Asymmetry in dopamine D_2/3 receptors of caudate nucleus is lost with age

Abstract

Molecular and functional imaging techniques reveal evidence for lateralization of human cerebral function. Based on animal data, we hypothesized that asymmetry in dopamine neurotransmission declines during normal aging. In order to test this hypothesis, we measured dopamine D2/3 receptor availability with [18F]desmethoxyfallypride-PET (DMFP) in putamen and caudate nucleus (NC) of 21 healthy, right-handed males (24–60 years; 35±10). For volumetric analysis, high-resolution T1-weighted MR-images were obtainedin 18 of the PET-subjects in order to assess possible age-related decreases in NC and putamen volume. The calculated DMFP binding potentials (BP) showed a right-ward asymmetry in NC of young subjects that decreased with age (r=0.577, p=0.006; Pearson correlation; two-tailed). An age-independent analysis showed a right-ward asymmetry in NC of the whole subject group (left: 1.49±0.35; right: 1.65±0.43 [mean±S.D.]; p=0.020). No such side lateralization or age-effects could be found in the putamen. Volumes tended to be asymmetric in the putamen (right: 4.85±0.56 cm³; left: 4.64±0.86 cm³ [mean±S.D.]; p=0.063), but not in NC. The decline of putamen volume during aging was significant in the right putamen (r =−0.613; p=0.007; Pearson correlation; two-tailed). There were no other significant correlations between striatal volumes and age or BP. Because ventral striatal dopamine neurotransmission is involved in cognitive processes, this loss of physiological asymmetry in NC dopamine transmission during aging might be involved in age-related declines of cognitive performance.

Introduction

The brain of healthy man is considerably asymmetric in both its gross anatomy (in review: Toga and Thompson (2003)) and its functional metabolism. Several morphological studies show the presence of relatively greater volume in the right frontal lobe and the left occipital lobe (Kertesz et al., 1990, LeMay, 1976, Petty, 1999). Moreover, positron emission tomography (PET) studies using ¹⁸F-fluorodeoxyglucose (FDG) have demonstrated asymmetric energy metabolism in the basal ganglia and some cortical regions (Kawachi et al., 2002, Willis et al., 2002). Evidence for a functional asymmetry of the human motor system is provided by an effect known as spontaneous turning bias; healthy right-handed men have a marked preference for turning towards their right side (Bracha et al., 1987). Interestingly, this lateralization is inversed in most cases of schizophrenia (Bracha, 1987, Lyon and Satz, 1991). Results from Mohr et al. (2005) suggest that these differences in turning behavior might be related to an underlying lateralization of dopamine transmission. Consistently, patients suffering from schizophrenia show aberrant asymmetry of their gross cerebral anatomy (Crow et al., 1989, Petty, 1999, Raz et al., 1987) and in PET studies of dopamine neurotransmission (Hietala et al., 1999).

Illness-related lateralization of brain morphology can be best understood in the context of effects of normal aging on brain structure (Good et al., 2001, Gunning-Dixon et al., 1998, Kovalev et al., 2003), and upon lateralization of activation during cognitive testing, which also declines in the healthy elderly (Cabeza et al., 1997, Grady et al., 2000). These results suggest that age-related changes of morphological asymmetry might be due in part to an evolving organization of cognition during aging. This scenario implies that neurotransmitter systems that are predominantly involved in cognitive performance should also show lateralization and age-related loss of asymmetry. Dopamine is a key neurotransmitter not only in the extrapyramidal motor system, but is also involved in the expression of motivation, emotion and cognition (Middleton and Strick, 2000) and thus presents itself as a major target for such investigations.

Measurements of D_2/3 receptor availability in healthy subjects using PET or single photon emission tomography (SPET) have shown a trend towards relatively higher radioligand binding in the right striatum (in review: Larisch et al., 1998). Interestingly, there is also evidence from animal studies of asymmetry in dopamine receptors that decreases with age (Giardino, 1996). However, no previous work has investigated possible differences in the asymmetry of D_2/3 receptor binding between young and old healthy human subjects. Thus the aim of the present study was to examine if age influences the lateralized distribution of D_2/3 receptors in the human brain.

To test our hypothesis, we obtained PET recordings using ¹⁸F-desmethoxyfallypride (DMFP) as radioligand in a group of healthy subjects. We have previously shown DMFP to be a suitable ligand for quantification of dopamine D_2/3 receptor availability in human extended striatum (Gründer et al., 2003a, Heinz et al., 2004, Vernaleken et al., 2004) by PET. We also obtained high-resolution, T1-weighted magnetic resonance (MR) images from almost all PET subjects for volumetric analysis of the subjects’ caudate nucleus (NC) and putamen. This approach was chosen in order to help distinguish possible age-related changes in dopamine receptor abundance from confounding gray matter changes. The subject group consisted solely of healthy right-handed men, since handedness and gender are known to have major impact on cerebral asymmetry (Shaywitz et al., 1995, Witelson and Kigar, 1992).