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 ?7 subtype of nicotinic acetylcholine receptors (?7-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 ?7-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 ?7-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 ?7-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 ?7- 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 ?7-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 ?4?2-nAChR subtype, we will examine in the same SCZ and control subjects for ?4?2-nAChR characteristics using our ?4?2-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 ?7- or the ?4?2-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 ?7- and ?4?2-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.
The objective of this R01 renewal is to quantify the ?7 subtype of the nicotinic acetylcholine receptors (?7-nAChR) in subjects with schizophrenia (SCZ) using the first successful PET tracer [18F]ASEM that we characterized in healthy volunteers in the previous grant period. We will confirm for first time in vivo that ?7-nAChR?s are reduced in SCZ versus healthy controls and important in relationships with cognition as has been predicted in animal models and post-mortem studies. The second objective is to compliment ?7-nAChR PET studies with PET of the prevalent ?4?2-nAChR that has been extensively studied in smokers and to a lesser extent in patients with SCZ of whom the majority smoke but also implicated in cognition potentially synergistically with ?7-nAChR.
| Coughlin, Jennifer M; Du, Yong; Rosenthal, Hailey B et al. (2018) The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [18F]ASEM. Neuroimage 165:118-124 |
| Phan, Jenny-Ann; Landau, Anne M; Jakobsen, Steen et al. (2017) Radioligand binding analysis of ? 2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding. Sci Rep 7:15979 |
