Evaluation of in Vivo Neuroinflammation Using 18F-NOS Positron Emission Tomography (PET/CT) in HIV Positive and Negative Subjects With Opioid Use Disorder and Healthy Controls

Opioids have direct effects on immune function and opioid receptors are expressed on immune cells, including T cells, B cells, macrophages, and microglia (3, 4). There is abundant evidence that opioids dysregulate CNS immune function (5-7). However, opioids' effects on immune function are complex, with both pro-inflammatory and immune suppressive effects having been reported (8, 9). Although the immunosuppressive effects of opioids can increase susceptibility to infection (6, 7), individuals with Opioid Use Disorder (OUD) have also been found to have higher levels of inflammation than healthy controls (HCs) (10, 11). Opioids have also been shown to enhance the expression of inducible nitric oxide synthase (iNOS), a marker of oxidative stress, effects that are reversed by NOS inhibitors and in iNOS knockout mice (12, 13). Increased expression of iNOS may also be a marker of morphine-induced microglial activation and long-term neurochemical changes in the brains of individuals with OUD may be due to elevated cytokine and NO levels via iNOS expression (14).

OUD is frequently accompanied by syndemic comorbidities, such as HIV infection (15). HIV infection itself is associated with neuroinflammation, even among patients receiving antiretroviral therapy (ART) (16-18). Thus, HIV may exacerbate the inflammatory effects of OUD (19). Indeed, morphine treatment alone decreases expression of iNOS by microglia (vs. control), but morphine and HIV in combination substantially increase iNOS expression beyond the effect of HIV alone (20). This study proposes to use [18F]NOS PET/CT imaging to evaluate neuroinflammation in HIV-positive and HIV-negative subjects with OUD, HIV-positive subjects without OUD, and HCs.

In dynamic PET/CT, kinetic analysis of the dynamic time-course of the radiotracer uptake is used to help distinguish delivery of the radiotracer from retention. For quantitation of dynamic studies, the time-course of uptake is most accurately determined when there is direct information available about the time-course of the radiotracer in the blood. This information is used to delineate the data obtained from PET imaging and can lead to better image-derived variables for study. The gold standard for kinetic modeling relies on having the time-course of the radiotracer in the arterial blood as an input to create an arterial input function (AIF) (21). To obtain direct arterial blood measurements, an arterial catheter is commonly placed in the radial artery of the wrist. Short-term arterial catheterization in healthy research subjects was reported to be safe with a low incidence of complications in 1,132 radial artery catheterizations performed for the purpose of PET research protocols (1 instance of symptomatic thrombotic occlusion was documented and resolved without intervention within weeks of the occurrence) by Everett et al (22).

Arterial catheterization is a laborious procedure requiring specialized training and often discourages people from participating in clinical studies. There may be alternative methods of creating an input function using venous blood sampling and/or image-derived input functions utilizing more limited blood sampling. Generally, arterial tracer kinetics are different from venous kinetics (23). It may be possible to substitute venous samples for arterial samples when taken during a transient equilibrium phase. Because the time at which this equilibrium is reached differs between tracers and often between species, it cannot be generalized. Thus, there is a limited time window of variable length that must be assessed individually for each new radiotracer by first sampling arterial blood to allow for correlation of the time course information. In addition, almost all radiotracers used in brain imaging produce variable amounts of radiometabolites. Imaging alone cannot distinguish the parent compound from its radioactive metabolites and plasma radioactivity from that of whole blood, and in most cases it is necessary to collect blood samples to correct for metabolites when performing kinetic modeling of image data. One potential way to estimate radiometabolite concentrations without arterial sampling is by using late venous blood samples, when the metabolite concentration is maximal and arterio-venous equilibrium has been reached. This approach must be validated for each new radiotracer as the relative concentrations of radiometabolites in venous and arterial blood may differ significantly and, therefore, venous samples do not accurately estimate arterial metabolite concentrations (21). However, whole-body dynamic imaging scans may not require arterial blood as an input to create an AIF, and consequently, venous blood can be used as an alternative to measure metabolites when the arterial blood pool is within the imaging field of view. Venous blood sampling is the preferred approach when working with some populations (e.g., IV drug users).