Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The ...synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand
CUCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.
Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using ...the novel positron emission tomography (PET) ligand
CUCB-J is a proxy measure of synaptic density. In this study we determined whether
CUCB-J binding, an in vivo measure of synaptic vesicle density, is altered in SCZ. SCZ patients (n = 13, 3 F) and age-, gender-matched healthy controls (HCs) (n = 15, 3 F) underwent PET imaging using
CUCB-J and high-resolution research tomography (HRRT).
CUCB-J distribution volume (V
) and binding potential (BP
) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower
CUCB-J BP
with significant differences in the frontal cortex (-10%, Cohen's d = 1.01), anterior cingulate (-11%, Cohen's d = 1.24), hippocampus (-15%, Cohen's d = 1.29), occipital cortex (-14%, Cohen's d = 1.34), parietal cortex (-10%, p = 0.03, Cohen's d = 0.85) and temporal cortex (-11%, Cohen's d = 1.23). These differences remained significant after partial volume correction.
CUCB-J BP
did not correlate with cumulative antipsychotic exposure or gray-matter volume. Consistent with the postmortem and in vivo findings, synaptic vesicle density is lower across several brain regions in SCZ. Frontal synaptic vesicle density correlated with psychosis symptom severity and cognitive performance on social cognition and processing speed. These findings indicate that
CUCB-J PET is a sensitive tool to detect lower synaptic density in SCZ and holds promise for future studies of early detection and disease progression.
Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is ...important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and
CUCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. 11CUCB-J binding potential (BP
) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower
CUCB-J BP
in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BP
persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study.
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
CUCB-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.
Kappa opioid receptors (KORs) have been characterized as an aversive system in the brain and implicated in social behavior in preclinical models. This work investigated the effect of social status on ...the KOR system in humans using positron emission tomography (PET) imaging with the novel KOR agonist radiotracer
CEKAP. Eighteen healthy participants (mean age 41.2 ± 9.3) completed the Barratt Simplified Measure of Social Status (BSMSS), an MRI and an
CEKAP PET scan on the High Resolution Research Tomograph. Arterial blood sampling and metabolite analysis were conducted to obtain the input function. Regions of interest were based upon an MR template and included the reward/aversion areas of the brain. The multilinear analysis-1 (MA1) method was applied to the regional time-activity curves (TACs) to calculate
CEKAP regional volume of distribution (V
). Mixed models and Pearson correlation coefficients were used for body mass index (BMI), gender and age, with age being dropped in subsequent analyses because of nonsignificance. An overall effect of primary ROIs (F
7.43, p < 0.0001), BSMSS score (F
7.45, p = 0.02), BMI (F
23.5, p < 0.001), and gender (F
23.75, p < 0.001), but not age (F
1.12, p = 0.35) was observed. Regional
CEKAP V
and BSMSS were found to be negatively correlated in the amygdala (r = -0.69, p < 0.01), anterior cingulate cortex (r = -0.56, p = 0.02), caudate (r = -0.66, p < 0.01), frontal cortex (r = -0.52, p = 0.04), hippocampus (r = -0.60, p = 0.01), pallidum (r = -0.59, p = 0.02), putamen (r = -0.62, p = 0.01), and ventral striatum (r = -0.66, p < 0.01). In secondary (non-reward) regions, correlations of
CEKAP V
and BSMSS were nonsignificant with the exception of the insula. There was an inverse correlation between social status and KOR levels that was largely specific to the reward/aversion (e.g., saliency) areas of the brain. This finding suggests the KOR system may act as a mediator for the negative effects of social behaviors in humans.
Purpose
Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer
18
FSynVesT-1 and demonstrated its ...excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with
11
CUCB-J.
Methods
Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (
V
T
) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (
BP
ND
) was calculated using centrum semiovale as the reference region.
Results
The dosimetry study showed high uptake in the urinary bladder and brain. In humans,
18
FSynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC
V
T
values (mL/cm
3
) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of
11
CUCB-J. Regional
BP
ND
values were 2.7–4.7 in gray matter areas, and mean
BP
ND
values across all ROIs were ~ 21% higher than those of
11
CUCB-J. The absolute test-retest variability of
V
T
and
BP
ND
was excellent (< 9%) across all brain regions.
Conclusions
18
FSynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such,
18
FSynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.
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.
PET has the potential to perform absolute in vivo radiotracer quantitation. This potential can be compromised by voluntary body motion (BM), which degrades image resolution, alters apparent tracer ...uptakes, introduces CT-based attenuation correction mismatch artifacts and causes inaccurate parameter estimates in dynamic studies. Existing body motion correction (BMC) methods include frame-based image-registration (FIR) approaches and real-time motion tracking using external measurement devices. FIR does not correct for motion occurring within a pre-defined frame and the device-based method is generally not practical in routine clinical use, since it requires attaching a tracking device to the patient and additional device set up time. In this paper, we proposed a data-driven algorithm, centroid of distribution (COD), to detect BM. In this algorithm, the central coordinate of the time-of-flight (TOF) bin, which can be used as a reasonable surrogate for the annihilation point, is calculated for every event, and averaged over a certain time interval to generate a COD trace. We hypothesized that abrupt changes on the COD trace in lateral direction represent BMs. After detection, BM is estimated using non-rigid image registrations and corrected through list-mode reconstruction. The COD-based BMC approach was validated using a monkey study and was evaluated against FIR using four human and one dog studies with multiple tracers. The proposed approach successfully detected BMs and yielded superior correction results over conventional FIR approaches.
Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer's disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not ...well-correlated with indices of clinical severity or neurodegeneration-at least in the dementia stage-as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau).
We measured SV2A binding (
CUCB-J) and Aβ deposition (
CPiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios (DVR) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches.
We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = - 0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z = - 1.80, P = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a "paradoxical" positive association between local Aβ deposition and SV2A binding in the hippocampus.
Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.
•For 11C-UCB-J, IY serves as a better PVC algorithm than MG.•11C-UCB-J is more sensitive to group differences than volumetric MRI measures.•Assumptions of each PVC algorithm should be carefully ...examined and validated.
11C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC).
We performed two PVC algorithms, Müller-Gärtner (MG) and ‘iterative Yang’ (IY), on 17 AD participants and 11 cognitive normal (CN) participants using the brain-dedicated HRRT scanner. Distribution volume VT, the rate constant K1, binding potential BPND (centrum semiovale as reference region), and tissue volume were compared.
In most regions, both PVC algorithms reduced the between-group differences. Alternatively, in hippocampus, IY increased the significance of between-group differences while MG reduced it (VT, BPND and K1 group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions.
11C-UCB-J binding is significantly reduced in AD hippocampus, but PVC is important to adjust for significant volume reduction. After correction, PET measures are substantially more sensitive to group differences than volumetric MRI measures. Assumptions of each PVC algorithm are important and should be carefully examined and validated. For 11C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG.
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