Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

Abstract

Objective Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [11C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. Methods Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [11C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. Results Regional [11C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=−0.56, corrected p = 0.0008) and putamen (r=−0.45, corrected p = 0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. Conclusion In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [11C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

Investigating the effects of norepinephrine α1 receptor blockade on dopamine levels: A pilot PET study with [11C]‐(+)‐PHNO in controls

“…It should be noted that the magnitude of increase found in the present study is consistent with the degree of decrease found in other studies using either [ 11 C]‐(+)‐PHNO (Di Ciano et al, ) or [ 11 C]‐raclopride (Martinez et al, ), suggesting that the changes observed in the present study were biologically relevant. In this regard, the basal level of BP ND observed in the DC, although small, is consistent with previous reports from a number of groups using [ 11 C]‐(+)‐PHNO (Di Ciano et al, ; Erritzoe et al, ; Matuskey et al, ; Matuskey et al, ; Matuskey et al, ; Searle et al, ). Thus, the increases observed in this study are not likely to be the result of an artefact due to low basal levels in the DC.…”

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

“…Specifically, this work demonstrated that OB individuals exhibited higher D 2/3 Rs in both extrastriatal (ie, SN/VTA and pallidum) and striatal (ie, VST) regions associated with reward and motivation with the latter finding being the first published difference in any addiction-like condition with [ 11 C](+)PHNO in the striatum. These results were unaffected by adjustment for potential confounding factors such as age (Ishibashi et al, 2009;Kim et al, 2011;Matuskey et al, 2016;Nakajima et al, 2015;Volkow et al, 2000) or tracer injection parameters, and were confirmed with a whole-brain voxel-wise analysis. Moreover, after adding a cohort of OW individuals, we observed a positive linear association between BMI and D 2/3 R availability in the aforementioned regions that also persisted after adjusting for age, gender, and tracer injection parameters.…”

“…As part of the secondary analyses, 14 otherwise healthy OW (BMI 25-29.9 kg/m 2 ) individuals were added to the analysis to examine the linear association between BMI and D 2/3 R availability in a large, broad-BMI-ranged cohort (see Tables 1 and 2 for means and standard deviations of demographics, injection parameters, and radioactivity data for all individuals studied). All participants with the exception of one D 2/3 R alterations in obesity EC Gaiser et al OW participant were non-nicotine/tobacco users and some have been reported on elsewhere (Matuskey et al, 2015;Matuskey et al, 2016). Once research participants were eligible for the study, they were asked to abstain from all food and liquids (except for water) the night prior to presenting to the Yale PET Center for imaging until the scanning procedures were completed.…”

“…PET data were used to construct a time-activity curve for the cerebellum, a region of minimal D 2/3 R binding, which was used as the reference region as in previous studies (Boileau et al, 2012;Ginovart et al, 2007;Matuskey et al, 2014Matuskey et al, , 2015Matuskey et al, , 2016Mizrahi et al, 2011;Payer et al, 2014;Searle et al, 2010). A summed image (0-10 min after injection) was created from the motion-corrected PET data and registered to the participant's MR image, which was nonlinearly registered to an MR template in Montreal Neurological Institute (MNI) space.…”

Reduced effects of age on dopamine D2 receptor levels in physically active adults

“…Using the high affinity radiotracer [18F]fallypride, we extended these findings, showing that there is also significant loss of presynaptic DRD2 in the midbrain, which may reflect either age-related decline in the number of dopamine neurons (as previously observed in postmortem human brains (Fearnley and Lees, 1991)) and/or the expression of autoreceptors on those neurons. PET studies using the DRD3-preferential tracer [11C]-(+)-PHNO have not observed age-dependent decline in midbrain BP ND (Matuskey et al, 2016; Nakajima et al, 2015), potentially suggesting that the age-related [18F]fallypride BP ND decline at least partially reflects autoreceptor loss with age rather than neuronal loss, which would have presumably been similarly detected by [11C]-(+)-PHNO.…”