Thursday, December 26, 2024
12/26/2024
This is a competitive renewal of an R01 that initially was funded on validation of the first positron emission tomography (PET) radiotracer, [18F] ASEM, which binds specifically to α7 subtype of nicotinic acetylcholine receptors (α7-nAChR) successfully in human studies. Our development and validation of [18F] ASEM in our prior funding period was critical for future and in the current application we proposed in vivo investigation of α7-nAChR in schizophrenia (SCZ), and cognitive function. Deficits in cognitive function are a core feature of SCZ. People with SCZ show marked deficits in attention, working and long-term memory, and executive functioning. A strong association between low α7-nAChR density and severity of cognitive deficits has been demonstrated in animal models, and with SCZ diagnosis in human post-mortem studies. The overarching goal of the current proposal is to determine α7-nAChR availability in SCZ in vivo in connection with cognitive deficits. In the prior funding period, we established age effects, excellent test/retest reproducibility, and specificity of binding of [18F] ASEM to α7- nAChR. In this renewal, we propose to enroll 60 patients with SCZ and 60 controls matched for smoking status, age, sex, race, and parental socioeconomic status. Subjects will be genotyped for a SCZ-linked polymorphism of α7-nAChR gene (rs3087454) which will be included as a covariate in our analysis. The majority of our planned SCZ subject population is anticipated to be on atypical antipsychotics (AP). To anticipate possible confounds of medication we will test the effects of 3 of the most common atypical APs of our SCZ population in baboons as a SubAim to confirm our no-effect of atypical AP findings in mice and 1 SCZ patient on- and off-Risperidone. Aim 1 We will test the hypothesis demonstrated in post-mortem studies and in our preliminary data, that [18F] ASEM binding will be decreased in SCZ. Effect of AP on [18F] ASEM binding will be tested in baboons as a SubAim1. Aim 2 Because of the high comorbidity of SCZ and tobacco use, and association between severity of cognitive deficits in SCZ and availability of the high-affinity α4β2-nAChR subtype, we will examine in the same SCZ and control subjects for α4β2-nAChR characteristics using our α4β2-nAChR selective PET tracer, [18F] AZAN. Our hypothesis is that [18F] AZAN binding will be lower in the brain regions of smoking participants with SCZ, when compared to matched smoking controls. In Aim 3 we will examine negative symptoms and cognitive deficits using a validated cognitive battery and in clinical scales for SCZ as primary outcomes. We will determine whether cognitive deficits are related to the α7- or the α4β2-nAChR availability, or, possibly, synergistically with these two subtypes. This will be the first study of cognitive deficits in SCZ using two human PET tracers with high selectivity for α7- and α4β2-nAChR. The long-term results is to determine a relationship between these two nAChR subtypes and cognitive function in SCZ, which ultimately will provide a better understanding of nAChR pathophysiology and guidance for future nicotinic drug development for SCZ.
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