Simplified Reference Tissue Model Research Articles

NIMG-44. ELEVATED TRANSLOCATOR PROTEIN 18KDA BINDING IN LOW MEAN DIFFUSIVITY CLUSTERS IS A FEATURE OF THE TRANSFORMING GLIOMA AND IDH MUTANT GLIOMA MICROENVIRONMENT

Abstract Around 95% of low-grade gliomas undergo anaplastic de-differentiation into high-grade gliomas, a process only partially understood from in vivo clinical imaging. 11 patients with suspected transforming gliomas underwent a combined magnetic resonance imaging (MRI) and positron emission tomography (PET) protocol, incorporating post-contrast T1-weighted/FLAIR acquisition for tumour delineation and diffusion tensor imaging. The PET radiotracer [11C]-(R)-PK11195 assessed translocator protein 18kDa (TSPO) distribution, whose upregulation is associated with inflammation/glioma progression. [11C]-(R)-PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model, with the grey-matter cerebellar time-activity curve serving as the reference tissue input function. KMeans clustering of mean diffusivity (MD) intensity values defined spatially distinct “habitats” of high/low MD voxels within the glioma microenvironment. BPND values within high/low MD clustering habitats were evaluated, across glioma grades and isocitrate dehydrogenase (IDH) mutational status. Across all grade 2 and 3 gliomas (n= 6), mean TSPO BPND values in low MD habitats (0.0383 ±0.102) were significantly greater than high MD habitats (-0.045 ±0.142) (p= 0.003). In grade 4 gliomas (n= 5), no significant difference was observed in mean BPND values between low (0.514 ±0.176) and high (0.465 ±0.296) MD habitats (p= 0.543). IDH mutant gliomas (n= 7) exhibited significantly higher mean BPND in low MD habitats (0.116 ±0.225), relative to high habitats (0.052 ±0.287) (p= 0.021). IDH wildtype gliomas (n= 4) showed no significant differences between BPND values in low (0.498 ±0.199) and high MD habitats (0.424 ±0.325) (p= 0.467). Our novel findings demonstrate spatial heterogeneity in TSPO expression within 2/3/IDH mutant gliomas, a characteristic absent from grade 4/IDH wildtype varieties. Regions of restricted diffusion with high TSPO signal in grade 2/3/IDH mutant tumours indicate the heterogenous distribution of active TSPO-expressing immune/neoplastic cell populations, contrasting the homogenous distribution in grade 4/IDH wildtype gliomas, highlighting differences between their inflammatory profile and pathological features.

Effects of cognitive training under hypoxia on cognitive proficiency and neuroplasticity in remitted patients with mood disorders and healthy individuals: ALTIBRAIN study protocol for a randomized controlled trial

BackgroundCognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects.MethodsIn sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [11C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region.DiscussionThe results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies.Trial registrationClinicalTrials.gov, NCT06121206. Registered on 31 October 2023.

Vitamin D’s Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [11C]-PHNO Positron Emission Tomography Study

BackgroundDopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans. MethodsHealthy, vitamin-D-sufficient adults (N=18; 32.8 ±6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving four total scans over two visits consisting of same-day pre-amphetamine and post-amphetamine (0.3 mg/kg) 11C-PHNO positron emission tomography (PET) scanning to examine D2/3 receptor availability (BPND) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least six days apart. Parametric images of 11C-PHNO PET BPND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra. ResultsFor pre-amphetamine scans, there was a medication-by-region-of-interest interaction (F4,153=2.59, p=0.039) and a main effect of medication (F1,153=4.88, p=0.029) on BPND, with higher BPND values on calcitriol in the ventral striatum (t=2.89, p=0.004) and dorsal putamen (t=2.15, p=0.033). There was a main effect of medication on post-amphetamine change in BPND (F4,153=5.93, p=0.016), with greater decreases on calcitriol in the ventral striatum (t=3.00, p=0.003), substantia nigra (t=2.49, p=0.014), and dorsal caudate (t=2.29, p=0.023). ConclusionsResults provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders involving dysregulated dopamine function. Clinical Trial RegistrationVitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD; https://clinicaltrials.gov/study/NCT03103750; ClinicalTrials.gov ID: NCT03103750

Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study.

The pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer's disease (AD). Positron emission tomography (PET) studies of mGluR5 using [18F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [11C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [18F]FPEB and [11C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD. Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [18F]FPEB to measure mGluR5 and [11C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [18F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [11C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region.. A strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group (r = 0.85, p <0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions. Medial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated Aβo toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.

Validation of a Simplified Tissue-to-Reference Ratio Measurement Using SUVR to Assess Synaptic Density Alterations in Alzheimer Disease with [11C]UCB-J PET.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [11C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60-90 or 70-90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

Noninvasive quantification of [18F]SynVesT-1 binding using simplified reference tissue model 2.

[18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions. Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated. The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates. Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.

Elevated cerebral blood flow proxy with increased beta-amyloid burden in Alzheimer’s disease preclinical phase evaluated by dual-phase 18F-florbetaben positron emission tomography

This study investigated the earliest change of cerebral blood flow (CBF) and its relationship with β-amyloid (Aβ) burden in preclinical Alzheimer’s disease (AD) employing dual-phase 18F-florbetaben (FBB) PET. Seventy-one cognitively normal (NC) individuals were classified as Aβ negative (Aβ−NC) or positive (Aβ+NC) based on two different cutoff values: an SUVR of > 1.08 and a Centiloid scale of > 20. The PET scans were acquired in two phases: an early phase (0–10 min, eFBB) and a delayed phase (90–110 min, dFBB), which were averaged to generate single-frame images for each phase. Furthermore, an R1 parametric map was generated from the early phase data using a simplified reference tissue model. We conducted regional and voxel-based analyses to compare the eFBB, dFBB, and R1 images between the Aβ positive and negative groups. In addition, the correlations between the CBF proxy R1 and the dFBB SUVR were analyzed. The Aβ+NC group showed significantly higher dFBB SUVR in both the global cerebral cortex and target regions compared to the Aβ−NC group, while no significant differences were observed in eFBB SUVR between the two groups. Furthermore, the Aβ+NC group exhibited significantly higher R1 values, a proxy for cerebral perfusion, in both the global cerebral cortex and target regions compared to the Aβ−NC group. Significant positive correlations were observed between R1 and dFBB SUVR in both the global cerebral cortex and target regions, which remained significant after controlling for demographics and cognitive profiles, except for the medial temporal and occipital cortices. The findings reveal increased CBF in preclinical AD and a positive correlation between CBF and amyloid pathology. The positive correlation between R1 and amyloid burden may indicate a compensatory mechanism in the preclinical stage of Alzheimer’s disease, but to elucidate this hypothesis, further longitudinal observational studies are necessary.

Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research

The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor.Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [11C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BPND), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region.Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg.These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience.

Simultaneous assessment of blood flow and myelin content in the brain white matter with dynamic [11C]PiB PET: a test-retest study in healthy controls.

Exploring the relationship between oxygen supply and myelin damage would benefit from a simultaneous quantification of myelin and cerebral blood flow (CBF) in the brain's white matter (WM). To validate an analytical method for quantifying both CBF and myelin content in the WM using dynamic [11C]PiB positron emission tomography (PET). A test-retest study was performed on eight healthy subjects who underwent two consecutive dynamic [11C]PiB-PET scans. Three quantitative approaches were compared: simplified reference tissue model 2 (SRTM2), LOGAN graphical model, and standardized uptake value ratio (SUVR). The sensitivity of methods to the size of the region of interest was explored by simulating lesion masks obtained from 36 subjects with multiple sclerosis. Reproducibility was assessed using the relative difference and interclass correlation coefficient. Repeated measures correlations were used to test for cross-correlations between metrics. Among the CBF measures, the relative delivery (R1) of the simplified reference tissue model 2 (SRTM2) displayed the best reproducibility in the white matter, with a strong influence of the size of regions analyzed, the test-retest variability being below 10% for regions above 68 mm3 in the supratentorial white matter. [11C]PiB PET-derived proxies of CBF demonstrated lower perfusion of white matter compared to grey matter with an overall ratio equal to 1.71 ± 0.09 when the SRTM2-R1 was employed. Tissue binding in the white matter was well estimated by the Logan graphical model through estimation of the distribution volume ratio (LOGAN-DVR) and SRTM2 distribution volume ratio (SRTM2-DVR), with test-retest variability being below 10% for regions exceeding 106 mm3 for LOGAN-DVR and 300 mm3 for SRTM2-DVR. SRTM2-DVR provided a better contrast between white matter and grey matter. The interhemispheric variability was also dependent on the size of the region analyzed, being below 10% for regions above 103 mm3 for SRTM2-R1 and above 110 mm3 for LOGAN-DVR. Whereas the 1 to 8-minute standardized uptake value ratio (SUVR1-8) showed an intermediary reproducibility for CBF assessment, SUVR0-2 for perfusion or SUVR50-70 for tissue binding showed poor reproducibility and correlated only mildly with SRTM2-R1 and LOGAN-DVR estimations respectively. [11C]PiB PET imaging can simultaneously quantify perfusion and myelin content in WM diseases associated with focal lesions. For longitudinal studies, SRTM2-R1 and DVR should be preferred over SUVR for the assessment of regional CBF and myelin content, respectively. European Union Clinical Trials Register EUDRACT; EudraCT Number: 2008-004174-40; Date: 2009-03-06; https//www.clinicaltrialsregister.eu ; number 2008-004174-40.

Dynamic neuroreceptor positron emission tomography in non-anesthetized rats using point source based motion correction: A feasibility study with [11C]ABP688

To prevent motion artifacts in small animal positron emission tomography (PET), animals are routinely scanned under anesthesia or physical restraint. Both may potentially alter metabolism and neurochemistry. This study investigates the feasibility of fully awake acquisition and subsequent absolute quantification of dynamic brain PET data via pharmacokinetic modelling in moving rats using the glutamate 5 receptor radioligand [11C]ABP688 and point source based motion correction. Five male rats underwent three dynamic [11C]ABP688 PET scans: two test-retest awake PET scans and one scan under anesthesia for comparison. Specific radioligand binding was determined via the simplified reference tissue model (reference: cerebellum) and outcome parameters BPND and R1 were evaluated in terms of stability and reproducibility. Test-retest measurements in awake animals gave reliable results with high correlations of BPND (y = 1.08 × −0.2, r = 0.99, p < 0.01) and an acceptable variability (mean over all investigated regions 15.7 ± 2.4%). Regional [11C]ABP688 BPNDs under awake and anesthetized conditions were comparable although in awake scans, absolute radioactive peak uptakes were lower and relative blood flow in terms of R1 was higher. Awake small animal PET with absolute quantification of neuroreceptor availability is technically feasible and reproducible thereby providing a suitable alternative whenever effects of anesthesia are undesirable, e.g. in sleep research.

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression

BackgroundDepression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. MethodsSix patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. ResultsDepression and anxiety symptoms improved after 3–6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LimitationsThis study was limited to the small sample size and lack of a healthy control group. ConclusionsChronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

Nonlinear Mixed-Effects Modeling Approach for Simplified Reference Tissue Model.

The conventional approach to the analysis of dynamic PET data can be described as a two-stage approach. In Stage 1, each individual's kinetic parameter estimates are obtained by modeling their PET data. Then in Stage 2, those parameter estimates are treated as though they are the observed data and compared across subjects and groups using standard statistical analyses. In this context, we explore the application of nonlinear mixed-effects (NLME) model under the assumptions of simplified reference tissue model. In the NLME framework, all subject's PET data are modeled simultaneously and the estimation of kinetic parameters and statistical inference across subjects are performed jointly. In simulated [ 11C]WAY100635 data, this NLME approach shows improved power (6-27% increase) for detecting group differences and greater consistency of population (1.13-1.44 times greater) and individual-level parameter estimation compared to the two-stage approach applying simplified reference tissue model for pharmacokinetic modeling of PET data. We applied our NLME approach to clinical PET data and observed shrinkage of individual-level parameters that is inherent in this modeling structure. The proposed approach is more powerful and accurate than the two-stage approach under the assumptions of simplified reference tissue model in PET data. The stability of the NLME approach not only improves the efficiency of collected data, but also comes with no additional financial cost and negligible computation cost.

Dynamic multi-pinhole collimated brain SPECT of Parkinson’s disease by [123I]FP-CIT: a feasibility study of fSPECT

We investigated the feasibility of using a dopamine transporter (DaT) tracer ligand ([123I]FP-CIT) along with novel multi-pinhole brain collimators for dynamic brain single photon emission computed tomography (SPECT) in suspected Parkinson's disease patients. Thirteen patients underwent dynamic tracer acquisitions before standard imaging. Uptake values were corrected for partial volume effects. Specific binding ratio (SBRcalc) was calculated, reflecting binding potential relative to non-displaceable binding (BPND) in the cortex. Additional pharmacokinetic parameters (BPND, R1, k2) were estimated using the simplified reference tissue model, revealing differences between Kahraman low-score (LS) and high-score (HS) groups. Results showed increasing striatal tracer uptake until 100 min post-injection, with consistent values afterward. Uptake and SBRcalc ratios matched visual assessment. LS patients had lower putamen than caudate nucleus tracer uptake, decreased BPND values, while R1 and k2 values were comparable to HS patients. In conclusion, dynamic multi-pinhole SPECT using DaT tracer with the extraction of pharmacokinetic parameters is feasible and could help enable early differentiation of reduced and normal DaT values.

PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator

Stimulation of the M4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M4 PAM radiotracer, [11C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [11C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [11C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials.

Exploring the nigrostriatal and digestive interplays in Parkinson's disease using dynamic total-body [11C]CFT PET/CT.

Dynamic total-body imaging enables new perspectives to investigate the potential relationship between the central and peripheral regions. Employing uEXPLORER dynamic [11C]CFT PET/CT imaging with voxel-wise simplified reference tissue model (SRTM) kinetic modeling and semi-quantitative measures, we explored how the correlation pattern between nigrostriatal and digestive regions differed between the healthy participants as controls (HC) and patients with Parkinson's disease (PD). Eleven participants (six HCs and five PDs) underwent 75-min dynamic [11C]CFT scans on a total-body PET/CT scanner (uEXPLORER, United Imaging Healthcare) were retrospectively enrolled. Time activity curves for four nigrostriatal nuclei (caudate, putamen, pallidum, and substantia nigra) and three digestive organs (pancreas, stomach, and duodenum) were obtained. Total-body parametric images of relative transporter rate constant (R1) and distribution volume ratio (DVR) were generated using the SRTM with occipital lobe as the reference tissue and a linear regression with spatial-constraint algorithm. Standardized uptake value ratio (SUVR) at early (1-3min, SUVREP) and late (60-75min, SUVRLP) phases were calculated as the semi-quantitative substitutes for R1 and DVR, respectively. Significant differences in estimates between the HC and PD groups were identified in DVR and SUVRLP of putamen (DVR: 4.82 ± 1.58 vs. 2.58 ± 0.53; SUVRLP: 4.65 ± 1.36 vs. 2.84 ± 0.67; for HC and PD, respectively, both p < 0.05) and SUVREP of stomach (1.12 ± 0.27 vs. 2.27 ± 0.65 for HC and PD, respectively; p < 0.01). In the HC group, negative correlations were observed between stomach and substantia nigra in both the R1 and SUVREP values (r=-0.83, p < 0.05 for R1; r=-0.94, p < 0.01 for SUVREP). Positive correlations were identified between pancreas and putamen in both DVR and SUVRLP values (r = 0.94, p < 0.01 for DVR; r = 1.00, p < 0.001 for SUVRLP). By contrast, in the PD group, no correlations were found between the aforementioned target nigrostriatal and digestive areas. The parametric images of R1 and DVR generated from the SRTM model, along with SUVREP and SUVRLP, were proposed to quantify dynamic total-body [11C]CFT PET/CT in HC and PD groups. The distinction in correlation patterns of nigrostriatal and digestive regions between HC and PD groups identified by R1 and DVR, or SUVRs, may provide new insights into the disease mechanism.

Inflammatory and synaptic PET imaging in behavioural variant frontotemporal dementia caused by a repeat expansion in C9orf72 (C9orf72‐FTD)

AbstractBackgroundPathophysiological mechanisms associated with neurodegeneration include chronic neuroinflammation and synaptic dysfunction/loss. Radiotracer [11C]PBR28 is a marker of inflammation which binds to a translocator protein expressed by activated microglia. [11C]UCB‐J is a marker of synaptic density which binds to synaptic vesicle protein 2A. We evaluated both tracers as biomarkers of C9orf72‐FTD.MethodThree individuals with C9orf72‐FTD (mean age 62.7 years) underwent two PET scans between 3 and 13 months apart using [11C]PBR28 and [11C]UCB‐J. Dynamic PET data were acquired for 90 minutes following injection of each tracer. Arterial plasma input functions were generated from arterial blood samples. Participants also had volumetric MRI scans for each PET scan. Age‐matched controls from different cohorts underwent the same procedures (n = 5 for [11C]PBR28; n = 17 for [11C]UCB‐J).Regions of interest (ROIs) were defined on co‐registered T1‐weighted MR images using the CIC anatomical atlas. [11C]PBR28 BPND values were generated using a simplified reference tissue model with a cerebellar reference region. [11C]UCB‐J DVR‐1 values were generated using regional VT normalised to the VT in the centrum semiovale. ROI volumes were expressed as a percentage of total intracranial volume. W‐scores computed from each control cohort, using age and gender as covariates, illustrated the magnitude of differences between cases and controls. W‐scores &gt;1.65 were considered abnormal for [11C]PBR28 and ←1.65 for [11C]UCB‐J and MRI.Result[11C]PBR28 w‐scores indicated significant neuroinflammation in FTD but varied between cases. Differences in BPND were greater than in volume in frontal/temporal/cingulate cortices in the individual with the longest disease duration (DD) (16‐17 years). Inversely, in the individual with the shortest DD (1‐2 years), there were greater differences in volume than BPND in most ROIs.[11C]UCB‐J w‐scores indicated significant synaptic dysfunction/loss and were lower than w‐scores of volume in all cortical ROIs. In the individual with the longest DD, differences in [11C]PBR28 were greater than in [11C]UCB‐J in most ROIs. An inverse pattern again observed in the individual with the shortest DD suggests synaptic dysfunction/loss may precede significant neuroinflammation.ConclusionInflammatory and synaptic PET may provide more sensitive biomarkers of C9orf72‐FTD than MRI. Variability in PET signal within this genotype may be explained by DD.

PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease

AbstractBackgroundRho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.MethodsThe ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.ResultsUptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).ConclusionsWe demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.

PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease

AbstractBackgroundRho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.MethodThe ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.ResultUptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).ConclusionWe demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.

In Vivo Serotonin 5-HT2A Receptor Availability and Its Relationship with Aggression Traits in Healthy Individuals: A Positron Emission Tomography Study with C-11 MDL100907.

Serotonergic neurotransmission has been associated with aggression in several psychiatric disorders. Human aggression is a continuum of traits, ranging from normal to pathological phenomena. However, the individual differences in serotonergic neurotransmission and their relationships with aggression traits in healthy individuals remain unclear. In this study, we explored the relationship between 5-HT2A receptor availability in vivo and aggression traits in healthy participants. Thirty-three healthy participants underwent 3-Tesla magnetic resonance imaging and positron emission tomography (PET) with [11C]MDL100907, a selective radioligand for 5-HT2A receptors. To quantify 5-HT2A receptor availability, the binding potential (BPND) was derived using the basis function implementation of the simplified reference tissue model, with the cerebellum as the reference region. The participants' aggression levels were assessed using the Buss-Perry Aggression Questionnaire. The voxel-based correlation analysis with age and sex as covariates revealed that the total aggression score was significantly positively correlated with [11C]MDL100907 BPND in the right middle temporal gyrus (MTG) pole, left fusiform gyrus (FUSI), right parahippocampal gyrus, and right hippocampus. The physical aggression subscale score had significant positive correlations with [11C]MDL100907 BPND in the left olfactory cortex, left orbital superior frontal gyrus (SFG), right anterior cingulate and paracingulate gyri, left orbitomedial SFG, left gyrus rectus, left MTG, left inferior temporal gyrus, and left angular gyrus. The verbal aggression subscale score showed significant positive correlations with [11C]MDL100907 BPND in the bilateral SFG, right medial SFG, left FUSI, and right MTG pole. Overall, our findings suggest the possibility of positive correlations between aggression traits and in vivo 5-HT2A receptor availability in healthy individuals. Future research should incorporate multimodal neuroimaging to investigate the downstream effects of 5-HT2A receptor-mediated signaling and integrate molecular and systems-level information in relation to aggression traits.

DUAL PET IMAGING OF NEOPLASTIC AND INflAMMATORY BIOMARKERS IN HIGH GRADE GLIOMA

Abstract AIMS To characterize spatial distributions of 18kDa translocator protein (TSPO) and amino acid uptake as measured through dynamic [11C] (R)-PK11195 and [11C]-methionine PET in high-grade glioma. METHOD Twelve patients with newly diagnosed high-grade glioma underwent dual PET studies. [11C] (R)-PK11195 binding potential (BPND) maps were generated using simplified reference tissue model with grey-matter cerebellar time- activity-curve as tissue input-function. [11C]-methionine uptake was calculated as tumour-to-background ratio (TBR). Volumes of interest (VOIs) were defined on T1W post-contrast MRI as contrast-enhancing (CE) tumour and a ‘peritumoural’ region 5mm from the CE edge. Voxel-wise comparison of the tracers used Pearson’s correlation coeffcient. VOIs were furthermore subdivided into higher/lower TSPO (BPND &amp;gt; 0.17) and higher/lower methionine (TBR &amp;gt; 1.7). RESULTS Within the CE, voxel-wise comparison showed a strong correlation (r &amp;gt; 0.7) in eight subjects, moderate correlation (r &amp;gt; 0.5) in three subjects and weak correlation (r &amp;lt; 0.5) in one subject. Volume (mm3) with high BPND/high TBR accounted for 62±29% whereas high BPND/low TBR accounted for 13±16%. Within the peritumoral area, there was a small reduction in the proportion of subjects in the strong correlation group (6/12) but the pro- portion of voxels with higher TSPO binding and lower methionine uptake was substantially greater (35±16%). CONCLUSIONS Within high-grade glioma, there is a strong overall correlation between TSPO expression and amino acid uptake. However, in the peritumoural region there are areas of elevated TSPO expression without increased methionine uptake which could represent an inflammatory component or a discrete neoplastic cell population that may not be adequately defined with standard imaging biomarkers.