St. Jude researchers improve brain disease diagnosis with PET imaging and ALS drug

Positron emission tomography (PET) is a nuclear imaging technique used to diagnose conditions such as cancer. An innovative advance from scientists at St. Jude Children's Research Hospital is enhancing the technique's ability to check for signs of neurological disease. The researchers repurposed the drug edaravone, an antioxidant used to treat amyotrophic lateral sclerosis (ALS), as a probe to be used with central nervous system PET imaging. With this technique, the researchers can detect oxidative stress, which leads to brain damage, offering a clear path to detecting neurological conditions. The findings were published today in Nature Biomedical Engineering. 

Neurodegenerative diseases, such as ALS and Alzheimer's disease, are largely diagnosed by physical symptoms that occur when treatment is often too late to be effective. Reactive oxygen and nitrogen species (RONS) are a group of chemically reactive molecules that play important roles in cell signaling and growth. However, accumulation of RONS can cause oxidative stress, leading to tissue injury and dysfunction. Oxidative stress is associated with diseases and conditions affecting the brain and other parts of the central nervous system, resulting in neurodegeneration. Detecting oxidative stress through a noninvasive imaging technique has the potential to shift the diagnosis, and thus treatment, of conditions like ALS and Alzheimer's disease much earlier when such care can be more beneficial. 

Radical burst helps track onset of brain damage 

In addition to neurodegenerative disease, oxidative stress is a factor in many other neurological diseases, such as stroke. In such cases, the harm does not just come from the initial injury. 

It's the subsequent secondary injury, which usually comes from the immune response, which causes the most neurological damage. Part of that immune response is a burst of reactive oxygen and nitrogen species, sometimes called an oxidative burst." 

Kiel Neumann, PhD, corresponding author, St. Jude Department of Radiology

The reactive chemicals released under oxidative bursts include hydroxyl and peroxyl radicals, short-lived chemicals that, in large amounts, can act as a detonator for a cascade of oxidative damage. As an antioxidant, edaravone naturally interacts with RONS, leading Neumann to hypothesize that the drug could be repurposed to enhance imaging efforts. Neumann's team radiolabeled edaravone, replacing atoms in the molecule with radioactive isotopes to allow him to track the movement and breakdown of the drug. When administered, the radiolabeled drug releases subatomic particles called positrons in amounts unnoticeable by all but a PET scan, wherein it lights up the area where the drug accumulates: alongside the build-up of RONS. 

"The goal in imaging is to promote contrast, so we want something that engages with its target rapidly but then also rapidly clears so you can see your target right away," explained Neumann. "What was unique about this drug is that when it reacts with oxidative stress, it undergoes a massive structural and polarity change which keeps it in the cell and promotes contrast." 

The drug's excellent ability to bind RONS in tiny doses means it is perfectly suited for PET imaging while it can still be used as an antioxidant treatment at standard doses - a diagnosis and treatment one-two punch. "Our diagnostic tests are on the order of nanograms to micrograms of material, so the body doesn't even know it's there," Neumann said. 

"Ultimately, our goal is to use this to impact clinical care. Therapeutic intervention using this technology for clinical disease management is the future." 

Authors and funding 

The study's first authors are Justin Wilde, University of Virginia, and Yu-Yo Sun, National Sun Yat-sen University. The study's other authors are Zhongxiao Fu, Emily Bian, Melissa Kinkaid, Aden Weybright, William Terrell, Zoraiz Qureshi, James Stone, Bijoy Kundu and Chia-Yi Kuan, University of Virginia; Spenser Simpson, Ethan Hill, Paulina Villanueva, Shashika Perera and Heather Sheppard, St. Jude. 

The study was supported by grants from the National Institutes of Health (R01EB028338-01, R01NS125788, R01NS125677, R01NS135793, R21NS127392, R21HD109025, NS135693) and ALSAC, the fundraising and awareness organization of St. Jude.