Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: A 2-[18F]fluoro-A-85380 PET study

Ellis, Julia; Villemagne, Victor L.; Nathan, Pradeep J.; Mulligan, Rachel; Gong, Sylvia; Chan, Janet; Sachinidis, John; O’Keefe, Graeme; Pathmaraj, Kunthi; Wesnes, Keith; Savage, Greg; Rowe, Christopher C.

doi:10.1016/j.nlm.2008.05.006

Cited by 52 publications

(36 citation statements)

References 113 publications

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“…Table 1 summarizes the characteristics of each diagnostic group with regard to demographics and cognitive function. HC subjects, subjects with MCI, and subjects with AD did not differ with respect to age (F 2 26) as an estimate of premorbid intelligence. In contrast, in measures of global function and cognitive performance, the 3 groups differed significantly, as shown in Table 1.…”

Section: Statistical Analysesmentioning

confidence: 92%

“…The divergent results among these studies may be related to several factors, including subject differences and outcome measures. Severity level may account for some differences because positive results were obtained in the studies of O'Brien et al (subjects with somewhat more advanced AD; MMSE score, 17.2 6 5.7) (24) and Sabri et al (subjects with moderate to severe AD) (25), whereas negative results were observed in subjects with milder AD in the study of Ellis et al (MMSE score, 22.5 6 2.5) (26) and the present study (MMSE score, 20.4 6 5.9). To be sure, these severity differences were not great and do not explain the discrepant results even in studies of MCI.…”

Section: Comparison With In Vivo Imaging Studiesmentioning

confidence: 98%

“…However, our results bear some similarity to those of Kadir et al in that the significant correlations in the HC group included the Trail Making Test, Part A, the Digit Symbol Test, and the Trail Making Test, Part B (which also has strong attentional demands but is thought to require more executive control and set shifting). In their study with 2-18 F-FA, Ellis et al (26) used an extensive neuropsychologic test battery and found that nAChR binding in the frontal cortex in patients with mild AD correlated significantly with performance on a simple reaction time task. After correcting for multiple comparisons, they observed no significant correlations for the HC group.…”

Section: Neuropsychologic Analysesmentioning

confidence: 99%

“…We also recently reported significant reductions in a 4 b 2 -nAChR in various brain regions across the normal life span (22,23). Several in vivo studies have thus far used A-85380 derivatives to investigate a 4 b 2 -nAChR binding in AD or MCI (24)(25)(26)(27), with mixed results (reviewed in the ''Discussion'' section).…”

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confidence: 99%

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

Mitsis¹,

Reech²,

Tamagnan³

et al. 2009

J Nucl Med

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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.

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Section: Statistical Analysesmentioning

confidence: 92%

Section: Comparison With In Vivo Imaging Studiesmentioning

confidence: 98%

Section: Neuropsychologic Analysesmentioning

confidence: 99%

mentioning

confidence: 99%

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

Mitsis¹,

Reech²,

Tamagnan³

et al. 2009

J Nucl Med

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“…To our knowledge, only a few PET imaging studies using a4b2-nAChR radiotracers have been attempted to study important neuropsychiatric disorders such as schizophrenia (7) and Alzheimer disease (37,38), as well as smoking (5,34,39). 18 F-AZAN provides an essential tool for the expansion of imaging research in these areas.…”

Section: Discussionmentioning

confidence: 99%

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with ¹⁸F-AZAN, a Radioligand with Optimal Brain Kinetics

et al. 2013

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We evaluated (2)-2-(6-[ 18 F]fluoro-2,39-bipyridin-59-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ( 18 F-AZAN), a novel radiotracer that binds to a4b2 nicotinic acetylcholine receptors (a4b2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. Methods: We tested safety tolerability and test-retest reliability (n 5 5) and proposed initial quantification of 18 F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the a4b2-nAChRselective partial agonist varenicline. Results: Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for 18 F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BP ND ) using plasma reference graphical analysis, which showed excellent reproducibility of BP ND (test-retest variability , 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP ND values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n 5 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of 18 F-AZAN brain uptake in smokers and varenicline-treated subjects. Conclusion: 18 F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity a4b2-nAChR in the living human brain.

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Synthesis of 2‐([ ¹⁸ F]Fluoro)‐3‐[(2 S )‐2‐Azetidinylmethoxy]Pyridine ([ ¹⁸ F]2FA)

Ravert

Holt

Dannals

2012

Radiochemical Syntheses

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Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: A 2-[18F]fluoro-A-85380 PET study

Cited by 52 publications

References 113 publications

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

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

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with ¹⁸F-AZAN, a Radioligand with Optimal Brain Kinetics

Synthesis of 2‐([ ¹⁸ F]Fluoro)‐3‐[(2 S )‐2‐Azetidinylmethoxy]Pyridine ([ ¹⁸ F]2FA)

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Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: A 2-[18F]fluoro-A-85380 PET study

Cited by 52 publications

References 113 publications

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

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

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with 18F-AZAN, a Radioligand with Optimal Brain Kinetics

Synthesis of 2‐([ 18 F]Fluoro)‐3‐[(2 S )‐2‐Azetidinylmethoxy]Pyridine ([ 18 F]2FA)

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Product

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

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

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with ¹⁸F-AZAN, a Radioligand with Optimal Brain Kinetics

Synthesis of 2‐([ ¹⁸ F]Fluoro)‐3‐[(2 S )‐2‐Azetidinylmethoxy]Pyridine ([ ¹⁸ F]2FA)