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
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.
Available from: Amy Price
- "Astrocytic swelling due to aquaporin-4 (AQP-4) up-regulation was documented in SID and may explain why most known delirium biomarkers are released by astrocytes (Papadopoulos and Verkman, 2013; Sfera et al., 2014; Thrane et al., 2014). It is reasonable to assume that astrocytic swelling (astroedema) along with hypocholinergia (due to silenced CHRNA 7 gene) activate the TLRs, engendering low grade inflammation which is considered a delirium vulnerability marker in elderly (Court et al., 2001; Mitsis et al., 2009). For example, in post-operative delirium activation of TLR-4 (expressed by microglia and astrocytes) was demonstrated (Jalleh et al., 2012; Sofroniew, 2015). "
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ABSTRACT: In elderly population sepsis is one of the leading causes of intensive care unit (ICU) admissions in the United States. Sepsis-induced delirium (SID) is the most frequent cause of delirium in ICU (Martin et al., 2010). Together delirium and SID represent under-recognized public health problems which place an increasing financial burden on the US health care system, currently estimated at 143–152 billion dollars per year (Leslie et al., 2008). The interest in SID was recently reignited as it was demonstrated that, contrary to prior beliefs, cognitive deficits induced by this condition may be irreversible and lead to dementia (Pandharipande et al., 2013; Brummel et al., 2014). Conversely, it is construed that diagnosing SID early or mitigating its full blown manifestations may preempt geriatric cognitive disorders. Biological markers specific for sepsis and SID would facilitate the development of potential therapies, monitor the disease process and at the same time enable elderly individuals to make better informed decisions regarding surgeries which may pose the risk of complications, including sepsis and delirium. This article proposes a battery of peripheral blood markers to be used for diagnostic and prognostic purposes in sepsis and SID. Though each individual marker may not be specific enough, we believe that together as a battery they may achieve the necessary accuracy to answer two important questions: who may be vulnerable to the development of sepsis, and who may develop SID and irreversible cognitive deficits following sepsis?
10/2015; 1(2). DOI:10.3389/fmolb.2015.00059
Available from: Samuel Samnick
- "(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.
Frontiers in Aging Neuroscience 08/2014; 6:213. DOI:10.3389/fnagi.2014.00213 · 4.00 Impact Factor
Available from: Matthias Vandesquille
- "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.
Neurobiology of aging 01/2013; 34(6). DOI:10.1016/j.neurobiolaging.2012.10.006 · 5.01 Impact Factor
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