Research round-up
Latest news on research into neurological conditions
Trial therapy appears to rapidly reverse sepsis-induced brain injury
Researchers have shown that an extremely large ‘megadose’ of sodium ascorbate can turn around sepsis-induced low oxygen levels, low blood flow and high temperature within the brain’s frontal cortex.
Sepsis is a deadly condition caused by the body’s excessive inflammatory response to infection that frequently causes damage to vital organs and can lead to death. There are currently no treatments.S
The researchers at the Florey Institute in Australia have shown that sepsis causes large falls in the blood flow and level of oxygen in the brain, and raises brain temperature. These changes may contribute to coma and delirium during sepsis and cognitive impairment in sepsis survivors.
A study led by Professor Clive May and Professor Yugeesh Lankadeva, published in the British Journal of Anaesthesia, shows that a formulation of sodium ascorbate developed by The Florey reverses these insults to the brain that can lead to brain injuries.
Professor May has been studying sepsis for over two decades.
“I have never seen such a dramatic response to treatment as occurred after we intravenously administered a megadose of sodium ascorbate to our clinically-relevant large animal model of sepsis,” he said.
“Before administering the sodium ascorbate, the test subjects were lethargic, unresponsive, lying down and not eating or drinking. Within one hour of receiving the intravenous formulation, they were more alert, and after four hours they had completely recovered their normal behavioural state. They stood up, responded to external stimuli and started eating and drinking. All of these changes suggest a beneficial effect of the treatment on the brain.”
Professor Lankadeva said the exciting results were important given the lack of current treatments for brain injury in sepsis. He said measurements in the test subjects’ brains showed that the megadose of sodium ascorbate restored microcirculatory blood flow, oxygen levels and temperature in the frontal cortex.
“Septic patients commonly suffer a range of brain-related complications from delirium to coma, and this can lead to ongoing cognitive impairment and disability in survivors,” Professor Lankadeva said.
“Our work indicates sodium ascorbate may reverse these detrimental symptoms before any persisting damage is done to the brain.”
The team has already completed a Phase Ia clinical trial of the treatment, and is moving to a larger nationwide trial of its efficacy in septic patients in intensive care units across Australia, with participants selected by treating clinicians. The treatment is not available to patients outside the trial.
“We’ve previously shown that sodium ascorbate has beneficial effects on the kidneys and cardiovascular system in septic patients. This latest study shows it is also beneficial to the brain,” Professor Lankadeva said.
This work was co-funded by the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, and the Australian Government’s Medical Research Future Fund.
The Florey is Australia’s leading brain research institute with a focus on improving the lives of people with neurological and psychiatric conditions. The Florey’s research missions are centred around dementia, epilepsy, mental health and developing ways to protect and repair the brain. These missions are strengthened by The Florey’s expertise in neurotherapeutics, neuroimaging, synaptic biology and systems neuroscience. With 600 researchers, The Florey is the largest research centre of its kind in the southern hemisphere.
Find out more about us on our website: www.florey.edu.au
Why sex and gender matter in Alzheimer’s research
An international panel of experts has issued a “consensus statement” on sex and gender disparities in resilience to Alzheimer’s disease; which they hope will help to shape future research.
Based on a review of a large body of literature, the panel identified sex and gender differences in dementia risk and identified a gap in the understanding of specific risk and resilience pathways.
While women tend to have an initial cognitive advantage, they decline faster than men as the disease progresses. This may be due to differential development of pathologies, known as resistance to Alzheimer’s disease, or different ability to maintain normal functioning over time and cope with pathology once this is present, known as cognitive resilience to Alzheimer’s disease.
In fact, women initially show greater resilience, coping better with brain pathology and atrophy and maintaining cognitive function. The greater initial resilience in women is supported by animal research showing a protective role of the X-Chromosome in Alzheimer’s disease (females typically have two X chromosomes, while males have one).
However, this initial resilience fades away as they progress towards a clinical diagnosis of mild cognitive impairment and Alzheimer’s disease, when they show greater vulnerability. Indeed, studies suggest that women are more likely to have an abnormal build-up of tau protein in the brain and show a higher burden of vascular pathologies, particularly after the menopause.
The authors propose various mechanisms explaining the difference in risk and resilience between women and men, including a higher prevalence of physical inactivity and affective disorders in women, but also biological factors. In this regard, genetic evidence suggests that resilience might be associated with immune pathways in females and cardiovascular pathways in men.
The panel was led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the “la Caixa” Foundation, under the umbrella of the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment. Its work has been published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Eider Arenaza-Urquijo, first author of the study, said: “Assessing how sex and gender interact is crucial to understanding the mechanisms that maintain cognitive function and reduce the accumulation of pathologies in ageing and Alzheimer’s disease, i.e. resilience and resistance factors.”
According to the research team, studies of resilience in Alzheimer’s disease have mainly focused on individual behaviour, without taking into account how social and cultural factors, such as gender, influence behaviour and therefore risk and resilience. Importantly, differences in cognitive function between men and women may be decreasing as gender inequalities also decrease due to more opportunities for women in education, workforce participation, and improvements in their economic status and living conditions.
“Protective factors, such as education, may have different effects in men and women. We need to understand the complexity of interactions between biological and social factors to understand resilience to Alzheimer’s disease”, argues Arenaza-Urquijo.
For this reason, the authors call for a sex- and gender-sensitive approach to resilience to better understand the complex interplay of biological and social determinants. “Focusing more on the differential effects of modifiable factors will help to determine whether a particular factor has a greater impact on cognitive or brain resilience in men or women”, remarks Arenaza-Urquijo.
To improve our understanding of how sex and gender affect cognitive resilience to ageing and Alzheimer’s disease, the researchers recommend several directions for future studies. First, they stress the need to explore how sex and gender factors interact across cultures, taking into account the demographic, genetic, social and clinical differences that influence dementia risk.
They point out that sex/gender differences in brain characteristics, such as brain connectivity, remain understudied as resilience factors for Alzheimer’s disease that may minimise the impact of pathologies on cognition.
The authors also argue that publishing negative results is crucial to avoid bias and that all studies should include sex-disaggregated results.
Finally, they point out the importance of considering sex and gender in a non-binary way, and of including LGTBIQ+ populations, who are often underrepresented and face a higher burden of chronic disease.
Brain organ plays key role in promoting repair after stroke
University of Cincinnati researchers have pioneered an animal model that sheds light on the role an understudied organ in the brain has in repairing damage caused by stroke.
The research, published in the Proceedings of the National Academy of Sciences, sought to learn more about how the adult brain generates new neurons to repair damaged tissue.
The research team focused on the choroid plexus, a small organ within brain ventricles that produces the brain’s cerebrospinal fluid (CSF). CSF circulates throughout the brain, carrying signalling molecules and other factors thought to be important for maintaining brain function. However, prior to this study, little was known about the roles the choroid plexus and CSF play in brain repair after injury due to a lack of available adult animal models.
“We have discovered a new use of an animal model to be able to allow us to manipulate the adult choroid plexus and CSF for the first time,” said Agnes (Yu) Luo, PhD, corresponding author on the study, and professor and vice chair in the Department of Molecular and Cellular Biosciences in UC’s College of Medicine. “Now that we’ve discovered it, this will be vitally applicable to allow researchers to manipulate the adult choroid plexus and CSF to study different disease models and biological processes.”
UC graduate student and study co-author Aleksandr Taranov explained that in a process called adult neurogenesis, the adult brain maintains a certain capacity to repair damage by regenerating newly born neurons.
“However, we still don’t know what actually regulates adult neurogenesis and how to redirect the neurons into the lesion site following a stroke,” Taranov said.
Using this new model, the researchers found that removing the choroid plexus — and the resulting loss of CSF in brain ventricles — led to a reduction of newly born immature neurons called neuroblasts. In a model of ischemic stroke, the team found the loss of the choroid plexus and CSF led to fewer neuroblasts migrating to the lesion site and repairing damage caused by a stroke.
“This suggests that the choroid plexus may be needed to retain these neuroblasts in the area where they usually reside,” Taranov said. “And the choroid plexus might actually be required to retain the neuroblasts so they can readily migrate into the stroke site whenever a stroke or other injury occurs.”
Essentially, Luo said, it appears the choroid plexus keeps a garrison of regenerative cells that are ready to be deployed to injured areas in the brain in animal models of stroke. Further research is needed to confirm whether this also occurs in human brains.
Moving forward, Taranov is studying how the loss of the choroid plexus and CSF affects the clearing of toxic proteins in a model of Alzheimer’s disease, and fellow graduate student Elliot Wegman is studying the same effects in a model of Parkinson’s disease.
Other study co-authors include UC’s Alicia Bedolla, and Eri Iwasawa, Farrah Brown, Sarah Baumgartner, Elizabeth Fugate, Joel Levoy, Steven A. Crone and June Goto of Cincinnati Children’s Hospital Medical Center.
Lifestyle changes significantly improve cognition and function in early Alzheimer’s in study first
An intensive lifestyle intervention, without drugs, significantly improved cognition and function after 20 weeks in many patients with mild cognitive impairment or early dementia due to Alzheimer’s disease in a newly-published randomised controlled clinical trial.
The multisite clinical study was published in the peer-reviewed Alzheimer’s translational research journal, Alzheimer’s Research and Therapy.
The study was directed by lifestyle medicine pioneer Dean Ornish, M.D., founder and president of the non-profit Preventive Medicine Research Institute and clinical professor of medicine at the University of California, San Francisco.
Dr Ornish said: “I’m cautiously optimistic and very encouraged by these findings, which may empower many people with new hope and new choices.
“We do not yet have a cure for Alzheimer’s, but as the scientific community continues to pursue all avenues to identify potential treatments, we are now able to offer an improved quality of life to many people suffering from this terrible disease.”
The research team recruited 51 participants with a diagnosis of mild cognitive impairment or early dementia due to Alzheimer’s disease and randomly assigned them to either an intensive lifestyle intervention group (no drugs added) or a usual-care control (comparison) group.
Members of the control group were instructed not to make any lifestyle changes during the 20-week trial.
The intervention group participated in an intensive lifestyle programme with four components:
1. A whole-foods, minimally processed plant-based diet low in harmful fats, refined carbohydrates, alcohol and sweeteners
2. Moderate aerobic exercise and strength training for at least 30 minutes per day
3. Stress management, including meditation, stretching, breathing and imagery, for one hour per day
4. Support groups for patients and their spouses or study partners, for one hour three times per week.
To measure pre- and post-trial cognitive function, the researchers utilised four standard tests used in FDA drug trials: the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Clinical Global Impression of Change (CGIC), Clinical Dementia Rating–Sum of Boxes (CDR-SB) and Clinical Dementia Rating Global (CDR-G).
Results after 20 weeks showed overall statistically significant differences between the intervention group and the randomised control group in cognition and function in three of these measures (CGIC, p = 0.001; CDR-SB, p = 0.032; CDR-G, p = 0.037), and differences of borderline significance in the fourth test (ADAS-Cog, p = 0.053).
When a mathematical outlier was excluded, all four measures showed significant differences in cognition and function in the experimental group.
Three of these measures showed improvement in cognition and function in the intervention group and one test showed significantly less disease progression.
In contrast, the randomised control group worsened in all four of these measures.
Not all patients in the intervention group improved; in the CGIC test, 71 per cent improved or were unchanged. In contrast, none of the patients in the control group improved, eight were unchanged and 17 (68 per cent) worsened.
Many patients who experienced improvement reported regaining lost cognition and function.
For example, several patients in the intervention group reported that they had been unable to read a book or watch a film because they kept forgetting what they had just read or viewed and had to keep starting over, but now they were able to do so and retain most of this information.
One individual reported that it used to take him weeks to finish reading a book, but after participating in the study he was able to do so in only three or four days and was able to remember most of what he read.
There was a statistically significant dose-response correlation between the degree of lifestyle changes in both groups and the degree of change in most measures of cognition and function testing.
In short, the more these patients changed their lifestyle in the prescribed ways, the greater was the beneficial impact on their cognition and function.
In addition to improvements in cognition and function, the intervention group also demonstrated significant improvements in several key blood-based biomarkers.
One of the most clinically relevant biomarkers is called the Aβ42/40 ratio, which is a measure of amyloid, thought to be an important mechanism in Alzheimer’s disease.
This measure improved in the lifestyle intervention group (with the presumption that this improvement reflected amyloid moving out of the brain and into the blood), but it worsened in the randomized control group, and these differences were statistically significant.
There was also a statistically significant dose-response correlation between the degree of lifestyle change and the degree of improvement in this amyloid ratio (p = 0.035).
This direction of change in amyloid was also a major finding with lecanemab, a drug approved for treating Alzheimer’s disease last year.
Also, the gut microbiome in the intervention group showed a significant decrease in organisms that raise the risk of Alzheimer’s disease and an increase in organisms that are protective against Alzheimer’s disease.
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