Noninvasive Measurement of [11C]PiB Distribution Volume Using Integrated PET/MRI

A noninvasive image-derived input function (IDIF) method using PET/MRI was applied to quantitative measurements of [11C] Pittsburgh compound-B (PiB) distribution volume (DV) and compared with other metrics. Fifty-three patients suspected of early dementia (71 ± 11 y) underwent 70 min [11C]PiB PET/MRI. Nineteen of them (68 ± 11 y) without head motion during the scan were enrolled in this study and compared with 16 age-matched healthy controls (CTL: 68 ± 11 y). The dynamic frames reconstructed from listmode PET data were used for DV calculation. IDIF with metabolite correction was applied to the Logan plot method, and DV was normalized into DV ratio (DVR) images using the cerebellar reference (DVRL). DVR and standardized uptake value ratio (SUVR) images were also calculated using the reference tissue graphical method (DVRr) and the 50–70 min static data with cerebellar reference, respectively. Cortical values were compared using the 3D-T1WI MRI segmentation. All patients were assigned to the early Alzheimer’s disease (eAD) group because of positive [11C]PiB accumulation. The correlations of regional values were better for DVRL vs. DVRr (r2 = 0.97) than for SUVR vs. DVRr (r2 = 0.88). However, all metrics clearly differentiated eAD from CTL with appropriate thresholds. Noninvasive quantitative [11C]PiB PET/MRI measurement provided equivalent DVRs with the two methods. SUVR images showed acceptable results despite inferior variability and image quality to DVR images.

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Region- and voxel-based quantification in human brain of [18F]LSN3316612, a radioligand for O-GlcNAcase

EJNMMI Research ◽

10.1186/s13550-021-00780-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jae-Hoon Lee ◽

Mattia Veronese ◽

Jeih-San Liow ◽

Cheryl L. Morse ◽

Jose A. Montero Santamaria ◽

...

Keyword(s):

Human Brain ◽

Arterial Input Function ◽

Impulse Response Function ◽

Standardized Uptake Value ◽

Compartment Model ◽

Input Function ◽

Strongly Correlated ◽

Parametric Images ◽

Logan Plot ◽

Positron Emission

Abstract Background Previous studies found that the positron emission tomography (PET) radioligand [18F]LSN3316612 accurately quantified O-GlcNAcase in human brain using a two-tissue compartment model (2TCM). This study sought to assess kinetic model(s) as an alternative to 2TCM for quantifying [18F]LSN3316612 binding, particularly in order to generate good-quality parametric images. Methods The current study reanalyzed data from a previous study of 10 healthy volunteers who underwent both test and retest PET scans with [18F]LSN3316612. Kinetic analysis was performed at the region level with 2TCM using 120-min PET data and arterial input function, which was considered as the gold standard. Quantification was then obtained at both the region and voxel levels using Logan plot, Ichise's multilinear analysis-1 (MA1), standard spectral analysis (SA), and impulse response function at 120 min (IRF120). To avoid arterial sampling, a noninvasive relative quantification (standardized uptake value ratio (SUVR)) was also tested using the corpus callosum as a pseudo-reference region. Venous samples were also assessed to see whether they could substitute for arterial ones. Results Logan and MA1 generated parametric images of good visual quality and their total distribution volume (VT) values at both the region and voxel levels were strongly correlated with 2TCM-derived VT (r = 0.96–0.99) and showed little bias (up to − 8%). SA was more weakly correlated to 2TCM-derived VT (r = 0.93–0.98) and was more biased (~ 16%). IRF120 showed a strong correlation with 2TCM-derived VT (r = 0.96) but generated noisier parametric images. All techniques were comparable to 2TCM in terms of test–retest variability and reliability except IRF120, which gave significantly worse results. Noninvasive SUVR values were not correlated with 2TCM-derived VT, and arteriovenous equilibrium was never reached. Conclusions Compared to SA and IRF, Logan and MA1 are more suitable alternatives to 2TCM for quantifying [18F]LSN3316612 and generating good-quality parametric images.

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Noninvasive Estimation of Normalized Distribution Volume: Application to the Muscarinic-2 Ligand [18F]FP-TZTP

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600530 ◽

2007 ◽

Vol 28 (2) ◽

pp. 420-430 ◽

Cited By ~ 10

Author(s):

Masanori Ichise ◽

Robert M Cohen ◽

Richard E Carson

Keyword(s):

Statistical Significance ◽

Free Fraction ◽

Cholinergic Receptor ◽

Distribution Volume ◽

Reference Region ◽

Reference Tissue ◽

Apoe Ε4 ◽

Arterial Blood ◽

Noninvasive Estimation ◽

Input Region

Reference tissue methods to estimate neuroreceptor binding are not applicable to [18F]FP-TZTP (a muscarinic-2 cholinergic receptor ligand), because there is no suitable receptor-free reference region. We evaluated a new method to estimate, without using arterial data or a receptor-free reference region, a receptor parameter called the normalized distribution volume, V*T, using a region containing receptors as the input tissue. V*T is defined as VT /K′1 (distribution volume ( VT) normalized by K′1 of the input region). We used a two-parameter multilinear reference tissue model (MRTM2) to generate parametric images of V*T and R1 ( R1 = K1/ K′1) from [18F]FP-TZTP PET data of healthy aged subjects (10 with apolipoprotein E-ε4 alleles (APOE-ε4(+)) and nine without (APOE-ε4(–)). VT and VT were normalized by plasma-free fraction, fP. By one-tissue kinetic analysis (1TKA) with metabolite-corrected plasma data, VT was previously reported as higher in the APOE-ε4(+) group. The noise magnitude of MRTM2 V*T and R1 images were nearly identical to those of 1TKA VT and K1 images. K′1 or fP was not different between the two groups. V*T (mins) (1,659 ± 497) and VT (mL/cm3) (701 ± 99) in APOE-ε4(+) were higher by 38 and 22% than those (1,209 ± 233 and 577 ± 112) in APOE-ε4(–), respectively. The statistical significance for V*T (0.041) was lower than that for VT (0.025), due to the higher intersubject variability of V*T (25%) than that of VT (17%). We conclude that MRTM2 V*T allows detection of group differences in receptor binding without arterial blood or a receptor-free reference region.

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Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

10.1101/2020.10.29.354696 ◽

2020 ◽

Author(s):

Naoyuki Obokata ◽

Chie Seki ◽

Takeshi Hirata ◽

Jun Maeda ◽

Hideki Ishii ◽

...

Keyword(s):

Arterial Input Function ◽

Inflammatory Diseases ◽

Input Function ◽

Binding Potential ◽

Dependent Manner ◽

Reference Tissue ◽

Molar Activity ◽

The Brain

AbstractPurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

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Simulating the effect of cerebral blood flow changes on regional quantification of [18F]flutemetamol and [18F]florbetaben studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20918029 ◽

2020 ◽

pp. 0271678X2091802

Author(s):

Fiona Heeman ◽

Maqsood Yaqub ◽

Isadora Lopes Alves ◽

Kerstin Heurling ◽

Santiago Bullich ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Time Window ◽

Standardized Uptake Value ◽

Volume Of Distribution ◽

Reference Tissue ◽

Time Activity ◽

Amyloid Load ◽

Flow Changes ◽

Simplified Reference Tissue Model

Global and regional changes in cerebral blood flow (CBF) can result in biased quantitative estimates of amyloid load by PET imaging. Therefore, the current simulation study assessed effects of these changes on amyloid quantification using a reference tissue approach for [18F]flutemetamol and [18F]florbetaben. Previously validated pharmacokinetic rate constants were used to simulate time-activity curves (TACs) corresponding to full dynamic and dual-time-window acquisition protocols. CBF changes were simulated by varying the tracer delivery ( K1) from +25 to −25%. The standardized uptake value ratio (SUVr) was computed and TACs were fitted using reference Logan (RLogan) and the simplified reference tissue model (SRTM) to obtain the relative delivery rate ( R1) and volume of distribution ratio (DVR). RLogan was least affected by CBF changes ( χ2 = 583 p < 0.001, χ2 = 81 p < 0.001, for [18F]flutemetamol and [18F]florbetaben, respectively) and the extent of CBF sensitivity generally increased for higher levels of amyloid. Further, SRTM-derived R1 changes correlated well with simulated CBF changes ( R2 > 0.95) and SUVr’s sensitivity to CBF changes improved for later uptake-times, with the exception of [18F]flutemetamol cortical changes. In conclusion, RLogan is the preferred method for amyloid quantification of [18F]flutemetamol and [18F]florbetaben studies and SRTM could be additionally used for obtaining a CBF proxy.

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The use of a reference tissue arterial input function with low-temporal-resolution DCE-MRI data

Physics in Medicine and Biology ◽

10.1088/0031-9155/55/16/016 ◽

2010 ◽

Vol 55 (16) ◽

pp. 4871-4883 ◽

Cited By ~ 18

Author(s):

M Heisen ◽

X Fan ◽

J Buurman ◽

N A W van Riel ◽

G S Karczmar ◽

...

Keyword(s):

Temporal Resolution ◽

Arterial Input Function ◽

Input Function ◽

Reference Tissue ◽

Dce Mri

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Building a database for brain 18 kDa translocator protein imaged using [11C]PBR28 in healthy subjects

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18771250 ◽

2018 ◽

Vol 39 (6) ◽

pp. 1138-1147 ◽

Cited By ~ 7

Author(s):

Soumen Paul ◽

Evan Gallagher ◽

Jeih-San Liow ◽

Sanche Mabins ◽

Katharine Henry ◽

...

Keyword(s):

Healthy Subjects ◽

High Performance ◽

Patient Characteristics ◽

Brain Regions ◽

Distribution Volume ◽

Translocator Protein ◽

Blood Samples ◽

Arterial Blood ◽

Logan Plot ◽

Translocator Protein 18 Kda

Translocator protein 18 kDa (TSPO) has been widely imaged as a marker of neuroinflammation using several radioligands, including [11C]PBR28. In order to study the effects of age, sex, and obesity on TSPO binding and to determine whether this binding can be accurately assessed using fewer radio high-performance liquid chromatography (radio-HPLC) measurements of arterial blood samples, we created a database of 48 healthy subjects who had undergone [11C]PBR28 scans (23 high-affinity binders (HABs) and 25 mixed-affinity binders (MABs), 20 F/28 M, age: 40.6 ± 16.8 years). After analysis by Logan plot using 23 metabolite-corrected arterial samples, total distribution volume ( VT) was found to be 1.2-fold higher in HABs across all brain regions. Additionally, the polymorphism plot estimated nondisplaceable uptake ( VND) as 1.40 mL · cm−3, which generated a specific-to-nondisplaceable ratio ( BPND) of 1.6 ± 0.6 in HABs and 1.1 ± 0.6 in MABs. VT increased significantly with age in nearly all regions and was well estimated with radio-HPLC measurements from six arterial samples. However, VT did not correlate with body mass index and was not affected by sex. These results underscore which patient characteristics should be accounted for during [11C]PBR28 studies and suggest ways to perform such studies more easily and with fewer blood samples.

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Kinetic Studies of Fibrinogen in Pregnant Rabbits

10.1055/s-0039-1682442 ◽

1977 ◽

Author(s):

R.-M. Moeller ◽

I. Mahn ◽

G. Müller-Berqhaus

Keyword(s):

Kinetic Studies ◽

Distribution Volume ◽

Fractional Catabolic Rate ◽

Third Trimester ◽

The Third ◽

Quantitative Measurements ◽

Catabolic Rate ◽

Average Acceleration ◽

The Mean ◽

Kinetics Of

During gestation increased concentrations of fibrin (ogen)derivatives are observed indicative of intravascular action of thrombin. The aim of this study was to elucidate the kinetics of fibrinogen during gestation. The elimination of homologous 1-125-fibrinogen was studied in 14 pregnant rabbits during the first as well as during the third trimesters of gestation. Control studies were performed with 10 non-pregnant rabbits.The mean distribution volume of labeled fibrinogen did not significantly differ between pregnant and non-pregnant rabbits. During the third trimester pregnant rabbits demonstrated a pronounced shortening of T 1/2 of labeled fibrinogen from a mean of 55.3 hr during the first to a mean of 29.7 hr during the third trimester. The experiments showed a significant increase in the fractional catabolic rate from 45.0 to 69.9% per day in the course of gestation. The shortening of T 1/2 of labeled fibrinogen correlated to the number of fetusses per litter.This study indicates an average acceleration of the fibrinogen turnover during gestation of about 50%. These direct quantitative measurements demonstrate that fibrinogen catabolism is pronouncedly accelerated during pregnancy.

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Relationship of amyloid-β1–42 in blood and brain amyloid: Ginkgo Evaluation of Memory Study

Brain Communications ◽

10.1093/braincomms/fcz038 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Oscar L Lopez ◽

William E Klunk ◽

Chester A Mathis ◽

Beth E Snitz ◽

Yuefang Chang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Pet Imaging ◽

Standardized Uptake Value ◽

Amyloid Plaques ◽

Amyloid Deposition ◽

Pittsburgh Compound B ◽

Blood Samples ◽

Apolipoprotein E4 ◽

The Brain ◽

Brain Amyloid Deposition

Abstract A blood test that predicts the extent of amyloid plaques in the brain and risk of Alzheimer’s disease would have important benefits for the early identification of higher risk of dementia and Alzheimer’s disease and the evaluation of new preventative therapies. The goal of this study was to determine whether plasma levels of amyloid-β1–42, 1–40 and the amyloid-β1–42/1–40 ratio among participants in the Pittsburgh centre of the Ginkgo Evaluation of Memory Study were related to the extent of brain fibrillar amyloid plaques measured in 2009 using Pittsburgh compound-B PET imaging, hippocampal volume, cortical thickness in the temporal lobe and white matter lesions. There were 194 participants who had Pittsburgh compound-B measurements in 2009 with the mean age of 85 years; 96% were white and 60% men. Pittsburgh compound-B positivity was defined as a standardized uptake value ratio of ≥1.57. Amyloid-β in blood was measured using a sandwich enzyme-linked immunosorbent assay developed by Eli Lilly and modified at the University of Vermont. All participants were nondemented as of 2008 at the time of study close out. The study sample included 160 with blood samples drawn in 2000–02 and 133 from 2009 and also had brain amyloid measured in 2009. All blood samples were analysed at the same time in 2009. Plasma amyloid-β1–42 was inversely related to the percent Pittsburgh compound-B positive (standardized uptake value ratio ≥1.57), β −0.04, P = 0.005. Practically all participants who were apolipoprotein-E4 positive at older ages were also Pittsburgh compound-B positive for fibrillar amyloid. Among apolipoprotein-E4-negative participants, quartiles of amyloid-β1–42 were inversely related to Pittsburgh compound-B positivity. In multiple regression models, plasma amyloid-β1–42 measured in 2000–02 or 2009 were significantly and inversely related to Pittsburgh compound-B positivity as was the amyloid-β1–42/1–40 ratio. There was a 4-fold increase in the odds ratio for the presence of Pittsburgh compound-B positivity in the brain in 2009 for the first quartile of amyloid-β1–42 as compared with the fourth quartile in the multiple logistic model. This is one of the first longitudinal studies to evaluate the relationship between amyloid-β1–42 in the blood and the extent of brain amyloid deposition measured by PET imaging using Pittsburgh compound-B. Our findings showed that remote and recent low plasma amyloid-β1–42 levels were inversely associated with brain amyloid deposition in cognitively normal individuals. However, changes in plasma amyloid-β1–42 over time (8 years) were small and not related to the amount of Pittsburgh compound-B.

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Evaluation of Simplified Kinetic Analyses for Measurement of Brain Acetylcholinesterase Activity Using N-[11C]Methylpiperidin-4-yl Propionate and Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000117689.98763.6a ◽

2004 ◽

Vol 24 (6) ◽

pp. 600-611 ◽

Cited By ~ 10

Author(s):

Koichi Sato ◽

Kiyoshi Fukushi ◽

Hitoshi Shinotoh ◽

Shinichiro Nagatsuka ◽

Noriko Tanaka ◽

...

Keyword(s):

Ache Activity ◽

Arterial Input Function ◽

Acetylcholinesterase Activity ◽

Input Function ◽

Previous Method ◽

Target Tissue ◽

Standard Analysis ◽

Reference Tissue ◽

Arterial Blood ◽

Positron Emission

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.

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