Now if our stroke medical 'professionals' would just followup more on #2; How to deliver more oxygen to the injured brain! Then we could finally get somewhere in stroke. But nothing will occur, nobody in stroke is thinking BHAG(Big Hairy Audacious or (Assed) Goals!
You'll have to ask your competent? doctor for the EXACT PROTOCOL from # 3!
Do you prefer your doctor, hospital and board of director's incompetence NOT KNOWING? OR NOT DOING? Your choice; let them be incompetent or demand action!
Here are all my ideas:
JAMA’s Top Neurology Studies of 2025: Key Insights From the Year’s Most Influential Research
Editor’s Note: Editors at JAMA have offered their first-ever Research of the Year, a roundup of studies they consider most influential across medicine. Of the nine chosen for 2025, three focused on neurology. Medscape Medical News spoke with the researchers behind these studies to explore the work driving the findings and what they could mean for brain health.
1. Natural Experiment to Overcome Healthy Vaccine Bias
The connection seemed almost too good to be true: Could a vaccine designed to prevent painful shingles also protect against dementia?
Pascal Geldsetzer, MD, PhD, MPH, assistant professor of medicine in the Division of Primary Care and Population Health at Stanford Medicine, Stanford, California, wasn’t just asking that question. He and his team had stumbled upon a natural experiment that could answer it.
In Australia, when the national shingles vaccination program launched in 2016, officials drew a hard eligibility line: Only people who were between the ages of 70 and 79 on November 1, 2016, could receive the free live attenuated vaccine Zostavax. Those who turned 80 on or before November 1 were excluded. Those who turned 80 after November 1 were in.
The strength of this design is that people born days apart are essentially identical in every meaningful way, such as health behaviors, genetics, and risk factors. Only vaccine eligibility separated them — allowing that critical variable to be isolated.
That design was one reason cited by editors of JAMA when they included the study in the journal’s inaugural Research of the Year roundup, which recognized pivotal studies published between October 2024 and September 2025.
The study, which JAMA Deputy Editor Mary McDermott, MD, called “timely and topical,” received more than 70,000 views and international news coverage.
This quasi-experimental approach addressed what Geldsetzer called “a very valid concern” in observational vaccine studies: the healthy vaccine bias. People who choose to get vaccinated are often healthier overall, making it impossible to know whether benefits come from the vaccine itself or from being the kind of person who gets vaccinated.
“We don’t really have the information in electronic health record data on things like diet and physical activity to be able to really adjust and control for all of these differences,” he noted.
‘Large Effects’
By analyzing primary care records from 65 general practices across Australia, ultimately examining over 101,000 patients, the team found that eligibility for the shingles vaccine decreased the probability of receiving a new dementia diagnosis over a 7.4 year-follow-up by 1.8 percentage points (P = .01).
In relative terms that translated into preventing 1 in 5 new dementia diagnoses over 7 years in the Welsh cohort, what Geldsetzer describes as “large effects.”
The study results replicated findings from research the team published in Nature from a Welsh cohort just weeks earlier. Together, they provide “a very compelling body of evidence that there seems to be a cause-and-effect relationship,” Geldsetzer said.
The consistency across different countries, healthcare systems, and datasets strengthens the case for causation beyond typical observational evidence, he added.
But why would a shingles vaccine affect dementia risk? Geldsetzer outlined several highly plausible mechanisms. The varicella zoster virus that causes chickenpox and shingles hibernates in the nervous system for life, creating ongoing inflammatory processes. “There’s increasing evidence that these may play a causative role in the development of dementia,” he explained.
Additionally, live attenuated vaccines may have broader effects on the immune system beyond their specific target.
“We don’t know which mechanism [in the immune system] is at play — or to what degree — with any certainty,” Geldsetzer acknowledged. But the uniformity of the findings across populations and the quasi-experimental design that minimizes bias make the protective effect difficult to dismiss.
Private Research Funding Needed
The team has since published additional findings in Cell showing the vaccine also protects against mild cognitive impairment and slows disease progression in people who already have dementia at vaccination, suggesting benefits “across the disease trajectory.”
Now comes the hard part: proving causation definitively through a randomized clinical trial. Ideally, the researchers could test the live attenuated vaccine specifically because that’s the one for which they have compelling observational evidence.
But there’s a catch: Zostavax is off patent, meaning no pharmaceutical company has commercial interest in funding such a trial.
“We’re just really hoping for funding from philanthropy and private foundations to be able to get this project off the ground,” Geldsetzer said.
For clinicians, though, the message is already clear: The vaccine is a safe, one-time, inexpensive intervention that may offer profound benefits.
“Patients are asking about [the vaccine and this research],” Geldsetzer said, “and many clinicians are also more actively recommending shingles vaccination now.”
2. When to Transfuse After Brain Injury? Asked and Answered
For years, intensivists caring for patients with acute brain injury have faced a persistent dilemma: When should they transfuse?
The injured brain demands oxygen, suggesting higher hemoglobin levels may have a protective effect. However, transfusions carry their own risks, including adverse reactions, infections, and pulmonary complications. Restrictive transfusion strategies have been favored across general ICU populations, but whether they apply to neurocritical care patients was unclear.
The TRAIN trial added much-needed clarity to the issue and may “actually change practice,” JAMA Senior Editor Philip Greenland, MD, wrote in the Research of the Year roundup.
“Prior to TRAIN, transfusion thresholds in neurocritical care were based on limited or extrapolated data, and the optimal approach for brain-injured patients was controversial due to conflicting results from smaller studies and meta-analyses,” Greenland said.
To address the uncertainty, TRAIN investigators randomly assigned 850 patients with traumatic brain injury (TBI), subarachnoid hemorrhage, and intracerebral hemorrhage across 72 ICUs in 22 countries to transfusions at either a liberal threshold (hemoglobin below 9 g/dL) or a restrictive threshold (< 7 g/dL).
As previously reported by Medscape Medical News, the results favored the liberal threshold with higher hemoglobin, an outcome that even surprised the investigators.
At 180 days, 62.6% of patients in the liberal strategy group had unfavorable neurologic outcomes, defined as death, vegetative state, or disability severe enough to limit independence, compared with 72.6% of those in the restrictive group (adjusted relative risk, 0.86; P = .002). Functional independence was achieved by 37% of patients in the liberal group compared with 27% of those in the restrictive group.
“My jaw dropped,” study coauthor Kirsten Møller, MD, PhD, of Copenhagen University Hospital in Copenhagen, Denmark, said. “I’d never expected it.”
Carla Bittencourt Rynkowski, MD, PhD, study coauthor and an intensivist and neurosonologist at Cristo Redentor Hospital in Porto Alegre, Brazil, echoed that sentiment.
“We were surprised [by the 10-percentage point difference in unfavorable outcomes]. There are so many problems happening with neurocritical patients…I thought many other factors could impact the outcome,” she said.
Setting a Higher Bar
Previous trials, including HEMOTION and SAHARA, failed to definitively show whether brain-injured patients benefitted from higher hemoglobin targets, though their effect sizes all pointed in the same direction.
Meanwhile, the landmark 1999 TRICC trial established that restrictive transfusion strategies were safe for general ICU patients, but this left intensivists without clear guidance for the injured brain.
“After many years, we finally could answer this question,” Rynkowski said.
Notably, TRAIN set a higher bar than most studies for what counted as a “good” outcome. Using the Glasgow Outcome Scale-Extended, which ranges from 1 (death) to 8 (no symptoms), most trials classify scores of 5 through 8 as favorable.
TRAIN was more stringent, counting only scores of 6 through 8 (representing functional independence) as good outcomes. A score of 5, where patients cannot participate in one or more life roles, was grouped with unfavorable results.
The benefit appeared driven not by survival, which was similar between groups, but by improved long-term neurologic recovery among survivors.
“I think it should be seen as a neuroprotective treatment,” said Møller. “So many other neuroprotective trials have failed, but this effect is almost unprecedented.”
Brain-injured patients face a cascade of potential complications in the ICU, such as sepsis, blood pressure instability, cerebral edema, and seizures, any of which can worsen neurologic outcomes. Rynkowski initially expected those variables to have an influence on the effect of transfusion strategy.
Instead, TRAIN’s randomized design helped ensure a fair comparison across injury types, centers, severity scores of TBI, subarachnoid hemorrhage, or intracerebral hemorrhage and baseline characteristics. The groups were well-matched in age, comorbidities, and initial hemoglobin levels. Patients’ level of consciousness at enrollment was also factored in.
A Simple Strategy With a Big Impact
Maintaining hemoglobin near 9 g/dl and using just one extra unit of blood is “something simple we can do for the first few days, and it has a real impact on patient outcome,” Rynkowski said.
The liberal strategy also appeared to reduce cerebral ischemic events (8.8% vs 13.5% in the restrictive group), though the investigators urged caution when interpreting the results. Ischemia detection wasn’t protocolized and it relied on a physician’s judgment about when to order imaging. This limitation was driven partly by the availability of different resources between participating centers.
“The ischemia detection can vary a bit between centers, according to each institutional and imaging method available, especially concerning high- or middle- and low-income countries,” Rynkowski explained.
Looking back, Rynkowski said principal investigator Fabio Silvio Taccone, MD, PhD, included these data, but they were not available from all participating centers. Gathering this information uniformly in future studies could yield more precise insights into cerebral ischemia.
Just 1 year after the study’s publication, implementation is already underway. At Erasmus Hospital in Brussels, Belgium, Taccone has adopted the liberal threshold as standard protocol, and Denmark is integrating it into its national transfusion guidelines.
In Brazil, progress has been slower because of blood supply constraints. Rynkowski’s team is now conducting a health economics analysis, noting that the liberal strategy required only about one additional unit of blood per patient.
Rynkowski said he hopes the TRAIN trial inspires other centers to contribute as they are able. “It depends on the reality of the centers,” she said. High-resource centers equipped with precise, expensive technologies are well positioned to tackle the remaining unknowns including ischemia detection and brain oxygenation monitoring.
For clinicians caring for patients with acute brain injury, the takeaway is clear, researchers said: avoid anemia. Maintaining hemoglobin near 9 g/dL — a strategy that often requires just one additional unit of blood — can meaningfully improve long-term neurologic outcomes.
3. Why Lifestyle Change Matters for Cognition
More than a decade ago, a study in Finland showed that a multidomain lifestyle intervention was associated with significant cognitive benefits in older adults at high risk for dementia.
However, cultural differences in diet, exercise habits, and healthcare access between Finland and the US left questions about whether similar approaches as those used in the FINGER trial would work in the US population.
“As a scientist, before we roll out recommendations for clinical care and change policy, we have to make sure our information is accurate,” study investigator Laura D. Baker, PhD, professor of gerontology and geriatrics at Wake Forest University School of Medicine in Winston-Salem, North Carolina, said.
“The FINGER trial showed protection in Finland, but until we know it works in the United States, we can't change recommendations.”
Participants were sedentary, had suboptimal diets, and met additional risk criteria including family history of memory impairment, elevated cardiometabolic risk factors, or membership in demographic groups at higher risk for cognitive decline.
As reported by Medscape Medical News when the findings were first presented at the Alzheimer’s Association International Conference last July, both groups showed cognitive improvement, but the structured multidomain lifestyle intervention produced a statistically significant greater benefit than a self-guided approach.
Generalizable Findings
Participants’ scores on a global cognitive composite increased 0.243 SD per year in the structured group compared with 0.213 SD in the self-guided group, a difference of 0.029 SD per year (P = .008).
US POINTER adapted FINGER’s multidomain approach and delivered definitive evidence needed for clinical implementation. The trial navigated COVID achieved 89% retention at 2 years, enrolled a diverse cohort across five US sites, and used objective outcome measures throughout.
“No one could have done it better than the way this trial was run. The message I always say now: don’t do another trial. We discovered that what worked for the Finns works for Americans,” said Baker.
The results drew two common criticisms that Baker believes miss the point of the trial’s achievements. The first was that the structured intervention was “too intensive” to be practical.
“What we’re really talking about is asking people to form new habits. You can’t have an endurable change unless you change a habit,” she said.
Far from being burdensome, Baker said participants consistently rated the team meetings as their favorite part of the study, citing the social connection and accountability that older adults — who often feel isolated — frequently crave.
Beyond Better Brain Function
The second criticism was that the 0.029 SD-per-year benefit was “too small” to be clinically meaningful. Baker’s team calculated that this SD improvement translates into slowing the cognitive aging clock by 1-2 years in real-world terms, a benefit participants overwhelmingly judged to be worthwhile. “If I get 1 more year of being sharp, I’ll take it,” participants told her.
“We’re weighing a positive side effect together with a positive benefit. It's kind of a no-brainer,” Baker said.
In selecting the study for inclusion in the Research in the Year roundup, JAMA Deputy Editor Christopher Muth, MD, noted that the trial “is important because it confirmed the benefits of a structured multidomain lifestyle intervention in a US population of older adults at risk of cognitive decline or dementia, including those from racial and ethnic groups often underrepresented in dementia clinical trials.”
In addition, the benefit of the lifestyle changes extended beyond improved brain function. Improvements in exercise, diet, and cardiovascular monitoring led many participants to reduce or discontinue medications for cholesterol and blood pressure.
“They became different people,” Baker said. “They feel empowered to live their best life.”
Those benefits are already translating into action. Baker’s team is collaborating with 10 healthcare systems nationwide to develop brain health programs that could tailor support based on individual needs, such as more intensive coaching for those starting from “ground zero,” and a lighter touch for those who just need to get back on track. Community partners, including Alzheimer’s Association chapters and Young Men’s Christian Associations, are positioned to scale the program.
Ongoing biomarker studies examining brain imaging, vascular health, sleep, and blood markers aim to identify which participants respond best and which intervention components are most critical. Extended 4-year follow-ups will reveal whether cognitive benefits persist.
Baker’s take-home message for the field is clear: “We are no longer in the space of needing another trial. We are now at implementation.”
The vaccine study was funded by the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University; National Institutes of Health/National Institute of Allergy and Infectious Diseases, National Institutes of Health/National Institute on Aging, and a Chan Zuckerberg Biohub investigator award. Geldsetzer and colleagues report no relevant disclosures.
The TRAIN study was funded by the European Society of Intensive Care Medicine and La Fondation des Gueules Cassées. Taccone reported receiving the ESICM NeXT grant; Rynkowski reported having no relevant financial relationships.
The POINTER study was supported by the Alzheimer’s Association. The US Highbush Blueberry Council provided monthly rebates for participants assigned to the structured intervention. Baker reported having no relevant financial relationships.
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