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Pioneering trial for ‘brain tsunamis’ gets under way

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The initial four patients have been enrolled in a first-of-its-kind trial to test a treatment for so-called ‘brain tsunamis’ often suffered by heart attack and stroke victims.

The phenomenon – officially called spreading depolarisations (SD) – can see brain cells die for weeks following head trauma.

This is because damaging seizure-like electrical waves can spread through the brain after a traumatic health event such as a stroke or heart attack, preventing it from communicating and gradually poisoning the nerve cells.

Now researchers in the United States believe they may have a way of intervening and treating SDs.

A team from the University of Cincinnati plans to enrol around 70 patients in total across trial sites at UC, the University of Pennsylvania, and the University of California San Francisco, to see if SDs can be treated when they are first spotted – and to discover if doing so will result in better outcomes for patients.

Jed Hartings, professor and vice chair of research in the Department of Neurosurgery in UC’s College of Medicine and principal investigator of the trial, explained that just like a battery, brain cells have a stored, or polarised, charge that enables them to send electrical signals to each other.

During SD, the brain cells lose their charge, becoming depolarised and unable to send electrical signals to each other.

“This happens en-masse in a local area of tissue and then spreads out like a wave, like ripples in a pond, and it interrupts every aspect of cell function. I sometimes explain that the brain cells become a swollen sack of saline, just a big bag of saltwater, that’s not functional anymore.”

SD can occur continuously in patients for up to a couple of days, but they can also endure on and off for up to two weeks after a severe brain injury.

Dr Jed Hartings Image: University of Cincinnati

Dr Hartings said: “It’s a big open question whether or not these might continue for many weeks or a month, and it’s also a big question to what extent do they occur in less severe injuries that don’t require surgery. There’s strong emerging evidence that they would occur even in something as mild as a concussion.”

Because SDs cause a complete shutdown in affected brain regions, they generate an electrical discharge measured at about 10 times the size of a typical seizure.

SDs were first discovered in animals in 1944, but research into how they affect human brains only began around 2002.

Dr Hartings said: “I think in the past maybe five to 10 years we’ve turned the corner and our results have shown that these are very common and that they are detrimental. They’re consistently associated with worse patient outcomes.”

Research has focused on patients that have required surgery because an electrode strip needs to be placed in the brain to monitor for SDs. However, it is estimated that SDs affect patients with virtually every type of acute brain injury, including different kinds of strokes and traumatic brain injuries (TBI).

Dr Hartings commented: “It’s across the spectrum and we have been monitoring all those different types of patients as an international research community.

“It’s in the range of 60% to 100% of all patients in these different disease categories. It’s just mind-boggling. This is the iceberg that’s been submerged under the water that we never knew about.”

There is currently no standard of care or treatment for SDs. This trial is the first Phase 2 testing the feasibility of treating patients with SDs.

“This is a pretty exciting moment for us here and globally in this community. We really rebooted and created a field of science globally, both basic scientists in the laboratory as well as clinical scientists who monitor the brain,” Dr Hartings said.

“There’s a large basic science community that’s been trying to understand these events better now that we know that they have clinical significance. Now this is for the first time in this global community that we actually have a trial that’s trying to intervene and treat them.”

Due to the need for surgery to place the electrode strip for monitoring, the trial is focused on patients with TBIs that need to be operated on. It is standard practice to place these electrode strips to monitor for seizures, but they will now be additionally used to look for SDs.

The patients will then be monitored while they are in the intensive care unit for signs of SDs. The trial will test three different tiers of treatments.

Certain ranges of blood pressure, blood sugar and body temperature measurements are associated with a higher likelihood of having SDs, so the first tier of treatment will focus on managing those levels.

The second tier will continue managing the physiologic measurements into a slightly higher range in combination with a low dose of the drug ketamine, which has been shown to be able to stop SDs. Tier three will involve a higher dose of ketamine.

As a feasibility study, Dr Hartings said the first goal of the trial is to test the practicality of the process of monitoring for SDs and then responding with treatments in a real-world clinical setting.

Dr Hartings said. “The concept that we can treat these in real time hasn’t been proven yet, so that’s the first step of feasibility.”

The study’s second goal is to determine if the treatments have an effect to positively impact brain health and prevent SDs. The study also marks the first step of providing personalized treatments for every patient with a TBI.

Dr Hartings began to study SDs in animal models shortly after he earned his doctorate and said it is rewarding to see the progress that has been and continues to be made in moving research in this area forward.

“It’s really a great success story of bench to bedside medicine, and of collaboration between physicians and academics from different disciplines.

“Since the initial animal studies, we’ve formed an international coalition of researchers and clinicians who have advanced and developed the science, from neurosurgeons all the way to computer scientists. Now we are testing a clinical methodology to see how these advances could positively impact patients.”

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Tai chi outperforms conventional exercise for seniors

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New findings from 12 studies involving 2,901 participants have demonstrated that tai chi outperforms conventional exercise in improving mobility and balance in seniors.

While tai chi is understood to be beneficial for functional mobility and balance in older adults, such benefits are not well understood due to large variance in research study protocols and observations.

This new review and analysis has now shown that tai chi can induce greater improvement in functional mobility and balance in relatively healthy older adults compared to conventional exercise.

The findings showed the following performance results:

  • The time to complete 50-foot walking was 1.84 seconds faster. 
  • The time to maintain a one-leg stance was 6 seconds longer when eyes were open and 1.65 seconds longer when eyes were closed. 
  • Individuals improved their timed-up-and-go test performance by 0.18 points, indicating quicker standing, walking, and sitting.
  • Individuals taking the functional reach test showed significant improvement with a standardised mean difference of 0.7, suggesting a noteworthy positive impact on the ability to reach and perform daily activities.

Secondary analyses revealed that the use of tai chi with relatively short duration of less than 20 weeks, low total time of less than 24 total hours, and/or focusing on the Yang-style of this ancient form of Chinese martial arts were particularly beneficial for functional mobility and balance as compared to conventional exercise.

“This systematic literature review and meta-analysis are exciting because they provide strong evidence that tai chi is a more efficient strategy to improve functional mobility and balance in relatively healthy older adults, as compared to conventional exercise,” said Brad Manor, Ph.D., director of the Mobility and Falls Program at Hebrew SeniorLife’s Hinda and Arthur Marcus Institute for Aging Research, and associate professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center.

“This research suggests that tai chi should be carefully considered in future studies and routines of rehabilitative programs for balance and mobility in older adults,” said Bao Dapeng, professor at Beijing Sport University.

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New standards for biomarkers of ageing

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A paper has put forward a new framework for standardising the development and validation of biomarkers of ageing to better predict longevity and quality of life.

Led by Harvard researchers, the team has zeroed in on biomarkers of ageing using omic data from population-based studies. 

The team included ageing and longevity expert Alex Zhavoronkov, PhD, founder and CEO of AI-driven drug discovery company Insilico Medicine, and the findings appeared in Nature Medicine

Ageing is associated with a number of biological changes including increased molecular and cellular damage, however, researchers do not yet have a standardised means to evaluate and validate biomarkers related to ageing. 

In order to create those standards as well as actionable clinical tools, the team analysed population-based cohort studies built on omic data (data related to biological molecules which can include proteomics, transcriptomics, genomics, and epigenomics) of blood-based biomarkers of ageing. The researchers then compared the predictive strength of different biomarkers, including study design and data collection approaches, and looked at how these biomarkers presented in different populations. 

In order to better assess the impact of ageing using biomarkers, the researchers found that clinicians needed to expand their focus to consider not only mortality as an outcome, but also how biomarkers of aging are associated with numerous other health outcomes, including functional decline, frailty, chronic disease, and disability. They also call for the standardisation of omic data to improve reliability. 

“Omics and biomarkers harmonisation efforts, such as the Biolearn project, are instrumental in validation of biomarkers of aging” said co-first author Mahdi Moqri, PhD, of the Division of Genetics. 

Biolearn is an open-source project for biomarkers of aging and is helping to harmonise existing ageing biomarkers, unify public datasets, and provide computational methodologies.

The team also emphasised the importance of continued collaborations among research groups on “large-scale, longitudinal studies that can track long-term physiological changes and responses to therapeutics in diverse populations”, and that further work is required to understand how implementation of biomarker evaluation in clinical trials might improve patient quality of life and survival.

“If we hope to have clinical trials for interventions that extend healthy lifespan in humans, we need reliable, validated biomarkers of ageing,” said co-first author Jesse Poganik, PhD, of the Division of Genetics. 

“We hope that our framework will help prioritise the most promising biomarkers and provide health care providers with clinically valuable and actionable tools.”

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Healthy aging research to receive $115 million

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Global non-profit Hevolution Foundation has announced $115 million in funding that makes up 49 new awards under its Geroscience Research Opportunities (HF-GRO) programme.  

As part of Hevolution’s mission to catalyse the healthspan scientific ecosystem and drive transformative breakthroughs in healthy aging, HF-GRO is funding promising pre-clinical research in aging biology and geroscience. 

Through this first wave of HF-GRO awards, Hevolution will invest up to $115 million in this first cohort of 49 selected projects over the next five years. Its second call for proposals under HF-GRO will be announced later this year, offering an additional $115 million to address the significant funding gaps in aging research.  

Dr. Felipe Sierra, Hevolution’s Chief Scientific Officer stated: “These 49 important research projects represent a significant step forward in deepening our understanding of healthy aging. Hevolution’s prime objective is to mobilise greater investment around uncovering the foundational mechanisms behind biological aging. 

“We are steadfast in our belief that by examining the root causes of aging, rather than solely focusing on its associated diseases, we can usher in a brighter future for humanity.” 

HF-GRO awardees include researchers at prestigious institutions across the United States, Canada, and Europe, including the U.S. National Institute on Aging, Brigham and Women’s Hospital, the Buck Institute, the Mayo Clinic, New York University, and the University of California San Francisco, among many others. 

The American Federation for Aging Research is providing programmatic support for the HF-GRO program, with grantees selected through a rigorous two-stage peer-review process involving 100 experts in aging biology and geroscience. 

Dr Berenice Benayoun, an HF-GRO grant recipient at the University of Southern California, stated: “I am extremely honored and excited that Hevolution selected our project for funding. This is a project close to my heart, which aims at understanding why and how the female and male innate immune aging differs. 

“This funding will support us as we start laying the foundation for a lasting improvement of women’s health throughout aging.” 

To date, Hevolution has committed approximately $250 million to transform the healthy aging sector, including the $40 million for specialised research and development in healthspan science recently announced at Hevolution’s Global Healthspan Summit. 

Hevolution is ramping up its investments to enable healthier aging for all and is now the second largest funder of aging biology research worldwide.  

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