Imaging Synapses With [11C] UCB-J in the Human Brain

Overview

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.

Interventions

• Drug [11C]UCB-J radiotracer
  I.V. bolus administration of up to 15 mCi (equivalent to 0.3 rems) in the antecubital vein
• Device PET-MR
  Positron emission tomography and magnetic resonance imaging, with a scan duration of up to 120 minutes

Primary outcome measures

• Cross-sectional differences in synaptic density between HC and SZ participants [Time frame: 120 minutes (scan duration)]

Eligibility criteria

Inclusion criteria

• 18 - 65 years in age
• For SZ participants:

• On a stable medication regimen for at least two weeks prior to testing
• A clinical diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder
• Able to complete a PET-MR scan without the use of sedation

Exclusion criteria

• Active substance use within three months of testing
• IQ < 70
• Major medical neurological illness or significant head trauma
• Pregnancy or breastfeeding
• Contraindication to MR scanning, including magnetic-resonance incompatible metal or hardware including pacemakers, cochlear implants, and bullets near a critical organ
• Weight > 350 lbs or a large body habitus that MR scanner cannot accommodate
• History of or current claustrophobia
• Inability to comply with basic study requirements such as following directions and punctuality
• For HC participants:

• Presence of a first degree relative with a psychotic disorder
• Lifetime diagnosis of major psychiatric illness
• For SZ participants:

• Unstable psychiatric symptoms at the time of testing, e.g. acute suicidality, prominent psychosis, or behavioral dyscontrol

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Other

Study locations

United States · 2 centers

• VA Palo Alto Health Care System — Palo Alto
• Stanford University — Stanford

Publications

• Chong HY, Teoh SL, Wu DB, Kotirum S, Chiou CF, Chaiyakunapruk N. Global economic burden of schizophrenia: a systematic review. Neuropsychiatr Dis Treat. 2016 Feb 16;12:357-73. doi: 10.2147/NDT.S96649. eCollection 2016. PMID 26937191
• Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE. Imaging synaptic density in the living human brain. Sci Transl Med. 2016 Jul 20;8(348):348ra96. doi: 10.1126/scitranslmed.aaf6667. PMID 27440727
• Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4. Nature. 2016 Feb 11;530(7589):177-83. doi: 10.1038/nature16549. Epub 2016 PMID 26814963
• Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Wood M, Lara-Jaime T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y. Synthesis and Preclinical Evaluation of 11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain. J Nucl Med. 2016 May;57(5):777-84. doi: 10.2967/jnumed.115.168179. Epub 2016 Feb 4. PMID 26848175
• Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res. 1982-1983;17(4):319-34. doi: 10.1016/0022-3956(82)90038-3. PMID 7187776
• Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, Gallezot JD, Henry S, Hannestad J, Huang Y, Carson RE. Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2018 Nov;38(11):2041-2052. doi: 10.1177/0271678X17724947. Epub 2017 Aug 9. PMID 28792356
• Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Oct 1;75(10):1215-1224. doi: 10.1001/jamaneurol.2018.1836. PMID 30014145
• Wu Y, Carson RE. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab. 2002 Dec;22(12):1440-52. doi: 10.1097/01.WCB.0000033967.83623.34. PMID 12468889

Identifiers

NCT: NCT04038840 · 46106

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗