Research
Pioneering trial for ‘brain tsunamis’ gets under way
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.”
NICE will review whether new Alzheimer’s drugs should be offered on the NHS after an appeal found their wider impact was not fully counted.
An appeal found that the National Institute for Health and Care Excellence had failed to properly account for the wider impact of the treatments, including the heavy burden on unpaid carers, when calculating the cost effectiveness of the medicines.
Both treatments, lecanemab and donanemab, will now return to a NICE committee for further consideration.
“Today’s ruling is an opportunity for NICE to consider the real cost of Alzheimer’s on people and their families, and we welcome the decision to look again at whether new medicines could be provided on the NHS,” said David Thomas, head of policy and public affairs at Alzheimer’s Research UK.
Lecanemab and donanemab do not cure Alzheimer’s, but they slow it by targeting and clearing clumps of amyloid proteins, sticky protein build-ups in the brain linked to the disease.
While the drugs are available privately in the UK for people who can afford them, NICE ruled last year that they were too expensive to be made available on the NHS in England and Wales.
It is estimated informal dementia care costs the economy more than £20bn a year.
Alzheimer’s Research UK wants NICE to update how it assesses the value of new dementia drugs and factor in the huge additional costs this condition places on society and the wider economy.
NICE and its expert committees assess whether new drugs are good value for money for the NHS based on a wide range of evidence.
This includes how treatments perform in clinical trials, the experiences of patients and carers, and the costs of new drugs as well as any changes to NHS services needed to provide access.
When NICE weighs up whether a new Alzheimer’s drug is cost effective for the NHS, it carries out a limited assessment of the impact dementia has on the health of carers.
But the condition takes an enormous toll on families and society because caring for someone with dementia can lead people to become more isolated and give up work.
It can have a major emotional impact and put families under financial strain.
Thomas said: “Research has delivered new treatments with the potential to provide people with valuable extra months of independence, lessening the burden on carers.
“While these treatments offer modest benefits and can cause serious side effects, they provide the foundation for a future where dementia becomes a treatable condition.
“Now we need NICE to look again at how these medicines could benefit both people with early Alzheimer’s and their carers.”
Chris, whose mother Shirley is living with Alzheimer’s disease, said: “The real cost of Alzheimer’s is far greater than many people realise.
“In order to give my mum the care she needed, I moved back home to help my dad as the care was too much for him alone. After my dad passed away from Covid in 2021, I became sole carer for my mum.
“It was a very difficult period, working a full-time job, caring for Mum and dealing with the loss of my dad. Eventually I got some in-home care support to help.
“The family has borne most of the cost of Mum’s care, both in time and fees, and the family home has been sold to finance it.”
“The emotional and financial strain Alzheimer’s has taken on our family is horrendous, and I know many families across the UK are experiencing this pressure.”
He is backing Alzheimer’s Research UK’s call for NICE to change how it evaluates new dementia treatments.
The timeframe for the next NICE meetings to discuss the drugs is still to be set, and it is not certain follow-up hearings would change NICE’s guidance on access to the medicines.
But Alzheimer’s Research UK is continuing to push to make sure dementia is now a main priority for political and NHS decision-makers.
The head of the ongoing independent review into adult social care, Baroness Louise Casey, has called on the government to act, show leadership and prioritise dementia.
She has proposed appointing a dementia tsar to drive forward the prevention, treatment and care of dementia.
Baroness Casey has also argued for more funding for dementia treatment trials.
With more than 130 Alzheimer’s drugs in clinical trials worldwide, the charity says it is vital the NHS runs trials of new treatments now to understand how to deliver them to eligible patients in future.
In addition to changing how NICE assesses new medicines, the health service needs to collect real-world evidence on new dementia drugs and prepare for diagnostic tests and innovative treatments that are coming.
“Alzheimer’s Research UK is calling on the government to give dementia the same political determination that transformed cancer care,” Thomas said.
“We urgently need investment and a clear UK-wide plan so new treatments can be assessed in the NHS and reach the people who stand to benefit.”
Health and social care secretary Wes Streeting has said dementia is “one of the greatest challenges of our time” and pledged that the UK should become a world leader in dementia clinical trials.
Osteoporosis drugs may lower dementia risk, with a study suggesting one widely used treatment could help prevent Alzheimer’s and related dementias.
The research found that nitrogen-containing bisphosphonates, drugs widely used to treat osteoporosis, may significantly reduce the risk of Alzheimer’s disease and related dementias in older adults with osteoporosis or fragility fractures.
Osteoporosis and dementia often coexist in older adults and share several risk factors, including advanced age, female sex and reduced physical activity.
Researchers at the University of Hong Kong’s department of pharmacology and pharmacy carried out a large study using the city’s electronic medical records, covering more than 120,000 patients aged 60 and above with osteoporosis or fragility fractures between 2005 and 2020.
The team found that NBP users had a 16 per cent lower risk of developing Alzheimer’s disease and related dementias than untreated patients, and a 24 per cent lower risk than those who received other osteoporosis medicines.
The association was especially marked in women and patients with hip fractures.
The researchers estimated that treating 48 patients with NBPs for five years could potentially prevent one case of dementia, underlining the possible public health value of NBPs in high-risk groups.
Professor Cheung Ching-lung, associate professor in the department of pharmacology and pharmacy at the University of Hong Kong, said: “Our study provides evidence that NBPs may offer dual benefits in strengthening bones and reducing fracture risk, as well as potentially preventing ADRD.
“Their potential neuroprotective role provides an empirical basis and supports future research on the actual effectiveness of this medication in preventing or delaying cognitive decline associated with ADRD.
“These findings are significant as they demonstrate a potential approach for reducing dementia risk in a vulnerable population using safe and widely available NBPs.
“In our rapidly ageing society, these findings suggest that while waiting for the novel therapies, existing medications can also provide additional protection for high-risk populations.”
The same research team has previously found that osteoporosis and fractures are independent risk factors for dementia, and that patients with dementia are at higher risk of falls and fractures.
This suggests treating osteoporosis may also help reduce the burden of dementia.
NBPs, including alendronate and zoledronate, are well established and commonly prescribed osteoporosis drugs.
Emerging biological research suggests the pathways affected by NBPs may also play a role in the development of Alzheimer’s disease and related dementias, raising the possibility that they could be repurposed for prevention.
A prebiotic fibre supplement may ease arthritis pain and improve grip strength in people with knee osteoarthritis, a study suggests.
The daily supplement, made from inulin, a dietary fibre found in chicory root, Jerusalem artichokes and other vegetables, also lowered pain sensitivity and saw fewer people drop out than a digital physiotherapy programme tested alongside it.
Dr Afroditi Kouraki, lead author of the study from the University of Nottingham, said: ‘Our findings suggest that targeting gut health with a prebiotic supplement is a safe, well-tolerated, and effective way to reduce pain in people with knee osteoarthritis.
“The very low dropout rate compared to the exercise group is also encouraging from a public health perspective, people were able to fit this supplement easily into their daily lives.’
Osteoarthritis of the knee, a wear-and-tear joint condition, affects hundreds of millions of people worldwide and is a leading cause of pain and disability, particularly in older adults.
Current treatments rely heavily on pain medication, which can cause side effects, or exercise programmes, which many patients find hard to maintain.
The INSPIRE trial, led by researchers at the University of Nottingham, involved 117 adults with knee osteoarthritis and tested four groups: inulin alone, digital physiotherapy-supported exercise alone, a combination of both, and a placebo. Both inulin and physiotherapy independently reduced knee pain.
However, inulin alone improved grip strength and reduced pain sensitivity, measures linked to how the nervous system processes pain, while physiotherapy did not.
The dropout rate for those taking the supplement was just 3.6 per cent, compared with 21 per cent for the physiotherapy group, suggesting a daily supplement may be easier for people to stick with than an exercise programme.
Inulin works as a prebiotic, meaning it feeds beneficial bacteria in the gut.
This leads to the production of compounds called short-chain fatty acids, particularly butyrate, which can affect inflammation and pain pathways throughout the body.
Participants taking inulin also showed increased levels of both butyrate and GLP-1, a gut hormone linked to pain regulation and muscle health.
Higher GLP-1 levels were associated with improved grip strength, pointing to a possible gut-muscle connection.
Senior author Professor Ana Valdes added: ‘The link we observed between GLP-1 and grip strength is particularly intriguing and points to a broader gut-muscle-pain axis that warrants further investigation. This could have implications not just for osteoarthritis, but for understanding how gut health influences ageing and physical resilience more broadly.’
Professor Lucy Donaldson, director of research at Arthritis UK, said: “The pain of arthritis can severely impact quality of life. Our recent lived experience survey showed that six in ten people are living in pain most or all of the time due to their arthritis.
“Researchers are starting to explore the role of the gut microbiome in our experience of pain.
“This exciting preliminary research highlights how diet and physiotherapy can act in different ways to have benefits for people with arthritis.
“We know a variety and balance of healthy foods, including fibre, and regular physical activity matter, and we’re glad to be supporting research that explores how they work to help people with arthritis.”
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