Synaptic density in psychotic disorders

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 participants 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-trifluorophenyl)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 will investigate if and how synaptic density may underlie cognitive deficits and whether functional connectivity is the intermediate step. In patients with psychotic disorders, cognitive functioning 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.

Synaptic density as well as functional connectivity is expected to be decreased in patients with schizophrenia as compared to healthy controls. Functional connectivity and synaptic density in first-degree relatives is hypothesized to follow a similar pattern as observed in schizophrenic patients, albeit abnormalities are anticipated to be less pronounced in first-degree relatives as compared to patients with schizophrenia.

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