The present study revealed a method-independent decline with age of the BPND of D2/3 receptors in the putamen, occipital, parietal and temporal cortices, determined with tracer [11C]raclopride in all regions. Unlike previous studies, the application of the same radioligand made direct comparison between cortical and subcortical regions possible. The declines determined here slightly exceeded the declines observed in previous studies of cortical regions. Second-order polynomial analysis further revealed a more complex pattern of decline with peak binding potentials being reached between the ages of 20 and 30 in most cortical regions. Some previous studies indicated non-linear or monoexponential decline, with similar declines at all ages (12, 20, 36). However, as the present study covers a narrower range of subject ages, it may not be directly comparable to previous studies with wider age ranges.
The dopaminergic system is known to be affected during normal aging with changes of cognitive and motor functions that are keys to investigations into the pathophysiology of neurological and psychiatric disorders (11). Here, we used [11C]raclopride with PET to quantify the availability of dopamine D2/3 receptors, both in striatum and cerebral cortices, and we estimated the age-related decline of this measure by means of VOI-based and voxelwise parametric mapping analyses. Previous in vivo studies of the human striatum with the tracer [11C]raclopride showed age-related reduction of the availability of dopamine D2/3 receptors at the average rate of decrement per decade of 7.9% in the striatum as a whole and 6%-8.2% in the putamen (12–14, 37).
The density of D2/3 receptors in extrastriatal regions is significantly lower than in striatum (38). In cortical regions, previous reports of the decline of dopamine receptors presented the binding potentials of the tracer [11C]FLB 457, a ligand with considerably higher affinity to the D2/3 receptors than [11C]raclopride (19–22). In these studies, the binding potentials declined at rates per decade of 9–13% in occipital, parietal, and temporal cortices.
Tracer [11C]raclopride previously was not considered ideal for quantification of D2/3 receptor availability in low-density areas, because of moderate in vivo affinity and a relatively low signal-to-noise ratio, based measures of specific binding relative to nonspecific binding. High-affinity radioligands such as [11C]FLB 457 and [18F]fallypride instead served to visualize and quantify extrastriatal D2/3 receptors, although they suffered from other disadvantages. Tracer [11C]FLB 457 clears from the striatum much more slowly than [11C]raclopride, rendering washout of the ligand from the striatum too slow to safely establish a secular equilibrium of binding when coupled to the rapid decay rate of carbon-11. Thus, the use of [11C]FLB 457 may be optimal only for the imaging of extrastriatal regions (39, 40). Tracer [18F]fallypride has been shown to provide quantitative measures of D2/3 receptor binding to both striatal and extrastriatal regions by prolongation of the imaging session. However, the slow decay of F-18 makes it impossible to complete multiple imaging sessions within the same day, with possible increases of within-subject variability and lower likelihood of detection of subtle changes of BPND. Although [11C]raclopride may be suboptimal in some attempts to measure extrastriatal dopaminergic transmission, there is evidence that declines of BPND of [11C]raclopride can be observed in extrastriatal regions after drug or behavioral challenges (39, 41).
Different rates of change in regions of the cerebral cortex may also depend on differences of affinity of the D2/3 receptors for [11C]raclopride and [11C]FLB 457, but previous studies did not reveal age–related changes of the apparent affinity constant IC50 of the D2 and D3 receptors in the striatum, tested in vivo or postmortem (42–44). Thus the present rates of decline of BPND are more likely to be related to changes of receptor density than to changes of endogenous ligand concentration in these regions.
In the present study, the value of BPND in the temporal cortex significantly exceeded the averages observed in other cortices, in agreement with the distribution of receptor densities demonstrated in a previous study with [11C]FLB 457 (38). The value of BPND of the caudate nucleus was no more than 80% of the value of the putamen (Table 4), in agreement with findings of other studies by investigators who compared estimates of the maximum binding capacity (Bmax) of the caudate nucleus with the value determined in the putamen in vitro (45, 46). A previous in vitro study also indicated no difference of estimates of the apparent KD between the caudate nucleus and the putamen (45). The present study documented proportions of binding in putamen of 5.5-6% of the values in frontal cortex, 5.6–6.7% in the occipital cortex, 5.3–5.7% in the parietal cortex, and 7.1–7.6% in the temporal cortex (Table 4).
Other studies revealed the percentages of receptor density compared to the putamen in the frontal, occipital, parietal, and temporal cortices to be approximately 3%, 2%, 3%, and 5%, respectively, as expressed by the calculated values of the Bmax of the regions measured with [11C]FLB 457, and of the striatum, measured with [11C]raclopride in vivo (38, 47). Similar values of KD in striatum and frontal and temporal cortices have been reported in vitro (45, 48), and in vivo, and the values of KD were not significantly different across cortices in a previous study (38).
As dopamine diffuses freely in the extracellular fluid, a difference of dopamine concentrations of two closely neighboring subdivisions of the striatum is improbable, except for partial volume effects (PVE). The PVE reflects the limited spatial resolution of a PET device with negative effect on the quantitative accuracy of the analysis of PET images. Several methods have been suggested to compensate for this complication (49). Although PVE correction methods may improve the quality and quantitative accuracy of PET images, limitations include prolonged computations that are impractical in clinical settings, increases of the image noise, and incomplete accounting for the spill-over effect.
The issue of whether the binding of [11C]raclopride reflects the true levels of specific binding to D2/3 receptors in the cortical areas has not yet been fully resolved. Stokes et al. (2010) used a tomograph with lower resolution (∼ 5 mm), the whole-body ECAT HR + 962 device (CTI/Siemens Medical Solutions, Knoxville, TN, USA), and reported cortical BPND values of close to 0.2 in right middle frontal and superior temporal gyri, in good agreement with the present study (41).
Alakurtti et al. (2015) used a high resolution tomograph (HRRT; Siemens Medical Solutions, Knoxville, TN, USA) to examine long-term reliability of striatal and extrastriatal dopamine D2/3 receptor binding estimates with [11C]raclopride (39). The authors reported values of BPND of close to 4 in putamen and caudate nucleus, and an order of magnitude lower (i.e., 0.3–0.7) in thalamus, dorsolateral prefrontal, orbitofrontal, and temporal cortices, applying the same SRTM method used in the present study.
Generally, PET is very sensitive to motion during image acquisition, especially in small structures or areas with low signal-to-noise ratio and this greatly biases BPND estimates. In addition to the use of a tomograph with higher spatial resolution, Alakurtti et al. (2015) corrected for head displacement that may otherwise have prevented the determination of higher BPND values compared to the present study (see Table 3). Notably, the subjects had a mean age of 24 years, not too different from the subjects of the current study with a mean age of 27 years. The difference in age is not likely to result in significantly lower BPND estimates, as predicted by the known decline of receptor availability with age. Alakurtti et al. (2015) thus showed that it is possible to improve the reliability of cortical measurements of [11C]raclopride binding with protocol optimization (39).
The parametric mapping (see Appendix) demonstrated significant foci of age-related decline bilaterally in putamen, in the right insula, and in regions of the temporal cortex (superior temporal gyrus, middle temporal gyrus) and regions of the frontal cortex (precentral gyrus). In the present study, we observed significant declines of values in insula and frontal cortex in the VOI analysis, as well by the parametric mapping analysis.
In the putamen of patients with early Parkinson’s disease, D2/3 receptors undergo up-regulation (50), whereas in the prefrontal cortex of individuals with advanced Parkinson’s disease, D2/3 receptors appear to decline (21). The combination of increased receptor density in the caudate nucleus and decreased values of BPND in the cortex has been reported for patients with schizophrenia (51, 52). In patients with Parkinson’s disease and schizophrenia, estimates of BPND with [11C]raclopride may therefore reveal changes of dopamine concentrations in the cerebral cortex, as well as in the striatum. Another interesting aspect to investigate would be the comparison between genders, of whom Fazio et al. (2017) found a negative correlation between BPND and age, and an effect of gender with higher values of BPND in females (53).