Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

Yale University School of Medicine, New Haven, CT 06510, USA.
Neurobiology of aging (Impact Factor: 5.01). 02/2008; 30(9):1490-7. DOI: 10.1016/j.neurobiolaging.2007.12.008
Source: PubMed


Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) availability in eight brain regions of living human subjects using the ligand [(123)I]5-IA-85380 ([(123)I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N=47) ranging in age from 18 to 85 were administered [(123)I]5-IA using a bolus plus constant infusion paradigm and imaged 6-8h later under equilibrium conditions. The effect of age on regional beta(2)-nAChR availability (V(T), regional brain activity/free plasma parent, a measure proportional to the binding potential) was analyzed using linear regression and Pearson's correlation (r). Age and regional beta(2)-nAChR availability were inversely correlated in seven of the eight brain regions analyzed, with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade. These results in living human subjects corroborate postmortem reports of decline in high affinity nicotine binding with age and may aid in elucidating the role of beta(2)-nAChRs in cognitive aging.

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    • "(ρ = 0.56, p < 0.05) but not contralateral putamen (ρ = 0.49, p = 0.07) (Mitsis et al., 2009a "
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    ABSTRACT: We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.
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    • "Considering the decrease of a4b2 - nAChRs during normal and pathologic aging ( Gotti et al . , 2006 ; Mitsis et al . , 2009 ; Picciotto and Zoli , 2002 ) , we can hypothesize that the selective involvement of mPFC a4b2 * - nAChRs by S 38232 would produce cholinergic transients and enhance attentional processes which in turn , would restore WM performance along with preventing the age - related increase of CREB phosphorylation in the PL . Moreover , considerin"
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    ABSTRACT: The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4β2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy.
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    • "Similarly, cross-sectional estimates of aging-related declines in the availability of serotonin receptors in various brain regions also range from 3% to 10% per decade (e.g., Pirker et al., 2000; Yamamoto et al., 2002; see also Eppinger, Hämmerer, & Li, 2011, for review). As for the cholinergic system, which is known to implicate neurodegenerative processes associated with dementia (see Court et al., 2001, for review), results from a recent receptor imaging study also showed that, on average, there is about 5% per decade decline of the nicotinic acetylcholine receptor in eight brain regions, including the frontal cortex and striatum (Mitsis et al., 2009). "
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