Multilinear Reference Tissue Model Research Articles

Non‐invasive kinetic modeling of [18F]‐florbetaben and [18F]‐PI‐2620 with total‐body dynamic EXPLORER PET

AbstractBackgroundThis study aims to quantify amyloid and tau buildup in older individuals with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and [18F]‐PI‐2620 total‐body EXPLORER PET.MethodFifteen adults (9 CU, 2 MCI, and 3 AD) aged 66‐86 underwent dynamic total‐body 18F‐florbetaben [110min] and PI‐2620 PET [90min] (United Imaging). 3 CU adults also underwent Tau PET for this initial analysis. IDIFs were derived from descending aorta ROIs. PET volumes were motion corrected (FSL‐MCFLIRT) and linearly registered (FSL‐FLIRT) to T1W image. The DKT ATLAS was used to segment brain cortical regions that are involved in neurodegeneration for PET SUVR measurements. PET SUVR means were calculated from 10 index regions and the cerebellar gray matter as the reference. Dynamic time activity curves were fit to the two‐tissue compartment model (2TCM) using joint estimation and population metabolite‐corrected IDIFs (Li, JNM 2021). The Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).Result[18F]‐Florbetaben Aβ+/Tau‐ SUVR was the highest in each brain index region, while PI‐2620 showed elevated SUVR in brain regions associated with early Braak stages I‐III in both Aβ‐/Tau‐ and Aβ+/Tau‐ (Fig 2). In our tau‐negative cohort, PI‐2620 signal in both cortical and reference regions, as expected, had low specific distribution volume (Vs) values (1.43 ±0.56) in both HC and AD. [18F]‐Florbetaben cortical Vs values were roughly 4 times higher than cerebellum in the Aβ+/Tau‐ (AD) individual and PI‐2620 cortical Vs values were 3.5 times higher compared to the cerebellum in both HC and AD. Mean k₁ values, which reflect regional blood flow, were similar in both AD and HC in both [18F]‐florbetaben and PI‐2620 PET analyses (Table 1). SUVR and DVR from MRTM kinetic models were correlated for each tracer; with slight overestimation of SUVR compared to DVR.ConclusionAbsolute quantification of amyloid and tau binding from total‐body PET data is feasible using aorta IDIFs and enables high quality kinetic modeling for accurate measures in clinical research of aging and dementia.

Non‐invasive kinetic modeling of [18F]‐florbetaben and [18F]‐PI‐2620 with total‐body dynamic EXPLORER PET

AbstractBackgroundThis study aims to quantify amyloid and tau buildup in older individuals with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and [18F]‐PI‐2620 total‐body EXPLORER PET.MethodFifteen adults (9 CU, 2 MCI, and 3 AD) aged 66‐86 underwent dynamic total‐body 18F‐florbetaben [110min] and PI‐2620 PET [90min] (United Imaging). 3 CU adults also underwent Tau PET for this initial analysis. IDIFs were derived from descending aorta ROIs. PET volumes were motion corrected (FSL‐MCFLIRT) and linearly registered (FSL‐FLIRT) to T1W image. The DKT ATLAS was used to segment brain cortical regions that are involved in neurodegeneration for PET SUVR measurements. PET SUVR means were calculated from 10 index regions and the cerebellar gray matter as the reference. Dynamic time activity curves were fit to the two‐tissue compartment model (2TCM) using joint estimation and population metabolite‐corrected IDIFs (Li, JNM 2021). The Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).Result[18F]‐Florbetaben Aβ+/Tau‐ SUVR was the highest in each brain index region, while PI‐2620 showed elevated SUVR in brain regions associated with early Braak stages I‐III in both Aβ‐/Tau‐ and Aβ+/Tau‐ (Fig 2). In our tau‐negative cohort, PI‐2620 signal in both cortical and reference regions, as expected, had low specific distribution volume (Vs) values (1.43 ±0.56) in both HC and AD. [18F]‐Florbetaben cortical Vs values were roughly 4 times higher than cerebellum in the Aβ+/Tau‐ (AD) individual and PI‐2620 cortical Vs values were 3.5 times higher compared to the cerebellum in both HC and AD. Mean k₁ values, which reflect regional blood flow, were similar in both AD and HC in both [18F]‐florbetaben and PI‐2620 PET analyses (Table 1). SUVR and DVR from MRTM kinetic models were correlated for each tracer; with slight overestimation of SUVR compared to DVR.ConclusionAbsolute quantification of amyloid and tau binding from total‐body PET data is feasible using aorta IDIFs and enables high quality kinetic modeling for accurate measures in clinical research of aging and dementia.

Is serotonin transporter brain binding associated with the cortisol awakening response? An independent non-replication.

Serotonergic brain signaling is considered critical for an appropriate and dynamic adaptation to stress, seemingly through modulating limbic system functions, such as the hypothalamic-pituitary-adrenal (HPA)-axis. This interplay is of great interest since it holds promise as a target for preventing stress-related brain disorders, e.g., major depression. Our group has previously observed that prefrontal serotonin transporter (5-HTT) binding, imaged with positron emission tomography (PET), is positively associated with the cortisol awakening response (CAR), an index of HPA axis stress hormone dynamics. The aim of this cross-sectional study was to replicate the previous finding in a larger independent group of healthy individuals. Molecular imaging and cortisol data were available for 90 healthy individuals. Prefrontal 5-HTT binding was imaged with [11C]DASB brain PET. Non-displaceable 5-HTT binding potential (BPND) was quantified using the Multilinear Reference Tissue Model 2 (MRTM2) with cerebellum as the reference region. CAR was based on five serial salivary cortisol samples within the first hour upon awakening. The association between CAR and prefrontal 5-HTT BPND was evaluated using a multiple linear regression model adjusted for age and sex. Further, we tested for sex differences in the association. Finally, an exploratory analysis of the association, was performed in 8 additional brain regions. We observed no statistically significant association between 5-HTT binding and CAR corrected for age and sex in the prefrontal cortex (β = -0.28, p = 0.26). We saw no interaction with sex on the association (p = 0.99). We could not confirm a positive association between CAR and prefrontal 5-HTT BPND in this independent dataset. Also, sex differences in the association were not apparent. Our data do not exclude that the serotonin transporter system is involved in the regulation of stress responses in at-risk or manifest depressed states.

Relationships of in vivo brain norepinephrine transporter and age, BMI, and gender.

Previous research reported an age-related decline in brain norepinephrine transporter (NET) using (S, S)-[11C]O-methylreboxetine ([11C]MRB) as a radiotracer. Studies with the same tracer have been mixed in regard to differences related to body mass index (BMI). Here, we investigated potential age-, BMI-, and gender-related differences in brain NET availability using [11C]MRB, the most selective available radiotracer. Forty-three healthy participants (20 females, 23 males; age range 18-49 years), including 12 individuals with normal/lean weight, 15 with overweight, and 16 with obesity were scanned with [11C]MRB using a positron emission tomography (PET) high-resolution research tomograph (HRRT). We evaluated binding potential (BPND ) in brain regions with high NET availability using multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. Brain regions were delineated with a defined anatomic template applied to subjects' structural MR scans. We found a negative association between age and NET availability in the locus coeruleus, raphe nucleus, and hypothalamus, with a 17%, 19%, and 14% decrease per decade, respectively, in each region. No gender or BMI relationships with NET availability were observed. Our findings suggest an age-related decline, but no BMI- or gender-related differences, in NET availability in healthy adults.

Non‐invasive quantification and SUVR validation of [18F]‐florbetaben with total‐body EXPLORER PET

AbstractBackgroundKinetic modeling of brain amyloid deposition with [18F]‐florbetaben more accurately quantifies the binding density to amyloid plaques compared to standardized uptake ratios (SUVR) (Becker, JNM2013). The total‐body EXPLORER PET scanner with an axial field of view of 194cm supports the acquisition of a full human body in one scan and permits noninvasive Image‐Derived Input Functions (IDIFs) as an alternative to arterial blood sampling (Badawi, JNM 2019). Our aim is to quantify amyloid buildup with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and validate with SUVR in an elderly cohort.MethodTwelve adults aged 66‐86 underwent dynamic total‐body 18F‐florbetaben PET for 110min, spatial resolution = 2.344mm, average tracer dose = 299.70 MBq. 8 cognitively‐normal, 3 Mild Cognitive Impairment (MCI), and 1 Alzheimer’s disease (AD). Regions of interests were drawn in the middle descending aorta and eroded to exclude the vessel walls to derive IDIFs (Fig.1). Next, regional brain analysis including PET image matching to previously acquired T1‐weighted MRI, normalization, and segmentation were performed in PMOD (v4.2) using the AAL atlas. PET SUVR (90‐110min) means were calculated from 7 index regions (lateral frontal, medial frontal, anterior cingulate, posterior cingulate, lateral temporal, lateral parietal, and precuneus) and the cerebellar gray matter. Dynamic time activity curves (TACs) from the same brain regions were fit to the two‐tissue compartment model (2TCM) using population metabolite‐corrected IDIFs; and the Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).ResultAmyloid‐positive patients showed the highest SUVR in brain index regions (Fig.2). High quality dynamic kinetic modeling was achieved (Fig.3), with high SUVR accumulation in index regions compared to cerebellum at later time points in amyloid‐positive cases. SUVR and DVR from kinetic models were strongly correlated; with slight overestimation of SUVR compared to DVR (Fig.4). DVR values from the MRTM were lower than (86.7% of) DVR quantified by 2TCM.ConclusionAbsolute quantification of amyloid binding from total‐body [18F]‐florbetaben PET data is feasible using aorta IDIFs with high agreement between dynamic binding parameters compared to SUVR in discriminating positive and negative scans.

Non‐invasive quantification and SUVR validation of [18F]‐florbetaben with total‐body EXPLORER PET

AbstractBackgroundKinetic modeling of brain amyloid deposition with [18F]‐florbetaben more accurately quantifies the binding density to amyloid plaques compared to standardized uptake ratios (SUVR) (Becker, JNM2013). The total‐body EXPLORER PET scanner with an axial field of view of 194cm supports the acquisition of a full human body in one scan and permits noninvasive Image‐Derived Input Functions (IDIFs) as an alternative to arterial blood sampling (Badawi, JNM 2019). Our aim is to quantify amyloid buildup with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and validate with SUVR in an elderly cohort.MethodTwelve adults aged 66‐86 underwent dynamic total‐body 18F‐florbetaben PET for 110min, spatial resolution = 2.344mm, average tracer dose = 299.70 MBq. 8 cognitively‐normal, 3 Mild Cognitive Impairment (MCI), and 1 Alzheimer’s disease (AD). Regions of interests were drawn in the middle descending aorta and eroded to exclude the vessel walls to derive IDIFs (Fig.1). Next, regional brain analysis including PET image matching to previously acquired T1‐weighted MRI, normalization, and segmentation were performed in PMOD (v4.2) using the AAL atlas. PET SUVR (90‐110min) means were calculated from 7 index regions (lateral frontal, medial frontal, anterior cingulate, posterior cingulate, lateral temporal, lateral parietal, and precuneus) and the cerebellar gray matter. Dynamic time activity curves (TACs) from the same brain regions were fit to the two‐tissue compartment model (2TCM) using population metabolite‐corrected IDIFs; and the Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).ResultAmyloid‐positive patients showed the highest SUVR in brain index regions (Fig.2). High quality dynamic kinetic modeling was achieved (Fig.3), with high SUVR accumulation in index regions compared to cerebellum at later time points in amyloid‐positive cases. SUVR and DVR from kinetic models were strongly correlated; with slight overestimation of SUVR compared to DVR (Fig.4). DVR values from the MRTM were lower than (86.7% of) DVR quantified by 2TCM.ConclusionsAbsolute quantification of amyloid binding from total‐body [18F]‐florbetaben PET data is feasible using aorta IDIFs with high agreement between dynamic binding parameters compared to SUVR in discriminating positive and negative scans.

HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls.

Alterations of hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = -0.49, p = 0.009). The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

Assessment of motion and model bias on the detection of dopamine response to behavioral challenge

Compartmental modeling analysis of 11C-raclopride (RAC) PET data can be used to measure the dopaminergic response to intra-scan behavioral tasks. Bias in estimates of binding potential (BPND) and its dynamic changes (ΔBPND) can arise both when head motion is present and when the compartmental model used for parameter estimation deviates from the underlying biology. The purpose of this study was to characterize the effects of motion and model bias within the context of a behavioral task challenge, examining the impacts of different mitigation strategies. Seventy healthy adults were administered bolus plus constant infusion RAC during a simultaneous PET/magnetic resonance (MR) scan with a reward task experiment. BPND and ΔBPND were estimated using an extension of the Multilinear Reference Tissue Model (E-MRTM2) and a new method (DE-MRTM2) was proposed to selectively discount the contribution of the initial uptake period. Motion was effectively corrected with a standard frame-based approach, which performed equivalently to a more complex reconstruction-based approach. DE-MRTM2 produced estimates of ΔBPND in putamen and nucleus accumbens that were significantly different from those estimated from E-MRTM2, while also decoupling ΔBPND values from first-pass k2′ estimation and removing skew in the spatial bias distribution of parametric ΔBPND estimates within the striatum.

Validation and test\u2013retest repeatability performance of parametric methods for [11C]UCB-J PET

[11C]UCB-J is a PET radioligand that binds to the presynaptic vesicle glycoprotein 2A. Therefore, [11C]UCB-J PET may serve as an in vivo marker of synaptic integrity. The main objective of this study was to evaluate the quantitative accuracy and the 28-day test–retest repeatability (TRT) of various parametric quantitative methods for dynamic [11C]UCB-J studies in Alzheimer’s disease (AD) patients and healthy controls (HC). Eight HCs and seven AD patients underwent two 60-min dynamic [11C]UCB-J PET scans with arterial sampling over a 28-day interval. Several plasma-input based and reference-region based parametric methods were used to generate parametric images using metabolite corrected plasma activity as input function or white matter semi-ovale as reference region. Different parametric outcomes were compared regionally with corresponding non-linear regression (NLR) estimates. Furthermore, the 28-day TRT was assessed for all parametric methods. Spectral analysis (SA) and Logan graphical analysis showed high correlations with NLR estimates. Receptor parametric mapping (RPM) and simplified reference tissue model 2 (SRTM2) BPND, and reference Logan (RLogan) distribution volume ratio (DVR) regional estimates correlated well with plasma-input derived DVR and SRTM BPND. Among the multilinear reference tissue model (MRTM) methods, MRTM1 had the best correspondence with DVR and SRTM BPND. Among the parametric methods evaluated, spectral analysis (SA) and SRTM2 were the best plasma-input and reference tissue methods, respectively, to obtain quantitatively accurate and repeatable parametric images for dynamic [11C]UCB-J PET.

Optimal parametric imaging methods for dual‐time‐window [18F]flutemetamol and [18F]florbetaben PET studies

AbstractBackgroundAccurate quantitative measures of amyloid beta (Aβ) plaques are needed to identify individuals with subthreshold Aβ levels or for measuring small changes over time. To this end, dynamic or dual‐time‐window scanning protocols are required. Optimal pharmacokinetic models for quantifying Aβ burden using both [18F]flutemetamol and [18F]florbetaben dual‐time‐window scans have previously been identified at a region of interest (ROI) level. This study aimed to determine optimal parametric methods for analyses of [18F]flutemetamol and [18F]florbetaben dual‐time‐window scans.MethodForty‐six participants were scanned on a PET/MR scanner using a dual‐time‐window protocol and either [18F]flutemetamol or [18F]florbetaben. The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two‐step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90‐110 min post injection interval. All parametric images were assessed visually for possible image artefacts and regional cortical outcome measures were compared with DVR derived using regional RLogan, based on AUC values for differentiating between Aβ‐positive and Aβ‐negative scans, Bland‐Altman plots and linear regression analyses.ResultVisually, RPM and SRTM2 performed best across tracers and, in addition to SUVR, provided the highest AUC values for differentiating between Aβ‐positive and Aβ‐negative scans ([18F]flutemetamol: range AUC=0.96‐0.97, [18F]florbetaben: range AUC=0.83‐0.85). Outcome parameters of most methods were highly correlated with those of the reference method (R2≥0.87), with lowest correlations observed for MRTM2 (R2=0.71‐0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. On the other hand, bias in SUVR was high for [18F]flutemetamol (mean bias>10%), but low for [18F]florbetaben (mean bias=1%) and strongly proportional with underlying Aβ burden for both tracers.ConclusionThe best overall compromise was provided by MRTM0, followed closely by SRTM2. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression. “This work has received support from the EU‐EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (grant No 115952).”

Feasibility of short imaging protocols for [18F]PI‐2620 tau‐PET in progressive supranuclear palsy

AbstractBackgroundDynamic 60‐minute positron‐emission‐tomography (PET) imaging with the novel tau radiotracer [18F]PI‐2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). We now aimed to investigate if shorter acquisition and static time windows of [18F]PI‐2620 tau‐PET can be used for imaging of patients with PSP.MethodWe evaluated 37 patients at five different centers with probable or possible PSP Richardson syndrome (PSP‐RS) together with ten HCs. [18F]PI‐2620 PET was performed by a dynamic 60 minute scan. Distribution volume ratios (DVRs, multilinear reference tissue model 2, cerebellar reference) were calculated using full and truncated scan durations (0‐60, 0‐50, 0‐40, 0‐30, and 0‐20 minutes p.i.). Standardized uptake value ratios (SUVrs, cerebellar reference) were obtained from static imaging windows with 20 minutes duration (20‐40, 30‐50, and 40‐60 minutes p.i.). All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP‐RS from HCs in predefined subcortical and cortical target regions (effect size, receiver operating area under the curve (AUC), multi‐region classifier). Finally, we tested if shorter [18F]PI‐2620 PET imaging can also be applied to patients with Alzheimer’s disease (n=11).ResultThe effect size of 0‐50 and 0‐40 DVR was equivalent to 0‐60 DVR (averaged Cohen’s d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0‐30 or 0‐20 DVR. The 20‐40 SUVr indicated the best performance of all short static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP and healthy controls at a similarly high level for 0‐60 DVR (AUC: 0.96), 0‐40 DVR (AUC: 0.96), and 20‐40 SUVr (AUC: 0.94). The multi‐region classifier sensitivity of these time windows was consistently 86%. 0‐40 DVR showed similar performance in Alzheimer’s disease when compared to 0‐60 DVR.ConclusionShort dynamic acquisition and static imaging windows can be used for [18F]PI‐2620 PET imaging of PSP. 0‐40 minute dynamic scanning offers the best balance between accuracy and economic scanning and is may also be suitable for [18F]PI‐2620 PET imaging of Alzheimer’s disease.

Central Noradrenergic Neurotransmission and Weight Loss 6 Months After Gastric Bypass Surgery in Patients with Severe Obesity

PurposeRoux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission.Materials and MethodsWe longitudinally studied 10 individuals with severe obesity (8 females; age 43.9 ± 13.1 years; body mass index (BMI) 46.5 ± 4.8 kg/m2) using (S,S)-[11C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex).ResultsThe participants responded to RYGB surgery with a reduction in BMI of 12.0 ± 3.5 kg/m2 (p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01).ConclusionReductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI.Graphical abstract

Parametric imaging of dual-time window [18F]flutemetamol and [18F]florbetaben studies

Optimal pharmacokinetic models for quantifying amyloid beta (Aβ) burden using both [18F]flutemetamol and [18F]florbetaben scans have previously been identified at a region of interest (ROI) level. The purpose of this study was to determine optimal quantitative methods for parametric analyses of [18F]flutemetamol and [18F]florbetaben scans. Forty-six participants were scanned on a PET/MR scanner using a dual-time window protocol and either [18F]flutemetamol (N=24) or [18F]florbetaben (N=22). The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two-step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90–110 min post injection interval. All parametric images were assessed visually. Regional outcome measures were compared with those from a validated ROI method, i.e. DVR derived using RLogan. Visually, RPM, and SRTM2 performed best across tracers and, in addition to SUVR, provided highest AUC values for differentiating between Aβ-positive vs Aβ-negative scans ([18F]flutemetamol: range AUC=0.96–0.97 [18F]florbetaben: range AUC=0.83–0.85). Outcome parameters of most methods were highly correlated with the reference method (R2≥0.87), while lowest correlation were observed for MRTM2 (R2=0.71–0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. The optimal parametric method differed per evaluated aspect; however, the best compromise across aspects was found for MRTM0 followed by SRTM2, for both tracers. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression.

A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7

PurposePhosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.MethodsSeven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.ResultsPET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET.ConclusionWe have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.

Kinetic Modelling and Test\u2013Retest Reproducibility for the Dopamine D1R Radioligand [11C]SCH23390 in Healthy and Diseased Mice

PurposeOur aim in this study was to compare different non-invasive pharmacokinetic models and assess test–retest reproducibility of the radioligand [11C]SCH23390 for the quantification of dopamine D1-like receptor (D1R) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington’s disease (HD) model.ProceduresAdult WT (n = 9) and HET (n = 14) mice underwent a 90-min [11C]SCH23390 positron emission tomography (PET) scan followed by computed tomography (CT) to evaluate the pharmacokinetic modelling in healthy and diseased conditions. Additionally, 5 WT mice and 7 HET animals received a second [11C]SCH23390 PET scan for test–retest reproducibility. Parallel assessment of the simplified reference tissue model (SRTM), the multilinear reference tissue model (MRTM) and the Logan reference tissue model (Logan Ref) using the striatum as a receptor-rich region and the cerebellum as a receptor-free (reference) region was performed to define the most suitable method for regional- and voxel-based quantification of the binding potential (BPND). Finally, standardised uptake value ratio (SUVR-1) was assessed as a potential simplified measurement.ResultsFor all models, we measured a significant decline in dopamine D1R density (e.g. SRTM = − 38.5 ± 5.0 %, p < 0.0001) in HET mice compared to WT littermates. Shortening the 90-min scan duration resulted in large underestimation of striatal BPND in both WT mice (SRTM 60 min: − 17.7 ± 2.8 %, p = 0.0078) and diseased HET (SRTM 60 min: − 13.1 ± 4.1 %, p = 0.0001). Striatal BPND measurements were very reproducible with an average test–retest variability below 5 % when using both MRTM and SRTM. Parametric BPND maps generated with SRTM were highly reliable, showing nearly perfect agreement to the regional analysis (r2 = 0.99, p < 0.0001). Finally, SRTM provided the most accurate estimate for relative tracer delivery R1 with both regional- and voxel-based analyses. SUVR-1 at different time intervals were not sufficiently reliable when compared to BPND (r2 < 0.66).ConclusionsNinety-minute acquisition and the use of SRTM for pharmacokinetic modelling is recommended. [11C]SCH23390 PET imaging demonstrates optimal characteristics for the study of dopamine D1R density in models of psychiatric and neurological disorders as exemplified in the Q175DN mouse model of HD.

Inverse changes in raphe and cortical 5-HT1B receptor availability after acute tryptophan depletion in healthy human subjects.

Serotonergic neurotransmission plays a key role in the pathophysiology and treatment of various neuropsychiatric diseases. The purpose of this study was to investigate changes in serotonergic neurotransmission after acute tryptophan depletion (ATD) using positron emission tomography (PET) with [11 C]P943, a 5-HT1B receptor radioligand previously shown to be sensitive to changes in 5-HT. Five healthy subjects were scanned on a high resolution PET scanner twice on the same day, before and approximately 5hours after ingesting capsules containing an amino acid mixture that lacks tryptophan. For each scan, emission data were acquired for 120min after intravenous bolus injection of [11 C]P943. Binding potential (BPND ) values were estimated from parametric images using the second version of the multilinear reference tissue model (MRTM2, t*=20min) with cerebellar grey matter used as a reference region. The change in [11 C]P943 binding (ΔBPND , %) was calculated as (BPND,post -BPND,pre )/(BPND,pre )×100, and correlation analysis was performed to measure linear associations of ΔBPND between raphe and other regions of interest (ROIs). ΔBPND ranged from -6% to 45% in the raphe, with positive values indicating reduced competition from 5-HT. In cortical regions, ΔBPND ranged from -28% to 7%. While these changes did not reach significance, there were significant negative correlations of ΔBPND of the raphe with those of cerebral cortical regions and the thalamus (e.g., r=-.96, p=.011 for average cortex). These findings support the hypothesis that raphe serotonin is a critical modulator of cortical serotonin release via projecting neurons in healthy human subjects.

A strategy to account for noise in the X-variable to reduce underestimation in Logan graphical analysis for quantifying receptor density in positron emission tomography

BackgroundThe Logan graphical analysis (LGA) algorithm is widely used to quantify receptor density for parametric imaging in positron emission tomography (PET). Estimating receptor density, in terms of the non-displaceable binding potential (BPND), from the LGA using the ordinary least-squares (OLS) method has been found to be negatively biased owing to noise in PET data. This is because OLS does not consider errors in the X-variable (predictor variable). Existing bias reduction methods can either only reduce the bias slightly or reduce the bias accompanied by increased variation in the estimates. In this study, we addressed the bias reduction problem by applying a different regression method.MethodsWe employed least-squares cubic (LSC) linear regression, which accounts for errors in both variables as well as the correlation of these errors. Noise-free PET data were simulated, for 11C-carfentanil kinetics, with known BPND values. Statistical noise was added to these data and the BPNDs were re-estimated from the noisy data by three methods, conventional LGA, multilinear reference tissue model 2 (MRTM2), and LSC-based LGA; the results were compared. The three methods were also compared in terms of beta amyloid (A β) quantification of 11C-Pittsburgh compound B brain PET data for two patients with Alzheimer’s disease and differing A β depositions.ResultsAmongst the three methods, for both synthetic and actual data, LSC was the least biased, followed by MRTM2, and then the conventional LGA, which was the most biased. Variations in the LSC estimates were smaller than those in the MRTM2 estimates. LSC also required a shorter computational time than MRTM2.ConclusionsThe results suggest that LSC provides a better trade-off between the bias and variability than the other two methods. In particular, LSC performed better than MRTM2 in all aspects; bias, variability, and computational time. This makes LSC a promising method for BPND parametric imaging in PET studies.

Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study

The norepinephrine transporter (NET) has been suggested to play a critical role in attention-deficit/hyperactivity disorder (ADHD). In this prospective controlled study we tested the a-priori-hypothesis that central NET availability is altered in adult ADHD patients compared to healthy controls. Study participants underwent single positron emission tomography-magnetic resonance imaging (PET-MRI). MRI sequences included high resolution T1-MPRAGE data for regions of interest (ROI) delineation and voxel-based morphometry (VBM) and T2-weighted fluid-attenuated inversion-recovery for detection and exclusion of pathological abnormalities. NET availability was assessed by NET-selective (S,S)-O-[11C]methylreboxetine; regional distribution volume ratios (DVR) were calculated based on individual PET-MRI data co-registration and a multi-linear reference tissue model with two constraints (MRTM2; reference region: occipital cortex). VBM analysis revealed no difference in local distribution of gray matter between the 20 ADHD patients (9 females, age 31.8 ± 7.9 years, 488 ± 8 MBq injected activity) and the 20 age-matched and sex-matched control participants (9 females, age 32.3 ± 7.9 years, 472 ± 72 MBq). In mixed-model repeated-measures analysis with NET availability as dependent and ROI as repeated measure we found a significant main effect group in fronto-parietal-thalamic-cerebellar regions (regions on the right: F1,25 = 12.30, p = .002; regions on the left: F1,41 = 6.80, p = .013) indicating a reduced NET availability in ADHD patients. None of the other investigated brain regions yielded significant differences in NET availability between groups after applying a Benjamini-Hochberg correction at a significance level of 0.05. Overall our findings demonstrate the pathophysiological involvement of NET availability in adult ADHD.

Evaluation of Dosimetry, Quantitative Methods, and Test-Retest Variability of 18F-PI-2620 PET for the Assessment of Tau Deposits in the Human Brain.

18F-PI-2620 is a next-generation tau PET tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry, and quantitative methods of 18F-PI-2620 in the human brain. Full kinetic modeling to quantify tau load was investigated. Noninvasive kinetic modeling and semiquantitative methods were evaluated against the full tracer kinetics. Finally, the reproducibility of PET measurements from test and retest scans was assessed. Methods: Three healthy controls (HCs) and 4 Alzheimer disease (AD) subjects underwent 2 dynamic PET scans, including arterial sampling. Distribution volume ratio (DVR) was estimated using full tracer kinetics (reversible 2-tissue-compartment [2TC] model and Logan graphical analysis [LGA]) and noninvasive kinetic models (noninvasive LGA [NI-LGA] and the multilinear reference tissue model [MRTM2]). SUV ratio (SUVR) was determined at different imaging windows after injection. The correlation between DVR and SUVR, effect size (Cohen's d), and test-retest variability (TRV) were evaluated. Additionally, 6 HCs received 1 tracer administration and underwent whole-body PET for dosimetry calculation. Organ doses and the whole-body effective dose were calculated using OLINDA 2.0. Results: A strong correlation was found across different kinetic models (R2 > 0.97) and between DVR(2TC) and SUVR between 30 and 90 min, with an R2 of more than 0.95. Secular equilibrium was reached at around 40 min after injection in most regions and subjects. TRV and effect size for SUVR across different regions were similar at 30-60 min (TRV, 3.8%; Cohen's d, 3.80), 45-75 min (TRV, 4.3%; Cohen's d, 3.77) and 60-90 min (TRV, 4.9%; Cohen's d, 3.73) and increased at later time points. Elimination was via the hepatobiliary and urinary systems. The whole-body effective dose was 33.3 ± 2.1 μSv/MBq for an adult female and 33.1 ± 1.4 μSv/MBq for an adult male, with a 1.5-h urinary bladder voiding interval. Conclusion:18F-PI-2620 exhibits fast kinetics, suitable dosimetry, and low TRV. DVR measured using the 2TC model with arterial sampling correlated strongly with DVR measured by NI-LGA, MRTM2, and SUVR. SUVR can be used for 18F-PI-2620 PET quantification of tau deposits, avoiding arterial blood sampling. Static 18F-PI-2620 PET scans between 45 and 75 min after injection provide excellent quantification accuracy, a large effect size, and low TRV.

Norepinephrine transporter availability in brown fat is reduced in obesity: a human PET study with [11C] MRB.

The energy-dissipating properties of brown adipose tissue (BAT) have been proposed as therapeutic targets for obesity and diabetes. Little is known about basal BAT activity. Capitalizing on the dense sympathetic innervation of BAT, we have previously shown that BAT can be detected in humans under resting room temperature (RT) conditions by using (S,S)-11C-O-methylreboxetine (MRB), a selective ligand for the norepinephrine transporter (NET). In this study, we determine whether MRB labeling of human BAT is altered by obesity. Fifteen healthy, nondiabetic Caucasian women (nine lean, age 25.6 ± 1.7, BMI 21.8 ± 1.3 kg/m2; six obese age 30.8 ± 8.8 BMI 37.9 ± 6.6 kg/m2) underwent PET-CT imaging of the neck/supraclavicular region using 11C-MRB under RT conditions. The distribution volume ratio (DVR) for 11C-MRB was estimated via multilinear reference tissue model 2 (MRTM2) referenced to the occipital cortex. Two women (one lean and one with obesity) had no detectable BAT. Of the women with detectable BAT, women with obesity had lower 11C-MRB DVR (0.80 ± 0.12 BAT DVR) compared to lean (1.15 ± 0.19 BAT DVR) (p = 0.004). Our findings are consistent with reports that NET is decreased in obesity and suggest that the sympathetic innervation of BAT is altered in obesity.