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.

PURPOSE: [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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia.

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression.

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a review of our findings demonstrating lower SV2A synaptic density in people with significant depressive symptoms and the use of a ketamine drug challenge to examine synaptogenesis in vivo. We then highlight the importance of performing translational PET imaging in animal models in conjunction with clinical imaging. We consider the ongoing challenges, possible solutions, and present preliminary findings from our lab demonstrating the translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress. Finally, we discuss methodological improvements and future directions for SV2A imaging, potentially in conjunction with other neural markers.

Performance Characteristics of the NeuroEXPLORER, a Next-Generation Human Brain PET/CT Imager.

The collaboration of Yale, the University of California, Davis, and United Imaging Healthcare has successfully developed the NeuroEXPLORER, a dedicated human brain PET imager with high spatial resolution, high sensitivity, and a built-in 3-dimensional camera for markerless continuous motion tracking. It has high depth-of-interaction and time-of-flight resolutions, along with a 52.4-cm transverse field of view (FOV) and an extended axial FOV (49.5 cm) to enhance sensitivity. Here, we present the physical characterization, performance evaluation, and first human images of the NeuroEXPLORER. Methods: Measurements of spatial resolution, sensitivity, count rate performance, energy and timing resolution, and image quality were performed adhering to the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. The system's performance was demonstrated through imaging studies of the Hoffman 3-dimensional brain phantom and the mini-Derenzo phantom. Initial 18F-FDG images from a healthy volunteer are presented. Results: With filtered backprojection reconstruction, the radial and tangential spatial resolutions (full width at half maximum) averaged 1.64, 2.06, and 2.51 mm, with axial resolutions of 2.73, 2.89, and 2.93 mm for radial offsets of 1, 10, and 20 cm, respectively. The average time-of-flight resolution was 236 ps, and the energy resolution was 10.5%. NEMA sensitivities were 46.0 and 47.6 kcps/MBq at the center and 10-cm offset, respectively. A sensitivity of 11.8% was achieved at the FOV center. The peak noise-equivalent count rate was 1.31 Mcps at 58.0 kBq/mL, and the scatter fraction at 5.3 kBq/mL was 36.5%. The maximum count rate error at the peak noise-equivalent count rate was less than 5%. At 3 iterations, the NEMA image-quality contrast recovery coefficients varied from 74.5% (10-mm sphere) to 92.6% (37-mm sphere), and background variability ranged from 3.1% to 1.4% at a contrast of 4.0:1. An example human brain 18F-FDG image exhibited very high resolution, capturing intricate details in the cortex and subcortical structures. Conclusion: The NeuroEXPLORER offers high sensitivity and high spatial resolution. With its long axial length, it also enables high-quality spinal cord imaging and image-derived input functions from the carotid arteries. These performance enhancements will substantially broaden the range of human brain PET paradigms, protocols, and thereby clinical research applications.

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder.

BACKGROUND: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD. METHODS: Positron emission tomography (PET) with [18F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25). RESULTS: Consistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028). LIMITATIONS: The modest sample size is the primary limitation. CONCLUSIONS: Deficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [18F]TZ4877 in Nonhuman Primates.

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR1-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR1 radiotracer, [18F]TZ4877, in nonhuman primates. Procedures: [18F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[18F]/F- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [18F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (f P). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR1-specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (V T/f P). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA. Results: [18F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [18F]TZ4877 f P was low (< 1%), and [18F]TZ4877 V T/f P values were 233-866 mL/cm3. TZ82112 dose-dependently reduced [18F]TZ4877 V T/f P, while ponesimod and endotoxin exhibited negligible effects on V T/f P, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate. Conclusions: [18F]TZ4877 exhibits reversible kinetic properties, but the low f P value limits quantification with this radiotracer. S1PR1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.

Synaptic density patterns in early Alzheimer's disease assessed by independent component analysis.

Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in post-mortem studies. Previously, we observed in vivo reductions of synaptic density with [11C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner. [11C]UCB-J binding to synaptic vesicle protein 2A was measured in 38 Alzheimer's disease (24 mild Alzheimer's disease dementia and 14 mild cognitive impairment) and 19 cognitively normal participants. [11C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components to which independent component analysis was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman's rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: Logical Memory II, Rey Auditory Verbal Learning Test-long delay, Clinical Dementia Rating sum of boxes and Mini-Mental State Examination. We observed significant differences in loading weights among cognitively normal, mild cognitive impairment and mild Alzheimer's disease dementia groups in 5 of the 18 independent components, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrated significant differences in group loading weights after correction for multiple comparisons. Excluding the cognitively normal group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019), Mini-Mental State Examination (r = 0.48, P = 0.0055) and Logical Memory II score (r = 0.44, P = 0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and Logical Memory II score (r = 0.34, P = 0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019) and Mini-Mental State Examination (r = 0.48, P = 0.0055) remained statistically significant. We demonstrated that independent component analysis could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the mild cognitive impairment/mild Alzheimer's disease dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest-based methods, revealing distinct patterns that differentiate between mild cognitive impairment and mild Alzheimer's disease dementia, marking a significant advancement in the field.

First-in-Human Study of 18F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding.

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(18F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V T). The regional nondisplaceable binding potential (BP ND) was calculated from 1TC V T, using the centrum semiovale (CS) as the reference region. Results: 18F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18F-SynVesT-2 is faster than the kinetics of 11C-UCB-J and 18F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

Synaptic loss and its association with symptom severity in Parkinson's disease.

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer's disease.

BACKGROUND: Effective, disease-modifying therapeutics for the treatment of Alzheimer's disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aß) is central to AD pathophysiology, and Aß oligomers are among the most toxic forms of Aß. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of Aß oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace Aß oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients. METHODS: The present phase 1/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100 mg or 300 mg per day of oral CT1812 for 24 weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration. RESULTS: No treatment differences relative to placebo were observed in the change from baseline at 24 weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated. CONCLUSIONS: The safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development. TRIAL REGISTRATION: The clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282).

Improving SUVR quantification by correcting for radiotracer clearance in tissue.

Standardized Uptake Value Ratio (SUVR) is a widely reported semi-quantitative positron emission tomography (PET) outcome measure, partly because of its ease of measurement from short scan durations. However, in brain, SUVR is often a biased estimator of the gold-standard distribution volume ratio (DVR) due to non-equilibrium conditions, i.e., clearance of the radiotracer in relevant tissues. Factors that affect radiotracer metabolism and clearance such as medication or subject groups could lead to artificial differences in SUVR. This work developed a correction that reduces the bias in SUVR (estimated from a short 15-30 min PET imaging session) by accounting for the effects of tracer clearance observed during the late SUVR time window. The proposed correction takes the form of a one-step non-linear algebraic transform of SUVR that is a function of radiotracer dependent parameters such as clearance rates from the reference and target tissues, and population averaged reference region clearance rate (k2,ref). An important observation was the need for accurate estimation of radiotracer clearance rate in target tissue, which was addressed with a regression based model. Simulations and human data from two different radiotracers (healthy controls for [11C]LSN3172176, healthy controls and Parkinson's disease subjects for [18F]FE-PE2I) were used to validate the correction and evaluate its benefits and limitations. SUVR correction in human data significantly reduced mean SUVR bias across brain regions and subjects (from ∼25% for SUVR to <10% for corrected SUVR). This correction also significantly reduced the variability of this bias across brain regions for both tracers (approximately 50% for [11C]LSN3172176, 20% for [18F]FE-PE2I). Future work should investigate the benefits of using corrected SUVR in other populations and with different tracers.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

Assessment of Gray Matter Microstructure and Synaptic Density in Alzheimer's Disease: A Multimodal Imaging Study With DTI and SV2A PET.

OBJECTIVE: Multimodal imaging techniques have furthered our understanding of how different aspects of Alzheimer's disease (AD) pathology relate to one another. Diffusion tensor imaging (DTI) measures such as mean diffusivity (MD) may be a surrogate measure of the changes in gray matter structure associated with AD. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has been used to quantify synaptic loss, which is the major pathological correlate of cognitive impairment in AD. In this study, we investigated the relationship between gray matter microstructure and synaptic density. METHODS: DTI was used to measure MD and [11C]UCB-J PET to measure synaptic density in 33 amyloid-positive participants with AD and 17 amyloid-negative cognitively normal (CN) participants aged 50-83. Univariate regression analyses were used to assess the association between synaptic density and MD in both the AD and CN groups. RESULTS: Hippocampal MD was inversely associated with hippocampal synaptic density in participants with AD (r = -0.55, p <0.001, df = 31) but not CN (r = 0.13, p = 0.62, df = 15). Exploratory analyses across other regions known to be affected in AD suggested widespread inverse associations between synaptic density and MD in the AD group. CONCLUSION: In the setting of AD, an increase in gray matter MD is inversely associated with synaptic density. These co-occurring changes may suggest a link between synaptic loss and gray matter microstructural changes in AD. Imaging studies of gray matter microstructure and synaptic density may allow important insights into AD-related neuropathology.

Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.

Markerless head motion tracking and event-by-event correction in brain PET.

Objective.Head motion correction (MC) is an essential process in brain positron emission tomography (PET) imaging. We have used the Polaris Vicra, an optical hardware-based motion tracking (HMT) device, for PET head MC. However, this requires attachment of a marker to the subject's head. Markerless HMT (MLMT) methods are more convenient for clinical translation than HMT with external markers. In this study, we validated the United Imaging Healthcare motion tracking (UMT) MLMT system using phantom and human point source studies, and tested its effectiveness on eight18F-FPEB and four11C-LSN3172176 human studies, with frame-based region of interest (ROI) analysis. We also proposed an evaluation metric, registration quality (RQ), and compared it to a data-driven evaluation method, motion-corrected centroid-of-distribution (MCCOD).Approach.UMT utilized a stereovision camera with infrared structured light to capture the subject's real-time 3D facial surface. Each point cloud, acquired at up to 30 Hz, was registered to the reference cloud using a rigid-body iterative closest point registration algorithm.Main results.In the phantom point source study, UMT exhibited superior reconstruction results than the Vicra with higher spatial resolution (0.35 ± 0.27 mm) and smaller residual displacements (0.12 ± 0.10 mm). In the human point source study, UMT achieved comparable performance as Vicra on spatial resolution with lower noise. Moreover, UMT achieved comparable ROI values as Vicra for all the human studies, with negligible mean standard uptake value differences, while no MC results showed significant negative bias. TheRQevaluation metric demonstrated the effectiveness of UMT and yielded comparable results to MCCOD.Significance.We performed an initial validation of a commercial MLMT system against the Vicra. Generally, UMT achieved comparable motion-tracking results in all studies and the effectiveness of UMT-based MC was demonstrated.

An update on the use of image-derived input functions for human PET studies: new hopes or old illusions?

BACKGROUND: The need for arterial blood data in quantitative PET research limits the wider usability of this imaging method in clinical research settings. Image-derived input function (IDIF) approaches have been proposed as a cost-effective and non-invasive alternative to gold-standard arterial sampling. However, this approach comes with its own limitations-partial volume effects and radiometabolite correction among the most important-and varying rates of success, and the use of IDIF for brain PET has been particularly troublesome. MAIN BODY: This paper summarizes the limitations of IDIF methods for quantitative PET imaging and discusses some of the advances that may make IDIF extraction more reliable. The introduction of automated pipelines (both commercial and open-source) for clinical PET scanners is discussed as a way to improve the reliability of IDIF approaches and their utility for quantitative purposes. Survey data gathered from the PET community are then presented to understand whether the field's opinion of the usefulness and validity of IDIF is improving. Finally, as the introduction of next-generation PET scanners with long axial fields of view, ultra-high sensitivity, and improved spatial and temporal resolution, has also brought IDIF methods back into the spotlight, a discussion of the possibilities offered by these state-of-the-art scanners-inclusion of large vessels, less partial volume in small vessels, better description of the full IDIF kinetics, whole-body modeling of radiometabolite production-is included, providing a pathway for future use of IDIF. CONCLUSION: Improvements in PET scanner technology and software for automated IDIF extraction may allow to solve some of the major limitations associated with IDIF, such as partial volume effects and poor temporal sampling, with the exciting potential for accurate estimation of single kinetic rates. Nevertheless, until individualized radiometabolite correction can be performed effectively, IDIF approaches remain confined at best to a few tracers.

Generation of Whole-Body FDG Parametric Ki Images from Static PET Images Using Deep Learning.

FDG parametric Ki images show great advantage over static SUV images, due to the higher contrast and better accuracy in tracer uptake rate estimation. In this study, we explored the feasibility of generating synthetic Ki images from static SUV ratio (SUVR) images using three configurations of U-Nets with different sets of input and output image patches, which were the U-Nets with single input and single output (SISO), multiple inputs and single output (MISO), and single input and multiple outputs (SIMO). SUVR images were generated by averaging three 5-min dynamic SUV frames starting at 60 minutes post-injection, and then normalized by the mean SUV values in the blood pool. The corresponding ground truth Ki images were derived using Patlak graphical analysis with input functions from measurement of arterial blood samples. Even though the synthetic Ki values were not quantitatively accurate compared with ground truth, the linear regression analysis of joint histograms in the voxels of body regions showed that the mean R2 values were higher between U-Net prediction and ground truth (0.596, 0.580, 0.576 in SISO, MISO and SIMO), than that between SUVR and ground truth Ki (0.571). In terms of similarity metrics, the synthetic Ki images were closer to the ground truth Ki images (mean SSIM = 0.729, 0.704, 0.704 in SISO, MISO and MISO) than the input SUVR images (mean SSIM = 0.691). Therefore, it is feasible to use deep learning networks to estimate surrogate map of parametric Ki images from static SUVR images.

Dose reduction in dynamic synaptic vesicle glycoprotein 2A PET imaging using artificial neural networks.

Objective. Reducing dose in positron emission tomography (PET) imaging increases noise in reconstructed dynamic frames, which inevitably results in higher noise and possible bias in subsequently estimated images of kinetic parameters than those estimated in the standard dose case. We report the development of a spatiotemporal denoising technique for reduced-count dynamic frames through integrating a cascade artificial neural network (ANN) with the highly constrained back-projection (HYPR) scheme to improve low-dose parametric imaging.Approach. We implemented and assessed the proposed method using imaging data acquired with11C-UCB-J, a PET radioligand bound to synaptic vesicle glycoprotein 2A (SV2A) in the human brain. The patch-based ANN was trained with a reduced-count frame and its full-count correspondence of a subject and was used in cascade to process dynamic frames of other subjects to further take advantage of its denoising capability. The HYPR strategy was then applied to the spatial ANN processed image frames to make use of the temporal information from the entire dynamic scan.Main results. In all the testing subjects including healthy volunteers and Parkinson's disease patients, the proposed method reduced more noise while introducing minimal bias in dynamic frames and the resulting parametric images, as compared with conventional denoising methods.Significance. Achieving 80% noise reduction with a bias of -2% in dynamic frames, which translates into 75% and 70% of noise reduction in the tracer uptake (bias, -2%) and distribution volume (bias, -5%) images, the proposed ANN+HYPR technique demonstrates the denoising capability equivalent to a 11-fold dose increase for dynamic SV2A PET imaging with11C-UCB-J.