A positron emission tomography (PET) investigation of the role of striatal dopamine (D2) receptor availability in spatial cognition
Introduction
Since the initial discovery of the association between nigrostriatal dopamine (DA) loss and motor deficits in patients with Parkinson's disease (Bernheimer and Hornykiewicz, 1965), the involvement of the dopaminergic system in the control of motor and visuo-motor co-ordination has been well documented (Graybiel, 1995, Jueptner et al., 1997a, Jueptner et al., 1997b). DA and the basal ganglia are now considered to have a central integrative role in the control of cognitive as well as motor processes (Frank, 2005) mediated via functionally discrete parallel loops connecting cortical, striatal and thalamic areas (Alexander et al., 1986, Middleton and Strick, 2000). Inefficiencies in the regulation of DA signalling within frontostriatal neurocircuitry are believed to underpin some of the deficits of attention, working memory and mental flexibility which are observed in patients with putative DA disorders and possibly during healthy ageing (Braver et al., 2001, Li et al., 2001, Nieoullon, 2002).
The relative contribution of DA neurotransmission to working memory modulation via the main DA receptor families [D1 and D2; (Kebabian and Calne, 1979)] remains poorly understood in humans (Kimberg and D'Esposito, 2003, Roesch-Ely et al., 2004). However, work in experimental animals has indicated a predominant role for DA (D1) relative to (D2) receptors in the prefrontal cortex (Sawaguchi and Goldman-Rakic, 1991, Williams and Goldman-Rakic, 1995, Wang et al., 2004) and DA (D2) receptors in the striatum (Arnsten et al., 1995, Goldman-Rakic et al., 2004, Mehta et al., 2004). In humans, involvement of striatal DA receptors in the control of motor and cognitive function has been investigated most extensively in patients with neurodegenerative disorders associated with striatal DA dysfunction. For example, in Huntington's disease, several aspects of spatial cognitive performance—spatial span, spatial working memory and the accuracy of spatial planning performance—have been found to be significantly and positively correlated with striatal DA (D2 and to a lesser extent D1) receptor availability (Lawrence et al., 1998, Pavese et al., 2003).
Given the empirically demonstrated role for DA in the modulation of cognitive processes, we wanted to examine the contribution of striatal DA (D2) receptor availability to spatial cognitive performance, within the context of healthy ageing.
Previous research in this area has been limited to two studies, both of which used [11C]-RAC PET to investigate the relationship between age-related reductions in striatal DA (D2) receptor availability and specific aspects of motor and cognitive function. Volkow et al. (1998) reported a positive linear association between [11C]-RAC binding in the striatum and several performance measures in 30 adults, some of which persisted after controlling for age effects. These included motor speed (Finger Tapping test), mental flexibility (Wisconsin Card Sorting Test) and response inhibition (Stroop Colour—Word Test interference score). Backman et al. (2000) reported similar linear associations between [11C]-RAC binding in the striatum and performance on tests of perceptual speed (Dots, Trail Making Test) and episodic (face and word) memory, after controlling for age. These data suggest that sub-clinical variations in striatal DA (D2) receptors may have measurable behavioural consequences. However, these studies did not specifically examine the contribution of DA (D2) receptor measures to the variance in visuo-spatial cognitive performance. This is surprising since visuo-spatial tests such as the Tower of London, which involve ‘self-directed’ goal-orientated behaviour (or planning and working memory) are sensitive indicators of striatal DA depletion (see for example Owen et al., 1995, Lawrence et al., 1998). Furthermore, neither of the above studies included adequate numbers of older (>75 years) adults to allow meaningful interpretation of the relationship between RAC binding and cognitive performance in later life.
In this study, we wanted to test the hypotheses that:
- (i)
Spatial cognitive performance (spatial span; spatial working memory; and spatial planning) would decline linearly with age and striatal [11C]-RAC binding potential (BP) in a healthy older sample.
- (ii)
After controlling for the effects of age, striatal BP measures would significantly and independently contribute to the variance in spatial span and the accuracy of SWM and planning performance.
The ‘Spatial Working Memory and Planning’ battery of the CANTAB (Cambridge Neuropsychological Test Automated Battery) comprises of spatial memory span, spatial working memory (SWM) and the Tower of London (TOL) test of spatial planning. This battery of cognitive tasks was chosen because it is known to be sensitive to ageing (Robbins et al., 1994, Robbins et al., 1998) as well as DA depletion associated with neurological illness (Lawrence et al., 1998, Pavese et al., 2003) and dopaminergic manipulations (Lange et al., 1992, Owen et al., 1995, Mehta et al., 1999, Cools et al., 2002). Since gender impacts upon spatial cognitive performance—men tend to outperform women (Koslov, 1987, Coleman et al., 1997)—and has an uncertain influence on age-related decline of striatal DA (D2) receptors (reviewed by Reeves et al., 2002), we restricted our subject sample to women. Furthermore, as oestrogen may modulate striatal dopaminergic activity (Nordstrom et al., 1998) and has been shown to influence cognitive performance (Keenan et al., 2001), our sample consisted only of older (post-menopausal) women. By restricting our volunteers to older (post-menopausal) females, we hoped to refine our investigation of the relationships between age, DA (D2) receptor measures and test scores.
Section snippets
Method
Thirty healthy female volunteers were recruited from day centres, luncheon clubs and other community-based groups for older people in the local area (South East London). All subjects gave written informed consent, and the study was approved by the Research Ethics Committees for the Hammersmith Hospital and the South London and Maudsley NHS Trust. Permission to administer [11C]-RAC was given by the Administration of Radioactive Substances Advisory Committee (ARSAC). A full medical and
Results
The mean age of the sample was 74 years (SD = 9; range = 58–91 years). 28 (93%) participants were right-handed, and 29 (97%) were non-smokers. As regards previous medical history, 19 (63%) were on antihypertensive medication; 7 (23%) had a history of cardiovascular disease; 2 (7%) had non-insulin dependent diabetes (diet controlled); 4 (13%) were prescribed regular inhalers; and 3 (10%) were prescribed cholesterol-lowering agents. The mean educational level—10 years of full-time education
Discussion
This is the first study to have demonstrated an association between striatal DA (D2) receptor availability measured with [11C]-RAC PET and specific aspects of visuo-spatial performance in healthy adults. Specifically, the accuracy of spatial planning performance on the more difficult problems was positively associated with [11C]-RAC binding across the whole striatum, and SWM within-search errors were positively associated with [11C]-RAC binding in the right caudate nucleus. Restriction of our
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