Synaptic Imaging for Schizophrenia
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byJong H Yoon, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Davidzon, Guido, M.D.
Must be taking: Antipsychotics
Disqualifiers: Substance use, Neurological illness, Pregnancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
The purpose of this study is to utilize the radioactive positron emission tomography (PET) tracer \[11C\]UCB-J to test the neural synaptic pruning hypothesis of schizophrenia. This imaging method allows for the quantification of synaptic density in the living human brain and has the unprecedented ability to directly examine the synaptic pathology underlying neuropsychiatric disease. The neural synaptic pruning hypothesis posits that a key pathogenic process of schizophrenia is the over-exuberant elimination of neural synapses during development. The confirmation of reduced synaptic density in schizophrenia as evidenced by \[11C\]UCB-J has the potential to lead to a number of ground-breaking clinical innovations, such as laboratory-based diagnostics and prognostics, and novel, disease-modifying treatments.
Will I have to stop taking my current medications?
The trial requires that participants with schizophrenia be on a stable medication regimen for at least two weeks before testing, so you will not need to stop taking your current medications.
What evidence supports the effectiveness of the drug [11C]UCB-J for schizophrenia?
Is the [11C]UCB-J radiotracer safe for use in humans?
The [11C]UCB-J radiotracer has been used in human studies to measure synaptic density, and whole-body scans have been performed to determine its radiation dosimetry, which is a measure of the radiation dose absorbed by the body. This suggests that it has been evaluated for safety in terms of radiation exposure in humans.14678
How does the drug 11C-UCB-J differ from other treatments for schizophrenia?
The drug 11C-UCB-J is unique because it uses PET imaging to measure synaptic vesicle density in the brain, which is a novel approach for understanding and potentially diagnosing schizophrenia. Unlike traditional treatments that focus on symptom management, this drug provides a way to visualize and quantify changes in synaptic density, offering insights into the underlying pathology of the condition.14678
Eligibility Criteria
This trial is for adults aged 18-65 with a clinical diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder. Participants must be on stable medication for at least two weeks and able to undergo a PET-MR scan without sedation.Inclusion Criteria
I have been diagnosed with schizophrenia or a related disorder.
I can undergo a PET-MR scan without needing sedation.
I am between 18 and 65 years old.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Imaging
Participants undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the [11C]UCB-J radiotracer
120 minutes
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after imaging
4 weeks
Treatment Details
Interventions
- [11C]UCB-J radiotracer (Radiotracer)
Trial OverviewThe study uses [11C]UCB-J radiotracer in a PET-MR imaging technique to measure synaptic density in the brain and test the neural synaptic pruning hypothesis related to schizophrenia.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Schizophrenia (SZ) ParticipantsExperimental Treatment2 Interventions
Participants will undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the \[11C\]UCB-J radiotracer
Group II: Healthy Control (HC) ParticipantsExperimental Treatment2 Interventions
Participants will undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the \[11C\]UCB-J radiotracer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
VA Palo Alto Health Care SystemPalo Alto, CA
Stanford UniversityStanford, CA
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Who Is Running the Clinical Trial?
Davidzon, Guido, M.D.Lead Sponsor
Weston Havens FoundationCollaborator
References
In vivo evidence of lower synaptic vesicle density in schizophrenia. [2023]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 [11C]UCB-J is a proxy measure of synaptic density. In this study we determined whether [11C]UCB-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 [11C]UCB-J and high-resolution research tomography (HRRT). [11C]UCB-J distribution volume (VT) and binding potential (BPND) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower [11C]UCB-J BPND 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. [11C]UCB-J BPND 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 [11C]UCB-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.
Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. [2023]Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo.  Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using [11C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution (VT). [11C]UCB-J VT was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen's d = 0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drug administration on SV2A levels in Sprague-Dawley rats using western blotting, [3H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them.
Reductions in synaptic marker SV2A in early-course Schizophrenia. [2023]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.
Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of Synaptic Vesicle Glycoprotein 2A. [2023]Label="BACKGROUND" NlmCategory="BACKGROUND">The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [11C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers.
Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes. [2023]Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview of these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or synaptic activity and that are relevant for understanding if there is lower synaptic density in the disorder. We conducted literature searches to identify meta-analyses or other relevant studies in patients with chronic or first-episode schizophrenia, or in people at high genetic or clinical risk for psychosis. We identified 18 meta-analyses including over 50,000 subjects in total, covering: structural MRI measures of gyrification index, grey matter volume, grey matter density and cortical thickness, neurite orientation dispersion and density imaging, PET imaging of regional glucose metabolism and magnetic resonance spectroscopy measures of N-acetylaspartate. We also review preclinical evidence on the relationship between ex vivo synaptic measures and structural MRI imaging, and PET imaging of synaptic protein 2A (SV2A). These studies show that schizophrenia is associated with lower grey matter volumes and cortical thickness, accelerated grey matter loss over time, abnormal gyrification patterns, and lower regional SV2A levels and metabolic markers in comparison to controls (effect sizes from ~ -0.11 to -1.0). Key regions affected include frontal, anterior cingulate and temporal cortices and the hippocampi. We identify several limitations for the interpretation of these findings in terms of understanding synaptic alterations. Nevertheless, taken with post-mortem findings, they suggest that schizophrenia is associated with lower synaptic density in some brain regions. However, there are several gaps in evidence, in particular whether SV2A findings generalise to other cohorts.
Human adult and adolescent biodistribution and dosimetry of the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J. [2023]The ability to quantify synaptic density in vivo in human adults and adolescents is of vital importance to understanding neuropsychiatric disorders. Here, we performed whole-body scans to determine organ radiation dosimetry of 11C-UCB-J in humans.
Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice. [2021]Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.
Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). [2020]Label="PURPOSE" NlmCategory="OBJECTIVE">Synaptic abnormalities have been implicated in a variety of neuropsychiatric disorders, including epilepsy, Alzheimer's disease, and schizophrenia. Hence, PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) may be a valuable in vivo biomarker for neurologic and psychiatric diseases. We previously developed [11C]UCB-J, a PET radiotracer with high affinity and selectivity toward SV2A; however, the short radioactive half-life (20 min for 11C) places some limitations on its broader application. Herein, we report the first synthesis of the longer-lived 18F-labeled counterpart (half-life: 110 min), [18F]UCB-J, and its evaluation in nonhuman primates.