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.
Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible ...signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand (11)CUCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that (11)CUCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, (11)CUCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders.
Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the ...brain. We measured the neuroinflammatory response produced by a systemic administration of theEscherichia colilipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer 11CPBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min 11CPBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second 11CPBR28 scan. LPS administration significantly increased 11CPBR28 binding 30–60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with 11CPBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.
Neuroimaging with positron emission tomography (PET) is the most powerful tool for understanding pharmacology, neurochemistry, and pathology in the living human brain. This technology combines ...high-resolution scanners to measure radioactivity throughout the human body with specific, targeted radioactive molecules, which allow measurements of a myriad of biological processes in vivo
.
While PET brain imaging has been active for almost 40 years, the pace of development for neuroimaging tools, known as radiotracers, and for quantitative analytical techniques has increased dramatically over the past decade. Accordingly, the fundamental questions that can be addressed with PET have expanded in basic neurobiology, psychiatry, neurology, and related therapeutic development. In this review, we introduce the field of human PET neuroimaging, some of its conceptual underpinnings, and motivating questions. We highlight some of the more recent advances in radiotracer development, quantitative modeling, and applications of PET to the study of the human brain.
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD.
CPBR28 Positron Emission ...Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.
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.
Abstract
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 (
k
2
,
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 11CLSN3172176, healthy controls and Parkinson’s disease subjects for 18FFE-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 11CLSN3172176, 20% for 18FFE-PE2I). Future work should investigate the benefits of using corrected SUVR in other populations and with different tracers.
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.
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