¹²³I-5-IA-85380 SPECT Imaging of Nicotinic Receptors in Alzheimer Disease and Mild Cognitive Impairment

Abstract

Postmortem binding studies have established that the concentration of a 4 b 2 -nicotinic acetylcholine receptors (a 4 b 2 -nAChR) is reduced in advanced Alzheimer disease (AD). However, the status of this receptor in mild or prodromal AD has remained the subject of controversy. Methods: We compared a 4 b 2 -nAChR availability in 8 brain regions of living human subjects who had AD and mild cognitive impairment (MCI) with that in age-matched healthy control subjects by using the ligand 123 I-5-IA-85380 ( 123 I-5-IA) and SPECT. All subjects (n 5 32) were nonsmokers; they were administered 123 I-5-IA as a bolus plus a constant infusion and imaged 6-8 h later under equilibrium conditions. The effect of diagnosis on regional a 4 b 2 -nAChR availability (regional brain activity/total parent concentration in plasma, proportional to the binding potential) was analyzed using multivariate analysis of covariance, controlling for the effects of age and sex. Results: Despite a significant overall effect of diagnostic group on mean a 4 b 2 -nAChR availability, univariate analyses revealed no group differences for any brain region analyzed. An exploratory analysis of the relationship between regional a 4 b 2 -nAChR availability and neuropsychologic variables yielded several plausible correlations. However, after Bonferroni adjustment, only the correlation between the anterior cingulate and the Trail Making Test, Part B, in the healthy control subjects remained significant. Conclusion: These results are consistent with several postmortem and in vivo studies suggesting the preservation of nAChRs during the prodromal and early stages of AD. They support the interpretation that nAChR and other cholinergic reductions in AD are late-stage phenomena.

The nicotinic acetylcholine receptor: smoking and alzheimer's disease revisited

“…Another PET study using 123 I-5IA-85380 SPECT showed the in vivo loss of alpha4beta2 (88). A different study using 123 I-5IA-85380 SPECT is consistent with the result that the decrease in nAChR and other cholinergic activities in AD are late-stage occurrences, and that nAChR is preserved in the earlier stages (79). …”

Mild cognitive impairment: pathology and mechanisms

“…In contrast, another (18)FA-85380 PET study reported that MCI (CDR=0.5) and mild-moderate AD patients had significant reductions in cortical and hippocampal α4β2 nAChR binding; interestingly, only those MCI who converted later to AD had deficient binding [80]. In this regard, α4β2 nAChRs were also examined using 123I-5-IA-85380 SPECT confirming reductions of these receptors in temporal lobe [178] or their preservation in the MCI brain [104]. Therefore, it appears that reductions in the predominant brain nAChR subtypes are altered early during disease progression and likely impact cholinergic function.…”

Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (−)-[18F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain

“…PET imaging of the most abundant nicotinic acetylcholine receptor (nAChR) subtype in the brain, ${\alpha }_4{\beta }_2^{\ast }$ nAChRs, is a vital tool to interrogate the acetylcholine system in vivo . Studies using ${\alpha }_4{\beta }_2^{\ast }$-nAChR specific radioligands from the A-85380 family, primarily 2-[ 18 F]FA-85380 PET (Gallezot et al, 2005) and 5-[ 123 I]IA-85380 SPECT (Vaupel et al, 1998), have led to important clinical findings in mood disorders (Saricicek et al, 2012; Hannestad et al, 2013), substance use disorders (Cosgrove et al, 2009; Esterlis et al, 2010; Brody et al, 2006; Brody et al, 2014), Alzheimer's disease (Kendziorra et al, 2011; Ellis et al, 2008; Mitsis et al, 2009), Parkinson's disease (Kas et al, 2009; Fujita et al, 2006), and schizophrenia (D'Souza et al, 2012; Esterlis et al, 2014). …”