An observational study using the radioligand [11C]-UCB-J for imaging synaptic density in healthy participants, patients with a psychotic disorder and their healthy siblings

Schizophrenia and related psychotic disorders (schizo-affective disorder and
schizophreniform disorder) are severe mental disorders, placing a significant
burden on global health. Patients suffer from a variety of psychotic, negative
and cognitive symptoms. Additionally, they are at increased risk of developing
metabolic syndrome and mortality with cardiovascular diseases is increased.
The genetic liability for psychotic disorders includes important loci in the
human leukocyte antigen (HLA) area, which predisposes subjects for increased
and prolonged activation of microglia. Activated microglial cells have been
reported to increase synaptic pruning in psychotic disorders, leaving the brain
in suboptimal condition. The decreased synaptic density, resulting from
accelerated pruning, is hypothesized to underlie cognitive dysfunction seen in
the majority of patients with psychotic disorders. Potential ways how the loss
of synaptic density may impair cognition is by affecting neuronal circuitry,
which can be reflected in reduced functional connectivity as assessed with
functional magnetic resonance imaging (fMRI). Although this theory has
face-value, evidence to support it is currently absent, as studies invariably
have either post-mortem material, which may evidence decreased synaptic
density, or performance data on cognition and functional connectivity, but
never the three together. Yet it is an important step to investigate whether
and how decreased synaptic density in patients with psychotic disorders is the
substrate of cognitive dysfunction and whether decreased functional
connectivity is an intermediate step. It is now possible to measure these three
variables: synaptic density, cognitive functioning and functional connectivity
at the same time since a new tracer has been developed to reflect synaptic
density.
[11C]-UCB-J((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophe
nyl)pyrrolidin-2-one) exhibits excellent Positron Emission Tomography (PET)
tracer characteristics, including short-term test re-test repeatability and
reproducibility across brain regions.

This study aims to investigate if and how synaptic density may underlie
cognitive deficits and whether functional connectivity is the intermediate
step. In patients with psychotic disorders, cognitive function and brain
connectivity may be decreased as a consequence of their genetic vulnerability.
However, the use of anti-psychotic medication and lack of education, secondary
to early disease onset may reinforce this effect. In an attempt to disentangle
genetic vulnerability from secondary disease and medication effects, we also
invite first-degree family members of the patients to participate.

Mono-center, observational, cross-sectional, non-therapeutic study in healthy
participants, schizophrenia-spectrum patients and their siblings.

All subjects will undergo one synaptic vesicle glycoprotein 2A (SV2a) PET scan.
Subjects will receive approximately 370 MBq (10 mCi) of [11C]-UCB-J per PET
study. A minimum of 270MBq (7.3 mCi) of activity is required in order to begin
a scan. Participation in the study will entail a PET scan session of
approximately 60 minutes. According to ICRP36, the radiation level of 1,7 mSv
is within the category IIb, minor to moderate risk (1-10 mSv). The burden in
radiation is comparable to the dose that passengers aboard an airplane receive
during 25 or more transatlantic flights.
For anatomical reference, which is lacking in PET, an MRI scan of the
subjects is needed, which is combined with the functional MRI scan. For all
subjects, an MRI scan will be made in addition to the PET scan. The MRI scan
will last 45 minutes and will pose no risk. Some people may become
claustrophobic in the narrow MRI scanner, in which case the scan is aborted
immediately, and subjects are freed instantly. The study has no direct benefit
for the participants. In the case of patients and family, participation may
increase their understanding of psychotic disorders. The risks associated with
participation and the benefits to the individuals are low. The potential
benefit to science and society in the future is considerable if the findings
lead to more insight into the brain basis underlying cognitive deficits in
psychotic disorders, as a treatment to decrease pruning may be a next step to
restore cognition.