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Dissolution dynamic nuclear polarisation (dDNP) of 13C‐labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised 13C‐labelled pyruvate (13C1‐pyruvate) and urea (13C‐urea), a nonmetabolised marker. A general mathematical model of pyruvate‐lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, Kip, and the forward and reverse fractional rate constants for pyruvate‐lactate signal exchange, kpl and klp. An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, Kiu. A spectral fitting procedure to blood time‐course data proved superior to assuming a gamma‐variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. Kiu equalled Kip, indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (kpo, klo and kuo, respectively) indicated that T1s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor‐product model, using the tumour pyruvate signal time‐course as the input for the corresponding lactate signal time‐course, was modified to account for the observed delay between them. The corresponding fractional rate constant, kavail, most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T1 for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required. [ABSTRACT FROM AUTHOR]

Background: Several radiotracers targeting tau pathology in Alzheimer's disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620. Methods: To date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1). Results: Tracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4. Conclusions: The tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets. Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask. Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images. Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions. Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM). [ABSTRACT FROM AUTHOR]

Background: [18F]MK6240 is a second‐generation radiotracer for imaging tau pathology in vivo. Regional thresholds that allow for an assessment of Braak stage have yet to be established and importantly may vary between regions. In this work we use a Z‐score approach to define regional thresholds and estimate Braak stage in Alzheimer's Disease. Method: All static MK6240 images used were downloaded from the Lantheus/Cerveau database, spatially normalised into MNI space using DARTEL and SUVR images were computed using an inferior cerebellum reference region. Three Braak meta‐ROIS, Braak I/II, Braak III/IV and Braak V/VI (Figure 1), were applied to 275 amyloid negative healthy control images to define regional thresholds for positivity in each ROI at the level of mean SUVR + 2 SD. These thresholds were then applied to 232 scans from subjects across the AD spectrum with associated MMSE data (88 healthy control, 68 MCI and 76 AD: 131 Aβ+ / 101 Aβ‐). Result: [18F]MK6240 showed similar mean values and low variability across all ROIs in the amyloid negative healthy controls (Figure 1). The regional SUVR cut‐off values were estimated as: Braak I/II = 1.29, Braak III/IV = 1.15 and Braak V/VI = 1.15. When these cut‐offs were applied to subjects across the AD spectrum with MMSE data (Figure 2), 118 out of 232 were negative for Braak pathology. These subjects were predominantly healthy controls and their mean MMSE was 27.3. For subjects that demonstrated Braak positivity in at least one region, 104 subjects demonstrated an ordering consistent with Braak staging whilst 10 subjects had an atypical ordering consistent with hippocampal sparing. 64 subjects were positive in all Braak regions with a mean MMSE of 23.4 and all but one of these subjects was either MCI or AD. Conclusion: Analysis of [18F]MK6240 images with thresholds that allow for the determination of Braak stage status provides data that are consistent with clinical status and MMSE score. This approach may be useful in natural history studies and clinical trials. [ABSTRACT FROM AUTHOR]

Background: The A/T/N classification system has emphasised the importance of considering multi‐channel biomarker readouts in AD research. Further, it is important to establish the relationship of these signals to cognitive performance and their relevance to enable optimum inclusion criteria for clinical trials. The IQ analytics platform provides powerful outcome measures for both Amyloid and Tau PET. In this work, we also consider hippocampal volume and investigate the relationship of these A/T/N biomarkers with cognitive performance at different stages of the disease process. Method: AmyloidIQ, TauIQ and MR Volumetric analytics were performed on cross‐sectional data from 605 subjects (CN=376, MCI=173, Dementia=56) downloaded from ADNI where each subject had [18F]Florbetapir, [18F]Flortaucipir and a T1 MRI scan. AmyloidIQ determines the overall amyloid burden as an Amyloid Load percentage (Figure 1 and 2) whilst the TauIQ algorithm deconstructs the more complex Tau signal into global signal and local signal (Figure 3 and Figure 4). The hippocampal volumes for each subject were derived in SPM. We performed a multiple regression analysis with ADAS‐COG as the outcome variable and Global Tau Load, Local Tau Load, Amyloid Load and Hippocampal Volume as predictors. All possible linear models (including interaction terms) were evaluated on each diagnosis group separately and the optimum model was selected at in each case by choosing the model with the lowest BIC. Result: The hippocampal volume was a statistically significant variable in the optimum model in all diagnosis groups but the statistically significant IQ analytics outcome measures were dependent on the diagnosis (Table 1); in the CN group the key parameter was Amyloid Load, in the MCI group, interestingly, both Local Tau Load and Amyloid Load were statistically significant, finally in the Dementia subjects only the Global Tau Load was found to be statistically significant. When evaluated on all subjects simultaneously, the optimum model explained 49% of the variance in ADAS‐Cog scores. Conclusion: The IQ analytics biomarkers provide orthogonal information that are related to cognitive function in different ways across the disease spectrum. Our results imply that the novel Local Tau Load outcome measure is an important biomarker for stratifying and following MCI subjects. [ABSTRACT FROM AUTHOR]

Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MCI) to Alzheimer's over 3 years, using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Measures included: demographics, APOE4 genotype, CSF (amyloid‐β42, total tau, phosphorylated tau), [18F]florbetapir, hippocampal volume and brain‐age. We examined: (a) the independent value of each biomarker; and (b) whether modelling nonlinear interactions between biomarkers improved predictions. Each measured added complementary information when predicting conversion to Alzheimer's. A linear model classifying stable from progressive MCI explained over half the variance (R2 = 0.51, p <.001); the strongest independently contributing biomarker was hippocampal volume (R2 = 0.13). When comparing sensitivity of different models to progressive MCI (independent biomarker models, additive models, nonlinear interaction models), we observed a significant improvement (p <.001) for various two‐way interaction models. The best performing model included an interaction between amyloid‐β‐PET and P‐tau, while accounting for hippocampal volume (sensitivity = 0.77, AUC = 0.826). Closely related biomarkers contributed uniquely to predict conversion to Alzheimer's. Nonlinear biomarker interactions were also implicated, and results showed that although for some patients adding additional biomarkers may add little value (i.e., when hippocampal volume is high), for others (i.e., with low hippocampal volume) further invasive and expensive examination may be warranted. Our framework enables visualisation of these interactions, in individual patient biomarker 'space', providing information for personalised or stratified healthcare or clinical trial design. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients.Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11 C]UCB-J, [11 C]SA-4503, and [18 F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments.Results: Reduced [11 C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11 C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11 C]SA-4503 and [18 F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11 C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline.Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity.Objectives: To assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden.Methods: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa-treated, 24 moderate-advanced l-dopa-treated patients with PD, and 22 healthy controls). All participants underwent [11 C]IMA107 PET, [11 C]PE2I PET, and 3-Tesla MRI scan.Results: Early de novo PD patients showed loss of [11 C]IMA107 and of [11 C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa-treated PD patients showed additional loss of [11 C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11 C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11 C]IMA107 correlated with lower [11 C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11 C]IMA107 in the caudate (rho = -0.72; P < 0.001) and putamen (rho = -0.48; P < 0.01), and with lower [11 C]PE2I only in the putamen (rho = -0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11 C]IMA107 in the caudate (rho = -0.42; P < 0.05) and putamen (rho = -0.41; P < 0.05), and with lower [11 C]PE2I only in the putamen (rho = -0.69; P < 0.001).Conclusion: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A).Objective: We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations.Methods: We studied 6 subjects with PDE10A and ADCY5 mutations using [11 C]IMA107 PET, [123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively.Results: We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices.Conclusions: Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The global amyloid‐β (Aβ) burden in Alzheimer's disease (AD) is routinely quantified from static amyloid PET scans using SUVR. We have previously used AmyloidIQ to analyse over 3000 18F‐Florbetapir, 18F‐Florbetaben and 18F‐Flutemetamol scans. These analyses demonstrated that the outcome measure amyloid load (AβL) derived from AmyloidIQ is more powerful than SUVR in cross‐sectional and longitudinal analyses (Whittington et al. 2018 JNM) as well as having a better agreement with visual reads (Whittington et al. HAI 2019). In this work, we extend the AmyloidIQ methodology to [18F]NAV4694 images downloaded from the Global Alzheimer's Association Interactive Network (GAAIN) website (http://www.gaain.org). Method: AβL is automatically calculated by the AmyloidIQ algorithm from an individual Aβ‐PET scan using voxel‐wise regression with two canonical images that represent non‐displaceable and specific binding signals. The canonical images were derived from 18F‐Florbetapir ADNI data (Whittington et al. 2018 JNM). A composite SUVR was also calculated for each scan. 52 [18F]NAV4694 scans (35 healthy controls, HC, 10 mild cognitive impaired, MCI, and 7 AD) were obtained from GAAIN. The effect sizes (Hedges' g) between HC and AD patients, and between HC and AD/MCI of AβL and SUVR were compared in [18F]NAV4694 cross‐sectional data. Result: The AmyloidIQ algorithm was successfully extended to [18F]NAV4694 data with accurate characterization of the data obtained with the previously derived canonical images, now demonstrating its applicability to four different Aβ tracers (Figure 1). In this small sample dataset the cross‐sectional analysis showed that, AβL had similar performance to SUVR (effect size between non‐HC patients and HC was 2.29 for AβL and 2.32 SUVR, and between HC and AD patients was 4.41 for AβL and 4.90 for SUVR). In previous works, AβL has shown better agreement with visual reads than SUVR (Figure 2) and more power in cross‐sectional analysis (Figure 3) with an average increase in effect size of 44% and 21% compared to SUVR for [18F]Florbetapir and [18F]Florbetaben respectively. Conclusion: AmyloidIQ is a powerful algorithm that has been successfully applied to four different Aβ tracers and that can be used for stratification. A larger sample is required to determine whether AmyloidIQ is more powerful than SUVR for [18F]NAV4694. [ABSTRACT FROM AUTHOR]

As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11 C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11 C]Ro15-4513 total distribution volume (VT ) in the right hippocampus in the GD group compared with HV. We found higher levels of the 'Negative Urgency' construct of impulsivity in GD, and these were positively associated with higher [11 C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11 C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment. [ABSTRACT FROM AUTHOR]

Background: The need for a light stable 4R tau PET tracer for use in diverse tauopathies is widely appreciated. We aimed to assess the initial human imaging profile of [18F]APN‐1701 as such a tracer and to compare its imaging profile to the well‐established but light‐sensitive tracer [18F]‐APN‐1607 that can detect 4R aggregates as well as 3R and mixed 3R/4R aggregates. [18F]APN‐1607 has progressed to a multicenter Phase 2 clinical trial for Alzheimer's disease (AD); therefore, prior imaging data with it was considered valuable for comparison. Method: One cognitively normal (CN) subject (male, 73yo) and one AD subject (female, 58 yo), who had undergone prior amyloid profiling using [18F]florbetapir PET and subsequent imaging with [18F]APN‐1607 in a proof‐of‐concept study and a test‐retest study, respectively, participated in the current study. Dynamic imaging with [18F]APN‐1701 was performed over 180 min to obtain kinetic data. Result: Overall, for both subjects [18F]APN‐1701 generally matched [18F]APN‐1607 findings, i.e., peak SUV values reached similar levels. The CN subject, who was amyloid negative, had slight, uniform cortical [18F]‐APN‐1701 uptake and more substantial uptake in the pallidum, pons and midbrain. SUVr images for the AD subject showed retention in similar brain regions for both tau tracers with the same rank order of regional SUV/SUVr. Notably, for this subject [18F]APN‐1701 continued to accumulate up to the end of image acquisition. Conclusion: [18F]APN‐1701 demonstrates cortical uptake generally similar to [18F]APN‐1607 but its slow kinetics are unfavorable for further development. [ABSTRACT FROM AUTHOR]

Background: A number of pathophysiological mechanisms are associated with neurodegeneration, including synaptic dysfunction and/or loss. Novel radiotracers which enable the quantification of synaptic proteins in vivo have not previously been explored in frontotemporal dementia (FTD). We used [11C]UCB‐J PET to measure the density of synaptic vesicle protein 2A (SV2A) in FTD. Method: Six participants with behavioural variant FTD (mean age 61.8, SD 5.4) and 17 cognitively normal participants (63.7, 12.5) underwent 90‐minute dynamic acquisition PET scans following injection of [11C]UCB‐J, with metabolite corrected arterial input function. Thirteen regions of interest (ROIs) were defined on individual MR images using the CIC anatomical atlas. Regional density was evaluated using the regional VT normalised to the VT in the centrum semiovale (DVR‐1). Groups were compared using Mann‐Whitney tests with Bonferroni correction for multiple comparisons. W‐scores were computed from the 17 controls, with age and gender as covariates, to compare the magnitude of group differences in regional volumes versus [11C]UCB‐J distribution. Volumes were expressed as a percentage of total intracranial volume. A w‐score of <‐1.65 was considered abnormal. Result: We found significant reductions in regional density of SV2A in FTD compared to controls in multiple cortical and subcortical regions: frontal, temporal, parietal, insula, anterior cingulate and posterior cingulate cortices (all 0.001), as well as the hippocampus, amygdala, thalamus and cerebellum (all 0.001). The w‐score analysis revealed significant reductions in SV2A density in FTD in all 13 ROIs, with the greatest reduction in the anterior cingulate (‐4.2), and in volume in 8 ROIs, with the greatest reduction in the temporal lobe (‐6.4). The magnitude of SV2A density loss was greater than the magnitude of volume loss in most ROIs (9/13), and there was more variability in the reduction in volume than there was in SV2A density (SD range [11C]UCB‐J 0.7‐2.1, volume 1.4‐3.9). Conclusion: Significant reductions in [11C]UCB‐J distribution indicate reduced synaptic density in disease‐relevant regions in FTD, which surpass reductions in volume. This suggests that [11C]UCB‐J PET imaging could be a sensitive biomarker of synaptic dysfunction in FTD, with future studies focused on its relationship with symptoms and whether it becomes abnormal before symptom onset. [ABSTRACT FROM AUTHOR]

ABSTRACT [11C]MP-10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [11C]MP-10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood-brain-barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re-evaluating [11C]MP-10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self-blocking scans with unlabeled MP-10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague-Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [11C]MP-10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP-10 reduced the binding of [11C]MP-10 in a dose-dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution ( VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [11C]MP-10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates. Synapse 69:86-95, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: In 2010 Jack et al. proposed sigmoidal curves for Amyloid‐β (Aβ) and tau accumulation in Alzheimer's Disease (AD) progression with Aβ preceding tau. Our recent work has shown that a logistic growth model consistent with this can describe the accumulation of Aβ as measured by imaging data (Whittington et al. 2018). Here, we use Aβ and Tau imaging data combined with mathematical modelling to characterise the temporal relationship between the two key pathological hallmarks of AD. Method: Under the assumption that tau accumulation can also be characterised by a logistic growth model, a pair of equations (Figure 1, Eqns 1 &2) for Aβ and tau accumulation can be derived. These equations can be solved by substitution to yield a function for Tau in terms of Aβ (Figure 1, Eqn 3) which has 4 parameters (rAβ & rTau: unconstrained exponential accumulation rates; T50Aβ & T50Tau : time of half maximal concentrations). rAβ and T50Aβ were previously estimated as 0.20 yrs‐1 and 14.9 yrs respectively (Whittington et al. 2018) and were fixed to these values in the current work. AmyloidIQ and TauIQ analysis (Whittington & Gunn, 2018) were performed on 233 subjects' data downloaded from ADNI where each subject had both an Aβ ([18F]Florbetapir) and Tau ([18F]Flortaucipir) scan to derive estimates of Aβ Load and Global Tau Load. Equation 3 was fitted to these data to estimate the parameters rTau & T50Tau and consequently the temporal relationship between Aβ and tau including the temporal lag parameter TLAG (= T50Tau ‐ T50Aβ). Results: The model fit described the data well (Figure 2A: Solid black line) and provided clear in vivo evidence that Tau accumulation follows Aβ (TLAG = 5.5+‐0.9SE yrs). The estimated tau exponential growth rate (rTau) was 0.13 yrs‐1 which was lower than that observed for Aβ (r Ab = 0.2 yrs‐1). These parameters then allowed for the generation of predicted population accumulation curves for Aβ and tau over time (Figure 2B). Conclusion: Using the IQ analytics platform and temporal regression modelling we provide clear in vivo evidence that in AD tau accumulation follows Aβ and characterise this temporal relationship. [ABSTRACT FROM AUTHOR]

Background: [18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation of scans as either negative (equating to none or sparse amyloid plaques in pathology SoT), or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of Nuclear Medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Data was collected from multiple sources to assess comparability of the two methods of image interpretation. Method: 9 separate studies where visual reading of [18F]flutemetamol and quantitative analysis of images was available were combined to form a single cohort to measure the percentage agreement between the two methods of image interpretation. Scans covered a wide range of cases (eg from cognitively unimpaired subjects to patients attending the memory clinics see table). Methods of quantifying amyloid ranged from using CE marked/510K cleared software (eg Cortex ID), to other research tools (eg PMOD, CapAIBL) as well as newer methods such as AmyloidIQ. Concordance between visual and quantiative imaging used thresholds robustly established using pathology as the standard of truth Result: A total of 2,566 [18F] flutemetamol images were collected from 9 clinical studies, visually interpreted by readers using the approved reading methodology and compared to quantitative measures using thresholds which had a binary delineation of amyloid. The mean concordance between visual read and quantitation was 95.01% (SD 3.00%), the median was 95.0%, and the range of the 9 studies was from 89.7% to 99.0%. A total of 379 images were compared using CE marked/510k cleared amyloid quantitation software and the percent agreement in these studies was 98.8% to 99.0%. Conclusion: Given the high concordance of visual and quantitation from over 2500 scans, users are able apply quantitative amyloid PET software methods to supplement visual inspection. The decision to use these methods as an adjunct to visual reading is left to the choice of the physician as both methods of image interpretation are comparable. The European Medicines Agency (EMA) have agreed to update the prescribing instructions for [18F]flutemetamol (Vizamyl) based upon this analysis. [ABSTRACT FROM AUTHOR]

Background: LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer's disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein, we report on nonclinical and clinical studies that assessed the effect of LY3372689 on brain OGA enzyme occupancy (EO). Method: Brain OGA EO of LY3372689 was measured in the frontal cortex of rats using tracer LSN3291920, a non‐fluorinated analog of a positron emission tomography (PET) radioligand 18F‐ LY3316612. A single oral dose study in healthy volunteers (HV) utilizing18F‐LY3316612 is ongoing to assess brain OGA EO of LY3372689 (NCT03944031). The study consists of up to 5 Cohorts (N = 3 – 6 subjects per Cohort). Upon completion, each subject will have participated in one cohort and have received a baseline PET scan and up to two post‐dose PET scans. In the initial cohorts, the post‐dose PET scans were conducted at approximately 2 and 24 hours after LY3372689 administration. The study design is adaptive to allow adjustment of the LY3372689 dose, timing of PET scans and pharmacokinetic samples, and number of subjects, pending results of prior cohorts. Result: In rat studies, LY3372689 demonstrated a dose‐dependent change in OGA EO following a single oral dose with a maximum EO of greater than 90%. In the human PET study, a total of 12 healthy volunteers across 3 dose cohorts (N = 4 HV per cohort) have been enrolled to date. A plasma concentration‐dependent increase in brain OGA EO was observed with EO exceeding 90% at 24 hours following the highest dose of LY3372689 administered. Conclusion: Non‐clinical and clinical EO studies demonstrated that occupancy of the OGA enzyme effectively translated from rats to humans after single doses of LY3372689. The human PET data can be used to support LY3372869 dose selection for efficacy trials in tauopathies. [ABSTRACT FROM AUTHOR]

Although [11C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [11C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [11C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 μg kg−1). The regional binding potential (BPND) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [11C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R ( Kd/ fND ∼ 0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R ( Kd/ fND ∼ 11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ∼ 10%) were estimated at ∼0.02-0.04 μg kg−1 injected mass for anesthetized primate and at 0.01-0.02 μg kg−1 for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [11C]-(+)-PHNO. Synapse, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development. [ABSTRACT FROM AUTHOR]

The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [11C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [11C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [11C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction ( f P: 0.8 vs. 8%) and delivery ( K1: 0.025 vs. 0.126 ml cm−3 min−1) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR( V T): 29-38%), but was improved using a pseudo reference tissue model (VAR(BPND): 16-23%). GSK1018921 EC50 estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively. Synapse, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

[11C] P943 is a recently developed PET radiotracer for serotonin 5-HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT1B and 5-HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. Six isoflurane-anesthetized baboons were scanned with [11C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB-616234-S (a 5-HT1B selective antagonist), SB-714786 (a 5-HT1D selective antagonist), as well as the administration of 5-HT releasing agents (fenfluramine, amphetamine) and 5-HT reuptake inhibitor (citalopram). [11C] P943 was observed to bind saturably and specifically to 5-HT1B receptors and to be sensitive to all three challenges known to alter 5-HT levels in the proximity of receptors. [11C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions. Synapse, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The article discusses a study on a proposed real-time adaptive sequential design (ASD) method for optimal acquisition of arterial spin labeling (ASL) data. The magnetic resonance imaging (MRI) technique of ASL can obtain quantitative noninvasive measurement of cerebral blood flow (CBF). The study found that adapted schedules accommodated the prolonged arterial transit times in the brain's occipital lobe. The simulations performed found that the ASD approach can incorporate pathologic parameter information into an optimal ASL scheduling design.

Examination of dopamine-D3 (D3) receptors with positron emission tomography (PET) have been hampered in the past by the lack of a PET ligand with sufficient selectivity for D3 over dopamine-D2 (D2) receptors. The two types co-localize in the brain, with D2 density significantly higher than D3, hence nonselective PET ligands inform on D2, rather than D3 status. [11C]-(+)-PHNO is a novel PET ligand with a preferential affinity for D3 over D2. We used the selective D3 antagonist, SB-277011 to dissect regional fractions of the [11C]-(+)-PHNO signal attributable to D3 and D2 in primate brain. The results were compared with quantitative autoradiography with 3H-(+)-PHNO in wild-type, D2-knock-out, and D3-knock-out mice examined at baseline and following administration of SB-277011. Both sets of results converged to indicate a predominant D3-related component to (+)-PHNO binding in extra-striatal regions, with binding in the midbrain being entirely attributable to D3. The midbrain is thus an excellent target region to examine D3 receptor occupancy with [11C]-(+)-PHNO PET in vivo. Synapse 63:782-793, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [11C]raclopride and [123I]IBZM, do not provide sufficient signal to noise ratio to quantify D2 receptors in extrastriatal areas, such as cortex, where the concentration of D2 receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D2 radioligands [11C]FLB 457 and [11C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. D2 receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg−1, oral), using both [11C]FLB 457 and [11C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BPND) in eight cortical regions. Under controlled conditions, [11C]FLB 457 BPND was 30-70% higher compared with [11C]fallypride BPND in cortical regions. Amphetamine induced DA release led to a significant decrease in [11C]FLB 457 BPND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [11C]fallypride BPND was detected in cortex following amphetamine. The difference between [11C]FLB 457 and [11C]fallypride ability to detect changes in the cortical D2 receptor availability following amphetamine is related to the higher signal to noise ratio provided by [11C]FLB 457. These findings suggest that [11C]FLB 457 is superior to [11C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447-461, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer's disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report on single dose (SD) and multiple dose (MD) clinical studies testing the effect of LY3372689 on brain OGA enzyme occupancy (EO). Method: A positron emission tomography (PET) radioligand, 18F‐LY3316612, was used to assess brain OGA EO in healthy volunteers (HV). In the SD study [NCT03944031], 0.25, 1 and 5 mg LY3372689 were evaluated across 4 cohorts (N = 4 HV per cohort). Each HV had PET scans at baseline and two post‐dose intervals. Post‐dose scans occurred at 2 and 24 hours at 0.25, 1, and 5 mg, with additional scans for 1 mg at 30 and 54 hours. The MD study [NCT04392271] consisted of 1 cohort (N = 4 HV) given 1 mg LY3372689 once daily for 14 days. Each HV had a baseline PET scan, and PET scans at 24 hours post‐dose after the 1st and 14th administration of LY3372689. Plasma pharmacokinetics was assessed in these studies. Result: In the SD study, the mean brain OGA EO at 5 mg was 98% at 2 hours and 93% at 24 hours. At 1 mg, the mean EO was 97% at 2 hours, 81% at 24 hours, 68% at 30 hours, and 30% at 54 hours. The EO at 0.25 mg was lower at 2 hours (26%) compared to 24 hours (46%). The Emax and EC50 values were estimated to be 97% and 0.1 ng/mL, respectively. In the MD study, the OGA EO at 24 hours after the 1st and 14th administration of 1 mg LY3372689 was 84%. Conclusion: PET studies in healthy volunteers demonstrated that LY3372689 can achieve high brain target occupancy of the OGA enzyme. Brain OGA EO was maintained after multiple dosing, supporting the durability of target engagement for longer clinical trials. The human PET data will be used to support LY3372869 dose selection for efficacy trials in tauopathies. [ABSTRACT FROM AUTHOR]

Quantitative measurement of cerebral blood flow (CBF) using arterial spin labeling (ASL) MRI requires the acquisition of multiple inversion times (TIs) and the application of an appropriate kinetic model. The choice of these sampling times will have an impact on the precision of the estimated parameters. Here, optimal sampling schedule (OSS) design techniques, based on the Fisher Information approach, are applied in order to derive an optimal sampling scheme for pulsed arterial spin labeling (PASL) experiments. Such an approach should improve the precision of parameter estimation from experimental data, and provide a formal framework for optimally selecting a limited number of samples. In this study, we aimed to optimize the estimation precision of CBF and bolus arrival time from the PASL data. The performance of OSS was compared to a more standard evenly distributed sampling schedule (EDS) using both simulated and measured experimental data sets. It was found that OSS was able to significantly improve the precision of parameter estimation in PASL studies that sought to estimate either both CBF and bolus arrival time, or CBF alone. Magn Reson Med, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Cyclic AMP (cAMP) is a continually produced nucleotide which is inactivated by hydrolysis to 5′AMP via phosphodiesterase 4 (PDE4) enzymes. Rolipram is a selective PDE4 inhibitor which exists in two enantiomeric forms, R(−) and S(+). Both of these enantiomers have previously been labelled with carbon-11 and used as positron emission tomography (PET) ligands for measuring PDE4 expression and function, and indirectly to explore the function of the cAMP second messenger, in vivo, using PET. The aim of these studies was to relate the in vitro affinities of the two rolipram enantiomers using standard pharmacological assays with the in vivo behaviour of the two enantiomers using PET. In vitro competition assays were performed using rat cortical membranes and [3H] R(−)- and [3H] S(+)-rolipram with increasing concentrations of either unlabelled R(−)- or S(+)-rolipram. In vivo, a series of PET studies were performed in the porcine brain using [11C] R(−)-rolipram with co-administration of increasing doses of either unlabelled R(−)- or S(+)-rolipram. Additional in vivo PET studies were performed using [11C] S(+)-rolipram with saturating doses of rolipram. In all studies, R(−)-rolipram exhibited a higher affinity for the PDE4 enzyme than S(+)-rolipram. The calculated affinity ratios were 7.97 from the in vitro studies; 12.5 from the in vivo studies using [11C] R(−)-rolipram; and 14.7 from the in vivo studies using [11C] S(+)-rolipram. To conclude, the in vitro affinities of R(−)- and S(+)-rolipram predict their apparent in vivo behaviour in the porcine brain, as measured by PET. Synapse 55:270-279, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]