Schizophrenia affects approximately 1% of people & is characterised by psychotic & negative symptoms, as well as cognitive impairments.2 It is amongst the top ten leading causes of disability in working-age adults in the world,2 & the top reason for NHS hospital bed occupancy.3 Health costs are ~100 billion Euros per year in Europe.4 Cognitive impairments are key determinants of long-term disability & healthcare burden in SCZ.5 Current drug treatments, antipsychotics, target psychotic symptoms but are ineffective or poorly tolerated in many patients.2 Moreover, they are ineffective for the cognitive impairments. There is, thus, a major need to understand the neurobiology underlying cognitive impairments in schizophrenia to identify novel treatment approaches. 

​

A leading hypothesis proposes that lower synaptic terminal levels underlies cognitive impairments in schizophrenia.

Supporting this, post-mortem studies show patients with SCZ have lower brain levels of synaptic terminal proteins, including synaptophysin & synaptic vesicle proteins, in frontal cortical regions with moderate-large effect sizes relative to controls. Reductions in mRNA levels of synaptic vesicle protein 2a (SV2a), & other synaptic terminal proteins, have also been reported in schizophrenia.

​

Thus, we now propose to investigate these intriguing preliminary findings further to test the following hypotheses:

1.         People with schizophrenia will have lower cortical SV2a levels in vivo relative to controls

2.         Lower cortical SV2a levels will be associated with poorer cognitive performance in schizophrenia

​

Exploratory hypothesis

1.         Lower cortical SV2a levels will be associated with lower cortical grey matter volume 

​

If the data from the proposed study support these hypotheses, this will identify synapses, and SV2a in particular, as potential targets for treatment of cognitive impairments in schizophrenia. There are already drugs available that target SV2a, and other drugs in development that promote synaptic plasticity. Findings from our proposed study would be important to establish whether it is worth moving to clinical trials of these drugs, and will also help determine if UCB-J PET could be used as a biomarker to help identify patients most likely to respond and guide dosing. 

 

​