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.

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.

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.

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.

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.

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.

Evaluating infusion methods and simplified quantification of synaptic density in vivo with [11C]UCB-J and [18F]SynVesT-1 PET.

For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for in vivo quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [11C]UCB-J and [18F]SynVesT-1. Observed mean standardized uptake values (SUV) in target tissue relative to that in plasma (CT/CP) or a reference tissue (SUVR-1) were calculated for 30-minute intervals across 120 or 150-minute dynamic scans and compared against one-tissue compartment (1TC) model estimates of volume of distribution (VT) and binding potential (BPND), respectively. We were unable to reliably achieve a state of equilibrium with [11C]UCB-J, and all 30-minute windows yielded overly large bias and/or variability for CT/CP and SUVR-1. With [18F]SynVesT-1, a 30-minute scan 90-120 minutes post-injection yielded CT/CP and SUVR-1 values that estimated their respective kinetic parameter with sufficient accuracy and precision (within 7±6%) . This B/I approach allows a clinically feasible scan at equilibrium with potentially better accuracy than a static scan SUVR following a bolus injection.

Principal component analysis of synaptic density measured with [11C]UCB-J PET in early Alzheimer's disease.

BACKGROUND: Synaptic loss is considered an early pathological event and major structural correlate of cognitive impairment in Alzheimer's disease (AD). We used principal component analysis (PCA) to identify regional patterns of covariance in synaptic density using [11C]UCB-J PET and assessed the association between principal components (PC) subject scores with cognitive performance. METHODS: [11C]UCB-J binding was measured in 45 amyloid + participants with AD and 19 amyloid- cognitively normal participants aged 55-85. A validated neuropsychological battery assessed performance across five cognitive domains. PCA was applied to the pooled sample using distribution volume ratios (DVR) standardized (z-scored) by region from 42 bilateral regions of interest (ROI). RESULTS: Parallel analysis determined three significant PCs explaining 70.2% of the total variance. PC1 was characterized by positive loadings with similar contributions across the majority of ROIs. PC2 was characterized by positive and negative loadings with strongest contributions from subcortical and parietooccipital cortical regions, respectively, while PC3 was characterized by positive and negative loadings with strongest contributions from rostral and caudal cortical regions, respectively. Within the AD group, PC1 subject scores were positively correlated with performance across all cognitive domains (Pearson r = 0.24-0.40, P = 0.06-0.006), PC2 subject scores were inversely correlated with age (Pearson r = -0.45, P = 0.002) and PC3 subject scores were significantly correlated with CDR-sb (Pearson r = 0.46, P = 0.04). No significant correlations were observed between cognitive performance and PC subject scores in CN participants. CONCLUSIONS: This data-driven approach defined specific spatial patterns of synaptic density correlated with unique participant characteristics within the AD group. Our findings reinforce synaptic density as a robust biomarker of disease presence and severity in the early stages of AD.

Reductions in synaptic marker SV2A in early-course Schizophrenia.

Excess synaptic pruning during neurodevelopment has emerged as one of the leading hypotheses on the causal mechanism for schizophrenia. It proposes that excess synaptic elimination occurs during development before the formal onset of illness. Accordingly, synaptic deficits may be observable at all stages of illnesses, including in the early phases. The availability of [11C]UCB-J, the first-in-human in vivo synaptic marker, represents an opportunity for testing this hypothesis with a relatively high level of precision. The first two published [11C]UCB-J schizophrenia studies have documented significant, widespread reductions in binding in chronic patients. The present study tested the hypothesis that reductions are present in early-course patients. 18 subjects completed [11C]UCB-J PET scans, (nine with schizophrenia, average duration of illness of 3.36 years, and nine demographically-matched healthy individuals). We compared binding levels, quantified as non-displaceable specific binding (BPND), in a set of a priori-specified brain regions of interest (ROIs). Eight ROIs (left and right hippocampus, right superior temporal and Heschl's gyrus, left and right putamen, and right caudal and rostral middle frontal gyrus) showed large reductions meeting Bonferroni corrected significant levels, p < 0.0036. Exploratory, atlas-wide analyses confirmed widespread reductions in schizophrenia. We also observed significant positive correlations between binding levels and cognitive performance and a negative correlation with the severity of delusions. These results largely replicate findings from chronic patients, indicating that extensive [11C]UCB-J binding deficits are reliable and reproducible. Moreover, these results add to the growing evidence that excess synaptic pruning is a major disease mechanism for schizophrenia.

Fast Reconstruction for Deep Learning PET Head Motion Correction.

Head motion correction is an essential component of brain PET imaging, in which even motion of small magnitude can greatly degrade image quality and introduce artifacts. Building upon previous work, we propose a new head motion correction framework taking fast reconstructions as input. The main characteristics of the proposed method are: (i) the adoption of a high-resolution short-frame fast reconstruction workflow; (ii) the development of a novel encoder for PET data representation extraction; and (iii) the implementation of data augmentation techniques. Ablation studies are conducted to assess the individual contributions of each of these design choices. Furthermore, multi-subject studies are conducted on an 18F-FPEB dataset, and the method performance is qualitatively and quantitatively evaluated by MOLAR reconstruction study and corresponding brain Region of Interest (ROI) Standard Uptake Values (SUV) evaluation. Additionally, we also compared our method with a conventional intensity-based registration method. Our results demonstrate that the proposed method outperforms other methods on all subjects, and can accurately estimate motion for subjects out of the training set. All code is publicly available on GitHub: https://github.com/OnofreyLab/dl-hmc_fast_recon_miccai2023.

Drug characteristics derived from kinetic modeling: combined 11C-UCB-J human PET imaging with levetiracetam and brivaracetam occupancy of SV2A.

BACKGROUND: Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer 11C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain 11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K1 (brain entry rate) of the drugs. METHOD: Displacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K1 (drug), K1(11C-UCB-J, displacement), K1(11C-UCB-J, post-dose), free fraction of 11C-UCB-J in brain (fND(11C-UCB-J)), and distribution volume of 11C-UCB-J (VT(UCB-J)). Other parameters (KD(drug), KD(11C-UCB-J), fP(drug), fP(11C-UCB-J, displacement), fP(11C-UCB-J, post-dose), fND(drug), koff(drug), koff(11C-UCB-J)) were fixed to literature or measured values. RESULTS: The proposed model described well the TACs in all subjects; however, estimates of drug K1 were unstable in comparison with 11C-UCB-J K1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K1/LEV K1, by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1; the same analysis was performed to find the highest LEV K1. The lower bound of the ratio BRV K1/LEV K1 was ~ 7. CONCLUSIONS: Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.

Imaging of Synaptic Density in Neurodegenerative Disorders.

PET technology has produced many radiopharmaceuticals that target specific brain proteins and other measures of brain function. Recently, a new approach has emerged to image synaptic density by targeting the synaptic vesicle protein 2A (SV2A), an integral glycoprotein in the membrane of synaptic vesicles and widely distributed throughout the brain. Multiple SV2A ligands have been developed and translated to human use. The most successful of these to date is 11C-UCB-J, because of its high uptake, moderate metabolism, and effective quantification with a 1-tissue-compartment model. Further, since SV2A is the target of the antiepileptic drug levetiracetam, human blocking studies have characterized specific binding and potential reference regions. Regional brain SV2A levels were shown to correlate with those of synaptophysin, another commonly used marker of synaptic density, providing the basis for SV2A PET imaging to have broad utility across neuropathologic diseases. In this review, we highlight the development of SV2A tracers and the evaluation of quantification methods, including compartment modeling and simple tissue ratios. Mouse and rat models of neurodegenerative diseases have been studied with small-animal PET, providing validation by comparison to direct tissue measures. Next, we review human PET imaging results in multiple neurodegenerative disorders. Studies on Parkinson disease and Alzheimer disease have progressed most rapidly at multiple centers, with generally consistent results of patterns of SV2A or synaptic loss. In Alzheimer disease, the synaptic loss patterns differ from those of amyloid, tau, and 18F-FDG, although intertracer and interregional correlations have been found. Smaller studies have been reported in other disorders, including Lewy body dementia, frontotemporal dementia, Huntington disease, progressive supranuclear palsy, and corticobasal degeneration. In conclusion, PET imaging of SV2A has rapidly developed, and qualified radioligands are available. PET studies on humans indicate that SV2A loss might be specific to disease-associated brain regions and consistent with synaptic density loss. The recent availability of new 18F tracers, 18F-SynVesT-1 and 18F-SynVesT-2, will substantially broaden the application of SV2A PET. Future studies are needed in larger patient cohorts to establish the clinical value of SV2A PET and its potential for diagnosis and progression monitoring of neurodegenerative diseases, as well as efficacy assessment of disease-modifying therapies.

Adaptive data-driven motion detection and optimized correction for brain PET.

Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis of dynamic datasets. Previously, we proposed a data-driven method, center of tracer distribution (COD), to detect head motion without an external motion tracking device. There, motion was detected using one dimension of the COD trace with a semiautomatic detection algorithm, requiring multiple user defined parameters and manual intervention. In this study, we developed a new data-driven motion detection algorithm, which is automatic, self-adaptive to noise level, does not require user-defined parameters and uses all three dimensions of the COD trace (3DCOD). 3DCOD was first validated and tested using 30 simulation studies (18F-FDG, N = 15; 11C-raclopride (RAC), N = 15) with large motion. The proposed motion correction method was tested on 22 real human datasets, with 20 acquired from a high resolution research tomograph (HRRT) scanner (18F-FDG, N = 10; 11C-RAC, N = 10) and 2 acquired from the Siemens Biograph mCT scanner. Real-time hardware-based motion tracking information (Vicra) was available for all real studies and was used as the gold standard. 3DCOD was compared to Vicra, no motion correction (NMC), one-direction COD (our previous method called 1DCOD) and two conventional frame-based image registration (FIR) algorithms, i.e., FIR1 (based on predefined frames reconstructed with attenuation correction) and FIR2 (without attenuation correction) for both simulation and real studies. For the simulation studies, 3DCOD yielded -2.3 ± 1.4% (mean ± standard deviation across all subjects and 11 brain regions) error in region of interest (ROI) uptake for 18F-FDG (-3.4 ± 1.7% for 11C-RAC across all subjects and 2 regions) as compared to Vicra (perfect correction) while NMC, FIR1, FIR2 and 1DCOD yielded -25.4 ± 11.1% (-34.5 ± 16.1% for 11C- RAC), -13.4 ± 3.5% (-16.1 ± 4.6%), -5.7 ± 3.6% (-8.0 ± 4.5%) and -2.6 ± 1.5% (-5.1 ± 2.7%), respectively. For real HRRT studies, 3DCOD yielded -0.3 ± 2.8% difference for 18F-FDG (-0.4 ± 3.2% for 11C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J.

INTRODUCTION: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. METHODS: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. RESULTS: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. CONCLUSION: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

Imaging the effect of ketamine on synaptic density (SV2A) in the living brain.

The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.

Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer 11C-TASP699.

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V1A, V1B, and V2). Among these subtypes, the V1B receptor (V1BR), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N-tert-butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V1BR. The purpose of this study was to characterize the pharmacokinetic and binding profiles of 11C-TASP699 in humans and determine its utility in an occupancy study of a novel V1BR antagonist, TS-121. Methods: Six healthy subjects were scanned twice with 11C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V1BR occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume (VT). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in VT after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results:11C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 VT estimates were similar to the 2TC VT estimates, MA1 was the model of choice. The TRV of VT was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced VT in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion:11C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of VT Therefore, this tracer is suitable for measurement of V1BR in the human pituitary and the V1BR occupancy of TS-121, a novel V1BR antagonist.

Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine.

Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain-wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = -0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = -0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL- and MRP-DA release patterns (ΔR2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL- and MRP-induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern-based characterization of drug-induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.

Association of entorhinal cortical tau deposition and hippocampal synaptic density in older individuals with normal cognition and early Alzheimer's disease.

Sites of early neuropathologic change provide important clues regarding the initial clinical features of Alzheimer's disease (AD). We have shown significant reductions in hippocampal synaptic density in participants with AD, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to hippocampus via the perforant path. In this study, [11C]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A) and [18F]flortaucipir binding to tau were measured via PET in 10 participants with AD (5 mild cognitive impairment, 5 mild dementia) and 10 cognitively normal participants. In the overall sample, ERC tau was inversely associated with hippocampal synaptic density (r = -0.59, p = 0.009). After correction for partial volume effects, the association of ERC tau with hippocampal synaptic density was stronger in the overall sample (r = -0.61, p = 0.007) and in the AD group where the effect size was large, but not statistically significant (r = -0.58, p = 0.06). This inverse association of ERC tau and hippocampal synaptic density may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus.

Lower prefrontal cortical synaptic vesicle binding in cocaine use disorder: An exploratory 11 C-UCB-J positron emission tomography study in humans.

Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.