During an earthquake, a fast slip happens when energy builds up underground and is released quickly along a fault. Blocks of earth rapidly slide against one another.

However, at an Antarctic glacier called Whillans Ice Plain, the earth scientists show that “slow slips” precede dozens of large magnitude 7 earthquakes. “We found that there is almost always a precursory ‘slow slip’ before an earthquake,” said lead author Grace Barcheck, research associate in Earth and Atmospheric Sciences at Cornell University.

Barcheck said that these slow-slip precursors — occurring as far as 20 miles away from the epicenter — are directly involved in starting the earthquake. “These slow slips are remarkably common,” she said, “and they migrate toward where the fast earthquake slip starts.”

Observations before several large tsunami-generating magnitude 8 and 9 earthquakes on subduction zone faults suggest a similar process may have occurred, according to Patrick Fulton, assistant professor and Croll Sesquicentennial Fellow in the Department of Earth and Atmospheric Sciences.

As these faults are mostly offshore and deep underwater, and because it is difficult to know when or where a large earthquake will occur, the start of large earthquakes is generally hard to observe.

To overcome these challenges, the scientists placed GPS sensors above an icy glacial fault at Whillans Ice Plain, where large magnitude 7 earthquakes occur nearly twice a day over a 60-mile-wide area of the glacier.

Within a period of two months in 2014, the group captured 75 earthquakes at the bottom of the Antarctic glacier. Data from GPS stations indicated that 73 — or 96% — of the 75 earthquakes showed a period of precursory slow motion.

The data from the GPS tracking stations and surface seismometers allowed the team to identify how the slow precursory slip triggers the fast earthquake slip.

“Our group was a little surprised to see so many precursors,” Barcheck said.

“In some cases, we can actually see the migration of the earthquake precursor towards where the earthquake begins.”

“Before we pored over the data, I thought that if we saw any precursors before the earthquakes, they would be rare and in the same place as the earthquake epicenter,” she said. “Instead, we found many slow-slip precursors — starting miles from the epicenters and migrating across the fault.”

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Materials provided by Cornell University. Original written by Blaine Friedlander. Note: Content may be edited for style and length.

The study shows that this brachytherapy cement can be placed into spinal bones to directly irradiate tumors without harming the spinal cord, and the radioactive material will stay localized in the bones, which promises to virtually eliminate side effects.

Lead researcher Joyce Keyak, UCI professor of radiological sciences, presented the results at the 2021 annual meeting of the Orthopaedic Research Society, which was held virtually Feb. 12-16.

Cancers that begin in the breast, prostate, lung, thyroid, kidney and other locations can spread to and erode bones, most commonly in the spine. Further complicating matters, normal radiation treatments for this problem can threaten the spinal cord and weaken the bones already compromised by the tumor’s erosion, increasing the risk of fracture.

Currently, multiple sessions of external beam radiation are used to treat cancer that has spread to the spine. This radiation causes unpleasant side effects (nausea, vomiting and diarrhea) and passes through the spinal cord, which often delays and limits treatment.

“Brachytherapy cement could be used without delay in a convenient, one-step, minimally invasive treatment to irradiate tumors,” Keyak said, “and would not irradiate the spinal cord or limit future treatment options.”

In animal and computational studies, the researchers evaluated the short-term safety of injecting brachytherapy cement into vertebrae; the possible migration of radioactivity into blood, urine or feces; the dose rate outside the injection site; and the radiation dose from phosphorus-32 emissions to the spinal cord and soft tissue.

At 17 weeks post-injection, physical examinations were all normal and no activity was detected in blood, urine or feces. The researchers found no evidence of the P-32 isotope in the circulating blood, no changes in blood work related to radioactivity and no neurological deficits.

“This localized treatment for bone tumors stays localized, and we did not see any effects outside the bone,” Keyak said. “This is important because traditional radiation therapy causes adverse effects such as nausea, vomiting and diarrhea.”

Bringing brachytherapy bone cement into being

Keyak and Dr. Harry Skinner, an orthopedic surgeon with St. Jude Heritage Medical Group, created the brachytherapy cement by infusing a common product of their trade, bone cement, with radioactive material already used in other treatments.

The brachytherapy bone cement does not have the same side effects as traditional radiation therapy, Keyak noted, because the injection directly targets the tumor and radiation doesn’t pass through other organs, such as the intestines or stomach. Previous studies also revealed that it can immediately reduce pain in the spine, potentially getting patients off strong painkillers that could carry additional side effects.

Normally, a bone cancer patient needs 10 or more sessions of radiation therapy. But with the brachytherapy bone cement, Keyak said, a single injection can provide an equivalent, targeted tumor treatment with significantly less threat to the spinal cord and nerves.

“You can have this procedure and be done with it,” she said. “And you can do it when tumors are smaller to prevent further bone and spinal cord damage, while limiting the pain and side effects that patients often feel.”

Keyak and Skinner have started a company, Bone-Rad Therapeutics, for their product and have licensed its intellectual property (four patents and one pending patent).

The next step, Keyak said, will be more animal studies, followed by an application for a clinical trial.

Mando Eijansantos, Katherine Rosecrance, Daniel Wong, Sayeh Feizi, Pranav Peddinti, Aleen Meldosian and Varun Sehgal of UCI and Clifford Les of Pedicaris Research in Birmingham, Michigan, also participated in the research.

“Lewy body dementia is a devastating brain disorder for which we have no effective treatments. Patients often appear to suffer the worst of both Alzheimer’s and Parkinson’s diseases. Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems that can be seen in both disorders,” said Sonja Scholz, M.D., Ph.D., investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We hope that these results will act as a blueprint for understanding the disease and developing new treatments.”

The study was led by Dr. Scholz’s team and researchers in the lab of Bryan J. Traynor, M.D., Ph.D., senior investigator at the NIH’s National Institute on Aging (NIA).

Lewy body dementia usually affects people over 65 years old. Early signs of the disease include hallucinations, mood swings, and problems with thinking, movements, and sleep. Patients who initially have cognitive and behavioral problems are usually diagnosed as having dementia with Lewy bodies, but are sometimes mistakenly diagnosed with Alzheimer’s disease. Alternatively, many patients, that are initially diagnosed with Parkinson’s disease, may eventually have difficulties with thinking and mood caused by Lewy body dementia. In both cases, as the disease worsens, patients become severely disabled and may die within 8 years of diagnosis.

A growing body of evidence suggests genetics may play a role in the disorder and that some cases may be inherited. Scientists have found that some of these rare cases can be caused by mutations in the gene for alpha-synuclein (SNCA), the main protein found in Lewy bodies. Further studies have found that variants in the gene for apolipoprotein E (APOE), which is known to play a role in Alzheimer’s disease, may also play one in Lewy body dementia.

“Compared to other neurodegenerative disorders, very little is known about the genetic forces behind Lewy body dementia,” said Dr. Traynor. “To get a better understanding we wanted to study the genetic architecture of Lewy body dementia.”

To do this, they compared the chromosomal DNA sequences of 2,981 Lewy body dementia patients with those of 4,931 healthy, age-matched control participants. Samples were collected from participants of European ancestry at 44 sites: 17 in Europe and 27 across North America. The DNA sequencing was led by Clifton Dalgard, Ph.D., and researchers at The American Genome Center, a series of state-of-the-art laboratories at the Uniformed Services University of the Health Sciences and supported by the Henry M. Jackson Foundation for the Advancement of Military Medicine.

Initially, they found that the sequences of five genes from the Lewy body dementia patients were often different from those of the controls, suggesting that these genes may be important. It was the first time that two of the genes, called BIN1 and TMEM175, had been implicated in the disease. These genes may also have ties to Alzheimer’s and Parkinson’s diseases. The other three genes, SNCA, APOE, and GBA, had been implicated in previous studies, and thus, strengthened the importance of the genes in Lewy body dementia.

The researchers also saw differences in the same five genes when they compared the DNA sequences of another 970 Lewy body dementia patients with a new set of 8,928 control subjects, confirming their initial results.

Further analysis suggested that changes in the activity of these genes may lead to dementia and that the GBA gene may have a particularly strong influence on the disease. The gene encodes instructions for beta-glucosylceramidase, a protein that helps a cell’s recycling system break down sugary fats. The researchers found that both common and rare variants in the GBA gene are tied to Lewy body dementia.

“These results provide a list of five genes that we strongly suspect play a role in Lewy body dementia,” said Dr. Traynor.

Finally, to examine the apparent links between Lewy body dementia and other neurodegenerative diseases, the researchers further analyzed data from previous studies on Alzheimer’s and Parkinson’s disease. They found that the genetic profiles of the patients in this study had higher chances of suffering from either Alzheimer’s or Parkinson’s disease than the age-matched control subjects. These predictions held even after they lowered the potential impact of known Alzheimer’s and Parkinson’s disease-causing genes, like APOE and SNCA. Interestingly, the patient’s genetic risk profiles for Alzheimer’s disease, on the one hand, or Parkinson’s disease, on the other, did not overlap.

“Although Alzheimer’s and Parkinson’s disease are molecularly and clinically very different disorders, our results support the idea that the problems that cause those diseases may also happen in Lewy body dementia,” said Dr. Scholz. “The challenge we face in treating these patients is determining which specific problems are causing the dementia. We hope studies like this one will help doctors find precise treatments for each patient’s condition.”

To help with this effort, the team published the genome sequence data from the study on the database of Genotypes and Phenotypes (dbGaP), a National Library of Medicine website that researchers can freely search for new insights into the causes of Lewy body dementia and other disorders.

This study was supported in part by the NIH Intramural Research Programs at the National Institute of Neurological Disorders and Stroke (NS003154) and the National Institute on Aging (AG000935).