Posts Tagged ‘dementia’

by Wilson Jacob

Dementia screening is more effective in winter and spring because that’s when tell-tale proteins flare up, new research suggests.

In a large-scale study of elderly people in the US, France and Canada, researchers found cognitive ability of over-70s in general is much sharper in summer and fall.

Brain-wise, healthy subjects seemed on average 4.8 years younger during those months than they did between November and May.

Those with Alzheimer’s pathology also experienced ‘dips’ in the winter, due to ‘seasonal rhythms’ in certain proteins, which seemed to make dementia-related genes more expressed in the brain.

The findings suggest that assessing people for the neurodegenerative disease in the latest and earliest months of the year might be the most effective way to detect the disease, for which there is still no definitive test.

People with dementia experience ‘dips’ in winter due to ‘seasonal rhythms’ in Alzheimer’s-related proteins, which seems to make dementia genes more expressed in the brain

According to lead author Dr Andrew Lim, assistant professor of neurology at the University of Toronto, the findings are a significant step towards improving Alzheimer’s diagnosis and treatment.

‘This association was independent of mood, sleep, physical activity, and thyroid status,’ he explained.

‘It was clinically significant, as reflected in a nearly 30 percent higher odds of meeting criteria for mild cognitive impairment or dementia in winter and spring compared to summer and fall, and it persisted in cases with pathologically confirmed Alzheimer’s disease.’

He adds: ‘There may be value in increasing dementia-related clinical resources in the winter and early spring when symptoms are likely to be most pronounced.

‘By shedding light on the mechanisms underlying the seasonal improvement in cognition in the summer and early fall, these findings also open the door to new avenues of treatment for Alzheimer’s disease.’

Several studies suggested season may be associated with cognitive function in some populations of younger adults.

But studies of the seasonal impact in older adults was lacking and little known about the underlying mechanisms.

So 3,353 older adults over 70 with and without Alzheimer’s in three cohort studies in the United States, Canada, and France were recruited.

They tested their thinking and concentration, and the Alzheimer-disease-related proteins in their spinal fluid measured.

Autopsies on those who died were performed and the brain was measured.

The average cognitive functioning was higher in the summer and autumn than the winter and spring, equivalent in cognitive effect to 4.8 years difference in age-related decline.

In addition, the odds of meeting the diagnostic criteria for mild cognitive impairment or dementia were higher in the winter and spring than summer or autumn.

There are several theories as to what could be the cause for these piques and troughs.

First, Dr Lim explains, there are environmental factors like more light and warmer temperatures which could boost general cognition in the summer and fall.

‘If true, then interventions such as phototherapy or temperature modification may be effective in sustaining this peak year-round,’ he says.

Second, in the summer, we tend to be more active, with a better diet, and better sleeping habits.

‘In this study, the association between season and cognition was independent of self-reported sleep and physical activity, although studies incorporating objective markers of these and other behaviors may reveal a more important role for behavioral factors.’

Third, there is the ominous seasonal depressive disorder, which afflicts so many in the winter months. Those seasonal rhythms in psychological state, he says, may also drive the association between season and cognition.

‘In this study, the seasonality of cognition was independent of depression; however, other psychological factors, such as negative affect, which has been associated with mild cognitive impairment and dementia, may be important.’

Lastly, there are the things going on inside the body. All those factors – environmental, lifestyle and psychological – impact our hormone and vitamin levels.

‘In our study adjusting for serum levels of thyroid-stimulating hormone did not substantially attenuate estimates of the association between season and cognition,’ Dr Lim explains.

‘However, additional metabolic factors that may potentially link season to cognition are vitamin D, sex hormones like testosterone, and melatonin.’

The study, published today in the journal PLOS Medicine, had one clear limitation, among others: the participants were only assessed once a season, and only included data on individuals from temperate northern-hemisphere regions, not from southern-hemisphere or equatorial regions.

However, Dr Lim insists they are on to something.

‘The persistence of a robust summer/fall peak in cognition suggests that even in pathologically confirmed Alzheimer’s disease, there remains substantial cognitive plasticity.

‘Identifying drivers or mediators of this effect may enable leveraging this plasticity to improve cognition year-round.’

Dr Rosa Sancho, Head of Research of Alzheimer’s Research UK, concurred. The study is just one piece of the puzzle but sheds light on a rarely discussed element of the lives of dementia patients.

‘For most people with dementia, symptoms get steadily worse over the course of several years but there are things that can also impact memory and thinking ability in the short term. We know that factors like sleep quality and mood can affect cognitive performance whether or not someone has dementia, and this study suggests that the time of year may also influence these skills,’ she said.

https://www.habaricloud.today/2018/09/05/over-70s-cognition-skills-get-worse-during-cold-months-and-dementia-related-proteins-flare-up/

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A machine learning-based model using data routinely gathered in primary care identified patients with dementia in such settings, according to research recently published in BJGP Open.

“Improving dementia care through increased and timely diagnosis is a priority, yet almost half of those living with dementia do not receive a timely diagnosis,” Emmanuel A. Jammeh, PhD, of the science and engineering department at Plymouth University in the United Kingdom, and colleagues wrote.

“A cost-effective tool that can be used by [primary care providers] to identify patients likely to be living with dementia, based only on routine data would be extremely useful. Such a tool could be used to select high-risk patients who could be invited for targeted screening,” they added.

The researchers used Read codes, a set of clinical terms used in the U.K. to summarize data for general practice, to develop a machine learning-based model to identify patients with dementia. The Read codes were selected based on their significant association with patients with dementia, and included codes for risk factors, symptoms and behaviors that are collected in primary care. To test the model, researchers collected Read-encoded data from 26,483 patients living in England aged 65 years and older.

Jammeh and colleagues found that their machine-based model achieved a sensitivity of 84.47% and a specificity of 86.67% for identifying dementia.

“This is the first demonstration of a machine-learning approach to identifying dementia using routinely collected [National Health Service] data, researchers wrote.

“With the expected growth in dementia prevalence, the number of specialist memory clinics may be insufficient to meet the expected demand for diagnosis. Furthermore, although current ‘gold standards’ in dementia diagnosis may be effective, they involve the use of expensive neuroimaging (for example, positron emission tomography scans) and time-consuming neuropsychological assessments which is not ideal for routine screening of dementia,” they continued.

The model will be evaluated with other datasets, and have its validation tested “more extensively” at general practitioner practices in the future, Jammeh and colleagues added. – by Janel Miller

https://www.healio.com/family-medicine/geriatric-medicine/news/online/%7B62392171-6ad7-481a-9289-bd69df49d4a4%7D/machine-learning-based-model-may-identify-dementia-in-primary-care

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Diagram of the brain of a person with Alzheimer’s Disease.

In recent years, researchers have largely converged on the role of inflammation in the development and progression of Alzheimer’s disease (AD). Studies over the past decade have revealed unexpected interactions between the brain and the immune system, and metabolic conditions such as obesity and diabetes may activate inflammatory responses that contribute to the development and progression of AD.

The activation of the inflammatory response is controlled by the inflammasome, a multi-protein oligomer that promotes the release of several pro-inflammatory cytokines including interleukin 1β (IL-1β) and interleukin 18 (IL-18). In an earlier study, a group of researchers with the University of Massachusetts Medical School, the University of Tokyo and the University of Bonn reported that mice with a cognate of Alzheimer’s disease that were additionally bred to knock out the NLRP3 gene encoding the inflammasome were completely protected from neurodegenerative effects of the disease. The researchers presumed that this was the result of their inability to produce IL-1β and IL-18.

This finding was quite promising, suggesting that targeting components of the inflammasome might be a path to Alzheimer’s treatments. In their new study, they sought to determine the effect of IL-18 by breeding IL-18 knockout mice. The researchers considered IL-18 to be a promising target, because levels are elevated in the cerebrospinal fluid of AD patients with mild cognitive impairment. Additionally, it is known to increase the production of amyloid peptide.

But the result of the new mouse study was startling, and completely unprecedented in Alzheimer’s research. The IL-18 knockout mice developed a lethal seizure disorder that the researchers attribute to an increase in neuronal network transmission. The authors write, “… the effects of IL-18 deletion were so dramatic that we were unable to identify previous evidence to help understand the phenomena.”

The finding that a proinflammatory cytokine might in some way ameliorate seizure-inducing neural activity seems counterintuitive, since inflammation is theorized to promote neurodegenerative symptoms in AD. The researchers believe that epilepsy is understudied in AD patients, even though it is a common complication; they point out that two-thirds of AD patients experience both motor and non-motor seizures. Additionally, AD patients with epilepsy are more likely to develop memory loss and other cognitive symptoms, and experience a more widespread loss of brain cells than AD patients without epilepsy, according to the researchers.

They theorize that IL-18 may be counteracting seizure-promoting effects of IL-1β, and suppressing IL-18 thus induced seizures in the test mice. “In fact,” they write, “the countereffect of IL-18 and IL-1β has been documented in a mouse model of cerebellar ataxia. Importantly, we found that the acute application of IL-18 protein reduced excitatory synaptic transmission in the hippocampus, providing evidence that IL-18 has a protective function in neuronal excitability. Thus, we speculate that IL-18 directly suppresses these proepileptogenic effects of IL-1β in APP/PS1 mice.”

However, the most important implication of the study may be that, while the inflammasome is a promising therapeutic target for Alzheimer’s, inhibiting specific cytokines could negatively affect people with the disease.

More information: Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice. Proceedings of the National Academy of Sciences (2018). doi.org/10.1073/pnas.1801802115

Abstract
Alzheimer’s disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.
Journal reference: Proceedings of the National Academy of Sciences

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Even the occasional drink is harmful to health, according to the largest and most detailed research carried out on the effects of alcohol, which suggests governments should think of advising people to abstain completely.

The uncompromising message comes from the authors of the Global Burden of Diseases study, a rolling project based at the University of Washington, in Seattle, which produces the most comprehensive data on the causes of illness and death in the world.

Alcohol, says their report published in the Lancet medical journal, led to 2.8 million deaths in 2016. It was the leading risk factor for premature mortality and disability in the 15 to 49 age group, accounting for 20% of deaths.

Current alcohol drinking habits pose “dire ramifications for future population health in the absence of policy action today”, says the paper. “Alcohol use contributes to health loss from many causes and exacts its toll across the lifespan, particularly among men.”

Most national guidelines suggest there are health benefits to one or two glasses of wine or beer a day, they say. “Our results show that the safest level of drinking is none.”

The study was carried out by researchers at the Institute of Health Metrics and Evaluation (IHME), who investigated levels of alcohol consumption and health effects in 195 countries between 1990 to 2016. They used data from 694 studies to work out how common drinking was and from 592 studies including 28 million people worldwide to work out the health risks.

Moderate drinking has been condoned for years on the assumption that there are some health benefits. A glass of red wine a day has long been said to be good for the heart. But although the researchers did find low levels of drinking offered some protection from heart disease, and possibly from diabetes and stroke, the benefits were far outweighed by alcohol’s harmful effects, they said.

Drinking alcohol was a big cause of cancer in the over-50s, particularly in women. Previous research has shown that one in 13 breast cancers in the UK were alcohol-related. The study found that globally, 27.1% of cancer deaths in women and 18.9% in men over 50 were linked to their drinking habits.

In younger people globally the biggest causes of death linked to alcohol were tuberculosis (1.4% of deaths), road injuries (1.2%), and self-harm (1.1%).

In the UK, the chief medical officer Sally Davies has said there is no safe level of drinking, but the guidance suggests that drinkers consume no more than 14 units a week to keep the risks low. Half a pint of average-strength lager contains one unit and a 125ml glass of wine contains around 1.5 units.

While the study shows that the increased risk of alcohol-related harm in younger people who have one drink a day is small (0.5%), it goes up incrementally with heavier drinking: to 7% among those who have two drinks a day (in line with UK guidance) and 37% for those who have five.

One in three, or 2.4 billion people around the world, drink alcohol, the study shows. A quarter of women and 39% of men drink. Denmark has the most drinkers (95.3% of women, and 97.1% of men). Pakistan has the fewest male drinkers (0.8%) and Bangladesh the fewest women (0.3%). Men in Romania and women in Ukraine drink the most (8.2 and 4.2 drinks a day respectively), while women in the UK take the eighth highest place in the female drinking league, with an average of three drinks a day.

“Alcohol poses dire ramifications for future population health in the absence of policy action today. Our results indicate that alcohol use and its harmful effects on health could become a growing challenge as countries become more developed, and enacting or maintaining strong alcohol control policies will be vital,” said the report’s senior author, Prof Emmanuela Gakidou.

“Worldwide we need to revisit alcohol control policies and health programmes, and to consider recommendations for abstaining from alcohol. These include excise taxes on alcohol, controlling the physical availability of alcohol and the hours of sale, and controlling alcohol advertising. Any of these policy actions would contribute to reductions in population-level consumption, a vital step toward decreasing the health loss associated with alcohol use.”

Dr Robyn Burton, of King’s College London, said in a commentary in the Lancet that the conclusions of the study were clear and unambiguous. “Alcohol is a colossal global health issue and small reductions in health-related harms at low levels of alcohol intake are outweighed by the increased risk of other health-related harms, including cancer,” she wrote.

“There is strong support here for the guideline published by the Chief Medical Officer of the UK who found that there is ‘no safe level of alcohol consumption’.”

Public health policy should be to prioritise measures to reduce the numbers who drink through price increases, taxation, or setting the price according to the strength of the drink (minimum unit pricing), followed by curbs on marketing and restricting the places where people can buy alcohol.

“These approaches should come as no surprise because these are also the most effective measures for curbing tobacco-related harms, another commercially mediated disease, with an increasing body of evidence showing that controlling obesity will require the same measures,” she wrote.

Ben Butler, a Drinkaware spokesperson, said: “This new study supports existing evidence about the harms associated with alcohol. Our research shows that over a quarter of UK adults typically exceed the low risk drinking guidelines and are running the risk of serious long term illnesses.”

But David Spiegelhalter, Winton professor for the public understanding of risk at the University of Cambridge, said the data showed only a very low level of harm in moderate drinkers and suggested UK guidelines were very low risk.

“Given the pleasure presumably associated with moderate drinking, claiming there is no ‘safe’ level does not seem an argument for abstention,” he said. “There is no safe level of driving, but government do not recommend that people avoid driving. Come to think of it, there is no safe level of living, but nobody would recommend abstention.”

https://www.theguardian.com/society/2018/aug/23/no-healthy-level-of-alcohol-consumption-says-major-study


Illustration of how pH imbalance inside endosomes may contribute to Alzheimer’s disease

Johns Hopkins Medicine scientists say they have found new evidence in lab-grown mouse brain cells, called astrocytes, that one root of Alzheimer’s disease may be a simple imbalance in acid-alkaline—or pH—chemistry inside endosomes, the nutrient and chemical cargo shuttles in cells.

Astrocytes work to clear so-called amyloid beta proteins from the spaces between neurons, but decades of evidence has shown that if the clearing process goes awry, amyloid proteins pile up around neurons, leading to the characteristic amyloid plaques and nerve cell degeneration that are the hallmarks of memory-destroying Alzheimer’s disease.

The new study, described online June 26 in Proceedings of the National Academy of Sciences, also reports that the scientists gave drugs called histone deacetylase (HDAC) inhibitors to pH-imbalanced mice cells engineered with a common Alzheimer’s gene variant. The experiment successfully reversed the pH problem and improved the capacity for amyloid beta clearance.

HDAC inhibitors are approved by the U.S. Food and Drug Administration for use in people with certain types of blood cancers, but not in people with Alzheimer’s. They cautioned that most HDAC inhibitors cannot cross the blood-brain barrier, a significant challenge to the direct use of the drugs for brain disorders. The scientists say they are planning additional experiments to see if HDAC inhibitors have a similar effect in lab-grown astrocytes from Alzheimer’s patients, and that there is the potential to design HDAC inhibitors that can cross the barrier.

However, the scientists caution that even before those experiments can happen, far more research is needed to verify and explain the precise relationship between amyloid proteins and Alzheimer’s disease, which affects an estimated 50 million people worldwide. To date, there is no cure and no drugs that can predictably or demonstrably prevent or reverse Alzheimer’s disease symptoms.

“By the time Alzheimer’s disease is diagnosed, most of the neurological damage is done, and it’s likely too late to reverse the disease’s progression,” says Rajini Rao, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. “That’s why we need to focus on the earliest pathological symptoms or markers of Alzheimer’s disease, and we know that the biology and chemistry of endosomes is an important factor long before cognitive decline sets in.”

Nearly 20 years ago, scientists at Johns Hopkins and New York University discovered that endosomes, circular compartments that ferry cargo within cells, are larger and far more abundant in brain cells of people destined to develop Alzheimer’s disease. This hinted at an underlying problem with endosomes that could lead to an accumulation of amyloid protein in spaces around neurons, says Rao.

To shuttle their cargo from place to place, endosomes use chaperones—proteins that bind to specific cargo and bring them back and forth from the cell’s surface. Whether and how well this binding occurs depends on the proper pH level inside the endosome, a delicate balance of acidity and alkalinity, or acid and base, that makes endosomes float to the surface and slip back down into the cell.

Embedded in the endosome membrane are proteins that shuttle charged hydrogen atoms, known as protons, in and out of endosomes. The amount of protons inside the endosome determines its pH.

When fluids in the endosome become too acidic, the cargo is trapped within the endosome deep inside the cell. When the endosome contents are more alkaline, the cargo lingers at the cell’s surface for too long.

To help determine whether such pH imbalances occur in Alzheimer’s disease, Johns Hopkins graduate student Hari Prasad scoured scientific studies of Alzheimer’s disease looking for genes that were dialed down in diseased brains compared with normal ones. Comparing a dataset of 15 brains of Alzheimer’s disease patients with 12 normal ones, he found that 10 of the 100 most frequently down-regulated genes were related to the proton flow in the cell.

In another set of brain tissue samples from 96 people with Alzheimer’s disease and 82 without it, gene expression of the proton shuttle in endosomes, known as NHE6, was approximately 50 percent lower in people with Alzheimer’s disease compared with those with normal brains. In cells grown from people with Alzheimer’s disease and in mouse astrocytes engineered to carry a human Alzheimer’s disease gene variant, the amount of NHE6 was about half the amount found in normal cells.

To measure the pH balance within endosomes without breaking open the astrocyte, Prasad and Rao used pH sensitive probes that are absorbed by endosomes and emit light based on pH levels. They found that mouse cell lines containing the Alzheimer’s disease gene variant had more acidic endosomes (average of 5.37 pH) than cell lines without the gene variant (average of 6.21 pH).

“Without properly functioning NHE6, endosomes become too acidic and linger inside astrocytes, avoiding their duties to clear amyloid beta proteins,” says Rao.

While it’s likely that changes in NHE6 happen over time in people who develop sporadic Alzheimer’s disease, people who have inherited mutations in NHE6 develop what’s known as Christianson syndrome in infancy and have rapid brain degeneration.

Prasad and Rao also found that a protein called LRP1, which picks up amyloid beta proteins outside the astrocyte and delivers them to endosomes, was half as abundant on the surface of lab grown mouse astrocytes engineered with a human gene variant called APOE4, commonly linked to Alzheimer’s disease.

Looking for ways to restore the function of NHE6, Prasad searched databases of yeast studies to find that HDAC inhibitors tend to increase expression of the NHE6 gene in yeast. This gene is very similar across species, including flies, mice and humans.

Prasad and Rao tested nine types of HDAC inhibitors on cell cultures of mouse astrocytes engineered with the APOE4 gene variant. Broad-spectrum HDAC inhibitors increased NHE6 expression to levels associated with mouse astrocytes that did not have the Alzheimer’s gene variant. They also found that HDAC inhibitors corrected the pH imbalance inside endosomes and restored LRP1 to the astrocyte surface, resulting in efficient clearance of amyloid beta protein.

More information: Hari Prasad et al. Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1801612115

https://medicalxpress.com/news/2018-08-ph-imbalance-brain-cells-contribute.html

Your age doesn’t determine how long you’ll live after a dementia diagnosis, new research contends.

“These findings suggest that, despite all efforts, and despite being younger and perhaps physically ‘healthier’ than older people, survival time in people with young-onset dementia has not improved since 2000,” said study author Dr. Hanneke Rhodius-Meester, from VU University Medical Center, in Amsterdam, the Netherlands.

For the study, Dutch researchers looked at nearly 4,500 people with early onset dementia. Median survival time was six years, but it varied depending on the type of dementia: 6.4 years for frontotemporal lobe degeneration; 6.2 years for Alzheimer’s disease; 5.7 years for vascular dementia; 5.1 years for dementia with Lewy bodies; and 3.6 years for rarer causes of dementia.

But survival times were similar among patients of all ages, whether they were younger or older than 65, the investigators found.

Previous research had suggested survival times after dementia diagnosis ranged between three and 12 years.

The latest findings were to be presented Sunday at the Alzheimer’s Association annual meeting, in Chicago. Such research is considered preliminary until published in a peer-reviewed journal.

“While these results still need to be replicated and confirmed, they do highlight the urgency of the need for better treatments and effective prevention strategies,” Rhodius-Meester said in a meeting news release.

The majority of the cells in the brain are no neurons, but Glia (from “glue”) cells, that support the structure and function of the brain. Astrocytes (“start cells”) are star-shaped glial cells providing many supportive functions for the neurons surrounding them, such as the provision of nutrients and the regulation of their chemical environment. Newer studies showed that astrocytes also monitor and modulate neuronal activity. For example, these studies have shown that astrocytes are necessary for the ability of neurons to change the strength of the connections between them, the process underlying learning and memory, and indeed astrocytes are also necessary for normal cognitive function. However, it is still unknown whether astrocytic activity is only necessary, or is it may also be sufficient to induce synaptic potentiation and enhance cognitive performance.

In a new study published in Cell, two graduate students, Adar Adamsky and Adi Kol, from Inbal Goshen’s lab, employed chemogenetic and optogenetic tools that allow specific activation of astrocytes in behaving mice, to explore their role in synaptic activity and memory performance. They found that astrocytic activation in the hippocampus, a brain region that plays an important role in memory acquisition and consolidation, potentiated the synaptic connections in this region, measured in brain slices. Moreover, in the intact brain, astrocytic activation enhanced hippocampal neuronal activity in a task-dependent way: i.e. only during when it was combined with memory acquisition, but not when mice were at their home cage with no meaningful stimuli. The ability of astrocytes to increase neuronal activity during memory acquisition had a significant effect on cognitive function: Specifically, astrocytic activation during learning resulted in enhanced memory in two memory tests. In contrast, direct neuronal activation in the hippocampus induced a non-selective increase in activity (during learning or in the home cage), and thus resulted in drastic memory impairment.

The results suggest that the memory enhancement induced by astrocytic activation during learning is not simply a result of a general increase in hippocampal neuronal activity. Rather, the astrocytes, which sense and respond to changes in the surrounding neuronal activity, can detect and specifically enhance only the neuronal activity involved in learning, without affecting the general activity. This may explain why general astrocytic activation improves memory performance, whereas a similar activation of neurons impairs it.

Memory is not a binary process (remember/don’t remember); the strength of a memory can vary greatly, either for the same memory or between different memories. Here, we show that activating astrocytes in mice with intact cognition improves their memory performance. This finding has important clinical implications for cognitive augmentation treatments. Furthermore, the ability of astrocytes to strengthen neuronal communication and improve memory performance supports the claim that astrocytes are able to take an active part in the neuronal processes underlying cognitive function. This perspective expands the definition of the role of astrocytes, from passive support cells to active cells that can modulate neural activity and thus shape behavior.

Link: https://www.cell.com/cell/pdf/S0092-8674(18)30575-0.pdf

https://elsc.huji.ac.il/content/article-month-june-2018-goshens-lab