“Our results suggest people using statins may have a lower risk of parkinsonism and that may be partly caused by the protective effect statins may have on arteries in the brain,” said study author Shahram Oveisgharan, MD, of Rush University Medical Center in Chicago. “Our results are exciting, because movement problems in older adults that come under the umbrella of parkinsonism are common, often debilitating and generally untreatable.”

The study looked 2,841 people with an average age of 76 who did not have parkinsonism at the start of the study. Of those, 936 people, or 33%, were taking statins.

Researchers followed up with participants annually for an average of six years to check the statins they were taking and to test for signs of parkinsonism.

People were considered to have parkinsonism if they met the requirement for mild impairment for two or more of the following symptoms: tremor, stiffness, parkinsonian gait, which is marked by small shuffling steps and a general slowness of movement, and bradykinesia, a hallmark of parkinsonism which is difficulty moving the body quickly on command.

By the end of the study, 1,432 people, or 50%, developed signs of parkinsonism. Out of 936 people taking statins, 418 people, or 45%, developed parkinsonism six years later, compared to 1,014 out of 1,905 people, or 53%, of those who had not been taking statins.

After controlling for age, sex and vascular risks like smoking and diabetes that could affect risk of parkinsonism, researchers found that people who had been taking statins, on average, had 16% lower risk of developing parkinsonism six years later compared to those who had not been taking statins. About 79% of people on statin therapy were taking moderate or high intensity statins. Researchers found that people taking higher intensity statins had a 7% lower risk of developing parkinsonism compared to those on low intensity statins.

Researchers also examined the brains of 1,044 people who died during the study. They found those who had been using statins had, on average, 37% lower odds of having atherosclerosis compared to those who had not been using statins.

“More research is needed, but statins could be a therapeutic option in the future to help reduce the effects of parkinsonism in the general population of older adults, not just people with high cholesterol or who are at risk for stroke,” Oveisgharan said. “At a minimum, our study suggests brain scans or vascular testing may be beneficial for older adults who show signs of parkinsonism but don’t have classic signs of Parkinson’s disease or do not respond to Parkinson’s disease medications.”

A limitation of the study is that parkinsonism evaluations were not performed by movement disorder specialists, so cases of Parkinson’s disease may have been misclassified.

The study was supported by the National Institutes of Health.

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“Heart failure with preserved ejection fraction affects millions of people around the globe, but we currently have little to offer these patients because the mechanisms behind it have been unknown. It’s been called the single greatest unmet need in cardiovascular medicine,” said the article’s senior author Joseph Hill, M.D., Ph.D., Professor of Internal Medicine and Molecular Biology and Chief of Cardiology at UT Southwestern. “We now have insight into this condition that we didn’t have even five years ago, observations that could lead to viable clinical targets.”

Dr. Hill explained that heart failure — the heart’s inability to effectively pump blood — comes in two broad types: heart failure with reduced ejection fraction (HFrEF), in which the amount of blood that leaves the heart with each beat declines, and heart failure with preserved ejection fraction (HFpEF), in which the heart is unable to fill with blood to capacity. While HFrEF has long been the most common form, HFpEF — which is associated with obesity, diabetes, and other components of metabolic syndrome — has grown in prevalence over the last several decades and overtaken HFrEF as the most common form.

Numerous treatments exist for various types of HFrEF, but these interventions have no discernible effect on HFpEF. This is because the two conditions are caused by different underlying mechanisms, said Dr. Hill, a topic that his lab has studied for years. Although HFpEF can be improved through weight loss, losing weight is something that many individuals struggle with, he added, prompting the need for treatments.

In the review article, Hill and his colleagues outline findings made over the past several years that point to joint metabolic and immune dysfunction as the root cause of HFpEF. For example, fat tissue secretes inflammatory molecules that migrate to the heart, recruiting immune cells evident in heart biopsy samples from individuals with HFpEF. At the same time, heart toxicity caused by overuse of fatty acids as fuel in individuals with metabolic syndrome appears to stimulate an immune response, leading to a vicious cycle.

Crosstalk between fat tissue, the immune system, and the heart appears to amplify both immune and metabolic stress, ultimately causing the heart to fail over time. But how this crosstalk occurs, the effects it produces, and how to block them remain unclear, Dr. Hill said. Research into this new field of immunometabolism is shedding some light on these questions, but more research will be necessary to produce effective interventions for HFpEF patients, he added.

“Research from our lab and others is raising possibilities of therapeutic targets that need to be investigated,” Dr. Hill said. “There’s a reasonable chance that we could have therapies available for this intractable condition within the next decade.”

U.S. News and World Report ranks UT Southwestern as the No.1 hospital in Texas for Cardiology and Heart Surgery and No.11 in the nation.

Dr. Hill holds the James T. Willerson, M.D., Distinguished Chair in Cardiovascular Diseases and the Frank M. Ryburn Jr. Chair in Heart Research.

Thomas G. Gillette, Ph.D., Associate Professor of Internal Medicine at UT Southwestern, contributed to the review article.

This work was supported by grants from the DZHK (German Centre for Cardiovascular Research); the Deutsche Forschungsgemeinschaft (German Research Foundation, SFB-1470-A02), IMI2-CARDIATEAM (no. 821508); the Netherlands Cardiovascular Research Initiative, Dutch Cardiovascular Alliance CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, no. 2017-21; National Institutes of Health (HL144477, HL122309, HL126012, HL128215, HL120732, HL147933 and HL155765), and the American Heart Association (19TPA34910006).

In 2015, researchers from Penn’s School of Veterinary Medicine learned that dogs could develop a form of inherited night blindness with strong similarities to the condition in people. In 2019, the team identified the gene responsible.

Today, in the journal Proceedings of the National Academy of Sciences, they’ve reported a major advance: a gene therapy that returns night vision to dogs born with CSNB. The success of this approach, which targets a group of cells deep in the retina called ON bipolar cells, charts a significant step toward a goal of developing a treatment for both dogs and people with this condition, as well as other vision problems that involve ON bipolar cell function.

Dogs with CSNB that received a single injection of the gene therapy began to express the healthy LRIT3 protein in their retinas and were able to ably navigate a maze in dim light. The treatment also appears lasting, with a sustained therapeutic effect lasting a year or longer.

“The results of this pilot study are very promising,” says Keiko Miyadera, lead author on the study and an assistant professor at Penn Vet. “In people and dogs with congenital stationary night blindness, the severity of disease is consistent and unchanged throughout their lives. And we were able to treat these dogs as adults, between 1 and 3 years of age. That makes these findings promising and relevant to the human patient population, as we could theoretically intervene even in adulthood and see an improvement in night vision.”

In the earlier work, the Penn Vet team, working in collaboration with groups from Japan, Germany, and the United States, discovered a population of dogs with CSNB and determined that mutations in the LRIT3 gene were responsible for the dogs’ night vision impairment. The same gene has been implicated in certain cases of human CSNB as well.

This mutation affects the ON bipolar cells’ function, but, unlike in some blinding diseases, the overall structure of the retina as a whole remained intact. That gave the research team hope that supplying a normal copy of the LRIT3 gene could restore night vision to affected dogs.

Yet while Penn Vet researchers from the Division of Experimental Retinal Therapies have developed effective gene therapies for a variety of other blinding disorders, none of these earlier treatments has targeted the ON bipolar cells, located deep within the middle layer of the retina.

“We’ve stepped into the no-man’s land of the retina with this gene therapy,” says William A. Beltran, a coauthor and professor at Penn Vet. “This opens the door to treating other diseases that impact the ON bipolar cells.”

The researchers overcame the hurdle of targeting these relatively inaccessible cells with two key findings. First, through a rigorous screening process conducted in collaboration with colleagues at the University of California, Berkeley, led by John Flannery and at the University of Pittsburgh led by Leah Byrne, they identified a vector for the healthy LRIT3 gene that would enable the treatment to reach the intended cells. And, second, they paired the healthy gene with a promoter — the genetic sequence that helps initiate the “reading” of the therapeutic gene — that would act in a cell-specific fashion.

“Prior therapies we’ve worked on have targeted photoreceptors or retinal pigment epithelium cells,” says coauthor Gustavo D. Aguirre, a Penn Vet professor. “But the promoter we use here is very specific in targeting the ON bipolar cells, which helps avoid potential off-target effects and toxicity.”

The researchers suspect that restoring the functional LRIT3 gene enables signals to cross from the photoreceptor cells to the ON bipolar cells. “LRIT3 is expressed at the ‘finger’ tips of these cells,” says Beltran. “Introducing this transgene is essentially allowing the two cells to shake hands and communicate again.”

An open question is whether targeting both photoreceptor cells and ON bipolar cells together could lead to even greater improvements in night vision. Other research groups studying these conditions in mice have targeted the therapy to photoreceptor cells and found some vision to be restored, suggesting a possible path to enhance the effects of gene therapy.

And while the therapy enabled functional recovery — dogs were able to navigate a maze when their treated eye was uncovered but not when it was covered — the healthy copy of the gene was only expressed as much as 30% of ON bipolar cells. In follow-up work, the researchers hope to augment this uptake.

“We had great success in this study, but we saw some dogs get better recovery than others,” says Miyadera. “We’d like to continue working to maximize the therapeutic benefit while still ensuring safety. And we’ve seen that this treatment is durable, but is it lifelong after one injection? That’s something we’d like to find out.”

The team also plans to amend the therapy to use the human version of the LRIT3 gene, a necessary step toward translating the treatment to people with CSNB with an eventual clinical trial.

Miyadera, Beltran, and Aguirre coauthored the study with Penn Vet’s Evelyn Santana, Karolina Roszak, Sommer Iffrig, Yu Sato, Alexa Gray, Ana Ripolles Garcia, and Valerie Dufour; Charles River Laboratories’ Simone Iwabe, Ryan F. Boyd, and, Joshua T. Bartoe; and the University of California, Berkeley’s Meike Visel, John G. Flannery, and Leah C. Byrne (now at the University of Pittsburgh).

Keiko Miyadera is an assistant professor of ophthalmology in Penn Vet’s Department of Clinical Sciences & Advanced Medicine.

William Beltran is a professor of ophthalmology in Penn Vet’s Department of Clinical Sciences & Advanced Medicine and director of the Division of Experimental Retinal Therapies.

Gustavo D. Aguirre is a professor of medical genetics and ophthalmology in Penn Vet’s Department of Clinical Sciences & Advanced Medicine.

The study was supported by the Margaret Q. Landenberger Research Foundation, National Eye Institute/National Institute of Health (Grant EY-006855), Foundation Fighting Blindness, Van Sloun Foundation for Canine Genetic Research, and Sanford and Susan Greenberg End Blindness Outstanding Achievement Prize.

Using advanced microscopy coupled with novel computer simulations that track atomic movement, researchers at the Georgia Institute of Technology conducted real-time atomic-level observations of grain boundary deformation in poly-grained metallic materials called polycrystalline materials. The team observed previously unrecognized processes that affect material properties, such as atoms that hop from one plane to another across a grain boundary. Their work, published in Science this March, pushes the limits of atomic-level probing, and enables a deeper understanding of how polycrystalline materials deform. Their work opens new avenues for the smarter design of new materials for extreme engineering applications.

“It is amazing to observe the step-by-step movements of atoms, and then use this information to decipher the dynamic sliding process of a grain boundary with complex structure,” said Ting Zhu, professor in the George W. Woodruff School of Mechanical Engineering and one of the lead authors on the study, which included collaborators from Beijing University of Technology.

To develop new and better polycrystalline materials, it is critical to understand how they deform at an atomic level. The team sought to achieve real-time observation of grain boundary sliding, a well-known mode of deformation which plays an important role in governing the strength and ductility of polycrystalline materials. They chose to work with platinum because its crystal structure is the same as other widely used polycrystalline materials like steel, copper, and aluminum. Using platinum, their results and insights would be generally applicable to a wide range of materials.

A Combination of Novel Methods

Several key innovations were required to carry out the experiment. The team used a transmission electron microscope (TEM) to capture highly magnified images of atoms at grain boundaries. The TEM sends an electron beam through a film-like platinum specimen, processed by the team to be thin enough for electron transmission. They also developed a small, millimeter-sized testing device that applies mechanical force to a specimen and is affixed to the microscope. The TEM and device work in tandem to create atomic-level images of grain boundaries during deformation.

To observe the atomic-scale grain boundary sliding more clearly than through viewing the TEM images alone, the researchers developed an automated atom tracking method. This method automatically labels each atom in every TEM image and then correlates them between images, enabling the tracking of all atoms and their movement during grain boundary sliding. Finally, the team conducted computer simulations of grain boundary sliding using atomic structures extracted from the TEM images. The simulated sliding helped the team analyze and interpret events that happened at the atomic scale. By combining those methods, they were able to visualize how individual atoms move at a deforming grain boundary in real time.

Results

While it was known that grain boundaries slide during deformation of polycrystalline materials, real-time imaging and analysis by Zhu and his team revealed a rich variety of atomic processes, some of them previously unknown.

They noticed that, during deformation, two neighboring grains slid against each other and caused atoms from one side of the grain boundary plane to transfer to the other. This process, known as atomic plane transfer, was previously unrecognized. They also observed that local atomic processes can effectively accommodate transferred atoms by adjusting grain boundary structures, which can be beneficial for achieving higher ductility. Image analysis and computer simulations showed that mechanical loads were high during the atomic processes, and that this facilitated the transfer of atoms and atomic planes. Their findings suggest that engineering the grain boundaries of fine-grained polycrystals is an important strategy for making materials stronger and more ductile.

Looking Ahead

Zhu and his team’s demonstrated ability to observe, track, and understand atomic-scale grain boundary deformation opens more research opportunities to further investigate interfaces and failure mechanisms in polycrystalline materials. Greater understanding of atomic-level deformation can inform how materials are evolved during grain boundary engineering, a necessity for creating exceptional strength and ductility combinations.

“We are now extending our approach to visualize atomic-scale deformation at higher temperatures and deformation rates, in pursuit of better materials for extreme applications,” said Xiaodong Han, another lead author of the paper and a professor at the Beijing University of Technology.

Zhu believes that the data-rich results from their real-time atomic-level observations and imaging could be integrated with machine learning for deeper investigation of material deformations, and this could accelerate the discovery and development of materials faster than previously thought possible.

“Our work shows the importance of using very high-resolution microscopy to understand atomic-level material behavior. This advancement will enable researchers to tailor materials for optimal properties using atomic design,” said Zhu.

Funding: X.D.H. and L.W. acknowledge support by the Beijing Outstanding Young Scientists Projects (grant BJJWZYJH01201910005018), the Basic Science Center Program for Multiphase Evolution in Hypergravity of the National Natural Science Foundation of China (grant 51988101), the Beijing Natural Science Foundation (grant Z180014), and the Natural Science Foundation of China (grants 51771004, 51988101, and 91860202).