Effects of Age and BMI on Histamine H3 Receptor Availability in Healthy Humans

Effects of Age and BMI on Histamine H3 Receptor Availability in Healthy Humans | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Age and BMI on Histamine H3 Receptor Availability in Healthy Humans Yanghong Yang, Waleed Ibrahim, Paul Gravel, Brian Pittman, Jocelyn Hoye, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4004389/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Sep, 2025 Read the published version in Molecular Imaging and Biology → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose To assess alterations in H3R availability with age and body mass index (BMI) in healthy humans using in vivo [ 11 C]GSK189254 positron emission tomography (PET) imaging. Procedure: Twenty-four healthy individuals (2 females, 22 males; age range 20–47 years) were scanned with [ 11 C] GSK189254. Regional V T (volume of distribution) values were computed using the two-tissue compartment model. Correlations were adjusted for BMI, scanner, and injection tracer dosage. Results V T displayed a negative correlation between receptor availability and age in the anterior cingulate cortex (r= -0.61, p = 0.004), frontal cortex (r= -0.50, p = 0.020), olfactory cortex (r= -0.50, p = 0.022), parietal cortex (r= -0.58, p = 0.006), cerebellum cortex (r= -0.53, p = 0.013), insula (r= -0.48, p = 0.027), putamen (r= -0.46, p = 0.034), thalamus (r= -0.45, p = 0.038), and hippocampus (r = 0.45, p = 0.039). No other significant correlations with age or BMI were found. Conclusion This in vivo H3R study found a significant age-related decline in most cortical and subcortical regions. Aging Histamine H3 Receptor [11C] GSK189254 PET imaging Figures Figure 1 Introduction Histamine is a neurotransmitter that plays a crucial role in regulating sleep/wakefulness, feeding, and memory processes. Histamine H3 receptors (H3R), a member of the histamine receptor family, are expressed in the cerebral cortex [1] and striatum [2] as well as in the peripheral nervous system. H3Rs regulate the synthesis and release of histamine as presynaptic autoreceptors [3] and function as heteroreceptors to mediate the release of not only histamine but other neurotransmitters including acetylcholine, dopamine, noradrenaline and serotonin [4-5]. In addition, postsynaptic H3R receptors interact with dopamine receptors in the basal ganglia to regulate striatal function (Bolam and Ellender, 2016; Rapanelli et al, 2016; Xu and Pittenger, 2023). Therefore, H3R has been implicated in many diseases, such as sleep-wake regulation [6-7], attention deficit hyperactivity disorder [8-10], learning and memory, seizure susceptibility [11], pain [12-13], stress and depression [14], food intake [15-16], and Tourette syndrome (Pittenger, 2020). Clinically, research studies have pursued H3R antagonists as potential drug targets for the treatment of cognitive dysfunction [17-18] and pitolisant, an H3 antagonist, is FDA approved for the treatment of narcolepsy, and somewhat more broadly approved for sleepiness in Europe (Fabara et al, 2021). However, it is unclear about if H3R availability can be influenced by human demographic factors including age and body mass index (BMI). Increased brain histamine is positively correlated with age [19] while age related changes of H3R still remains unclear. Terao et al. reported H3R mRNA level of 24-month-old mice which was robustly lower than 3-month-old mice in the medulla [20]. However, a human [ 3 H]GSK189254 autoradiography study indicated no significant age dependent changes in any brain regions in dementia with Lewy Body (DLB) and Alzheimer’s disease (AD) participants or demographic matched healthy controls (age range: 60-80 years old) [21]. BMI has been shown to be associated with differences in a variety of in vivo brain receptors [22-25]. However, there is currently no direct evidence showing whether BMI has an impact on H3R. There are several studies investigated the effect of H3 agonists and antagonists on weight changes in rats however. Administration of H3 agonists increased food intake in rats without weight changes [26]. Similarly, orexin-A increased food intake tenfold in wild-type mice but had no effect on food intake in H3 receptor knockout mice or when treated with H3 pharmacological blockade [27]. In comparison, H3 receptor antagonists (including ciproxifan and thioperamide) decreased food intake and body weight in mice [28]. Up to date, no in vivo human study has explored H3R availability with respect to age or BMI. Therefore, in our study, we explored for associations using positron emission tomography (PET) imaging with the selective H3R antagonist radioligand [ 11 C]GSK189254. Methods Twenty-four healthy individuals (2 females, 22 males; age range = 20-47 years) were studied. Each participant had a comprehensive screening assessment that included a clinical interview, complete physical examination with the medical history, vital signs, routine blood tests, hepatitis screen, height and weight, 12-lead electrocardiogram, urine toxicology and pregnancy test (if female). Individuals were excluded if they have metal implants, claustrophobia, prior radiation exposure over the Radioactive Drug Research Committee (RDRC) annual limit for research subjects, drug/alcohol abuse, hepatitis, abnormal laboratory values, current or past neurological illness (including a history of head injury with loss of consciousness); current and /or lifetime psychiatric disorder; diabetes, cardiac disease, abnormal ECG, and insufficient arterial patency. The study was performed under protocols approved by the Yale Human Investigation Committee, the Yale University Radiation Safety Committee, the Yale-New Haven Hospital Radioactive Drug Research Committee, and the Yale MRI Safety Committee. Subjects were recruited from Connecticut and surrounding states by paper and web advertisements, as well as personal referrals. Written informed consent was obtained from all participants at the beginning of screening after a full explanation of study procedures was performed. Structural MR imaging was performed on a Siemens 3-T Trio system (Siemens Medical Solutions, Malvern, Pennsylvania) with a circularly polarized head coil for purposes of excluding individuals with anatomical abnormalities and anatomically coregistering with PET scans. The dimension and voxel size of MR images were 256 × 256 × 176 voxels and 0.98 × 0.98 × 1.0 mm 3 , respectively. [ 11 C]GSK189254 was prepared as previously reported [29]. Among 24 participants, 14 participants used a high-resolution research tomograph (HRRT) (Siemens/CTI, Knoxville, TN, USA), which acquires 207 slices (1.2 mm slice separation) with a reconstructed image resolution of ~ 3 mm; 10 participants used a HR plus (HR+) scanner (Siemens/CTI, Knoxville, TN, USA), which acquires 63 slices with a reconstructed image resolution of ~6 mm. PET scans were acquired for 120 min at rest with an average radioactivity dose of 303.73 ± 175.80 MBq and injected mass of 12 ± 5 ng/kg (max 22 ng/kg). Dynamic data were binned into 33 frames (6 x 0.5 min, 3 x 1 min, 2 x 2 min, 22 x 5 min) and reconstructed with the Ordered Subset Expectation Maximization algorithm, MOLAR, including corrections for attenuation, normalization, scatter, randoms, and deadtime. Image voxel size was 1.22 x 1.22 x 1.23 mm for HRRT images and 2.06 x 2.06 x 2.42 mm for HR+ images. A summed image (0–10 min after injection) was created from the motion-corrected PET data and registered to the subject's 3T MR image, which in turn was linearly registered to a MR template by using a 12-parameter linear transform. The cerebellum was defined by an Anatomical Automatic Labeling (AAL) template [30] delineated on MR. Then each HRRT frame image was smoothed using a Gaussian filter with a full width at half maximum (FWHM) of 5.2mm for harmonization with HR+ images. The PET scans were acquired using i.v. bolus administration of 303 ± 176 mBq or less of high-specific activity [ 11 C]GSK189254 using a 120 min dynamic PET scan for each injection. In the first phase of the study (5-10 min), the arterial input functions were measured with an automated blood counting system (PBS-101, Veenstra Instruments, Joure, The Netherlands) with a continuous withdrawal system where the radioactivity in whole blood was measured with a calibrated radioactivity monitor. Subsequently, individual blood samples were taken and counted at various time points. Samples were centrifuged to obtain plasma and counted, and selected samples were assayed for the presence of the parent radiotracer compound that had not been metabolized. These measurements were performed by a high-performance liquid chromatography HPLC as previous study [31], are used for the fraction of plasma radioactivity unbound to protein. Automatic regions-of-interest (ROI) (Anatomical Automatic Labeling (AAL) for SPM2) were then applied to generate time-activity curves (TACs) in 15 gray matter ROIs (amygdala, caudate, hippocampus, hypothalamus, pallidum, putamen, cerebellum, thalamus, and cortical regions of the frontal, temporal, parietal, occipital, insula, anterior cingulate, and olfactory areas). The TACs were fitted with one- and two-tissue models (1T and 2T) over 120 minutes post injection, with the arterial input function and no metabolite correction. Regional volumes of distribution ( V T ) for [ 11 C]GSK189254 were computed using the two-tissue compartment (2TC) model with the parameters k4 and K1/k2 shared across all regions (2TC shared), as in previous studies [32]. For exploring possible metabolic effects on the primary results, we also normalized V T value by plasma free fraction ( fp ). All outcomes were summarized descriptively and assessed for normality prior to analysis using normal probability plots and Kolmogorov test statistics. All outcomes were approximately normal. A linear mixed model was used to model the independent and joint effects of age (continuous) and brain region (within-subject factor) on V T values and V T / fp values. Slopes were estimated within each region post-hoc and decline per decade was calculated as a percent of the fitted value at age 20. Within-subject correlations were accounted for by fitting three variance–covariance structures to the data (unstructured, compound symmetry, and heterogeneous compound symmetry) and then selecting the best-fitting structure according to the Bayesian Information Criterion (BIC) [33-34]. Similar models were used when assessing the joint effects of BMI and region. Given the exploratory nature of the study, we did not adjust p-values for multiple testing, as in previous studies [22, 35]. Analyses were conducted using SAS, version 9.4 (Cary, NC). Results Background characteristics of the 24 subjects are summarized in Table 1. Healthy volunteers were primarily male (92%), with a mean age of 31.6 (± 9.8) years (range: 18-55) and mean BMI of 26.7 (± 4.8) ranging from 21.9-31.5. Consistent with previous PET imaging studies using [ 11 C]GSK189254, H3R availability was found to have the highest distribution in the striatum, intermediate in cortical regions, and the lowest in the cerebellum in humans [31-32]. Effect of Age on H3R availability : Examining the multivariate effects of age on H3R availability after adjusting for BMI, scanner, and injection tracer dosage, there was a significant overall age by ROI interaction (F(14,19)=8.39, p<0.0001) owing to varying magnitude of association across regions. Specifically, negative effects of age on V T were observed primarily in cortical regions, including the anterior cingulate cortex (r= -0.61, p= 0.004), frontal cortex (r= -0.50, p= 0.020), olfactory cortex (r= -0.50, p= 0.023), parietal cortex (r= -0.58, p= 0.006), cerebellum cortex (r= -0.53, p= 0.013), and in subcortical areas including insula (r= -0.48, p= 0.027), putamen (r= -0.46, p= 0.034), thalamus (r= -0.45, p= 0.038), and hippocampus (r=0.45, p=0.039) ( Table 2 ). No significant associations were observed in the hypothalamus, amygdala, caudate, or temporal cortex. Three representative regions including the olfactory cortex, parietal cortex, and putamen are examples with individual data points and adjusted correlation coefficients are shown in Figure 1 and in remaining ROIs in Figure S1 (supplementary data). We also applied similar analysis with V T / fp across all the regions of interest, which listed in Table S1 (supplementary data). Effect of BMI on H3R availability : After adjusting for age, scan, and injection dosage, no significant associations between BMI and V T were observed in any of the brain regions (Supplementary data: Table S3 ). Same analysis with V T / fp across all the regions of interest listed in Table S2 (supplementary data). Table 1. Demographics of Subjects (n=24) Demographic Range Mean±SD or n (%) Age (years) 20-47 32 ± 9.8 Male N/A 91.7% BMI (kg/m 2 ) 20-40.7 26.7 ± 4.8 Ethnicity Caucasian N/A 8 (33.3) African American N/A 2 (8.3) Other N/A 14 (58.3) Injected activity dose (MBq) 129.8-730.1 303 ± 176 Mass dose (μg/kg) 0.007-0.021 0.012 ± 0.005 Table 2. [ 11 C]GSK189254 V T and correlation with age . All ROIs examined are presented with average [ 11 C]GSK189254 V T (with standard deviations), Pearson’s correlations with age, percent of change per decade studies, slope and unadjusted p values. Slope corresponds to the change in V T per one year. Correlations between age and [ 11 C]GSK189254 V T were calculated separately for each region, and p values unadjusted for multiple comparisons are reported (*<0.05; **<0.01). ROI Mean V T Slope Correlation with age Change per decade P value Amygdala 21.66 (7.80) -0.18 -0.37 -8% 0.10 Anterior cingulate cortex 25.75 (6.21) -0.31 -0.61 -12% <0.01** Caudate 29.56 (8.70) -0.3 -0.41 -10% 0.06 Cerebellum 13.25 (2.31) -0.11 -0.53 -8% 0.01* Frontal cortex 16.92 (3.36) -0.17 -0.5 -10% 0.02* Hippocampus 13.66 (3.24) -0.1 -0.45 -7% 0.04* Hypothalamus 24.64 (11.23) -0.26 -0.24 -11% 0.29 Insula 22.27 (5.65) -0.2 -0.48 -9% 0.03* Occipital Cortex 13.95 (2.66) -0.12 -0.47 -9% 0.03* Olfactory Cortex 25.59 (7.53) -0.38 -0.5 -15% 0.02* Pallidum 44.30 (18.14) -0.58 -0.56 -13% <0.01** Parietal Cortex 14.87 (2.92) -0.15 -0.58 -10% 0.01* Putamen 42.05 (12.13) -0.44 -0.46 -11% 0.03* Temporal cortex 15.96 (3.12) -0.1 -0.38 -6% 0.08 Thalamus 16.54 (3.61) -0.16 -0.45 -10% 0.04* Discussion To our knowledge, this was the first in vivo study in human to systematically examine age and BMI related effects on H3R availability in healthy individuals (n = 24) using the PET ligand [ 11 C]GSK189254. Our main findings were significant age effects on regional H3R availability in most of the brain regions examined including the anterior cingulate cortex, frontal cortex, olfactory cortex, parietal cortex, cerebellum cortex and subcortical areas including insula, putamen, thalamus, and hippocampus and nonsignificant age-related reduction in the hypothalamus, amygdala, and temporal cortex. The reduction per decade was greatest in the olfactory cortex (15%) followed by pallidum (13%). Our results contrast with a previous animal study that found age related changes in H3R mRNA limited to the medulla, with 32% decrease in a 24-month group versus 3-month group [ 20 ]. The findings of an age-related decline in H3R availability are largely consistent with literature from the histamine H1 receptor (H1R) however. Age related changes in H1R were studied using [ 11 C]pyrilamine and [ 11 C]doxepin PET and found frontal, parietal, and temporal cortices age related decreases in binding of approximately 13% per decade [ 36 ]. A noted difference was they found no apparent decrease in H1R binding in the thalamus with aging, while the reduction per decade in H3R in the thalamus was 10% (p = 0.04) in our study. While the alterations of H3R availability and function remain unclear, the relevance of H3R in diseases of cognitive impairment have been investigated by some studies. Medhurst et. al found no significant differences of [ 3 H]GSK189254 binding between control (n = 12; age range = 72 ~ 78 y.o.) and AD groups (n = 27; age range = 80 ~ 83 y.o.) in the neocortex, although within AD the frontal cortex density was higher in patients with lower MMSE score (i.e., the more severe dementia cases had higher H3R) [ 37 ]. They hypothesized that this may lead to a further exacerbation of cognitive deficits through decreases in neurotransmitters [ 37 ]. The field has examined H3R selective antagonists in clinical trials for cognitive impairment treatment, but the results are mixed [ 37 – 43 ]. A 12 week randomized study on the H3R antagonist ABT-288 in 242 patients (mean age = 70.2 y.o ) with mild-to-moderate Alzheimer’s disease found no significant effect on clinical scores compared to placebo [ 39 ]. However, researchers found different results with CEP-26401, which is an H3R antagonist/inverse agonist with high-affinity. Healthy volunteers (mean age = 30 years, N = 48) improved cognitive function at a low dose 80ug [ 44 ]. Unfortunately, the follow up study (mean age = 27 years, N = 40) found no improvement on any cognitive tests with CEP-26401 in all doses tested (5 ug, 25 ug, 125 ug), but it possible the young age of the cohort contributed to this finding [ 45 ]. Additionally, other H3R antagonists (PF-03654746, MK-0249, and GSK239512) had no positive effects on cognition in patients with mild-to-moderate AD [ 46 – 47 ]. Cognitive effects were beyond our current study, but age-related changes of H3R should be explored in healthy aging, AD, and other clinical disorders. The present study has several limitations that should be acknowledged. First, this study only included a range of 22 to 41 years old subjects with a BMI of 22 to 31 kg/m 2 . Regardless, significant age effects in H3R appeared in this relative narrow age range. We did not observe any consistent trend or concrete alterations of H3R availability in this limited BMI range, however. Additionally, gender dependent changes of H3R were unable to explored because of a limited female sample size (n = 2). Future work could focus on these variables to address those limitations. Secondly, there were two PET scanners used in this study: HRRT and HR+. The results of HRRT combined with harmonized HR + and HRRT alone were mostly comparable ( Tables S4 and S5 ). Third, diurnal variation been documented in histamine [ 48 ]which could’ve affected the current results. In our dataset, most subjects were scanned before 12:00 pm, and five subjects were checked between 12:00 and 2:00 pm. We found no significant difference between these two groups with 2 sample t-tests. Lastly, this study only considers the effect of age and BMI on H3R availability and does not consider about other potential factors, such as genetic factors, lifestyle, environmental exposure, which could be potentially of high interest. In conclusion, we have shown a significant age effect of H3R in healthy humans. Given the uncertainty of H3R on function in neurodegenerative disorders, our study provides important perspectives on H3R alterations in normal aging. Declarations Acknowledgments We thank the staff of the Yale PET Center, the Clinical Neuroscience Research Unit (CNRU) at the Connecticut Mental Health Center (CMHC) of the Connecticut Department of Mental Health and Addiction Services (DMHAS), the Hospital Research Unit (HRU) at Yale–New Haven Hospital (YNHH), and the Yale Magnetic Resonance Research Center (MRRC). Author Contribution Yanghong Yang: Conceptualization, Formal Analysis, Writing – Original Draft Preparation. Waleed Ibrahim: Writing, Review & Editing Brian Pittman; Paul Gravel; Jocelyn Hoye; Jean-Dominique Gallezot: Methodology, Investigation, Data Curation. Ryan Cool; Faranak Ebrahimian Sadabad; Christopher Pittenger; Richard E. Carson/ Henry Huang: Writing – Review & Editing, Visualization, Project Administration. Rajiv Radhakrishnan; Conceptualization, Data curation. David Matuskey: Conceptualization, Supervision and Review. 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Curr Top Behav Neurosci 59:413–425 Supplementary Files CBANSupplementaldatamolYYHr1.docx Cite Share Download PDF Status: Published Journal Publication published 12 Sep, 2025 Read the published version in Molecular Imaging and Biology → Version 1 posted Reviewers agreed at journal 15 May, 2024 Reviewers invited by journal 07 May, 2024 Editor assigned by journal 11 Apr, 2024 First submitted to journal 10 Apr, 2024 Editorial decision: Major revisions 30 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4004389","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":299835777,"identity":"a52803eb-bf9c-4e29-a941-d2ce6298dfdd","order_by":0,"name":"Yanghong Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie3LsUvDQBTH8XccXJZr63hHkPRPsATiUGz+lYRAswTpVDKIHBRudXWo/hmZIw90iXbt4FARuhihIkrBxTiIU466Cd53+b3hfQBstj8a/TlzgO7X8t1JBcB+R4jegRzc3OLTJL8fKZGsH94u0WOOIqtnbSDV8Xh4Xq0TJcaH/n6BA81LOrgwkTIL/I7GBEQUuLJAokXE3I6JLOpvkr67co6h9lbOh5EsM/+xISMQWSBfFMZaAKMmIpd1QHmFEeP11IXrNNE8nsn5XTvpLjL/lecY9py0kNuT4dGZg1ebetpO+iUw0Wys9yKgHGbNTVT7f5OngG6aDaFXAtnCqfHbZrPZ/mefiolSKhrPSLgAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6816-1252","institution":"Yale University","correspondingAuthor":true,"prefix":"","firstName":"Yanghong","middleName":"","lastName":"Yang","suffix":""},{"id":299835778,"identity":"c893a15a-18c4-4e2b-b9e1-2b0b8017cd9f","order_by":1,"name":"Waleed Ibrahim","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Waleed","middleName":"","lastName":"Ibrahim","suffix":""},{"id":299835779,"identity":"72d00a85-ff83-4b1b-91ea-23169ee19f68","order_by":2,"name":"Paul Gravel","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Gravel","suffix":""},{"id":299835780,"identity":"f422e7e1-e459-4e7c-a4c7-83dfc122505e","order_by":3,"name":"Brian Pittman","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Brian","middleName":"","lastName":"Pittman","suffix":""},{"id":299835781,"identity":"3f2d30e0-4cf2-48d8-a44f-e9630ccaa7b2","order_by":4,"name":"Jocelyn Hoye","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Jocelyn","middleName":"","lastName":"Hoye","suffix":""},{"id":299835782,"identity":"d429d4c4-4112-4324-9d05-f89fe7e5fb4d","order_by":5,"name":"Ryan Cool","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Cool","suffix":""},{"id":299835783,"identity":"8fd0eef8-924c-43eb-88e4-d7c116905fd7","order_by":6,"name":"Faranak Ebrahimian Sadabad","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Faranak","middleName":"Ebrahimian","lastName":"Sadabad","suffix":""},{"id":299835784,"identity":"0db570b9-3136-4ac7-8b47-0c43bc05be91","order_by":7,"name":"Christopher Pittenger","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Pittenger","suffix":""},{"id":299835785,"identity":"53930172-ecf8-49e8-80a8-221ca34badcf","order_by":8,"name":"Jean-Dominique Gallezot","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Jean-Dominique","middleName":"","lastName":"Gallezot","suffix":""},{"id":299835786,"identity":"0210950f-ac9f-4a4b-9fbb-9569ef64b3ad","order_by":9,"name":"Richard E. Carson","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"E.","lastName":"Carson","suffix":""},{"id":299835787,"identity":"86501996-d6a6-46e8-afb3-cdb94833c387","order_by":10,"name":"Henry Huang","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Henry","middleName":"","lastName":"Huang","suffix":""},{"id":299835788,"identity":"e395022c-5d0c-4c21-9d0b-06ff81c7216a","order_by":11,"name":"Rajiv Radhakrishnan","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Rajiv","middleName":"","lastName":"Radhakrishnan","suffix":""},{"id":299835789,"identity":"af35ca9f-795e-4c0a-bb26-d6482c608d78","order_by":12,"name":"David Matuskey","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Matuskey","suffix":""}],"badges":[],"createdAt":"2024-03-01 20:05:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4004389/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4004389/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11307-025-02047-8","type":"published","date":"2025-09-12T15:57:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56550264,"identity":"391b77fd-cd3d-4a10-a0b9-4149c5445d64","added_by":"auto","created_at":"2024-05-15 15:50:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":183310,"visible":true,"origin":"","legend":"\u003cp\u003eExamples from individual data points and adjusted correlation coefficients (r values) with \u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e and age in years shown for: A. Olfactory cortex. B. Parietal cortex C. Putamen. (All regions are shown in supplemental data \u003cstrong\u003eFigure S1\u003c/strong\u003e.)\u003c/p\u003e","description":"","filename":"Manuscriptfig.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4004389/v1/dcd79cf15451f838bb0b2175.jpg"},{"id":91817648,"identity":"8f77d785-7587-4101-8e4b-39d84fcd64a1","added_by":"auto","created_at":"2025-09-22 07:00:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":822620,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4004389/v1/7b3f3ae7-55ef-4f3e-b372-e48e1e2ef94e.pdf"},{"id":56551019,"identity":"024c8dd6-e6ea-4802-aa05-341a3e6a385c","added_by":"auto","created_at":"2024-05-15 15:58:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":334042,"visible":true,"origin":"","legend":"","description":"","filename":"CBANSupplementaldatamolYYHr1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4004389/v1/116269cb9cd667e017a4f72a.docx"}],"financialInterests":"","formattedTitle":"Effects of Age and BMI on Histamine H3 Receptor Availability in Healthy Humans","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHistamine is a neurotransmitter that plays a crucial role in regulating sleep/wakefulness, feeding, and memory processes. Histamine H3 receptors (H3R), a member of the histamine receptor family, are expressed in the cerebral cortex\u0026nbsp;[1]\u0026nbsp;and striatum\u0026nbsp;[2]\u0026nbsp;as well as in the peripheral nervous system. H3Rs regulate the synthesis and release of histamine as presynaptic autoreceptors\u0026nbsp;[3]\u0026nbsp;and function as heteroreceptors to mediate the release of not only histamine but other neurotransmitters including acetylcholine, dopamine, noradrenaline and serotonin\u0026nbsp;[4-5]. In addition, postsynaptic H3R receptors interact with dopamine receptors in the basal ganglia to regulate striatal function (Bolam and Ellender, 2016; Rapanelli et al, 2016; Xu and Pittenger, 2023). \u0026nbsp;Therefore, H3R has been implicated in many diseases, such as sleep-wake regulation\u0026nbsp;[6-7], attention deficit hyperactivity disorder\u0026nbsp;[8-10], learning and memory, seizure susceptibility\u0026nbsp;[11], pain\u0026nbsp;[12-13], stress and depression\u0026nbsp;[14], food intake\u0026nbsp;[15-16], and Tourette syndrome (Pittenger, 2020). Clinically, research studies have pursued H3R antagonists as potential drug targets for the treatment of cognitive dysfunction\u0026nbsp;[17-18]\u0026nbsp;and\u0026nbsp;pitolisant, an H3 antagonist, is FDA approved for the treatment of narcolepsy, and somewhat more broadly approved for sleepiness in Europe\u0026nbsp;(Fabara et al, 2021). However, it is unclear about if H3R availability can be influenced by human demographic factors including age and body mass index (BMI).\u003c/p\u003e\n\u003cp\u003eIncreased brain histamine is positively correlated with age\u0026nbsp;[19]\u0026nbsp;while age related changes of H3R still remains unclear. Terao et al. reported H3R mRNA level of 24-month-old mice which was robustly lower than 3-month-old mice in the medulla\u0026nbsp;[20]. However, a human [\u003csup\u003e3\u003c/sup\u003eH]GSK189254 autoradiography study indicated no significant age dependent changes in any brain regions in dementia with Lewy Body (DLB) and Alzheimer\u0026rsquo;s disease (AD) participants or demographic matched healthy controls (age range: 60-80 years old)\u0026nbsp;[21].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI has been shown to be associated with differences in a variety of \u003cem\u003ein vivo\u003c/em\u003e brain receptors\u0026nbsp;[22-25]. However, there is currently no direct evidence showing whether BMI has an impact on H3R.\u0026nbsp;There are\u0026nbsp;several studies investigated the effect of H3 agonists and antagonists on weight changes in rats however.\u0026nbsp;Administration of H3 agonists increased food intake in rats without weight changes\u0026nbsp;[26]. Similarly, orexin-A increased food intake tenfold in wild-type mice but had no effect on food intake in H3 receptor knockout mice or when treated with H3 pharmacological blockade\u0026nbsp;[27]. In comparison, H3 receptor antagonists (including ciproxifan and thioperamide) decreased food intake and body weight in mice\u0026nbsp;[28].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUp to date, no \u003cem\u003ein vivo\u003c/em\u003e human study has explored H3R availability with respect to age or BMI. Therefore, in our study, we explored for associations using positron emission tomography (PET) imaging with the selective H3R antagonist radioligand\u0026nbsp;[\u003csup\u003e11\u003c/sup\u003eC]GSK189254.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eTwenty-four healthy individuals (2 females, 22 males; age range = 20-47 years) were studied.\u0026nbsp;Each participant had a comprehensive screening assessment that included a clinical interview, complete physical examination with the medical history, vital signs, routine blood tests, hepatitis screen, height and weight, 12-lead electrocardiogram, urine toxicology and pregnancy test (if female). Individuals were excluded if they have metal implants, claustrophobia, prior radiation exposure over the Radioactive Drug Research Committee (RDRC) annual limit for research subjects, drug/alcohol abuse, hepatitis, abnormal laboratory values, current or past neurological illness (including a history of head injury with loss of consciousness); current and /or lifetime psychiatric disorder; diabetes, cardiac disease, abnormal ECG, and insufficient arterial patency.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was performed under protocols approved by the Yale Human Investigation Committee, the Yale University Radiation Safety Committee, the Yale-New Haven Hospital Radioactive Drug Research Committee, and the Yale MRI Safety Committee. Subjects were recruited from Connecticut and surrounding states by paper and web advertisements, as well as personal referrals. Written informed consent was obtained from all participants at the beginning of screening after a full explanation of study procedures was performed.\u003c/p\u003e\n\u003cp\u003eStructural MR imaging was performed on a Siemens 3-T Trio system (Siemens Medical Solutions, Malvern, Pennsylvania) with a circularly polarized head coil for purposes of excluding individuals with anatomical abnormalities and anatomically coregistering with PET scans. The dimension and voxel size of MR images were 256 \u0026times; 256 \u0026times; 176 voxels and 0.98 \u0026times; 0.98 \u0026times; 1.0 mm\u003csup\u003e3\u003c/sup\u003e, respectively.\u003c/p\u003e\n\u003cp\u003e[\u003csup\u003e11\u003c/sup\u003eC]GSK189254\u0026nbsp;was prepared as previously reported\u0026nbsp;[29]. Among 24 participants, 14 participants used a high-resolution research tomograph (HRRT) (Siemens/CTI, Knoxville, TN, USA), which acquires 207 slices (1.2 mm slice separation) with a reconstructed image resolution of ~ 3 mm; 10 participants\u0026nbsp;used a HR plus (HR+) scanner (Siemens/CTI, Knoxville, TN, USA), which acquires 63 slices with a reconstructed image resolution of ~6 mm. PET scans were acquired for 120 min at rest with an average radioactivity dose of 303.73 \u0026plusmn; 175.80 MBq and injected mass of 12 \u0026plusmn; 5 ng/kg (max 22 ng/kg). Dynamic data were binned into 33 frames (6 x 0.5 min, 3 x 1 min, 2 x 2 min, 22 x 5 min) and reconstructed with the Ordered Subset Expectation Maximization algorithm, MOLAR, including corrections for attenuation, normalization, scatter, randoms, and deadtime. Image voxel size was 1.22 x 1.22 x 1.23 mm for HRRT images and 2.06 x 2.06 x 2.42 mm for HR+ images.\u003c/p\u003e\n\u003cp\u003eA summed image (0\u0026ndash;10 min after injection) was created from the motion-corrected PET data and registered to the subject\u0026apos;s 3T MR image, which in turn was linearly registered to a MR template by\u0026nbsp;using a 12-parameter linear transform.\u0026nbsp;The cerebellum was defined by an Anatomical Automatic Labeling (AAL) template\u0026nbsp;[30]\u0026nbsp;delineated on MR. Then each HRRT frame image was smoothed using a Gaussian filter with a full width at half maximum (FWHM) of 5.2mm for harmonization with HR+ images.\u003c/p\u003e\n\u003cp\u003eThe PET scans were acquired using i.v. bolus administration of 303 \u0026plusmn; 176 mBq or less of high-specific activity [\u003csup\u003e11\u003c/sup\u003eC]GSK189254 using a 120 min dynamic PET scan for each injection. In the first phase of the study (5-10 min), the arterial input functions were measured with an automated blood counting system (PBS-101, Veenstra Instruments, Joure, The Netherlands) with a continuous withdrawal system where the radioactivity in whole blood was measured with a calibrated radioactivity monitor. Subsequently, individual blood samples were taken and counted at various time points. Samples were centrifuged to obtain plasma and counted, and selected samples were assayed for the presence of the parent radiotracer compound that had not been metabolized. These measurements were performed by a high-performance liquid chromatography\u0026nbsp;HPLC as previous study\u0026nbsp;[31], are used for the fraction of plasma radioactivity unbound to protein.\u003c/p\u003e\n\u003cp\u003eAutomatic regions-of-interest (ROI) (Anatomical Automatic Labeling (AAL) for SPM2) were then applied to generate time-activity curves (TACs) in 15 gray matter ROIs (amygdala, caudate,\u0026nbsp;hippocampus,\u0026nbsp;hypothalamus, pallidum,\u0026nbsp;putamen, cerebellum, thalamus, and \u0026nbsp;cortical regions of the frontal, temporal, parietal, occipital, insula, anterior cingulate, and\u0026nbsp;olfactory areas). The TACs were fitted with one- and two-tissue models (1T and 2T) over 120 minutes\u0026nbsp;post injection, with the arterial input function and no metabolite correction.\u0026nbsp;Regional volumes of distribution (\u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e) for [\u003csup\u003e11\u003c/sup\u003eC]GSK189254 were computed using the two-tissue compartment (2TC) model with the parameters k4 and K1/k2 shared across all regions (2TC shared), as in previous studies [32]. For exploring possible metabolic effects on the primary results, we also normalized \u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e value by plasma free fraction (\u003cstrong\u003e\u003cem\u003efp\u003c/em\u003e\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAll outcomes were summarized descriptively and assessed for normality prior to analysis using normal probability plots and Kolmogorov test statistics. All outcomes were approximately normal. A linear mixed model was used to model the independent and joint effects of age (continuous) and brain region (within-subject factor) on \u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u0026nbsp;\u003c/sub\u003evalues and\u0026nbsp;\u003cstrong\u003e\u003cem\u003eV\u003csub\u003eT\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e/\u003cem\u003efp\u003c/em\u003e\u003c/strong\u003e values. Slopes were estimated within each region post-hoc and decline per decade was calculated as a percent of the fitted value at age 20. Within-subject correlations were accounted for by fitting three variance\u0026ndash;covariance structures to the data (unstructured, compound symmetry, and heterogeneous compound symmetry) and then selecting the best-fitting structure according to the Bayesian Information Criterion (BIC) [33-34]. Similar models were used when assessing the joint effects of BMI and region. Given the exploratory nature of the study, we did not adjust p-values for multiple testing, as in previous studies [22, 35]. Analyses were conducted using SAS, version 9.4 (Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBackground characteristics of the 24 subjects are summarized in Table 1. Healthy volunteers were primarily male (92%), with a mean age of 31.6 (\u0026plusmn; 9.8) years (range: 18-55) and \u0026nbsp;mean BMI of 26.7 (\u0026plusmn; 4.8) ranging from 21.9-31.5.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsistent with previous PET imaging studies using [\u003csup\u003e11\u003c/sup\u003eC]GSK189254, H3R availability was found to have the highest distribution in the striatum, intermediate in cortical regions, and the lowest in the cerebellum in humans\u0026nbsp;[31-32].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of Age on H3R availability\u003c/strong\u003e: Examining the multivariate effects of age on H3R availability after adjusting for BMI, scanner, and injection tracer dosage, there was a significant overall age by ROI interaction (F(14,19)=8.39, p\u0026lt;0.0001) owing to varying magnitude of association across regions. Specifically, negative effects of age on\u0026nbsp;\u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e \u0026nbsp;were observed primarily in cortical regions, including the anterior cingulate cortex (r= -0.61, p= 0.004), frontal cortex (r= -0.50, p= 0.020), olfactory cortex (r= -0.50, p= 0.023), parietal cortex (r= -0.58, p= 0.006), cerebellum cortex (r= -0.53, p= 0.013), and in subcortical areas including insula (r= -0.48, p= 0.027), putamen (r= -0.46, p= 0.034), thalamus (r= -0.45, p= 0.038), and hippocampus (r=0.45, p=0.039) (\u003cstrong\u003eTable 2\u003c/strong\u003e). No significant associations were observed in the hypothalamus, amygdala, caudate, or temporal cortex. Three representative regions including the olfactory cortex, parietal cortex, and putamen are examples with individual data points and adjusted correlation coefficients are shown in Figure 1 and in remaining ROIs in Figure S1 (supplementary data).\u0026nbsp;We also applied similar analysis with\u0026nbsp;\u003cstrong\u003e\u003cem\u003eV\u003csub\u003eT\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e/\u003cem\u003efp\u003c/em\u003e\u003c/strong\u003e across all the regions of interest, which listed in Table S1 (supplementary data).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of BMI on H3R availability\u003c/strong\u003e: After adjusting for age, scan, and injection dosage, no significant associations between BMI and \u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e were observed in any of the brain regions (Supplementary data:\u003cstrong\u003e\u0026nbsp;Table S3\u003c/strong\u003e). Same analysis with\u0026nbsp;\u003cstrong\u003e\u003cem\u003eV\u003csub\u003eT\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e/\u003cem\u003efp\u003c/em\u003e\u003c/strong\u003e across all the regions of interest listed in\u0026nbsp;\u003cstrong\u003eTable S2\u003c/strong\u003e (supplementary data).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Demographics of Subjects (n=24)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026plusmn;SD or n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003e20-47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e32 \u0026plusmn; 9.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e91.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003e20-40.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e26.7 \u0026plusmn; 4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eEthnicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Caucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e8 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; African American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e2 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e14 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eInjected activity dose (MBq)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003e129.8-730.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e303 \u0026plusmn; 176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eMass dose (\u0026mu;g/kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.15972222222222%\" valign=\"top\"\u003e\n \u003cp\u003e0.007-0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.71527777777778%\" valign=\"top\"\u003e\n \u003cp\u003e0.012 \u0026plusmn; 0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003e [\u003cstrong\u003e\u003csup\u003e11\u003c/sup\u003eC]GSK189254\u003cem\u003e\u0026nbsp;V\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e and correlation with age\u003c/strong\u003e. All ROIs examined are presented with average [\u003csup\u003e11\u003c/sup\u003eC]GSK189254 \u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e (with standard deviations), Pearson\u0026rsquo;s correlations with age, percent of change per decade studies, slope and unadjusted p values. \u0026nbsp;Slope corresponds to the change in\u003cem\u003e\u0026nbsp;V\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e per one year.\u0026nbsp;\u0026nbsp;Correlations between age and [\u003csup\u003e11\u003c/sup\u003eC]GSK189254 \u003cem\u003eV\u003c/em\u003e\u003csub\u003eT\u003c/sub\u003e were calculated separately for each region, and p values unadjusted for multiple comparisons are reported (*\u0026lt;0.05; **\u0026lt;0.01).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;ROI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u003cem\u003eV\u003csub\u003eT\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSlope\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCorrelation with age\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChange per decade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eAmygdala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e21.66 (7.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eAnterior cingulate cortex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e25.75 (6.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-12%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eCaudate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e29.56 (8.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eCerebellum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e13.25 (2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.01*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eFrontal cortex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e16.92 (3.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.02*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eHippocampus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e13.66 (3.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.04*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eHypothalamus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e24.64 (11.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-11%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eInsula\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e22.27 (5.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-9%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.03*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eOccipital Cortex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e13.95 (2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.03*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eOlfactory Cortex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e25.59 (7.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-15%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.02*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003ePallidum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e44.30 (18.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-13%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.01**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eParietal Cortex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e14.87 (2.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.01*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003ePutamen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e42.05 (12.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-11%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.03*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eTemporal cortex \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e15.96 (3.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.0896309314587%\" valign=\"top\"\u003e\n \u003cp\u003eThalamus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.817223198594025%\" valign=\"top\"\u003e\n \u003cp\u003e16.54 (3.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.653778558875219%\" valign=\"top\"\u003e\n \u003cp\u003e-0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.035149384885763%\" valign=\"top\"\u003e\n \u003cp\u003e-0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76274165202109%\" valign=\"top\"\u003e\n \u003cp\u003e-10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.641476274165202%\" valign=\"top\"\u003e\n \u003cp\u003e0.04*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this was the first \u003cem\u003ein vivo\u003c/em\u003e study in human to systematically examine age and BMI related effects on H3R availability in healthy individuals (n\u0026thinsp;=\u0026thinsp;24) using the PET ligand [\u003csup\u003e11\u003c/sup\u003eC]GSK189254.\u003c/p\u003e \u003cp\u003eOur main findings were significant age effects on regional H3R availability in most of the brain regions examined including the anterior cingulate cortex, frontal cortex, olfactory cortex, parietal cortex, cerebellum cortex and subcortical areas including insula, putamen, thalamus, and hippocampus and nonsignificant age-related reduction in the hypothalamus, amygdala, and temporal cortex. The reduction per decade was greatest in the olfactory cortex (15%) followed by pallidum (13%). Our results contrast with a previous animal study that found age related changes in H3R mRNA limited to the medulla, with 32% decrease in a 24-month group versus 3-month group [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe findings of an age-related decline in H3R availability are largely consistent with literature from the histamine H1 receptor (H1R) however. Age related changes in H1R were studied using [\u003csup\u003e11\u003c/sup\u003eC]pyrilamine and [\u003csup\u003e11\u003c/sup\u003eC]doxepin PET and found frontal, parietal, and temporal cortices age related decreases in binding of approximately 13% per decade [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. A noted difference was they found no apparent decrease in H1R binding in the thalamus with aging, while the reduction per decade in H3R in the thalamus was 10% (p\u0026thinsp;=\u0026thinsp;0.04) in our study.\u003c/p\u003e \u003cp\u003eWhile the alterations of H3R availability and function remain unclear, the relevance of H3R in diseases of cognitive impairment have been investigated by some studies. Medhurst et. al found no significant differences of [\u003csup\u003e3\u003c/sup\u003eH]GSK189254 binding between control (n\u0026thinsp;=\u0026thinsp;12; age range\u0026thinsp;=\u0026thinsp;72\u0026thinsp;~\u0026thinsp;78 y.o.) and AD groups (n\u0026thinsp;=\u0026thinsp;27; age range\u0026thinsp;=\u0026thinsp;80\u0026thinsp;~\u0026thinsp;83 y.o.) in the neocortex, although within AD the frontal cortex density was higher in patients with lower MMSE score (i.e., the more severe dementia cases had higher H3R) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. They hypothesized that this may lead to a further exacerbation of cognitive deficits through decreases in neurotransmitters [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The field has examined H3R selective antagonists in clinical trials for cognitive impairment treatment, but the results are mixed [\u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. A 12 week randomized study on the H3R antagonist ABT-288 in 242 patients (mean age\u0026thinsp;=\u0026thinsp;70.2 y.o ) with mild-to-moderate Alzheimer\u0026rsquo;s disease found no significant effect on clinical scores compared to placebo [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, researchers found different results with CEP-26401, which is an H3R antagonist/inverse agonist with high-affinity. Healthy volunteers (mean age\u0026thinsp;=\u0026thinsp;30 years, N\u0026thinsp;=\u0026thinsp;48) improved cognitive function at a low dose\u0026thinsp;\u0026lt;\u0026thinsp;20ug, while it worsened cognition function at dose\u0026thinsp;\u0026gt;\u0026thinsp;80ug [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Unfortunately, the follow up study (mean age\u0026thinsp;=\u0026thinsp;27 years, N\u0026thinsp;=\u0026thinsp;40) found no improvement on any cognitive tests with CEP-26401 in all doses tested (5 ug, 25 ug, 125 ug), but it possible the young age of the cohort contributed to this finding [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Additionally, other H3R antagonists (PF-03654746, MK-0249, and GSK239512) had no positive effects on cognition in patients with mild-to-moderate AD [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Cognitive effects were beyond our current study, but age-related changes of H3R should be explored in healthy aging, AD, and other clinical disorders.\u003c/p\u003e \u003cp\u003eThe present study has several limitations that should be acknowledged. First, this study only included a range of 22 to 41 years old subjects with a BMI of 22 to 31 kg/m\u003csup\u003e2\u003c/sup\u003e. Regardless, significant age effects in H3R appeared in this relative narrow age range. We did not observe any consistent trend or concrete alterations of H3R availability in this limited BMI range, however. Additionally, gender dependent changes of H3R were unable to explored because of a limited female sample size (n\u0026thinsp;=\u0026thinsp;2). Future work could focus on these variables to address those limitations.\u003c/p\u003e \u003cp\u003eSecondly, there were two PET scanners used in this study: HRRT and HR+. The results of HRRT combined with harmonized HR\u0026thinsp;+\u0026thinsp;and HRRT alone were mostly comparable (\u003cb\u003eTables S4 and S5\u003c/b\u003e). Third, diurnal variation been documented in histamine [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]which could\u0026rsquo;ve affected the current results. In our dataset, most subjects were scanned before 12:00 pm, and five subjects were checked between 12:00 and 2:00 pm. We found no significant difference between these two groups with 2 sample t-tests. Lastly, this study only considers the effect of age and BMI on H3R availability and does not consider about other potential factors, such as genetic factors, lifestyle, environmental exposure, which could be potentially of high interest.\u003c/p\u003e \u003cp\u003eIn conclusion, we have shown a significant age effect of H3R in healthy humans. Given the uncertainty of H3R on function in neurodegenerative disorders, our study provides important perspectives on H3R alterations in normal aging.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the staff of the Yale PET Center, the Clinical Neuroscience Research Unit (CNRU) at the Connecticut Mental Health Center (CMHC) of the Connecticut Department of Mental Health and Addiction Services (DMHAS), the Hospital Research Unit (HRU) at Yale\u0026ndash;New Haven Hospital (YNHH), and the Yale Magnetic Resonance Research Center (MRRC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYanghong Yang: Conceptualization, Formal Analysis, Writing \u0026ndash; Original Draft Preparation.\u003c/p\u003e\n\u003cp\u003eWaleed Ibrahim: Writing, Review \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eBrian Pittman; Paul Gravel; Jocelyn Hoye; Jean-Dominique Gallezot: Methodology, Investigation, Data Curation.\u003c/p\u003e\n\u003cp\u003eRyan Cool; Faranak Ebrahimian Sadabad; Christopher Pittenger; Richard E. Carson/ Henry Huang: Writing \u0026ndash; Review \u0026amp; Editing, Visualization, Project Administration.\u003c/p\u003e\n\u003cp\u003eRajiv Radhakrishnan; Conceptualization, Data curation.\u003c/p\u003e\n\u003cp\u003eDavid Matuskey: Conceptualization, Supervision and Review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of Conflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have no financial conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJin CY, Panula P (2005) The laminar histamine receptor system in human prefrontal cortex suggests multiple levels of histaminergic regulation. 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NeuroImage 130:241\u0026ndash;247\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYanai K, Watanabe T, Meguro K et al (1992) Age-dependent decrease in histamine H1 receptor in human brains revealed by PET. NeuroReport 3:433\u0026ndash;436\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedhurst AD, Roberts JC, Lee J et al (2009) Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice. Br J Pharmacol 157:130\u0026ndash;138\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKubo M, Kishi T, Matsunaga S, Iwata N (2015) Histamine H3 Receptor Antagonists for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. J Alzheimers Dis 48:667\u0026ndash;671\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaig GM, Pritchett Y, Meier A et al (2014) A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer's dementia. 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Br J Clin Pharmacol 85:970\u0026ndash;985\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEgan M, Yaari R, Liu L et al (2012) Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD. Curr Alzheimer Res 9:481\u0026ndash;490\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrove RA, Harrington CM, Mahler A et al (2014) A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer's disease. Curr Alzheimer Res 11:47\u0026ndash;58\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMochizuki T (2022) Histamine as an Alert Signal in the Brain. Curr Top Behav Neurosci 59:413\u0026ndash;425\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-imaging-and-biology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mibi","sideBox":"Learn more about [Molecular Imaging and Biology](http://link.springer.com/journal/11307)","snPcode":"11307","submissionUrl":"https://www.editorialmanager.com/mibi/default2.aspx","title":"Molecular Imaging and Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Aging, Histamine H3 Receptor, [11C] GSK189254, PET imaging","lastPublishedDoi":"10.21203/rs.3.rs-4004389/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4004389/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess alterations in H3R availability with age and body mass index (BMI) in healthy humans using \u003cem\u003ein vivo\u003c/em\u003e [\u003csup\u003e11\u003c/sup\u003eC]GSK189254 positron emission tomography (PET) imaging.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-four healthy individuals (2 females, 22 males; age range 20–47 years) were scanned with [\u003csup\u003e11\u003c/sup\u003eC] GSK189254. Regional \u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003eT\u003c/em\u003e\u003c/sub\u003e (volume of distribution) values were computed using the two-tissue compartment model. Correlations were adjusted for BMI, scanner, and injection tracer dosage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eV\u003c/em\u003e \u003csub\u003e\u003cem\u003eT\u003c/em\u003e\u003c/sub\u003e\u003csub\u003e \u003c/sub\u003edisplayed a negative correlation between receptor availability and age in the anterior cingulate cortex (r= -0.61, p = 0.004), frontal cortex (r= -0.50, p = 0.020), olfactory cortex (r= -0.50, p = 0.022), parietal cortex (r= -0.58, p = 0.006), cerebellum cortex (r= -0.53, p = 0.013), insula (r= -0.48, p = 0.027), putamen (r= -0.46, p = 0.034), thalamus (r= -0.45, p = 0.038), and hippocampus (r = 0.45, p = 0.039). No other significant correlations with age or BMI were found.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis \u003cem\u003ein vivo\u003c/em\u003e H3R study found a significant age-related decline in most cortical and subcortical regions.\u003c/p\u003e","manuscriptTitle":"Effects of Age and BMI on Histamine H3 Receptor Availability in Healthy Humans","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-15 15:50:04","doi":"10.21203/rs.3.rs-4004389/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-05-15T09:34:24+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-07T16:49:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-11T11:14:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Imaging and Biology","date":"2024-04-10T08:50:12+00:00","index":"","fulltext":""},{"type":"decision","content":"Major revisions","date":"2024-03-30T19:39:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-imaging-and-biology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mibi","sideBox":"Learn more about [Molecular Imaging and Biology](http://link.springer.com/journal/11307)","snPcode":"11307","submissionUrl":"https://www.editorialmanager.com/mibi/default2.aspx","title":"Molecular Imaging and Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"011db7f4-f48b-4994-8003-09563a2eff9d","owner":[],"postedDate":"May 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T06:51:54+00:00","versionOfRecord":{"articleIdentity":"rs-4004389","link":"https://doi.org/10.1007/s11307-025-02047-8","journal":{"identity":"molecular-imaging-and-biology","isVorOnly":false,"title":"Molecular Imaging and Biology"},"publishedOn":"2025-09-12 15:57:23","publishedOnDateReadable":"September 12th, 2025"},"versionCreatedAt":"2024-05-15 15:50:04","video":"","vorDoi":"10.1007/s11307-025-02047-8","vorDoiUrl":"https://doi.org/10.1007/s11307-025-02047-8","workflowStages":[]},"version":"v1","identity":"rs-4004389","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4004389","identity":"rs-4004389","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}