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Richard E. Carson

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YNIMG Journal 2026 Journal Article

Dose reduction for synaptic density PET imaging in Parkinson’s disease

  • Andi Li
  • Mika Naganawa
  • Praveen Honhar
  • Kathryn Fontaine
  • Paul Gravel
  • David Matuskey
  • Richard E. Carson
  • Jing Tang

OBJECTIVE: C-UCB-J enables in vivo quantification of synaptic vesicle glycoprotein 2A (SV2A), with prior reports of lower synaptic density in areas such as the brainstem nuclei and substantia nigra (SN) in Parkinson's disease (PD). Lowering PET dose reduces radiation exposure but increases noise and compromises quantification. This study evaluated a self-supervised two-step deep image prior (TS-DIP) denoising method for SV2A PET using 1/10 of the standard dose. METHODS: ) maps were estimated. Performance was assessed by comparing group differences and correlations with motor severity against full-count results. RESULTS: in SN (-39%, p = 0.003) and red nucleus (RN; -27%, p = 0.009) in PDs versus HCs. With 1/10-count data, SN differences remained significant, but RN differences were inconsistent. TS-DIP introduced minimal bias, restored statistical significance across all noise realizations, and improved recovery of correlations with motor scores (SN: r = -0.43 ± 0.02; RN: r = -0.42 ± 0.04) compared with those from unprocessed 1/10-count data. CONCLUSIONS: Dynamic SV2A PET imaging at substantially reduced doses is feasible when combined with advanced DL-based denoising techniques such as TS-DIP, supporting its potential for broader clinical application.

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YNICL Journal 2023 Journal Article

Principal component analysis of synaptic density measured with [11C]UCB-J PET in early Alzheimer’s disease

  • Ryan S. O'Dell
  • Albert Higgins-Chen
  • Dhruva Gupta
  • Ming-Kai Chen
  • Mika Naganawa
  • Takuya Toyonaga
  • Yihuan Lu
  • Gessica Ni

BACKGROUND: C]UCB-J PET and assessed the association between principal components (PC) subject scores with cognitive performance. METHODS: C]UCB-J binding was measured in 45 amyloid + participants with AD and 19 amyloid- cognitively normal participants aged 55-85. A validated neuropsychological battery assessed performance across five cognitive domains. PCA was applied to the pooled sample using distribution volume ratios (DVR) standardized (z-scored) by region from 42 bilateral regions of interest (ROI). RESULTS: Parallel analysis determined three significant PCs explaining 70.2% of the total variance. PC1 was characterized by positive loadings with similar contributions across the majority of ROIs. PC2 was characterized by positive and negative loadings with strongest contributions from subcortical and parietooccipital cortical regions, respectively, while PC3 was characterized by positive and negative loadings with strongest contributions from rostral and caudal cortical regions, respectively. Within the AD group, PC1 subject scores were positively correlated with performance across all cognitive domains (Pearson r = 0.24-0.40, P = 0.06-0.006), PC2 subject scores were inversely correlated with age (Pearson r = -0.45, P = 0.002) and PC3 subject scores were significantly correlated with CDR-sb (Pearson r = 0.46, P = 0.04). No significant correlations were observed between cognitive performance and PC subject scores in CN participants. CONCLUSIONS: This data-driven approach defined specific spatial patterns of synaptic density correlated with unique participant characteristics within the AD group. Our findings reinforce synaptic density as a robust biomarker of disease presence and severity in the early stages of AD.

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YNIMG Journal 2022 Journal Article

Adaptive data-driven motion detection and optimized correction for brain PET

  • Enette Mae Revilla
  • Jean-Dominique Gallezot
  • Mika Naganawa
  • Takuya Toyonaga
  • Kathryn Fontaine
  • Tim Mulnix
  • John A. Onofrey
  • Richard E. Carson

C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner.

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YNIMG Journal 2022 Journal Article

Age, gender and body-mass-index relationships with in vivo CB1 receptor availability in healthy humans measured with [11C]OMAR PET

  • Rajiv Radhakrishnan
  • Patrick D. Worhunsky
  • Ming-Qiang Zheng
  • Soheila Najafzadeh
  • Jean-Dominique Gallezot
  • Beata Planeta
  • Shannan Henry
  • Nabeel Nabulsi

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18–55 years; 44 male; BMI=27. 01±5. 56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (V T) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in V T remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.

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YNIMG Journal 2022 Journal Article

An objective evaluation method for head motion estimation in PET—Motion corrected centroid-of-distribution

  • Chen Sun
  • Enette Mae Revilla
  • Jiazhen Zhang
  • Kathryn Fontaine
  • Takuya Toyonaga
  • Jean-Dominique Gallezot
  • Tim Mulnix
  • John A. Onofrey

Head motion presents a continuing problem in brain PET studies. A wealth of motion correction (MC) algorithms had been proposed in the past, including both hardware-based methods and data-driven methods. However, in most real brain PET studies, in the absence of ground truth or gold standard of motion information, it is challenging to objectively evaluate MC quality. For MC evaluation, image-domain metrics, e.g., standardized uptake value (SUV) change before and after MC are commonly used, but this measure lacks objectivity because 1) other factors, e.g., attenuation correction, scatter correction and parameters used in the reconstruction, will confound MC effectiveness; 2) SUV only reflects final image quality, and it cannot precisely inform when an MC method performed well or poorly during the scan time period; 3) SUV is tracer-dependent and head motion may cause increases or decreases in SUV for different tracers, so evaluating MC effectiveness is complicated. Here, we present a new algorithm, i.e., motion corrected centroid-of-distribution (MCCOD) to perform objective quality control for measured or estimated rigid motion information. MCCOD is a three-dimensional surrogate trace of the center of tracer distribution after performing rigid MC using the existing motion information. MCCOD is used to inform whether the motion information is accurate, using the PET raw data only, i.e., without PET image reconstruction, where inaccurate motion information typically leads to abrupt changes in the MCCOD trace. MCCOD was validated using simulation studies and was tested on real studies acquired from both time-of-flight (TOF) and non-TOF scanners. A deep learning-based brain mask segmentation was implemented, which is shown to be necessary for non-TOF MCCOD generation. MCCOD is shown to be effective in detecting abrupt translation motion errors in slowly varying tracer distribution caused by the motion tracking hardware and can be used to compare different motion estimation methods as well as to improve existing motion information.

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YNIMG Journal 2021 Journal Article

Effect of age on brain metabotropic glutamate receptor subtype 5 measured with [18F]FPEB PET

  • Adam P. Mecca
  • Kelly Rogers
  • Zachary Jacobs
  • Julia W. McDonald
  • Hannah R. Michalak
  • Nicole DellaGioia
  • Wenzhen Zhao
  • Ansel T Hillmer

OBJECTIVE: Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain mGluR5 availability. METHODS: in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined. RESULTS: F]FPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction. CONCLUSION: F]FPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss.

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YNIMG Journal 2021 Journal Article

Identifying brain networks in synaptic density PET (11C-UCB-J) with independent component analysis

  • Xiaotian T. Fang
  • Takuya Toyonaga
  • Ansel T. Hillmer
  • David Matuskey
  • Sophie E. Holmes
  • Rajiv Radhakrishnan
  • Adam P. Mecca
  • Christopher H. van Dyck

BACKGROUND: C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI. METHODS: C-UCB-J data using independent component analysis (ICA), a data-driven analysis method. Using a population of 80 healthy controls, we applied ICA to two 40-sample subsets and compared source network replication across samples. We examined the identified source networks at multiple model orders, as the ideal number of maximally independent components (IC) is unknown. In addition, we investigated the relationship between the strength of the loading weights for each source network and age and sex. RESULTS: Thirteen source networks replicated across both samples. We determined that a model order of 18 components provided stable, replicable components, whereas estimations above 18 were not stable. Effects of sex were found in two ICs. Nine ICs showed age-related change, with 4 remaining significant after correction for multiple comparison. CONCLUSION: This study provides the first evidence that human brain synaptic density can be characterized into organized covariance patterns. Furthermore, we demonstrated that multiple synaptic density source networks are associated with age, which supports the potential utility of ICA to identify biologically relevant synaptic density source networks.

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YNIMG Journal 2021 Journal Article

Partial volume correction analysis for 11C-UCB-J PET studies of Alzheimer's disease

  • Yihuan Lu
  • Takuya Toyonaga
  • Mika Naganawa
  • Jean-Dominique Gallezot
  • Ming-Kai Chen
  • Adam P. Mecca
  • Christopher H. van Dyck
  • Richard E. Carson

PURPOSE: C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC). METHODS: (centrum semiovale as reference region), and tissue volume were compared. RESULTS: group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions. CONCLUSION: C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG.

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YNIMG Journal 2020 Journal Article

Separating dopamine D2 and D3 receptor sources of [11C]-(+)-PHNO binding potential: Independent component analysis of competitive binding

  • Kelly Smart
  • Jean-Dominique Gallezot
  • Nabeel Nabulsi
  • David Labaree
  • Ming-Qiang Zheng
  • Yiyun Huang
  • Richard E. Carson
  • Ansel T. Hillmer

Development of medications selective for dopamine D2 or D3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson’s disease. The positron emission tomography (PET) radiotracer [11C]-(+)-PHNO, an agonist that binds with high affinity to both D2 and D3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D2 and D3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D2-and D3-related signal in [11C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [11C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D3-preferring antagonist ABT-728 (150–1000 ​mg). Parametric binding potential (BP ND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [11C]-(+)-PHNO BP ND. Spatial source maps for each component were consistent with respective regional patterns of D2-and D3-related binding. ICA-derived occupancy estimates from each component were similar to D2-and D3-specific occupancy estimated from a region-based approach (intraclass correlation coefficients ​> ​0. 95). ICA-derived estimates of D3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [11C]-(+)-PHNO binding related to D3 receptors was generated for each subject and values showed good agreement with region-based model estimates and prior literature values. In summary, ICA successfully separated D2-and D3-related components of the [11C]-(+)-PHNO binding signal, establishing this approach as a powerful data-driven method to quantify distinct biological features from PET data composed of mixed data sources.

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YNIMG Journal 2017 Journal Article

Regional and source-based patterns of [ 11 C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D 2 and D 3 receptor availability in cocaine-use disorder

  • Patrick D. Worhunsky
  • David Matuskey
  • Jean-Dominique Gallezot
  • Edward C. Gaiser
  • Nabeel Nabulsi
  • Gustavo A. Angarita
  • Vince D. Calhoun
  • Robert T. Malison

Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BP ND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BP ND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BP ND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BP ND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BP ND in the D2R-rich dorsal striatum and greater BP ND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BP ND that were correlated with regional estimates of D2R-related and D3R-related proportions of BP ND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

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YNIMG Journal 2016 Journal Article

Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

  • David Matuskey
  • Patrick Worhunksy
  • Elizabeth Correa
  • Brian Pittman
  • Jean-Dominique Gallezot
  • Nabeel Nabulsi
  • Jim Ropchan
  • Venkatesh Sreeram

Objective Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [11C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. Methods Forty-two healthy control subjects (9 females, 33 males; age range 19–55years) were scanned with [11C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BP ND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. Results Regional [11C](+)PHNO BP ND displayed a negative correlation between receptor availability and age in the caudate (r =−0. 56, corrected p =0. 0008) and putamen (r =−0. 45, corrected p =0. 02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. Conclusion In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [11C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

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YNIMG Journal 2014 Journal Article

Decreased norepinephrine transporter availability in obesity: Positron Emission Tomography imaging with (S,S)-[11C]O-methylreboxetine

  • Chiang-shan R. Li
  • Marc N. Potenza
  • Dianne E. Lee
  • Beata Planeta
  • Jean-Dominique Gallezot
  • David Labaree
  • Shannan Henry
  • Nabeel Nabulsi

Objectives Noradrenergic dysfunction is implicated in obesity. The norepinephrine transporter (NET) regulates the synaptic availability of norepinephrine. However, NET availability has not been previously characterized in vivo in obese people using Positron Emission Tomography (PET) imaging. Here we report findings evaluating NET availability in individuals with obesity and matched lean (i. e. , normal weight) comparison subjects. Methods Seventeen obese but otherwise healthy individuals with a mean±SD body mass index (BMI) of 34. 7±2. 6 and 17 lean individuals with a mean±SD BMI of 23. 1±1. 4 were studied using a high-resolution research tomograph (HRRT) and (S, S)-[11C]O-methylreboxetine ([11C]-MRB), a radioligand selective for the NET. The regional brain NET binding potential (BP ND) was estimated by the multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. BP ND for regions of interest were obtained with the Automated Anatomic Labeling (AAL) template registered to individual's structural MR scans. Results Obese individuals had lower NET BP ND values in the thalamus (p <0. 038, 27% reduction) including within the pulvinar (p <0. 083, 30% reduction), but not in the hypothalamus, locus coeruleus or the raphe nuclei, compared to lean individuals. When age was included as a covariate, the difference in NET BP ND values remained significant in the thalamus (p <0. 025) and pulvinar (p <0. 042). Conclusions These results indicate that NET availability is decreased in the thalamus, including the pulvinar, in obese individuals. These findings further support data indicating noradrenergic dysfunction in obesity and suggest impaired NE clearance in obesity.

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YNIMG Journal 2014 Journal Article

Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

  • Mika Naganawa
  • Leslie K. Jacobsen
  • Ming-Qiang Zheng
  • Shu-fei Lin
  • Anindita Banerjee
  • Wonkyung Byon
  • David Weinzimmer
  • Giampaolo Tomasi

Introduction Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [11C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test–retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V ND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. Methods For determination of a kinetic model and evaluation of test–retest reproducibility, 11 subjects were scanned twice with [11C]GR103545. Seven subjects were scanned before and 75min after oral administration of naltrexone (150mg). For the KOR occupancy study, six subjects were scanned at baseline and 1. 5h and 8h after an oral dose of PF-04455242 (15mg, n =1 and 30mg, n =5). Metabolite-corrected arterial input functions were measured and all scans were 150min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V T). Relative test–retest variability (TRV), absolute test–retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test–retest reproducibility of regional V T. Occupancy plots were computed for blocking studies to estimate occupancy and V ND. The half maximal inhibitory concentration (IC 50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [11C]GR103545 in vivo K D was also estimated. Results Regional TACs were well described by the 2TC model and MA1. However, 2TC V T was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test–retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V T was reduced in all regions; thus no suitable reference region is available for the radiotracer. V ND was estimated reliably from the occupancy plot of naltrexone blocking (V ND =3. 4±0. 9mL/cm3). The IC 50 of PF-04455242 was calculated as 55ng/mL. [11C]GR103545 in vivo K D value was estimated as 0. 069nmol/L. Conclusions [11C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.

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YNIMG Journal 2013 Journal Article

Optimization of PET–MR registrations for nonhuman primates using mutual information measures: A Multi-Transform Method (MTM)

  • Christine M. Sandiego
  • David Weinzimmer
  • Richard E. Carson

An important step in PET brain kinetic analysis is the registration of functional data to an anatomical MR image. Typically, PET–MR registrations in nonhuman primate neuroreceptor studies used PET images acquired early post-injection, (e. g. , 0–10min) to closely resemble the subject's MR image. However, a substantial fraction of these registrations (~25%) fail due to the differences in kinetics and distribution for various radiotracer studies and conditions (e. g. , blocking studies). The Multi-Transform Method (MTM) was developed to improve the success of registrations between PET and MR images. Two algorithms were evaluated, MTM-I and MTM-II. The approach involves creating multiple transformations by registering PET images of different time intervals, from a dynamic study, to a single reference (i. e. , MR image) (MTM-I) or to multiple reference images (i. e. , MR and PET images pre-registered to the MR) (MTM-II). Normalized mutual information was used to compute similarity between the transformed PET images and the reference image(s) to choose the optimal transformation. This final transformation is used to map the dynamic dataset into the animal's anatomical MR space, required for kinetic analysis. The chosen transforms from MTM-I and MTM-II were evaluated using visual rating scores to assess the quality of spatial alignment between the resliced PET and reference images. One hundred twenty PET datasets involving eleven different tracers from 3 different scanners were used to evaluate the MTM algorithms. Studies were performed with baboons and rhesus monkeys on the HR+, HRRT, and Focus-220. Successful transformations increased from 77. 5%, 85. 8%, to 96. 7% using the 0–10min method, MTM-I, and MTM-II, respectively, based on visual rating scores. The Multi-Transform Methods proved to be a robust technique for PET–MR registrations for a wide range of PET studies.

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YNIMG Journal 2012 Journal Article

Endotoxin-induced systemic inflammation activates microglia: [11C]PBR28 positron emission tomography in nonhuman primates

  • Jonas Hannestad
  • Jean-Dominique Gallezot
  • Thomas Schafbauer
  • Keunpoong Lim
  • Tracy Kloczynski
  • Evan D. Morris
  • Richard E. Carson
  • Yu-Shin Ding

Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediate the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [11C]PBR28. Methods Six female baboons (Papio anubis) were scanned before and at 1h and/or 4h and/or 22h after intravenous administration of E. coli lipopolysaccharide (LPS; 0. 1mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (V T) of [11C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in V T from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO. Results LPS administration increased [11C]PBR28 binding (F(3, 6)=5. 1, p =. 043) with a 29±16% increase at 1h (n =4) and a 62±34% increase at 4h (n =3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [11C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes. Conclusion In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [11C]PBR28 PET. The effect of LPS on [11C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.

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YNIMG Journal 2011 Journal Article

Evaluation of [11C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates

  • Jean-Dominique Gallezot
  • David Weinzimmer
  • Nabeel Nabulsi
  • Shu-fei Lin
  • Krista Fowles
  • Christine Sandiego
  • Timothy J. McCarthy
  • R. Paul Maguire

[11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [11C]MRB volume of distribution was observed after correction for [11C]MRB plasma free fraction. ATX IC 50 was estimated to be 31±10ng/mL plasma. This corresponds to an effective dose (ED 50) of 0. 13mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1. 0–1. 5mg/kg). [11C]MRB binding potential BP ND in the thalamus was estimated to be 1. 8±0. 3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC 50 estimate obtained using MRTM2 BP ND without arterial blood sampling was 21±3ng/mL (using caudate as the reference region). This study demonstrated that [11C]MRB is suitable for drug occupancy studies of NET.

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YNIMG Journal 2007 Journal Article

Imaging signal transduction via arachidonic acid in the human brain during visual stimulation, by means of positron emission tomography

  • Giuseppe Esposito
  • Giampiero Giovacchini
  • Margaret Der
  • Jeih-San Liow
  • Abesh K. Bhattacharjee
  • Kaizong Ma
  • Peter Herscovitch
  • Michael Channing

Background: Arachidonic acid (AA, 20: 4n-6), an important second messenger, is released from membrane phospholipid following receptor mediated activation of phospholipase A2 (PLA2). This signaling process can be imaged in brain as a regional brain AA incorporation coefficient K*. Hypothesis: K* will be increased in brain visual areas of subjects submitted to visual stimulation. Subjects and methods: Regional values of K* were measured with positron emission tomography (PET), following the intravenous injection of [1-11C]AA, in 16 healthy volunteers subjected to visual stimulation at flash frequencies 2. 9 Hz (8 subjects) or 7. 8 Hz (8 subjects), compared with the dark (0 Hz) condition. Regional cerebral blood flow (rCBF) was measured with intravenous [15O]water under comparable conditions. Results: During flash stimulation at 2. 9 Hz or 7. 8 Hz vs. 0 Hz, K* was increased significantly by 2. 3–8. 9% in Brodmann areas 17, 18 and 19, and in additional frontal, parietal and temporal cortical regions. rCBF was increased significantly by 3. 1–22%, often in comparable regions. Increments at 7. 8 Hz often exceeded those at 2. 9 Hz for both K* and rCBF. Decrements in both parameters also were produced, particularly in frontal brain regions. Conclusions: AA plays a role in signaling processes provoked by visual stimulation, since visual stimulation at flash frequencies of 2. 9 and 7. 8 Hz compared to 0 Hz modifies both K* for AA and rCBF in visual and related areas of the human brain. The two-stimulus condition paradigm of this study might be used with PET to image effects of other functional activations and of drugs on brain signaling via AA.

Details DOI

YNIMG Journal 2005 Journal Article

Differential effects of paroxetine on raphe and cortical 5-HT1A binding: A PET study in monkeys

  • Giampiero Giovacchini
  • Lixin Lang
  • Ying Ma
  • Peter Herscovitch
  • William C. Eckelman
  • Richard E. Carson

Positron emission tomography (PET) ligands that are sensitive to transient changes in serotonin (5-HT) concentration are desirable for studies of neuropsychiatric diseases. Few studies, however, have sought to demonstrate that variations in 5-HT concentration can be closely tracked with available serotonergic ligands. Microdialysis studies in rats have shown a maximal increase in 5-HT concentration in raphe nuclei after systemic infusion of selective serotonergic re-uptake inhibitors (SSRIs). We performed PET scans with [18F]FPWAY, an intermediate-affinity antagonist of 5-HT1A receptors, in 4 anesthetized rhesus monkeys in control studies and after systemic paroxetine administration (5 mg/kg, i. v.). In addition, a paired [11C]DASB study revealed that this paroxetine regimen produced an occupancy of 54–83% of the serotonin transporters. According to the conventional receptor competition model, increased 5-HT concentration produces decreased binding of the radioactive ligand. Over a 3-h period following paroxetine infusion, a progressively increasing reduction (ranging from 8 ± 6% to 27 ± 10%) of [18F]FPWAY-specific binding was found in the raphe nuclei. This result is interpreted as an SSRI-induced increase in 5-HT concentration, potentially combined with reduced binding to internalized 5-HT1A receptors. In addition, a transient (1 h) increase in cerebral cortical binding was observed, attributed primarily to a reduction in cortical 5-HT due to the effects of raphe autoreceptor inhibition. This study is the first demonstration of the feasibility of quantifying dynamic changes in 5-HT neurotransmission in the raphe and the cortex with PET. These results lend promise to the use of these serotonergic neuroimaging techniques to study neuropsychiatric disorders.

Details DOI
v2026.09.13