How microglia contribute to Alzheimer's disease

A breakdown of lipid metabolism in these brain cells promotes inflammation and interferes with neuron activity, a new study finds

August 4, 2022

Science Daily/Massachusetts Institute of Technology

One of the hallmarks of Alzheimer's disease is a reduction in the firing of some neurons in the brain, which contributes to the cognitive decline that patients experience. A new study from MIT shows how a type of cells called microglia contribute to this slowdown of neuron activity.

The study found that microglia that express the APOE4 gene, one of the strongest genetic risk factors for Alzheimer's disease, cannot metabolize lipids normally. This leads to a buildup of excess lipids that interferes with nearby neurons' ability to communicate with each other.

"APOE4 is a major genetic risk factor, and many people carry it, so the hope is that by studying APOE4, that will also provide a bigger picture of the fundamental pathophysiology of Alzheimer's disease and what fundamental cell processes have to go wrong to result in Alzheimer's disease," says Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory and the senior author of the study.

The findings suggest that if researchers could find a way to restore normal lipid metabolism in microglia, that might help to treat some of the symptoms of the disease.

MIT postdoc Matheus Victor is the lead author of the paper, which appears today in Cell Stem Cell.

Lipid overload

About 14 percent of the population has the APOE4 variant, making it the most common genetic variant that has been linked to late-onset, nonfamilial Alzheimer's disease. People who carry one copy of APOE4 have a threefold higher risk of developing Alzheimer's, and people with two copies have a tenfold higher risk.

"If you look at this another way, if you look at the entire Alzheimer's disease population, about 50 percent of them are APOE4 carriers. So, it's a very significant risk, but we still don't know why this APOE4 allele presents such a risk," Tsai says.

The APOE gene also comes in two other forms, known as APOE2, which is considered protective against Alzheimer's, and the most common form, APOE3, which is considered neutral. APOE3 and APOE4 differ by just one amino acid.

For several years, Tsai's lab has been studying the effects of APOE4 on a variety of cell types in the brain. To do this, the researchers use induced pluripotent stem cells, derived from human donors, and engineer them to express a specific version of the APOE gene. These cells can then be stimulated to differentiate into brain cells, including neurons, microglia, and astrocytes.

In a 2018 study, they showed that APOE4 causes neurons to produce large quantities of amyloid beta peptide 42, an Alzheimer's-linked molecule that causes the neurons to become hyperactive. That study found that APOE4 also affects the functions of microglia and astrocytes, leading to cholesterol accumulation, inflammation, and failure to clear amyloid beta peptides.

A 2021 follow-up showed that APOE4 astrocytes have dramatic impairments in their ability to process a variety of lipids, which leads to a buildup of molecules such as triglycerides, as well as cholesterol. In that paper, the researchers also showed that treating engineered yeast cells expressing APOE4 with choline, a dietary supplement that is a building block for phospholipids, could reverse many of the detrimental effects of APOE4.

In their new study, the researchers wanted to investigate how APOE4 affects interactions between microglia and neurons. Recent research has shown that microglia play an important role in modulating neuronal activity, including their ability to communicate within neural ensembles. Microglia also scavenge the brain looking for signs of damage or pathogens, and clear out debris.

The researchers found that APOE4 disrupts microglia's ability to metabolize lipids and prevents them from removing lipids from their environment. This leads to a buildup of fatty molecules, especially cholesterol, in the environment. These fatty molecules bind to a specific type of potassium channel embedded in neuron cell membranes, which suppresses neuron firing.

"We know that in late stages of Alzheimer's disease, there is reduced neuron excitability, so we may be mimicking that with this model," Victor says.

The buildup of lipids in microglia can also lead to inflammation, the researchers found, and this type of inflammation is believed to contribute to the progression of Alzheimer's disease.

Restoring function

The researchers also showed that they could reverse the effects of lipid overload by treating APOE4 microglia with a drug called Triacsin C, which interferes with the formation of lipid droplets. When APOE4 microglia were exposed to this drug, the researchers found that normal communication between microglia and neighboring neurons was restored.

"We can rescue the suppression of neuronal activity by APOE4 microglia, presumably through lipid homeostasis being restored, where now fatty acids are not accumulating extracellularly," Victor says.

Triacsin C can be toxic to cells, so it would likely not be suitable to use as a drug to treat Alzheimer's, but the researchers hope that other approaches to restore lipid homeostasis could help combat the disease. In Tsai's 2021 APOE4 study, she showed that choline also helps to restore normal microglia activity.

"Lipid homeostasis is actually critical for a number of cell types across the Alzheimer's disease brain, so it's not singularly a microglia problem," Victor says. "The question is, how do you restore lipid homeostasis across multiple cell types? It's not an easy task, but we're tackling that through choline, for example, which might be a really interesting angle."

The researchers are now further studying how microglia transition from a healthy state to a "lipid-burdened," inflammatory state, in hopes of discovering ways to block that transition. In previous studies in mice, they have shown that exposure to LED light flickering at a specific frequency can help to rejuvenate microglia, stimulating the cells to resume their normal functions.

https://www.sciencedaily.com/releases/2022/08/220804130645.htm

Education, job, and social life may help protect brain from cognitive decline

August 3, 2022

Science Daily/American Academy of Neurology

Why do some people with amyloid plaques in their brains associated with Alzheimer's disease show no signs of the disease, while others with the same amount of plaque have clear memory and thinking problems? Researchers looked at genetic and life course factors that may help create a "cognitive reserve" that provides a buffer against the disease in a study published in the August 3, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology.

They found that factors such as taking part in clubs, religious groups, sports or artistic activities, along with educational attainment by age 26, occupation and reading ability, may affect the brain's cognitive reserve. The study suggests that continuing to learn over a lifetime may help protect the brain, which is true even for people who have lower scores on cognitive tests in childhood. Previous studies have shown that people with low scores in childhood are more likely to have a steeper cognitive decline in old age than people with high scores.

"These results are exciting because they indicate that cognitive ability is subject to factors throughout our lifetime and taking part in an intellectually, socially and physically active lifestyle may help ward off cognitive decline and dementia," said study author Dorina Cadar, PhD, Brighton and Sussex Medical School in the United Kingdom. "It's heartening to find that building up one's cognitive reserve may offset the negative influence of low childhood cognition for people who might not have benefited from an enriching childhood and offer stronger mental resilience until later in life."

The study involved 1,184 people who were born in 1946 in the United Kingdom. They took cognitive tests when they were eight years old and again when they were 69 years old. A cognitive reserve index combined people's education level at age 26, participation in enriching leisure activities at age 43 and occupation up to age 53. Their reading ability at age 53 was also tested as a measure of overall lifelong learning separate from education and occupation.

The cognitive test participants took at age 69 has a maximum total score of 100. The average score for this group was 92, with the lowest score being 53 and the highest score being 100.

The researchers found that higher childhood cognitive skills, a higher cognitive reserve index and higher reading ability were all associated with higher scores on the cognitive test at age 69. Researchers found that for every unit increase in childhood test scores, the old-age cognitive test score increased by 0.10 points on average. For every unit increase in the cognitive reserve index, cognitive scores increased by 0.07 points on average, and for every unit increase in reading ability, cognitive scores increased by 0.22 points on average.

People with a bachelor's degree or other higher education qualifications scored 1.22 points more on average than those with no formal education. People who engaged in six or more leisure activities such as adult education classes, clubs, volunteer work, social activities and gardening scored 1.53 points more on average than people who engaged in up to four leisure activities. Those with a professional or intermediate level job scored 1.5 points more on average than those with partly skilled or unskilled occupations.

The study also found that for people with a higher cognitive reserve index and reading ability, their scores on cognitive tests did not decline as rapidly as people with lower scores, regardless of their test scores at age eight.

Michal Schnaider Beeri, PhD, of Icahn School of Medicine at Mount Sinai in New York, who wrote an editorial accompanying the study, said, "From a public health and societal perspective, there may be broad, long-term benefits in investing in high education, widening opportunities for leisure activities and providing cognitive challenging activities for people, especially those working in less skilled occupations."

A limitation of the study is that the people who remained involved in the study until age 69 may be more likely to be healthier, have better overall thinking skills and be more socially advantaged than those who did not complete the study, so the results may not reflect the general population.

https://www.sciencedaily.com/releases/2022/08/220803161028.htm

The brain already benefits from moderate physical activity

Brain regions with high oxygen demand show the largest effects

August 3, 2022

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Even moderate physical activity has a positive effect on the brain. DZNE researchers led by Dr. Dr. Ahmad Aziz deduce this from examinations of 2,550 participants of the Bonn "Rhineland Study." According to their findings, certain areas of the brain are larger in physically active individuals than in those who are less active. In particular, brain regions that have a relatively high oxygen demand benefit from this effect. The research results are published in Neurology®, the medical journal of the American Academy of Neurology.

Exercise keeps body and mind healthy -- but little is known about exactly how and where physical activity affects our brains. "In previous research, the brain was usually considered as a whole," says Fabienne Fox, neuroscientist and lead author of the current study. "Our goal was to take a more detailed look at the brain and find out which regions of the brain physical activity impacts most."

Extensive Data from the Rhineland study

For their research, Fox and colleagues used data from the Rhineland Study, a large-scale population-based study conducted by DZNE in the Bonn city area. Specifically, they analyzed physical activity data from 2,550 volunteers aged 30 to 94 years, as well as brain images obtained by magnetic resonance imaging (MRI). To sample physical activity, the study participants wore an accelerometer on their upper thigh for seven days. The MRI scans provided information particularly on brain volume and thickness of the cortex.

The More Active, the Greater the Effects

"We were able to show that physical activity had a noticeable effect on almost all brain regions investigated. Generally, we can say that the higher and more intense the physical activity, the larger the brain regions were, either with regard to volume or cortical thickness," Fabienne Fox summarizes the research results. "In particular, we observed this in the hippocampus, which is considered the control center of memory. Larger brain volumes provide better protection against neurodegeneration than smaller ones." However, the dimensions of the brain regions do not increase linearly with physical activity. The research team found the largest, almost sudden volume increase when comparing inactive and only moderately physically active study participants -- this was particularly evident in older individuals over the age of 70.

"In principle, this is very good news -- especially for those who are reluctant to exercise," says Ahmad Aziz, who heads the research group "Population and Clinical Neuroepidemiology" at DZNE. "Our study results indicate that even small behavioral changes, such as walking 15 minutes a day or taking the stairs instead of the elevator, may have a substantial positive effect on the brain and potentially counteract age-related loss of brain matter and the development of neurodegenerative diseases. In particular, older adults can already profit from modest increases of low intensity physical activity."

Young and somewhat athletic subjects who usually engaged in moderate to intense physical activity also had relatively high brain volumes. However, in even more active subjects, these brain regions were slightly larger. Also here it showed: the more active, the greater the effect, although at high levels of physical activity, the beneficial effects tended to level off.

Brain Regions that Benefit the Most

To characterize the brain regions that benefited most from physical activity, the research team searched databases for genes that are particularly active in these brain areas. "Mainly, these were genes that are essential for the functioning of mitochondria, the power plants of our cells," says Fabienne Fox. This means that there are particularly large numbers of mitochondria in these brain regions. Mitochondria provide our body with energy, for which they need a lot of oxygen. "Compared to other brain regions, this requires increased blood flow. This is ensured particularly well during physical activity, which could explain why these brain regions benefit from exercise," says Ahmad Aziz.

Exercise Protects

The bioinformatic analysis further showed that there is a large overlap between genes whose expression is affected by physical activity and those that are impacted by neurodegenerative diseases such as Alzheimer's, Parkinson's, or Huntington's disease. This could offer a potential explanation for why physical activity has a neuroprotective effect, the research team concludes. "With our study, we were able to characterize brain regions that benefit from physical activity to an unprecedented level of detail," says Ahmad Aziz. "We hope our results will provide important leads for further research."

And also approaches for everyday use: "With our results, we want to provide a further impetus to become more physically active -- to promote brain health and prevent neurodegenerative diseases," says Fabienne Fox. "Even modest physical activity can help. Thus, it's just a small effort -- but with a big impact."

https://www.sciencedaily.com/releases/2022/08/220803112611.htm

Microscopic blood vessel disease in the brain's white matter associated with worse cognition in Alzheimer's

August 2, 2022

Science Daily/Medical College of Georgia at Augusta University

Disease of the microscopic blood vessels that feed the white matter of our brain is associated with worse cognitive function and memory deficits in individuals with Alzheimer's, scientists report.

"The main message of this paper is the mixed pathology as we call it -- microvascular disease and Alzheimer's -- is associated with more brain damage, more white matter damage and more inflammation," says Dr. Zsolt Bagi, vascular biologist in the Department of Physiology at the Medical College of Georgia at Augusta University.

Theirs and other recent findings suggest that some people with Alzheimer's who have brain changes widely associated with the condition, like amyloid plaques, may not develop dementia without this underlying vascular dysfunction, the researchers write in the journal GeroScience.

"We are proposing that if you prevent development of the microvascular component, you may at least add several years of more normal functioning to individuals with Alzheimer's," Bagi says.

He and by Dr. Stephen Back, pediatric neurologist, Clyde and Elda Munson Professor of Pediatric Research and an expert in white matter injury and repair in the developing and adult brain at Oregon Health & Science University, are co-corresponding authors of the new study.

The good news is that vascular disease is potentially modifiable, Bagi says, by reducing major contributors like hypertension, obesity, diabetes and inactivity.

The scientists looked at the brains of 28 individuals who participated in the Adult Changes in Thought Study, or ACT, a joint initiative of Kaiser Permanente Washington Research Institute and the University of Washington, whose scientists also were collaborators on the new study.

ACT is a longitudinal study of the cognitive health of community volunteers from the Seattle, Washington area with the goal of finding ways to delay or prevent memory decline. Participants age 65 or older with no cognitive problems upon enrollment are followed until their death, and about 25% agree to autopsy and making genomic DNA from their blood and/or brain tissue available to scientists.

The individuals that served as controls for the study had no indication of Alzheimer's or vascular disease in their brain. Other groups had Alzheimer's without vascular disease, vascular disease without indicators of Alzheimer's or both Alzheimer's and vascular disease.

Their focus in the studies was the white matter, which accounts for about 50% of the brain mass, enables different regions of the brain to communicate and is packed with long arms called axons that connect neurons to each other and to other cells across the body like muscle cells; and, the microscopic arterioles that directly feed white matter with blood, oxygen and nutrients.

They wanted to test their theory that when these hair-thin arterioles had difficulty dilating and so supporting this part of the brain, it resulted in changes to the white matter that were evident on sophisticated MRIs, especially when microvascular problems coexisted with the more classic brain changes of Alzheimer's.

They found that the arterioles of those who had been diagnosed with Alzheimer's and dysfunction of these tiny arteries did have an impaired ability to dilate in response to the powerful blood vessel dilator bradykinin, compared to those without obvious microvascular dysfunction. Problems with dilation were associated with white matter injury and changes to the white matter structure that were visible on MRI.

Expression of the precursor for the also-powerful blood vessel dilator nitric oxide also was reduced in these individuals with both conditions while the expression of superoxide generating NOX1, which damages blood vessels, was increased.

Arteriole dysfunction also was associated with more white matter injury based on what was visible on those sophisticated MRI scans and the increased number of brain cells, called astrocytes, which support neurons.

The investigators had previously reported an increase in these astrocytes in brains with the microvascular changes. This time they saw that when Alzheimer's and the microvascular changes were both present, the astrocytes became more reactive, inflammatory and damaging.

Colleagues at Oregon Health & Science University, led by Back, looked at the same brain tissue with a sophisticated MRI technique called diffusion tensor imaging, that uses water diffusion between cells to look at the microstructure of white matter and its connectivity.

They could not visualize individual arterioles because they are too small -- about 30 microns or .0011811 inches -- to see without a microscope. But they could see the white matter damage that resulted from arteriole disease, and again found the correlation between the vascular impairment and tissue damage that Bagi described from directly visualizing the tissue. This type of blood vessel disease was present in 50% of the brains they studied, and other autopsy studies have indicated a similarly high rate.

In those with less indicators of brain changes, they found the arterioles were better able to dilate, that area of the brain had better connectivity and less damage apparent on the postmortem MRI.

Impaired ability of these small vessels in the white matter to dilate is known to be associated with white matter injury, like that visible on the specialized MRI scans. And there is evidence in both laboratory studies and humans that this vascular dysfunction does not just worsen but plays a role in the development of cognitive decline and dementia in people with Alzheimer's, the investigators write.

In fact, the vascular dysfunction may be present before the damage to the brain tissue and cognitive dysfunction is apparent. In research animals bred to develop Alzheimer's, for example, there is evidence of problems with the microvasculature in areas of the brain associated with Alzheimer's, like the hippocampus, a center of learning and memory, at a very young age.

The new work confirms the growing concept that small blood vessel disease may help predict the severity of dementia and/or use of DTI MRI may help identify those patients with early enough disease that strategies to reduce or slow small blood vessel disease may help delay or reduce their cognitive loss. The technique might also help assess the potential benefit of intervention.

"These individuals might especially benefit if they would exercise, control blood sugar level and control their blood pressure," Bagi says.

Some patients with Alzheimer's disease are known to have white matter hyperintensities on MRI scan, basically damaged areas that show up particularly bright on the scan and are associated with problems like dementia. A significant proportion of individuals with Alzheimer's also have conditions like high lipid levels in their blood and hypertension that are known to impair blood vessel function, including the smallest vasculature, Bagi notes. Small blood vessel disease in the brain also is common in aging and may indicate an increased risk of problems like stroke or dementia. Sophisticated brain scans also often indicate microinfarcts, essentially microscopic strokes, which also tend to increase with age and are associated with memory impairment.

Age and a family history are major risk factor for Alzheimer's and there are two categories of genes associated with an increased risk, including risk genes, like APOE-e4, the first gene identified and the one that has the strongest impact on risk, according to the Alzheimer's Organization. Then there are those genes that can directly cause Alzheimer's, called deterministic genes, which impact production or processing of beta-amyloid, the main component of the plaque associated with Alzheimer's, but even having these rare genes are not a guarantee of disease.

"You have some genetic predisposition but people realize that not everybody develops memory decline or cognitive deficits unless something else is coming in," Bagi says. He notes that they have not yet analyzed the genes for this study.

Next steps include studying the associations they found in more human brains and more studies to better understand exactly how the small blood vessel disease happens, which could point toward new targets to intervene.

https://www.sciencedaily.com/releases/2022/08/220802105025.htm

Common viruses may be triggering the onset of Alzheimer's disease

Shingles infection may activate dormant neurological herpes viruses, causing inflammation and accumulation of Alzheimer's associated proteins in the brain

August 2, 2022

Science Daily/Tufts University

Alzheimer's disease can begin almost imperceptibly, often masquerading in the early months or years as forgetfulness that is common in older age. What causes the disease remains largely a mystery.

But researchers at Tufts University and the University of Oxford, using a three-dimensional human tissue culture model mimicking the brain, have shown that varicella zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), another common virus, to set in motion the early stages of Alzheimer's disease.

Normally HSV-1 -- one of the main variants of the virus -- lies dormant within the neurons of the brain, but when it is activated it leads to accumulation of tau and amyloid beta proteins, and loss of neuronal function -- signature features found in patients with Alzheimer's.

"Our results suggest one pathway to Alzheimer's disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain," said Dana Cairns, GBS12, a research associate in the Biomedical Engineering Department. "While we demonstrated a link between VZV and HSV-1 activation, it's possible that other inflammatory events in the brain could also awaken HSV-1 and lead to Alzheimer's disease."

The study is published in the Journal of Alzheimer's Disease.

Viruses Lying in Wait

"We have been working off a lot of established evidence that HSV has been linked to increased risk of Alzheimer's disease in patients," said David Kaplan, Stern Family Professor of Engineering and chair of the Department of Biomedical Engineering at Tufts' School of Engineering. One of the first to hypothesize a connection between herpes virus and Alzheimer's disease is Ruth Itzhaki of the University of Oxford, who collaborated with the Kaplan lab on this study.

"We know there is a correlation between HSV-1 and Alzheimer's disease, and some suggested involvement of VZV, but what we didn't know is the sequence of events that the viruses create to set the disease in motion," he said. "We think we now have evidence of those events."

According to the World Health Organization, an estimated 3.7 billion people under the age of 50 have been infected with HSV-1 -- the virus that causes oral herpes. In most cases it is asymptomatic, lying dormant within nerve cells.

When activated, it can cause inflammation in nerves and skin, causing painful open sores and blisters. Most carriers -- and that's one in two Americans according to the CDC -- will have between very mild to no symptoms before the virus becomes dormant.

Varicella zoster virus is also extremely common, with about 95 percent of people having been infected before the age of 20. Many of those cases are expressed as chicken pox. VZV, which is a form of herpes virus, can also remain in the body, finding its way to nerve cells before then becoming dormant.

Later in life, VZV can be reactivated to cause shingles, a disease characterized by blisters and nodules in the skin that form in a band-like pattern and can be very painful, lasting for weeks or even months. One in three people will eventually develop a case of shingles in their lifetime.

The link between HSV-1 and Alzheimer's disease only occurs when HSV-1 has been reactivated to cause sores, blisters, and other painful inflammatory conditions.

How Sleeping Viruses May Wake

To better understand the cause-and-effect relationship between the viruses and Alzheimer's disease, the Tufts researchers re-created brain-like environments in small 6 millimeter-wide donut-shaped sponges made of silk protein and collagen.

They populated the sponges with neural stem cells that grow and become functional neurons capable of passing signals to each other in a network, just as they do in the brain. Some of the stem cells also form glial cells, which are typically found in the brain and help keep the neurons alive and functioning.

The researchers found that neurons grown in the brain tissue can be infected with VZV, but that alone did not lead to the formation of the signature Alzheimer's proteins tau and beta-amyloid -- the components of the tangled mess of fibers and plaques that form in Alzheimer's patients' brains -- and that the neurons continued to function normally.

However, if the neurons already harbored quiescent HSV-1, the exposure to VZV led to a reactivation of HSV, and a dramatic increase in tau and beta-amyloid proteins, and the neuronal signals begin to slow down.

"It's a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble," said Cairns.

"It's still possible that other infections and other pathways of cause and effect could lead to Alzheimer's disease, and risk factors such as head trauma, obesity, or alcohol consumption suggest they may intersect at the re-emergence of HSV in the brain," she added.

The researchers observed that the VZV infected samples started to produce a higher level of cytokines -- proteins which are often involved in triggering an inflammatory response. Kaplan noted that VZV is known in many clinical cases to cause inflammation in the brain, which could possibly lead to activation of dormant HSV and increased inflammation.

Repeat cycles of HSV-1 activation can lead to more inflammation in the brain, production of plaques, and accumulation of neuronal and cognitive damage.

A vaccine for VZV -- to prevent chickenpox and shingles -- has also been shown to considerably reduce the risk of dementia. It's possible that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.

The researchers also noted the long-term neurological effects that some COVID patients have experienced from the SARS-CoV-2 virus, particularly among the elderly, and that both VZV and HSV-1 can be reactivated after a COVID infection. Keeping an eye on possible follow-on cognitive effects and neurodegeneration would be advisable in these cases, they said.

https://www.sciencedaily.com/releases/2022/07/220729173148.htm

COVID-19 infection in crucial brain regions may lead to accelerated brain aging

Study finds this may put vulnerable individuals at risk for irreversible neurological conditions

July 28, 2022

Science Daily/Houston Methodist

A new study by Houston Methodist researchers reviews the emerging insights and evidence that suggest COVID-19 infections may have both short- and long-term neurological effects. Major findings include that COVID-19 infections may predispose individuals to developing irreversible neurological conditions, may increase the likelihood of strokes and may increase the chance of developing persistent brain lesions that can lead to brain bleeding.

Led by corresponding authors Joy Mitra, Ph.D., Instructor, and Muralidhar L. Hegde, Ph.D., Professor of Neurosurgery, with the Division of DNA Repair within the Center for Neuroregeneration at the Houston Methodist Research Institute, the research team described their findings in an article titled "SARS-CoV-2 and the Central Nervous System: Emerging Insights into Hemorrhage-Associated Neurological Consequences and Therapeutic Considerations" online in press July 16 in the journal Ageing Research Reviews.

Still a major burden on our daily lives, a great deal of research has shown that the impacts of the disease go far beyond the actual time of infection. Since the onset of the pandemic, COVID-19 has surpassed a death toll of over 5.49 million worldwide and over 307 million confirmed positive cases, with the U.S. accounting for almost 90 million of those cases, according to the Our World in Data website.

COVID-19 is known to invade and infect the brain, among other major organs. While a lot of research has been done to help us understand the evolution, infection and pathology of the disease, there is still a great deal that remains unclear about the long-term effects, especially on the brain.

The coronavirus infection can cause long-term and irreversible neurodegenerative diseases, particularly in the elderly and other vulnerable populations. Several brain imaging studies on COVID-19 victims and survivors have confirmed the formation of microbleed lesions in deeper brain regions related to our cognitive and memory functions. In this review study, researchers have critically evaluated the possible chronic neuropathological outcomes in aging and comorbid populations if timely therapeutic intervention is not implemented.

Microbleeds are emerging neuropathological signatures frequently identified in people suffering from chronic stress, depressive disorders, diabetes and age-associated comorbidities. Based on their earlier findings, the investigators discuss how COVID-19-induced microhemorrhagic lesions may exacerbate DNA damage in affected brain cells, resulting in neuronal senescence and activation of cell death mechanisms, which ultimately impact brain microstructure-vasculature. These pathological phenomena resemble hallmarks of neurodegenerative conditions like Alzheimer's and Parkinson's diseases and are likely to aggravate advanced-stage dementia, as well as cognitive and motor deficits.

The effects of COVID-19 infection on various aspects of the central nervous system are currently being studied. For instance, 20-30% of COVID-19 patients report a lingering psychological condition known as "brain fog" where individuals suffer from symptoms such as memory loss, difficulty in concentrating, forgetting daily activities, difficulty in selecting the right words, taking longer than usual time to complete a regular task, disoriented thought processes and emotional numbness.

More severe long-term effects analyzed in the Houston Methodist review article include predispositions for Alzheimer's, Parkinson's and related neurodegenerative diseases, as well as cardiovascular disorders due to internal bleeding and blood clotting-induced lesions in the part of the brain that regulates our respiratory system, following the COVID-19 symptoms. Additionally, cellular aging is thought to be accelerated in COVID-19 patients. A plethora of cellular stresses inhibit the virus-infected cells from undergoing their normal biological functions and let them enter into "hibernation mode" or even die completely.

The study also suggests various strategies to improve some of these long-term neuropsychiatric and neurodegenerative outcomes, as well as outlines the importance of the therapeutic regimen of the "nanozyme" in combination with various FDA-approved drugs that may prove successful to fight against this catastrophic disease.

However, given the ever-evolving nature of this field, associations like the ones described in this review show the fight against COVID-19 is far from over, say the investigators, and reinforce the message that getting vaccinated and maintaining proper hygiene are key in trying to prevent such long-term and detrimental consequences.

https://www.sciencedaily.com/releases/2022/07/220728143030.htm

Rapid loss of smell predicts dementia and smaller brain areas linked to Alzheimer's

July 28, 2022

Science Daily/University of Chicago Medical Center

Though we often undervalue our ability to smell compared to our abilities to see and hear, our olfactory sense provides our brain with critical information, from detecting potential dangers like smoke to recognizing the sweet smell of baking cookies.

Researchers at the University of Chicago Medicine have discovered another reason to appreciate our sniffers. Not only can a decline in a person's sense of smell over time predict their loss of cognitive function, it can foretell structural changes in regions of the brain important in Alzheimer's disease and dementia.

The findings, based on a longitudinal study of 515 older adults published July 2 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, could lead to the development of smell-test screening to detect cognitive impairment earlier in patients.

"This study provides another clue to how a rapid decline in the sense of smell is a really good indicator of what's going to end up structurally occurring in specific regions of the brain," said senior author Jayant M. Pinto, MD, a professor of surgery at the University of Chicago and ENT specialist who studies olfactory and sinus disease.

It's estimated more than 6 million Americans have Alzheimer's disease, which is characterized by memory loss and other symptoms, such as mood changes and trouble completing everyday tasks. There is no cure for Alzheimer's, but some medications can temporarily slow its symptoms.

Memory plays a critical role in our ability to recognize smells, and researchers have long known of a link between the sense of smell and dementia. The plaques and tangles that characterize tissue affected by Alzheimer's disease often appear in olfactory and memory- associated areas before developing in other parts of the brain. It's still unknown if this damage actually causes the decline in a person's sense of smell.

Pinto and his team wanted to see whether it was possible to identify alterations in the brain that correlated with a person's loss of smell and cognitive function over time.

"Our idea was that people with a rapidly declining sense of smell over time would be in worse shape -and more likely to have brain problems and even Alzheimer's itself -than people who were slowly declining or maintaining a normal sense of smell," said Rachel Pacyna, a rising fourth-year medical student at the University of Chicago Pritzker School of Medicine and lead author of the study.

The team tapped anonymized patient data from Rush University's Memory and Aging Project (MAP), a study group begun in 1997 to research chronic conditions of aging and neurodegenerative disease such as Alzheimer's disease. MAP participants are older adults living in retirement or senior housing communities in Northern Illinois and are tested annually for their ability to identify certain smells, for cognitive function and for signs of dementia, among other health parameters. Some participants also received an MRI scan.

The UChicago Medicine scientists found that a rapid decline in a person's sense of smell during a period of normal cognition predicted multiple features of Alzheimer's disease, including smaller gray matter volume in the areas of the brain related to smell and memory, worse cognition and higher risk of dementia in these older adults. In fact, the risk of sense of smell loss was similar to carrying the APOE-e4 gene, a known genetic risk factor for developing Alzheimer's.

The changes were most noticeable in the primary olfactory regions, including the amygdala and entorhinal cortex, which is a major input to the hippocampus, a critical site in Alzheimer's disease.

"We were able to show that the volume and shape of grey matter in olfactory and memory-associated areas of the brains of people with rapid decline in their sense of smell were smaller compared to people who had less severe olfactory decline," said Pinto.

An autopsy is the gold standard for confirming whether someone had Alzheimer's, and Pinto hopes to eventually extend these findings by examining brain tissue for markers of Alzheimer's. The team also hopes to study the effectiveness of using smell tests in clinics -- in ways similar to how vision and hearing tests are used -- as a means of screening and tracking older adults for signs of early dementia, and to develop new treatments.

Smell tests are an inexpensive, easy-to-use tool that consists of a series of sticks that are similar in appearance to felt-tip pens. Each stick is infused with a distinct scent that individuals must identify from a set of four choices.

"If we could identify people in their 40s, 50s and 60s who are at higher risk early on, we could potentially have enough information to enroll them into clinical trials and develop better medications," said Pacyna.

The study was limited in that participants received only one MRI scan, which meant the team lacked the data to pinpoint when structural changes in the brains began or how quickly brain regions shrunk.

"We have to take our study in the context of all of the risk factors that we know about Alzheimer's, including the effects of diet and exercise," said Pinto. "Sense of smell and change in the sense of smell should be one important component in the context of an array of factors that we believe affect the brain in health and ageing.

Also, because most MAP participants were white, additional research is needed to determine whether underrepresented populations are similarly affected. The team's prior work showed marked disparities by race, with African Americans facing the most severe impairment in smell function.

Pinto's previous studies have examined the sense of smell as an important marker for declining health in older adults. His 2014 paper revealed older adults with no sense of smell were three times more likely to die within five years -- a better predictor of death than a diagnosis of lung disease, heart failure or cancer.

https://www.sciencedaily.com/releases/2022/07/220728075930.htm

Chores, exercise, and social visits linked to lower risk of dementia

July 27, 2022

Science Daily/American Academy of Neurology

Physical and mental activities, such as household chores, exercise, and visiting with family and friends, may help lower the risk of dementia, according to a new study published in the July 27, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study looked at the effects of these activities, as well as mental activities and use of electronic devices in people both with and without higher genetic risk for dementia.

"Many studies have identified potential risk factors for dementia, but we wanted to know more about a wide variety of lifestyle habits and their potential role in the prevention of dementia," said study author Huan Song, MD, PhD, of Sichuan University in Chengdu, China. "Our study found that exercise, household chores, and social visits were linked to a reduced risk of various types of dementia."

The study involved 501,376 people from a UK database without dementia with an average age of 56.

Participants filled out questionnaires at the beginning of the study, including one on physical activities. They were asked how often they participated in activities such as climbing a flight of stairs, walking, and participating in strenuous sports. They were also asked about household chores, job-related activities, and what kind of transportation they used, including walking or biking to work.

Participants completed another questionnaire on mental activities. They were asked about their education level, whether they attend adult education classes, how often they visit with friends and family, visit pubs or social clubs or religious groups, and how often they use electronic devices such as playing computer games, watching TV, and talking on the phone.

Additionally, participants reported whether they had any immediate family members with dementia. This helped researchers determine if they had a genetic risk for Alzheimer's disease. Study participants were followed an average of 11 years. At the end of the study, 5,185 people had developed dementia.

After adjusting for multiple factors such as age, income, and smoking, researchers found that most physical and mental activities studied showed links to the risk of dementia. Importantly, the findings remain after considering the high correlations and interactions of these activities. People who were highly engaged in activity patterns including frequent exercises, household chores, and daily visits of family and friends had 35%, 21%, and 15% lower risk of dementia, respectively, compared to people who were the least engaged in these activity patterns.

Researchers also looked at dementia incidence rates by identified activity patterns. The rate in people who exercised frequently was 0.45 cases for every 1,000 person-years compared to 1.59 for people who rarely exercised. Person-years take into account the number of people in a study as well as the amount of time spent in the study. Those who frequently did household chores had a rate of 0.86 cases for every 1,000 person-years compared to 1.02 for people who rarely did household chores. People who visited family daily had a rate of 0.62 cases for every 1,000 person-years compared to 0.8 cases for those who only visited friends and family once every few months.

"Our study has found that by engaging more frequently in healthy physical and mental activities people may reduce their risk of dementia," Song said. "More research is needed to confirm our findings. However, our results are encouraging that making these simple lifestyle changes may be beneficial."

The researchers found that all participants benefited from the protective effect of physical and mental activities, whether or not they had a family history of dementia.

A limitation of the study was that people reported their own physical and mental activity, so they may not have remembered and reported these activities correctly.

https://www.sciencedaily.com/releases/2022/07/220727163109.htm

Eating more ultra-processed foods associated with increased risk of dementia

July 27, 2022

Science Daily/American Academy of Neurology

People who eat the highest amounts of ultra-processed foods like soft drinks, chips and cookies may have a higher risk of developing dementia than those who eat the lowest amounts, according to a new study published in the July 27, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. Researchers also found that replacing ultra-processed foods in a person's diet with unprocessed or minimally processed foods was associated with a lower risk. The study does not prove that ultra-processed foods cause dementia. It only shows an association.

Ultra-processed foods are high in added sugar, fat and salt, and low in protein and fiber. They include soft drinks, salty and sugary snacks, ice cream, sausage, deep-fried chicken, yogurt, canned baked beans and tomatoes, ketchup, mayonnaise, packaged guacamole and hummus, packaged breads and flavored cereals.

"Ultra-processed foods are meant to be convenient and tasty, but they diminish the quality of a person's diet," said study author Huiping Li, PhD, of Tianjin Medical University in China. "These foods may also contain food additives or molecules from packaging or produced during heating, all of which have been shown in other studies to have negative effects on thinking and memory skills. Our research not only found that ultra-processed foods are associated with an increased risk of dementia, it found replacing them with healthy options may decrease dementia risk."

For the study, researchers identified 72,083 people from the UK Biobank, a large database containing the health information of half a million people living in the United Kingdom. Participants were age 55 and older and did not have dementia at the start of the study. They were followed for an average of 10 years. By the end of the study, 518 people were diagnosed with dementia.

During the study, participants filled out at least two questionnaires about what they ate and drank the previous day. Researchers determined how much ultra-processed food people ate by calculating the grams per day and comparing it to the grams per day of other foods to create a percentage of their daily diet. They then divided participants into four equal groups from lowest percentage consumption of ultra-processed foods to highest.

On average, ultra-processed foods made up 9% of the daily diet of people in the lowest group, an average of 225 grams per day, compared to 28% for people in the highest group, or an average of 814 grams per day. One serving of items like pizza or fish sticks was equivalent to 150 grams. The main food group contributing to high ultra-processed food intake was beverages, followed by sugary products and ultra-processed dairy.

In the lowest group, 105 of the 18,021 people developed dementia, compared to 150 of the 18,021 people in the highest group.

After adjusting for age, gender, family history of dementia and heart disease and other factors that could affect risk of dementia, researchers found that for every 10% increase in daily intake of ultra-processed foods, people had a 25% higher risk of dementia.

Researchers also used study data to estimate what would happen if a person substituted 10% of ultra-processed foods with unprocessed or minimally processed foods, like fresh fruit, vegetables, legumes, milk and meat. They found that such a substitution was associated with a 19% lower risk of dementia.

"Our results also show increasing unprocessed or minimally processed foods by only 50 grams a day, which is equivalent to half an apple, a serving of corn, or a bowl of bran cereal, and simultaneously decreasing ultra-processed foods by 50 grams a day, equivalent to a chocolate bar or a serving of fish sticks, is associated with 3% decreased risk of dementia," said Li. "It's encouraging to know that small and manageable changes in dietmay make a difference in a person's risk of dementia."

Li noted that further research is needed to confirm the findings.

Maura E. Walker, PhD, of Boston University in Massachusetts, who wrote an editorial accompanying the study, said, "While nutrition research has started to focus on food processing, the challenge is categorizing such foods as unprocessed, minimally processed, processed and ultra-processed. For example, foods like soup would be classified differently if canned versus homemade. Plus, the level of processing is not always aligned with diet quality. Plant-based burgers that qualify as high quality may also be ultra-processed. As we aim to understand better the complexities of dietary intake, we must also consider that more high-quality dietary assessments may be required."

A limitation of the study was that cases of dementia were determined by looking at hospital records and death registries rather than primary care data, so milder cases may have been overlooked. .

https://www.sciencedaily.com/releases/2022/07/220727163045.htm

Finding the right memory strategy to slow cognitive decline

A new study compares two popular forms of cognitive training that people often use to improve learning and memory

July 25, 2022

Science Daily/Michigan Medicine - University of Michigan

What's the best way to improve your memory as you age? Turns out, it depends, a new study suggests. But your fourth-grade math teacher may have been onto something with that phrase to help you remember how to work out a complicated problem: Please Excuse My Dear Aunt Sally.

A new study led by researchers from the University of Michigan and Penn State College of Medicine compared two approaches for people with an early form of memory loss.

The two are mnemonic strategy training, which aims to connect what someone is trying to remember to something else like a word, phrase or song (such as the Dear Aunt Sally mnemonic), and spaced retrieval training, which gradually increases the amount of time between tests of remembering something.

People with mild cognitive impairment, which can but does not always lead to a later Alzheimer's disease diagnosis, were better able to remember information when using one of these cognitive training approaches. However, the data, and brain scans that revealed which areas of the brain were more active, showed each activity works differently.

"Our research shows that we can help people with mild cognitive impairment improve the amount of information they learn and remember; however, different cognitive training approaches engage the brain in distinct ways," said lead and corresponding author Benjamin Hampstead, Ph.D. Hampstead is a professor of psychiatry at Michigan Medicine and the VA Ann Arbor Healthcare System. He directs the Research Program on Cognition and Neuromodulation Based Interventions and leads the Clinical Core and co-leads the Neuroimaging Core at the federally funded Michigan Alzheimer's Disease Research Center.

"Mnemonic strategy training increased activity in brain areas often affected by Alzheimer's disease, which likely explains why this training approach helped participants remember more information and for longer," Hampstead said "In contrast, those completing rehearsal-based training showed reduced brain activity, which suggests they were processing the information more efficiently."

Hampstead and his team worked with Krish Sathian, MBBS, Ph.D., professor and chair of Penn State's Department of Neurology and director of Penn State Neuroscience Institute. Sathian noted that cognitive training approaches are likely to become increasingly important in synergy with the new pharmacological treatments on the horizon for those with neurodegenerative disorders.

Moving forward, Hampstead said researchers and clinicians can use this type of information to help identify the best-fit non-pharmacologic treatments for their patients with memory impairment.

https://www.sciencedaily.com/releases/2022/07/220722123233.htm