associations Are Seen for C957T C-homozygotes

To assess whether correlations become gradually stronger when apparent affinity varies from low to high (C/C < C/T < T/T; Hirvonen, Laakso, et al., 2009), BPND–cognition associations were compared among the three allelic groups. The strongest 11C-raclopride BPND–cognition associations were found for C-homozygotes and, in particular, when considering episodic memory and BPND in hippocampus, caudate, and DLPFC (Table 4 and Figure 2). Notably, hippocampal 11C-raclopride BPND in C-homozygotes was positively associated with performance in all three cognitive domains. Hippocampal 11C-raclopride BPND–episodic memory correlations differed significantly between C- and T-homozygotes (z = 2.49, p < .05) and between heterozygotes and T-homozygotes (z = 2.21, p < .05). Similarly, correlations to perceptual speed differed between C- and T-homozygotes (z = 2.88, p < .01) and between C-homozygotes and heterozygotes (z = 3.64, p < .001). A trend was also found when comparing C-homozygotes and heterozygotes for measures of working memory (z = 1.92, p = .05). Moreover, correlations between 11C-raclopride BPND in DLPFC and episodic memory differed significantly between C- and T-homozygotes (z = 3.40, p < .001) and between C/C and C/T groups (z = 2.23, p < .05). Although the association concerning caudate BPND appeared stronger in C-homozygotes, it was not statistically different from those in the C/T and T-homozygote groups (z = 1.06 and z = 0.94, respectively; ps > .05).

Table 4.
11C-raclopride BPND–Cognition Associations in C/C (n = 32), C/T (n = 92), and T/T (n = 55) Allelic Groups
Episodic MemoryWorking MemoryPerceptual Speed
Hippocampus
C/C .41*# .38* .59***##§§§
C/T .24*# −.01 −.10
T/T −.14 .13 .01
Caudate
C/C .37* .12 .24
C/T .16 −.17 −.13
T/T .17 .07 −.08
DLPFC
C/C .57***###§ −.06 −.03
C/T .17 −.02 −.11
T/T −.14 −.16 .21
Putamen
C/C .16 .10 .07
C/T .13 −.12 −.03
T/T −.04 −.07 −.15
Occipital cortex
C/C −.12 −.10 .06
C/T .11 .08 −.19
T/T −.19 −.02 .06
Amygdala
C/C .28 .10 .29
C/T .07 −.04 .05
T/T −.01 .23 −.03
Globus pallidus
C/C .07 −.07 .23
C/T .11 −.21 −.19
T/T −.09 −.04 .19
Episodic MemoryWorking MemoryPerceptual Speed
Hippocampus
C/C .41*# .38* .59***##§§§
C/T .24*# −.01 −.10
T/T −.14 .13 .01
Caudate
C/C .37* .12 .24
C/T .16 −.17 −.13
T/T .17 .07 −.08
DLPFC
C/C .57***###§ −.06 −.03
C/T .17 −.02 −.11
T/T −.14 −.16 .21
Putamen
C/C .16 .10 .07
C/T .13 −.12 −.03
T/T −.04 −.07 −.15
Occipital cortex
C/C −.12 −.10 .06
C/T .11 .08 −.19
T/T −.19 −.02 .06
Amygdala
C/C .28 .10 .29
C/T .07 −.04 .05
T/T −.01 .23 −.03
Globus pallidus
C/C .07 −.07 .23
C/T .11 −.21 −.19
T/T −.09 −.04 .19

Values in bold indicate significant correlations at *p < .05 and ***p < .001. Comparisons of correlations were carried out between C/C–T/T and C/T–T/T groups (#p < .05, ##p < .01, ###p > .001) and between C/C and C/T groups (§p < .05, §§§p < .001).

Figure 2.

Associations of 11C-raclopride BPND in hippocampus (A), caudate (B), and DLPFC (C) and episodic memory in C957T C/C (n = 32), C/T (n = 92), and T/T (n = 55) allelic groups.

Figure 2.

Associations of 11C-raclopride BPND in hippocampus (A), caudate (B), and DLPFC (C) and episodic memory in C957T C/C (n = 32), C/T (n = 92), and T/T (n = 55) allelic groups.

Furthermore, intraindividual differences were present when comparing striatal–extrastriatal 11C-raclopride BPND correlations among allelic groups. Specifically, caudate and hippocampal BPND values were most highly correlated in C-homozygotes (r = .55, p < .01), followed by C/T (r = .37, p < .001) and T-homozygotes (r = .22, p > .1).

### Highest Cognitive Performance in C957T C-homozygotes with High 11C-raclopride BPND

Two-way ANOVAs demonstrated that 11C-raclopride BPND predicts cognitive performance as a function of C957T genotype. Interaction effects from Allelic Group × Hippocampal 11C-raclopride BPND measures were found for episodic memory, F(2, 173) = 4.13, p = .02, and, at trend level, for working memory, F(2, 173) = 2.34, p = .10 (Figure 3A and B). A similar trend was found for episodic memory performance for Genotype × 11C-raclopride BPND measures in DLPFC, F(2, 170) = 2.62, p = .08 (Figure 3C), but not for those in the caudate (p > .10; data not shown).

Figure 3.

Interactions between C957T allelic group and 11C-raclopride BPND status for cognitive performance. C-homozygotes with high hippocampal BPND exhibited the best episodic memory (A) and working memory (B) performance. Similarly, C-homozygotes with high BPND in DLPFC had the highest episodic memory performance (C). *p < .05.

Figure 3.

Interactions between C957T allelic group and 11C-raclopride BPND status for cognitive performance. C-homozygotes with high hippocampal BPND exhibited the best episodic memory (A) and working memory (B) performance. Similarly, C-homozygotes with high BPND in DLPFC had the highest episodic memory performance (C). *p < .05.

In line with the correlational findings, performance differences were only found between individuals with high versus low 11C-raclopride BPND in C-carriers (hippocampus: t(24) = 2.93, p = .01 in C/C, and t(90) = 2.25, p = .03 in C/T for episodic memory; t(30) = 1.9, p = .07 for C/C for working memory; DLPFC: t(29) = 2.09, p = .05 in C/C), but not in T-homozygotes.

When comparing the Allelic Groups × 11C-raclopride BPND groups, cognitive performance tended to peak in C-homozygotes with high 11C-raclopride BPND measures and most evidently so for episodic memory performance when considering hippocampal BPND, F(5, 173) = 3.20, p = .02 (in C/C vs. C/T).

## DISCUSSION

The frequent use of receptor availability, or BP, as the outcome measure in PET studies relates to its many advantages. It requires only one PET session per participant, is easily and reliably calculated, and has higher test–retest reliability than Bmax and KD assessed separately (Hietala et al., 1999; Logan et al., 1990, 1996). If the apparent affinity term for a radioligand can be assumed to be constant in interindividual comparisons, then the BP value likely reflects individual differences in DA system integrity via receptor density. However, when apparent affinity of a radioligand varies because of biological differences, BP values may not have the same meaning between individuals. In agreement with this hypothesis, we demonstrated increased striatal 11C-raclopride BPND values and absent BPND–cognition associations for individuals with a genetic predisposition for high 11C-raclopride apparent affinity (T-homozygotes of C957T; Hirvonen, Laakso, et al., 2009). Critically, 11C-raclopride BPND–cognition correlations were only found in individuals with low-to-average affinity (C-carriers of the SNP C957T) and were strongest in the low-affinity group.

The present work demonstrated stronger 11C-raclopride BPND–cognition associations when excluding a group in which ligand apparent affinity has been shown to be elevated (C957T T-homozygotes, ≈30% of the total sample). Hence, individual differences in ligand apparent affinity may overshadow differences in BP between experimental groups. In C-carriers of C957T, 11C˗raclopride BPND–episodic memory associations were found for hippocampus, pFC, and striatum. These areas, and their D2DRs, are important for episodic memory performance (Nyberg et al., 2016; Takahashi et al., 2012; Liggins, 2009; Bäckman et al., 2000; Tulving & Markowitsch, 1998). The lack of DLPFC 11C˗raclopride BPND–working memory association may be due to a more crucial role of cortical D1DRs in working memory (Arnsten, Wang, & Paspalas, 2012; Takahashi et al., 2012). Although D2DR density is low in cortical areas, acceptable reliability has been shown for extrastriatal BPND measurements with 11C-raclopride (Alakurtti et al., 2015). Importantly, no differences were observed between allelic groups for ligand concentration injected or radioactivity dose. Future directions may involve using a high-affinity D2DR ligand, such as 18F-Fallypride, to further assess effects of C957T on extrastriatal D2DR BPND.

The highest 11C-raclopride BPND–episodic memory correlations were observed in C-homozygotes. The same group also exhibited hippocampal BPND associations with working memory and perceptual speed, supporting hippocampal D2DRs as key players for a broad range of cognitive functions (Rocchetti et al., 2015; Liggins, 2009; Takahashi et al., 2007, 2008). The relatively low affinity observed for this group may reflect high extracellular DA levels, as 11C-raclopride is sensitive to competition by endogenous DA (Laruelle, 2000). Consequently, the 11C-raclopride BPND values in C-homozygotes may mirror DA system integrity and D2DR status accurately, thereby rendering stronger BPND–cognition associations. The opposite scenario would serve as an example of the lack of BPND–cognition associations in T-homozygotes, that is, reduced DA levels giving rise to elevated 11C-raclopride affinity and resulting BPND values that are not representative of DA system status and do not relate to cognitive performance. No between-group differences were found when inspecting the Logan plots. Furthermore, BP values obtained from Logan analysis versus simplified reference tissue model were coherent and similar for all three groups (rs > .84 for putamen, caudate, and hippocampus; data not shown but available upon request from the first author). We therefore find it unlikely that the group differences arise from data modeling issues. Moreover, caudate–hippocampal BPND correlations were highest in C-homozygotes, hence individual differences in striatal BP may be reflected to a greater degree in extrastriatal areas in this subgroup. Striatal–hippocampal DA receptor coherence is indeed important for cognitive performance (Nyberg et al., 2016) and declines in aging (Rieckmann et al., 2011).

For definite quantification of the constituents of a BP value, receptor density and apparent affinity should be assessed separately. The resource-demanding nature of this task, requiring typically at least two PET sessions per participant, precludes such an approach for large-scale studies. Instead, we used a proxy to estimate apparent affinity, which relates to previous findings for the C957T SNP (Hirvonen, Laakso, et al., 2009). C957T is located in Exon 7 of the D2DR gene and has been shown to regulate D2DR availability (Smith et al., 2017; Hirvonen, Laakso, et al., 2009; Hirvonen, Lumme, et al., 2009; Duan et al., 2003; Grandy et al., 1989). Central to our work, this SNP has been associated with differences in 11C˗raclopride apparent affinity. Notably, the between-group differences in striatal BP values reported by Hirvonen and colleagues (Hirvonen, Laakso, et al., 2009) were found in our sample as well. Recently, this finding was replicated when using another D2DR ligand, 18F-fallypride (Smith et al., 2017); thus, increased striatal BP values in T-homozygotes are consistent between studies.

Differences in 11C-raclopride apparent affinity to D2DRs between C957T allelic groups may result from altered characteristics of D2DRs or, as previously suggested (Hirvonen, Laakso, et al., 2009), variations in extracellular DA levels. Although C957T is a silent mutation, it has functional implications for D2DR function. The T allele was associated with reduced D2DR protein-synthesis levels, significantly faster messenger RNA decay, and reduced DA-induced upregulation of D2DRs (Duan et al., 2003). Thus, the T allele gives rise to a less stable D2DR transcript and altered D2DR responses to DA levels. Given the role of D2DRs in presynaptic control of DA synthesis and reuptake, effects on DA levels are to be expected if this regulatory system is different in T-carriers. Further insight into how individual differences in extrastriatal DA levels affect the 11C˗raclopride BPND–cognition association may be achieved by considering other DA gene polymorphisms previously linked to differences in extracellular DA levels and behavior, such as the 40-basepair variable number tandem repeat polymorphism located in the DA transporter gene (rs2836317; Brewer et al., 2015; Li et al., 2013; Vandenbergh et al., 1992).

Evidence for C957T as a functional DA polymorphism is also found at behavioral levels. C957T has been associated with reward-related behaviors such as overconsumption of alcohol, nicotine, and food (Davis et al., 2012; Swagell et al., 2012; Voisey et al., 2012) and with an increased risk for developing schizophrenia (Monakhov, Golimbet, Abramova, Kaleda, & Karpov, 2008; Lawford et al., 2005). Moreover, T- but not C-homozygotes improved cognitive performance after supplementation of the DA precursor tyrosine (Colzato et al., 2016). Tyrosine conversion is inhibited by feedback mechanisms when DA levels are sufficient (Daubner, Le, & Wang, 2011; Weiner, Lee, Barnes, & Dreyer, 1977), suggesting that reduced DA levels in T-homozygotes underlie the group-specific performance improvements. The present work showed that C-homozygotes with high 11C-raclopride BPND values had the highest cognitive performance, which is consistent with past research (Papenberg et al., 2014; Colzato, van den Wildenberg, & Hommel, 2013; Li et al., 2013). The lower mean ages of samples in previous studies indicate that the C957T-mediated allelic group differences in the DA system are present already at younger ages (Colzato et al., 2016; Hirvonen, Laakso, et al., 2009). Consequently, the results presented here may generalize across differences in sample age. However, as DA and cognitive decline occur throughout senescence (Bäckman et al., 2006) and the influence of genetics is magnified at older ages (Lindenberger et al., 2008), we cannot exclude that the effects from C957T reported here are exacerbated by aging, as previously suggested (Papenberg et al., 2014; Li et al., 2013).

The current findings emphasize the importance to consider how interindividual differences in genetic background may affect results derived from 11C-raclopride assessments. Misleading interpretations of BP values may be detrimental to our understanding of the fate of the DA system and DA–behavior relations in healthy aging and in a variety of psychiatric and neurological disorders. This conclusion resonates well with the general plea to move toward a personalized and mechanistic account of psychopathology (Stephan et al., 2016; Insel & Cuthbert, 2015).

## Acknowledgments

This work was funded by the Swedish Research Council, Umeå University, the Umeå University–Karolinska Institute Strategic Neuroscience Program, the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, an Alexander von Humboldt Research award, a donation from the Jochnick Foundation, the Swedish Brain Power, the Swedish Brain Foundation, the Västerbotten County Council, the Innovation Fund of the Max Planck Society, and the Gottfried Wilhelm Leibniz Research Award 2010 of the German Research Foundation.

The Freesurfer analyses were performed on resources provided by the Swedish National Infrastructure for Computing at HPC2N in Umeå.

Reprint requests should be sent to Nina Karalija, Diagnostic Radiology, Department of Radiation Sciences, Umeå University, SE 901 87 Umeå, Sweden, or via e-mail: nina.karalija@umu.se.

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