123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Phase
Open accessAbstract
UNLABELLED: The study of the effects of sex and hormones on brain chemistry and neurotransmission is of increasing importance as evidence emerges of sex differences in behavioral symptoms and treatment response in neuropsychiatric disorders. The nicotinic acetylcholine receptor (nAChR) system has been implicated in a variety of psychiatric disorders, including tobacco smoking, for which there is strong evidence supporting sex differences in behaviors and response to smoking cessation treatments. We examined the availability of nAChR containing the beta(2) subunit in healthy men and women and the influence of menstrual phase among women. METHODS: Ten men and 19 women nonsmokers underwent one (123)I-5-IA-85380 ((123)I-5-IA) SPECT scan and one MRI scan. A subset of 9 women, aged 18-39 y, underwent a second (123)I-5-IA scan. These 9 women were scanned during the early follicular (days 4-7 in 8 subjects and day 11 in 1 subject) and mid-luteal (days 19-25) phases of their menstrual cycle. Hormone levels were measured in all women to confirm the phase of the cycle. RESULTS: Regional brain activity (kBq/cm(3)) was higher (39%-54%) in women than in men nonsmokers. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (V(T)'), differences of 10%-16% were observed, with women greater than men. In contrast, when regional brain activity was normalized to free plasma parent (V(T)), there was less than a 4% difference by sex in regional brain beta(2)-nAChR availability. These sex differences in kBq/cm(3) and V(T)' resulted from significantly higher levels of total plasma parent, free fraction (f(1)), and free plasma parent in women than in men nonsmokers. No differences in plasma measures or brain beta(2)-nAChR availability were observed across the menstrual cycle for any outcome measure. CONCLUSION: Overall, these findings demonstrate no significant difference in brain beta(2)-nAChR availability between men and women nonsmokers or across the menstrual cycle. Importantly, these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding and highlight the critical need to measure plasma radiotracer levels and f(1) in studies that include both sexes.
AI snapshot
Written from the paper’s full text.
TL;DR
In healthy nonsmokers, brain β2-nicotinic acetylcholine receptor availability did not differ significantly between men and women or across the menstrual cycle. However, women showed higher uncorrected brain radiotracer activity and higher total plasma parent, free fraction, and free plasma parent, highlighting sex differences in radiotracer metabolism and protein binding.
Key findings
- No significant sex difference in β2-nAChR availability when using V_T, which corrects for both radiotracer metabolism and plasma protein binding; V_T differences were less than 4% by sex.
- Uncorrected regional brain activity (kBq/cm³) was 39%–54% higher in women than men, and V_T′ differences were 10%–16%, but these appeared driven by plasma factors rather than receptor availability.
- Women had significantly greater free fraction (f₁; t₂₇ = 2.50, P = 0.02), total plasma parent (t₂₇ = 2.03, P = 0.05), and free plasma parent (t₂₇ = 2.05, P = 0.05) than men.
- No significant differences in plasma measures or brain β2-nAChR availability were observed between early follicular and mid-luteal phases in the 9 women scanned twice.
Methods
- Ten men and 19 women nonsmokers underwent one ¹²³I-5-IA-85380 SPECT scan and one MRI scan; a subset of 9 women underwent a second SPECT scan in early follicular and mid-luteal phases.
- Regional brain activity, V_T′, and V_T were measured in β2-nAChR-containing regions including frontal, parietal, anterior cingulate, temporal, and occipital cortices, thalamus, striatum, and cerebellum.
- For study 1, principal-component analysis reduced correlated regional measures, followed by unpaired t tests; for study 2, paired t tests compared menstrual phases.
Limitations
- Stated: the study could not determine the effect of race on β2-nAChR availability; it examined nonsmokers under age 45, so effects across the lifespan are unknown; and no sex difference in nonsmokers does not preclude a difference in smokers.
- Stated: ¹²³I-5-IA SPECT may be confounded by endogenous acetylcholine occupancy, it is unclear whether cell-surface or internalized receptors are measured, and other nAChR subtypes may underlie behavioral sex differences.
- Evident from the text: there is no appropriate reference region for this radiotracer, so nondisplaceable uptake could not be measured; study 2 was not counterbalanced for scan order, and 4 women had luteal progesterone levels suggesting anovulatory cycles, though results did not differ when they were excluded.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
Regional brain activity (kBq/cm3) was 39%-54% higher in women than in men nonsmokers.
“Regional brain activity (kBq/cm 3 ) was higher (39%-54%) in women than in men nonsmokers.”
- Also stated in: § DISCUSSION · boosted
“the profound sex difference in uncorrected (kBq/cm 3 ) measures of regional brain uptake (39%-54%)”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Findingown data
When regional brain activity was normalized to total plasma parent (VT9), women showed 10%-16% greater values than men.
“When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (V T 9), differences of 10%-16% were observed, with women greater than men.”
- Also stated in: § DISCUSSION · plain
“as compared with the outcome measure that corrected for metabolism only (but not protein binding), V T 9 (10%-16%).”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
When regional brain activity was normalized to free plasma parent (VT), there was less than a 4% difference by sex in regional brain b2-nAChR availability.
“In contrast, when regional brain activity was normalized to free plasma parent (V T ), there was less than a 4% difference by sex in regional brain b 2 -nAChR availability.”
- Also stated in: § Study 1: The Effect of Sex · plain
“The main V T component did not differ significantly between women and men.”
- Also stated in: § DISCUSSION · plain
“there was no difference in b 2 -nAChR availability as evaluated by the outcome measure (V T ) that corrected for both radiotracer metabolism and the f 1 of radiotracer.”
Quote in the paperSubstantial claim - Also stated in: § Study 1: The Effect of Sex · plain
- Findingown data
There were no differences in plasma measures or brain b2-nAChR availability across the menstrual cycle for any outcome measure.
“No differences in plasma measures or brain b 2 -nAChR availability were observed across the menstrual cycle for any outcome measure.”
- Also stated in: § DISCUSSION · plain
“Radiotracer metabolism, plasma protein binding, and brain b 2 -nAChR availability did not differ between the early follicular and mid-luteal phases of the menstrual cycle in women nonsmokers.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
No significant differences in VT were observed in women between the early follicular and mid-luteal phases in any region of interest.
“Similarly, no significant differences in V T were observed”
Quote in the paperSubstantial claim
- Findingnone given
These findings demonstrate sex differences in radiotracer metabolism and plasma protein binding.
“Importantly, these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding and highlight the critical need to measure plasma radiotracer levels and f 1 in studies that include both sexes.”
Quote in the paperSubstantial claim - Findingown data
In correlational analyses, there was no relationship between b2-nAChR availability and plasma estrogen or progesterone levels or in their ratio.
“Additionally, in correlational analyses, we observed no relationship between b 2 -nAChR availability and plasma estrogen or progesterone levels or in their ratio.”
Quote in the paperSubstantial claim - Findingown data
Four subjects did not have luteal-phase progesterone levels greater than 3 ng/mL.
“4 subjects did not have luteal-phase progesterone levels greater than 3 ng/mL”
Quote in the paperNot a substantial claim - Findingown data
There is no sex difference in b2-nAChR availability between nonsmoking men and women, as measured by VT.
“The significant difference in f 1 led us to evaluate the data with the outcome measure V T , which indicated that there is no sex difference in b 2 -nAChR availability between nonsmoking men and women.”
Quote in the paperSubstantial claim - Findingown data
There is no difference in b2-nAChR availability between the early follicular and mid-luteal phases of the menstrual cycle in healthy women nonsmokers.
“This study also found no difference in b 2 -nAChR availability between the early follicular and mid-luteal phases of the menstrual cycle in healthy women nonsmokers.”
- Also stated in: § CONCLUSION · plain
“No significant differences in V T , total parent, f 1 , or free parent were found between early follicular and mid-luteal phases of menstrual cycle.”
Quote in the paperSubstantial claim - Also stated in: § CONCLUSION · plain
- Findingown data
There were no correlations between estrogen or progesterone obtained on scan days and b2-nAChR availability using VT9 or VT.
“there were no correlations between estrogen or progesterone obtained on scan days and b 2 -nAChR availability using the outcome measure V T 9 or V T”
Quote in the paperSubstantial claim - Findingown data
No significant differences in VT9 were observed in women between the early follicular and mid-luteal phases in any region of interest.
“No significant differences in V T 9 were observed in women between the early follicular and mid-luteal phases in any region of interest”
Quote in the paperSubstantial claim - Findingown data
The main kBq/cm3 and VT9 components were significantly greater in women than in men.
“the main kBq/cm 3 and V T 9 components were significantly greater in women than in men”
Quote in the paperSubstantial claim - Findingown data
The main VT component did not differ significantly between women and men.
“The main V T component did not differ significantly between women and men.”
Quote in the paperNot a substantial claim - Findingcitation
In an earlier preliminary analysis of 12 subjects, the authors reported a sex difference in b2-nAChR availability.
“In an earlier preliminary analysis of 12 subjects (6 men and 6 women), we reported a sex difference in b 2 -nAChR availability (33).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33]
Not checked in the free run.
- Findingown data
There was no evidence in the current study that estrogen or progesterone levels were associated with f1.
“There was no evidence in the current study that estrogen or progesterone levels were associated with f 1 .”
Quote in the paperNot a substantial claim - Premisecitation
Women often experience more difficulty in quitting smoking than men.
“Women often experience more difficulty in quitting smoking than men (4)(5)(6)(7)(8)(9),”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4]
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- cites [5]
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- cites [6]
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- Premisecitation
Progesterone and its A-ring metabolites noncompetitively inhibit nAChR.
“Progesterone (13)(14)(15) and its A-ring metabolites (14) noncompetitively inhibit nAChR.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [13]
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- cites [14]
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- cites [15]
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- Interpretationown data
The preclinical finding of higher nAChR numbers in female animals could not be generalized to humans.
“however, this finding could not be generalized to humans.”
Quote in the paperSubstantial claim - Premisecitation
Sex differences exist in a variety of behaviors related to tobacco smoking, such as craving, sensitivity to nicotine, and response to nicotine replacement therapy.
“Sex differences exist in a variety of behaviors related to tobacco smoking, such as craving, sensitivity to nicotine, and response to nicotine replacement therapy (2,3);”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2]
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- cites [3]
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- Premisecitation
A higher f1 is associated with higher radiotracer uptake by the brain.
“A higher f 1 is associated with a higher radiotracer uptake by the brain (29);”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29]
Not checked in the free run.
- Interpretationown data
The sex differences in kBq/cm3 and VT9 resulted from higher total plasma parent, f1, and free plasma parent in women than in men.
“These sex differences in kBq/cm 3 and V T 9 resulted from significantly higher levels of total plasma parent, free fraction (f 1 ), and free plasma parent in women than in men nonsmokers.”
- Also stated in: § DISCUSSION · plain
“the sex difference is due to a higher 123 I-5-IA uptake in women than in men but not to a greater b 2 -nAChR availability.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Premisecitation
Preclinical studies indicated that nicotine-naïve female animals had higher global nAChR numbers than male animals.
“Preclinical studies in nicotine-na ïve rats (11) and mice (12) suggested higher nAChR numbers in female than in male rats.”
- Also stated in: § The Effect of Sex on b 2 -nAChR Availability · hedged
“Preclinical studies indicated that nicotine-na ïve female animals had higher global nAChR numbers than did male animals (30,31);”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11]
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- cites [12]
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- Also stated in: § The Effect of Sex on b 2 -nAChR Availability · hedged
- Interpretationreasoning
There appears to be a relationship between steroid hormones and nAChR numbers.
“Thus, there appears to be a relationship between steroid hormones and nAChR numbers.”
Quote in the paperSubstantial claim - Interpretationown data
If not corrected for in brain outcome measures, sex differences in radiotracer metabolism and protein binding may lead to the appearance of a sex difference in nAChR availability.
“Importantly, if not corrected for in the brain outcome measures, these differences may lead to the appearance of a sex difference in nAChR availability.”
Quote in the paperSubstantial claim - Premisecitation
Women who quit smoking during the luteal phase reported significantly more tobacco withdrawal and depressive symptoms than women who quit during the follicular phase.
“women who quit smoking during the luteal phase of the menstrual cycle reported significantly more tobacco withdrawal and depressive symptoms than did women who quit smoking during the follicular phase”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10]
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- Study design and conductreasoning
Because imaging occurred during the early follicular phase and the mid-luteal phase, we cannot rule out the possibility that estrogen and progesterone have opposing regulatory effects on b2-nAChR availability.
“Alternatively, because we imaged during the early follicular phase, when estrogen and progesterone levels are low, and the mid-luteal phase, when both estrogen and progesterone levels are high, we cannot rule out the possibility that estrogen and progesterone have opposing regulatory effects on b 2 -nAChR availability.”
Quote in the paperSubstantial claim - Study design and conductown data
Results did not differ when the 4 subjects without luteal-phase progesterone >3 ng/mL were eliminated from analyses.
“Results did not differ when these subjects were eliminated from the analyses.”
Quote in the paperSubstantial claim - Study design and conductreasoning
One limitation of having studied women during the early to mid-follicular and midluteal phases of the menstrual cycle is that the relative effects of estradiol and progesterone on b2-nAChR could not be discerned.
“One limitation of having studied women during the early to mid-follicular and midluteal phases of the menstrual cycle is that the relative effects of estradiol and progesterone on b 2 -nAChR could not be discerned.”
Quote in the paperSubstantial claim - Study design and conductreasoning
A limitation of this study was that we could not determine the effect of race on b2-nAChR availability.
“One limitation of this study was that we could not determine the effect of race on b 2 -nAChR availability.”
Quote in the paperNot a substantial claim - Interpretationown data
These results suggest that sex-steroid hormones do not acutely regulate b2-nAChRs.
“These results suggest that sex-steroid hormones do not acutely regulate b 2 -nAChRs.”
Quote in the paperSubstantial claim - Premisenone given
The radioligands used in preclinical studies do not selectively measure the b2 subtype of nAChR.
“the radioligands used, 3 H-cytisine and (6)-exo-2-(2-123 I-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane), an analog of epibatidine, do not selectively measure the b 2 subtype of nAChR.”
Quote in the paperSubstantial claim - Study design and conductcitation
The measure of b2-nAChR availability by 123I-5-IA SPECT may be confounded by occupancy of the receptor by endogenous acetylcholine.
“Although 123 I-5-IA SPECT measures the availability of b 2 -nAChR, this measure may be confounded by occupancy of the receptor by endogenous acetylcholine (46).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46]
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- Study design and conductown data
Because of high correlations between brain regions, the P values in Table 1 cannot be treated as independent.
“Because of the high correlations between brain regions, the P values in Table 1 cannot be treated as independent.”
Quote in the paperSubstantial claim - Study design and conductown data
Hormone levels on scan days confirmed the accuracy of self-reported phase of the cycle.
“Hormone levels obtained on each SPECT scan day during the early follicular (mean estrogen, 38.1 pg/mL; mean progesterone, 0.7 ng/mL) and mid-luteal (mean estrogen, 121.1 pg/mL; mean progesterone, 6.4 ng/mL) phases confirmed the accuracy of the self-reported phase of the cycle.”
Quote in the paperSubstantial claim - Study design and conductreasoning
These findings do not rule out sex differences in receptor internalization or synthesis.
“Also, it is not clear if 123 I-5-IA is measuring only cell-surface receptors or also internalized receptors; thus, these findings do not rule out sex differences in receptor internalization or synthesis.”
Quote in the paperNot a substantial claim - Premisecitation
Differences in nAChR distribution between species have been reported.
“Differences in nAChR distribution between species have been reported (32);”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32]
Not checked in the free run.
- Interpretationcitation
The 4 subjects with luteal-phase progesterone <3 ng/mL likely had an anovulatory cycle.
“suggesting an anovulatory cycle as occurs in as many as 38% of cycles in young women (27) and is consistent with other studies (28).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27]
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- cites [28]
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- May combine two claims. 13
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown dataWomen nonsmokers had significantly higher total plasma parent, free fraction (f1), and free plasma parent than men nonsmokers.
“These sex differences in kBq/cm 3 and V T 9 resulted from significantly higher levels of total plasma parent, free fraction (f 1 ), and free plasma parent in women than in men nonsmokers.”
- Also stated in: § Study 1: The Effect of Sex · plain
“Statistical analyses (t test) also determined that women have significantly greater f 1 (t 27 5 2.50, P 5 0.02), total parent (t 27 5 2.03, P 5 0.05), and plasma free parent (t 27 5 2.05, P 5 0.05) than do men (Fig. 3).”
Quote in the paperSubstantial claim- Also stated in: § Study 1: The Effect of Sex · plain
May combine two claims.
Findingown dataRadiotracer metabolism and plasma protein binding did not change between the early follicular and mid-luteal phases of the menstrual cycle.
“Radiotracer metabolism and plasma protein binding-for example, total parent and f 1 -did not change between the early follicular and mid-luteal phases of the menstrual cycle (Fig. 4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSingle principal components explained 96% of variance in kBq/cm3, 88% in VT9, and 91% in VT across brain regions.
“single components explained 96% of the variance in kBq/cm 3 , 88% of the variance in V T 9, and 91% of the variance in V T across brain regions.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn this study, significant sex differences were found, with higher f1 and total and free parent in women than in men.
“Specifically, in this study, significant sex differences were found, with higher f 1 and total and free parent in women than in men.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWomen have significantly greater f1, total parent, and plasma free parent than men.
“women have significantly greater f 1 (t 27 5 2.50, P 5 0.02), total parent (t 27 5 2.03, P 5 0.05), and plasma free parent (t 27 5 2.05, P 5 0.05) than do men”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe sex difference in VT9 is due to higher 123I-5-IA uptake in women than in men, not to greater b2-nAChR availability.
“thus, because V T 9 does not correct for protein binding, the sex difference is due to a higher 123 I-5-IA uptake in women than in men but not to a greater b 2 -nAChR availability.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation123I-5-IA SPECT has demonstrated significantly higher b2-nAChR availability in recently abstinent tobacco smokers than in age-and sex-matched nonsmokers.
“123 I-5-IA SPECT has demonstrated significantly higher b 2 -nAChR availability in recently abstinent tobacco smokers than in age-and sex-matched nonsmokers (23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationEstradiol potentiates acetylcholine-evoked currents in human neuronal nAChRs by interacting at the a4 subunit.
“estradiol has been shown to potentiate acetylcholine-evoked currents in human neuronal nAChRs by interacting at the a 4 subunit (18).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18]
Not checked in the free run.
May combine two claims.
Interpretationown dataRadiotracer metabolism and plasma protein binding differ between men and women.
“these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding”
- Also stated in: § DISCUSSION · hedged
“suggesting that the radiotracer 123 I-5-IA is metabolized differently between men and women and that the amount of 123 I-5-IA bound to plasma proteins differs between men and women.”
Quote in the paperSubstantial claim- Also stated in: § DISCUSSION · hedged
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHigh test-retest reliability and validity were recently reported for 123I-5-IA SPECT.
“High test-retest reliability and validity were recently reported for 123 I-5-IA SPECT (22),”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22]
Not checked in the free run.
May combine two claims.
PremisecitationVT9 had been shown to be a more reliable and less variable outcome measure than VT.
“V T 9 had been shown to be a more reliable and less variable outcome measure than V T (34).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe second SPECT scan for study 2 subjects was coregistered to the same position as the first scan to apply the same ROI template.
“the second SPECT scan for the subjects in study 2 was coregistered to the same position as the first scan in order to apply the same region-of-interest template for each subject.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe sex difference in f1 and total parent became significant when sample size increased to 29 and was a contributing factor to the observed sex difference in brain b2-nAChR availability.
“when the sample size increased to 29 (19 women and 10 men), the sex difference in f 1 and total parent became significant and a contributing factor to the observed sex difference in brain b 2 -nAChR availability.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll women of childbearing age were required to have a negative pregnancy test during screening and before radiotracer injection on each study day.
“All women of childbearing age were required to have a negative pregnancy test during the screening process and before radiotracer injection on each study day.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe subjects were not counterbalanced for the order of follicular versus mid-luteal scans.
“The subjects were not counterbalanced for the order of follicular versus mid-luteal scans.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenIn the menstrual cycle study, use of hormonal contraceptives within the previous 6 months was exclusionary.
“In the menstrual cycle study, use of hormonal contraceptives within the previous 6 mo was exclusionary.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA 57Co-distributed source was measured with each experiment to control for day-to-day variation in camera sensitivity.
“A 57 Co-distributed source was measured with each experiment to control for day-to-day variation in camera sensitivity.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataAll subjects received a medical examination to exclude major medical issues or neurologic disorders.
“All subjects received a medical examination by a study physician to exclude any major medical issues or neurologic disorders.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe study was approved by the Yale University School of Medicine Human Investigation Committee, the West Haven Veterans Administration Human Subjects Subcommittee, the Radiation Safety Committee, and the Food and Drug Administration.
“This study was approved by the Yale University School of Medicine Human Investigation Committee, the West Haven Veterans Administration Human Subjects Subcommittee, the Radiation Safety Committee, and the Food and Drug Administration.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenNonsmoking status was confirmed by plasma cotinine <15 ng/mL, urine cotinine <100 ng/mL, and carbon monoxide <11 ppm on the day of intake and the day of the scan.
“Nonsmoking status was confirmed by plasma cotinine levels of less than 15 ng/mL, urine cotinine levels of less than 100 ng/mL and carbon monoxide levels of less than 11 ppm on the day of intake and the day of the scan.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenHormone levels were measured in all women to confirm the phase of the cycle.
“Hormone levels were measured in all women to confirm the phase of the cycle.”
- Also stated in: § Subjects · plain
“Hormones were analyzed to confirm the phase of the cycle and the premenopausal status.”
Quote in the paperSubstantial claim- Also stated in: § Subjects · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAnovulatory cycles occur in as many as 38% of cycles in young women.
“as occurs in as many as 38% of cycles in young women (27)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataTwo raters conducted the analysis, with variability between raters less than 12% across regions of interest.
“Two raters conducted the analysis.Variability between the raters was less than 12% across regions of interest.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAnother limitation of this study was that we examined men and women nonsmokers under the age of 45 y.
“Another limitation of this study was that we examined men and women nonsmokers under the age of 45 y.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductcitationThere is no appropriate reference region for 123I-5-IA, so nondisplaceable 123I-5-IA uptake could not be measured.
“As described previously (25), there is no appropriate reference region for this radiotracer, so nondisplaceable 123 I-5-IA uptake could not be measured.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBonferroni correction for multiple comparisons across 8 brain regions indicated that P values less than 0.00625 were highly significant.
“Bonferroni correction for multiple comparisons across 8 brain regions indicated that P values of less than 0.00625 were highly significant.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe small size and blood volume of mice and rats precludes appropriate plasma analysis.
“Unfortunately, the small size and blood volume of mice and rats precludes appropriate plasma analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSubjects were interviewed using the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders to rule out any Axis I disorder.
“The subjects were interviewed using the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders to rule out any Axis I disorder.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenIt is likely that radioligand metabolism or protein binding were different between male and female animals.
“Additionally, it is likely that radioligand metabolism or protein binding were different between male and female animals.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
There is no change in affinity of the radiotracer for b2-nAChRs.
“given the assumptions that there is no change in affinity”
The authors state this as an assumption.
Nondisplaceable (nonspecific and free) uptake does not differ between subjects or between comparison groups.
“and that nondisplaceable (nonspecific and free) uptake does not differ between subjects or between comparison groups.”
The paper relies on this without support.
It is not known whether nicotinic receptor availability differs between living men and women.
“It is not known whether nicotinic receptor availability differs between living men and women.”
The paper relies on this without support.
The mechanisms underlying sex differences in smoking behaviors are unclear.
“however, the mechanisms underlying these differences are unclear.”
The paper relies on this without support.
Few in vivo PET or SPECT neuroreceptor imaging studies have examined sex differences or changes in neurotransmitter levels or receptors across the menstrual cycle in living humans, and there are virtually no data on the effects of menstrual phase on human brain derived from postmortem studies.
“Few in vivo PET or SPECT neuroreceptor imaging studies have examined sex differences or changes in neurotransmitter levels or receptors across the menstrual cycle in living humans, and there are virtually no data on the effects of menstrual phase on human brain derived from postmortem studies.”
The paper relies on this without support.
Studies examining the effect of sex and menstrual phase on the brain are important because many psychiatric disorders are marked by sex differences in signs and symptoms that may be a consequence of sex differences in brain chemistry.
“Studies examining the effect of sex and menstrual phase on the brain are important because many psychiatric disorders are marked by sex differences in signs and symptoms that may be a consequence of sex differences in brain chemistry.”
The paper relies on this without support.
A limitation of many neuroreceptor imaging studies is that f1 often is not measured or reported.
“A limitation of many neuroreceptor imaging studies is that f 1 often is not measured or reported.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The continued significant decrease in β2*-nAChR availability in fully recovered, euthymic, medication-free rMDD subjects suggests that the changes in MDD are not an epiphenomenon of treatment or illness but may be associated with trait vulnerability to depression.
“The continued, significant decrease in β2*-nAChR availability in fully recovered, euthymic, medication free rMDD subjects suggests that the changes in MDD are not an epiphenomenon of treatment or illness but may be associated with trait vulnerability to depression as demonstrated by us previously for other targets (26, 41, 42).”
From Persistent β <sub>2</sub> *-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder (2012) · cites this paper as [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Study 2 age range falls outside the Study 1 cohort
MinorAll nine Study 2 women participated in Study 1, whose women's age range starts at 20 years. The Study 2 range nevertheless starts at 18 years.
“Ten men (mean age 6 SD, 27.7 6 7.3 y; range, 20-41 y; 10 Caucasian) and 19 women (mean age, 26.2 6 6.8 y; range, 20-39 y; 9 Caucasian, 5 Hispanic, 4 African American, and 1 Asian) underwent one 123 I-5-IA scan and one MRI scan.”
“Nine women (mean age, 27.0 6 7.8 y; range, 18-39 y; 4 white, 2 Hispanic, 2 African American, and 1 Asian) who participated in study 1 were recruited to participate in study 2, which involved undergoing a second 123 I-5-IA scan.”
Reported total dose for men exceeds the stated 8-hour dose
MinorThe stated mean bolus plus eight hours of infusion is 323.4 MBq, not 345.1 MBq.
Reported 345.1 · recomputed 323.4
“In study 1, men were injected with a bolus of 150.6 6 23.6 MBq and a continuous infusion of 21.6 6 3.4 MBq/h and women with a bolus of 152.6 6 18.5 MBq and a continuous infusion of 22.1 6 2.9 MBq/h.Thus, the total dose was 345.1 6 54.3 MBq for men and 349.6 6 41.2 MBq for women.”
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- Authors
- Cosgrove, K. P., Mitsis, E. M., Bois, F., Frohlich, E., Tamagnan, G. D., Krantzler, E., Perry, E., Maciejewski, P. K., Epperson, C. N., Allen, S., O'Malley, S., Mazure, C. M., Seibyl, J. P., van Dyck, C. H., & Staley, J. K.
- Affiliations
- Yale University (US)
- United States Department of Veterans Affairs (US)
- University of Minnesota (US)
- Institute for Neurodegenerative Disorders (US)
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2007-10-01
- Volume
- 48
- Issue
- 10
- Pages
- 1633-1640
- ISSN
- 0161-5505 (ISSN-L)
- OpenAlex
- W2078012392
- Semantic Scholar
- b4c1c5e9bc9ec94d59fa976874c3e2ed5b679ffe
- Cited by
- 31
- References
- 49
- Citations by year
- 2025: 1 · 2024: 1 · 2020: 2 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 4
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (P50AA015632, P50-AA15632)
- National Institute of Mental Health (K02MH073090)
- National Institute on Drug Abuse (KO1DA020651, K02DA021863, R01DA015577, KO2DA021863, K01DA020651, R01DA018359)
- National Institute of Neurological Disorders and Stroke (NS-044316, K25NS044316)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nicotinic acetylcholine receptors, beta2 subunit, sex differences, menstrual cycle, non-smokers, SPECT imaging, plasma protein binding, radiotracer metabolism
- MeSH terms
- Adult, Azetidines, Brain, Female, Humans, Male, Menstrual Cycle, Pyridines, Receptors, Nicotinic, Sex Factors, Smoking, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Radiopharmaceuticals
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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