Reporter's Notebook: SNMMI 2016
Vol. 17 No. 8 P. 26
Editor's note: This article is based on press materials provided by SNMMI at its Annual Scientific Meeting in San Diego in June.
PET/CT Reveals Adaptations of the Alcoholic Brain
Alcoholism is a devastating disorder that often leads to a perpetual cycle of abuse. An emerging molecular imaging technique may provide a way to break that cycle. It could signal patients' heightened risk and lead to targeted drug treatments that reduce the compulsion to drink, said researchers presenting at the 2016 Annual Meeting of SNMMI.
According to 2016 statistics from the National Institute on Alcohol Abuse and Alcoholism, almost 7% of adults older than 18 had a drinking disorder in 2014. Alcohol-related deaths were deemed the fourth leading cause of preventable death, accounting for nearly 88,000 deaths in the same year.
Images of brains lit up like fireworks as people experience pleasure and reward are a familiar sight, but sometimes the reward needs to be taken away. In this groundbreaking study, researchers imaged the brains of recently recovering alcoholics and found an inverse and compensatory adaptation in a particular receptor involved in memory, learning, and the sensations of pain and anxiety. This receptor, called metabotropic glutamate receptor subtype 5 (mGluR5), is found throughout the central and peripheral nervous systems but, in certain areas of the brain, it is implicated in intense cravings and addictive relapse. It seems that the brains of recovering alcoholics have adapted to the enduring state of chemical dependency by significantly hindering mGluR5 receptors in the cerebral cortex and limbic system, thereby reducing cravings.
"Alcohol addiction is a complex, chronic brain disorder associated with enormous physical, social, and financial consequences worldwide, and yet current therapies remain unsatisfactory," said senior author Koen Van Laere, MD, PhD, of the University Hospital Gasthuisberg in Leuven, Belgium. "Our team was able to investigate, for the first time, these marked changes in the brain circuitry of alcohol-dependent humans."
Understanding this relationship between mGluR5 and the compulsion to drink could be the key to long-term sobriety by allowing doctors to predict if patients are liable to relapse. Additionally, this research could lead to new targeted drugs that limit receptor activity in patients who lack this neuroadaptation or are otherwise at increased risk of returning to alcohol abuse.
For this study, researchers combined PET with CT. The PET imaging agent F-18 FPEB, which binds with mGluR5 receptors, was administered to 16 recently sober subjects, ranging from 32 to 57 years of age, and 32 healthy controls with no alcoholism in their backgrounds. Participants then underwent quantitative PET/CT imaging that measured respective mGluR5 receptor binding. Subjects also provided a drinking history and underwent hair analysis to evaluate their drinking pattern. Quantitative PET/CT results showed significantly reduced mGluR5 availability in the bilateral cingulate, caudate, and insular cortex of the limbic systems in alcohol-dependent subjects, regardless of age, gender, or smoking status when compared with healthy controls.
"Collectively, these findings strongly substantiate the development of mGluR5-targeted therapies that heal or protect against the dysfunctional brain circuitry that characterizes alcohol addiction," according to Gil Leurquin-Sterk, MD, first author of the study.
PET Detects Neuroinflammation in Multiple Sclerosis
The triggers of autoimmune inflammation in multiple sclerosis (MS) have eluded scientists for many years, but molecular imaging is bringing researchers closer to identifying them, while providing a means of evaluating next-generation therapies for MS, say researchers introducing a study at the 2016 Annual Meeting of SNMMI.
According to estimates from the National Multiple Sclerosis Society, MS affects more than 2.3 million people worldwide. The disease is marked by inflammation and the systematic destruction of neuronal fibers, specifically myelin, in the nervous system. Myelin is the fatty layer that both protects the fibers and increases the speed of signaling along the axon of nerve cells. Similar inflammatory processes are typical in the pathology of other neurodegenerative diseases such as Parkinson's and Alzheimer's, gastrointestinal diseases like Crohn's and ulcerative colitis, and the vascular inflammation that leads to atherosclerosis.
"Inflammation is the body's physiological defense to harmful stimuli, and it plays a critical role in the immune response to injury and infection," said senior investigator, Zhude Tu, PhD, a professor of PET radiochemistry at the Washington University School of Medicine in St. Louis. "However, despite the benefits of acute inflammation in promoting healing, these same processes are associated with numerous pathological conditions when chronic inflammation is left unchecked."
This study furthers a growing body of research pointing to a process called sphingolipid signaling as a primary mechanism in inflammatory disease processes. The FDA approval in 2010 of fingolimod for relapsing MS further supports the hypotheses that the sphingosine-1-phosphate receptor 1 (S1P1) is an ideal biomarker for imaging and new therapies. Fingolimod works by turning down the autoimmune response via immune cell S1P1.
First author of the study, Adam J. Rosenberg, PhD, and his colleagues produced a library of S1P1-targeted small molecules and radiolabeled them with fluorine-18. These radiotracers bind directly to S1P1 receptors and can be imaged with preclinical PET through noninvasive methodology to investigate the physiological functions of S1P1 receptors in animal models as a precursor for human studies. In this case, researchers imaged S1P1 in rodent models of inflammatory disease and healthy controls. They found that the PET imaging agents not only were able to detect an increase in S1P1 expression in animals with an inflammatory response when compared with healthy controls but that the compounds also crossed the blood brain barrier in healthy animals, a significant limiting factor in the development of central nervous system drugs.
"These compounds represent promising PET tracers for imaging MS and other inflammatory diseases by quantitative assessment of S1P1 expression in the body," Tu said.
CT-Based Calculations Improve Accuracy of PET for Cancer Patients
Cancer patients often experience significant fluctuations in weight and lean body mass (LBM). Neglecting to account for these changes can prevent clinicians from obtaining precise data from molecular imaging, but a new method of measuring LBM takes changes in individual body composition into account for better staging of disease and therapy monitoring, said researchers at the 2016 Annual Meeting of SNMMI.
PET has become a standard of care in cancer patient management. Fluorine-18 FDG (F-18 FDG) is a radiotracer that closely resembles the metabolic activity of glucose in cells throughout the body. F-18 FDG emits a signal that is detected by the PET scanner. Image reconstructions of these signals let clinicians know where there are areas of abnormally increased metabolic activity, quantified by standardized uptake values (SUVs). Accurate tumor SUVs enable clinicians to assess disease progression, reflected by an increased SUV; stable disease, reflected by no significant changes in SUV; and successful response to therapy, reflected by a decrease in SUV.
Radiotracer tumor SUVs are quantitatively measured using patient weight. However, F-18 FDG is distributed almost exclusively in LBM, not fatty tissue. Current methods of SUV normalization tend to focus on overall weight and may significantly over- or underestimate LBM in cancer patients. For this study, researchers developed a CT technique that determines patient-specific LBM. This method of SUV normalization, using patient-specific LBM, is termed SULps.
"Patients with advanced cancer tend to lose muscle and may gain fat, and these changes in body composition can significantly modify PET results, independent of the actual metabolic activity of the tumor," said Alexander McEwan, MD, principal author of the study from the University of Alberta in Edmonton, Alberta, Canada. "Our study shows that CT-derived SULps is a more robust measurement for patients with advanced cancer undergoing PET imaging. If adopted, this simple change in imaging protocol could lead to significantly more effective care for cancer patients."
Researchers analyzed CT scans in three-month intervals to gauge changes in body composition of patients with advanced cancer. A total of 1,080 intervals of CT were evaluated and just over 50%, or 546 intervals, reflected stable LBM. Of this smaller group with stable LBM, 40% experienced a decrease in adipose tissue, 35% showed no change in adipose tissue, and 25% showed an increase in adipose tissue. These changes affect SUV using all calculations except SULps, which accurately reflected metabolic activity via F-18 FDG PET/CT.More precise PET measurements made with the use of CT data could increase the accuracy of PET imaging interpretation in groundbreaking clinical trials for new cancer therapies and for more personalized medicine in the clinic.