Posts Tagged ‘brain’


Brain tissue from deceased patients with Alzheimer’s has more tau protein buildup (brown spots) and fewer neurons (red spots) as compared to healthy brain tissue.

By Yasemin Saplakoglu

Alzheimer’s disease might be attacking the brain cells responsible for keeping people awake, resulting in daytime napping, according to a new study.

Excessive daytime napping might thus be considered an early symptom of Alzheimer’s disease, according to a statement from the University of California, San Francisco (UCSF).

Some previous studies suggested that such sleepiness in patients with Alzheimer’s results directly from poor nighttime sleep due to the disease, while others have suggested that sleep problems might cause the disease to progress. The new study suggests a more direct biological pathway between Alzheimer’s disease and daytime sleepiness.

In the current study, researchers studied the brains of 13 people who’d had Alzheimer’s and died, as well as the brains from seven people who had not had the disease. The researchers specifically examined three parts of the brain that are involved in keeping us awake: the locus coeruleus, the lateral hypothalamic area and the tuberomammillary nucleus. These three parts of the brain work together in a network to keep us awake during the day.

The researchers compared the number of neurons, or brain cells, in these regions in the healthy and diseased brains. They also measured the level of a telltale sign of Alzheimer’s: tau proteins. These proteins build up in the brains of patients with Alzheimer’s and are thought to slowly destroy brain cells and the connections between them.

The brains from patients who had Alzheimer’s in this study had significant levels of tau tangles in these three brain regions, compared to the brains from people without the disease. What’s more, in these three brain regions, people with Alzheimer’s had lost up to 75% of their neurons.

“It’s remarkable because it’s not just a single brain nucleus that’s degenerating, but the whole wakefulness-promoting network,” lead author Jun Oh, a research associate at UCSF, said in the statement. “This means that the brain has no way to compensate, because all of these functionally related cell types are being destroyed at the same time.”

The researchers also compared the brains from people with Alzheimer’s with tissue samples from seven people who had two other forms of dementia caused by the accumulation of tau: progressive supranuclear palsy and corticobasal disease. Results showed that despite the buildup of tau, these brains did not show damage to the neurons that promote wakefulness.

“It seems that the wakefulness-promoting network is particularly vulnerable in Alzheimer’s disease,” Oh said in the statement. “Understanding why this is the case is something we need to follow up in future research.”

Though amyloid proteins, and the plaques that they form, have been the major target in several clinical trials of potential Alzheimer’s treatments, increasing evidence suggests that tau proteins play a more direct role in promoting symptoms of the disease, according to the statement.

The new findings suggest that “we need to be much more focused on understanding the early stages of tau accumulation in these brain areas in our ongoing search for Alzheimer’s treatments,” senior author Dr. Lea Grinberg, an associate professor of neurology and pathology at the UCSF Memory and Aging Center, said in the statement.

The findings were published Monday (Aug. 12) in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

https://www.livescience.com/alzheimers-attacks-wakefulness-neurons.html?utm_source=notification

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A mouse exploring one of the custom hologram generators used in the experiments at Stanford. By stimulating particular neurons, scientists were able to make engineered mice see visual patterns that weren’t there.

By Carl Zimmer

In a laboratory at the Stanford University School of Medicine, the mice are seeing things. And it’s not because they’ve been given drugs.

With new laser technology, scientists have triggered specific hallucinations in mice by switching on a few neurons with beams of light. The researchers reported the results on Thursday in the journal Science.

The technique promises to provide clues to how the billions of neurons in the brain make sense of the environment. Eventually the research also may lead to new treatments for psychological disorders, including uncontrollable hallucinations.

“This is spectacular — this is the dream,” said Lindsey Glickfeld, a neuroscientist at Duke University, who was not involved in the new study.

In the early 2000s, Dr. Karl Deisseroth, a psychiatrist and neuroscientist at Stanford, and other scientists engineered neurons in the brains of living mouse mice to switch on when exposed to a flash of light. The technique is known as optogenetics.

In the first wave of these experiments, researchers used light to learn how various types of neurons worked. But Dr. Deisseroth wanted to be able to pick out any individual cell in the brain and turn it on and off with light.

So he and his colleagues designed a new device: Instead of just bathing a mouse’s brain in light, it allowed the researchers to deliver tiny beams of red light that could strike dozens of individual brain neurons at once.

To try out this new system, Dr. Deisseroth and his colleagues focused on the brain’s perception of the visual world. When light enters the eyes — of a mouse or a human — it triggers nerve endings in the retina that send electrical impulses to the rear of the brain.

There, in a region called the visual cortex, neurons quickly detect edges and other patterns, which the brain then assembles into a picture of reality.

The scientists inserted two genes into neurons in the visual cortices of mice. One gene made the neurons sensitive to the red laser light. The other caused neurons to produce a green flash when turned on, letting the researchers track their activity in response to stimuli.

The engineered mice were shown pictures on a monitor. Some were of vertical stripes, others of horizontal stripes. Sometimes the stripes were bright, sometimes fuzzy. The researchers trained the mice to lick a pipe only if they saw vertical stripes. If they performed the test correctly, they were rewarded with a drop of water.

As the mice were shown images, thousands of neurons in their visual cortices flashed green. One population of cells switched on in response to vertical stripes; other neurons flipped on when the mice were shown horizontal ones.

The researchers picked a few dozen neurons from each group to target. They again showed the stripes to the mice, and this time they also fired light at the neurons from the corresponding group. Switching on the correct neurons helped the mice do better at recognizing stripes.

Then the researchers turned off the monitor, leaving the mice in darkness. Now the scientists switched on the neurons for horizontal and vertical stripes, without anything for the rodents to see. The mice responded by licking the pipe, as if they were actually seeing vertical stripes.

Anne Churchland, a neuroscientist at Cold Spring Harbor Laboratory who was not involved in the study, cautioned that this kind of experiment can’t reveal much about a mouse’s inner experience.

“It’s not like a creature can tell you, ‘Oh, wow, I saw a horizontal bar,’” she said.

Dr. Churchland said that it would take more research to better understand why the mice behaved as they did in response to the flashes of red light. Did they see the horizontal stripes more clearly, or were they less distracted by misleading signals?

One of the most remarkable results from the study came about when Dr. Deisseroth and his colleagues narrowed their beams of red light to fewer and fewer neurons. They kept getting the mice to lick the pipe as if they were seeing the vertical stripes.

In the end, the scientists found they could trigger the hallucinations by stimulating as few as two neurons. Thousands of other neurons in the visual cortex would follow the lead of those two cells, flashing green as they became active.

Clusters of neurons in the brain may be tuned so that they’re ready to fire at even a slight stimulus, Dr. Deisseroth and his colleagues concluded — like a snowbank poised to become an avalanche.

But it doesn’t take a fancy optogenetic device to make a few neurons fire. Even when they’re not receiving a stimulus, neurons sometimes just fire at random.

That raises a puzzle: If all it takes is two neurons, why are we not hallucinating all the time?

Maybe our brain wiring prevents it, Dr. Deisseroth said. When a neuron randomly fires, others may send signal it to quiet down.

Dr. Glickfeld speculated that attention may be crucial to triggering the avalanche of neuronal action only at the right times. “Attention allows you to ignore a lot of the background activity,” she said.

Dr. Deisseroth hopes to see what other hallucinations he can trigger with light. In other parts of the brain, he might be able to cause mice to perceive more complex images, such as the face of a cat. He might be able to coax neurons to create phantom sounds, or even phantom smells.

As a psychiatrist, Dr. Deisseroth has treated patients who have suffered from visual hallucinations. In his role as a neuroscientist, he’d like to find out more about how individual neurons give rise to these images — and how to stop them.

“Now we know where those cells are, what they look like, what their shape is,” he said. “In future work, we can get to know them in much more detail.”

A study by Stanford University School of Medicine investigators has revealed that immune cells infiltrate the rare newborn nerve-cell nurseries of the aging brain. There’s every reason to think those interlopers are up to no good. Experiments in a dish and in living animals indicate they’re secreting a substance that chokes off new nerve cell production.

While most of the experiments in the study were carried out in mice, the central finding—the invasion, by immune cells called killer T cells, of neurogenic niches (specialized spots in the brain where new nerve cells, or neurons, are generated)—was corroborated in tissue excised from autopsied human brains.

The findings could accelerate progress in hunting down the molecules in the body that promote the common deterioration of brain function in older individuals and in finding treatments that might stall or even reverse that deterioration. They also signify a crack in the wall of dogma that’s deemed the healthy brain impervious to invasion by the body’s immune cells, whose unbridled access to the organ could cause damage.

“The textbooks say that immune cells can’t easily get into the healthy brain, and that’s largely true,” said Anne Brunet, Ph.D., professor of genetics and senior author of the study. “But we’ve shown that not only do they get into otherwise healthy aging brains—including human brains—but they reach the very part of the brain where new neurons arise.”

Lead authorship of the study, to be published online July 3 in Nature, is shared by medical student Ben Dulken, Ph.D., graduate student Matthew Buckley and postdoctoral scholar Paloma Navarro Negredo, Ph.D.

The cells that aid memory

Many a spot in a young mammal’s brain is bursting with brand new neurons. But for the most part, those neurons have to last a lifetime. Older mammals’ brains retain only a couple of neurogenic niches, consisting of several cell types whose mix is critical for supporting neural stem cells that can both differentiate into neurons and generate more of themselves. New neurons spawned in these niches are considered essential to forming new memories and to learning, as well as to odor discrimination.

In order to learn more about the composition of the neurogenic niche, the Stanford researchers catalogued, one cell at a time, the activation levels of the genes in each of nearly 15,000 cells extracted from the subventricular zone (a neurogenic niche found in mice and human brains) of healthy 3-month-old mice and healthy 28- or 29-month-old mice.

This high-resolution, single-cell analysis allowed the scientists to characterize each cell they looked at and see what activities it was engaged in. Their analysis confirmed the presence of nine familiar cell types known to compose the neurogenic niche. But when Brunet and her colleagues compared their observations in the brains of young mice (equivalent in human years to young adults) with what they saw in the brains of old mice (equivalent to people in their 80s), they identified a couple of cell types in the older mice not typically expected to be there—and barely present in the young mice. In particular, they found immune cells known as killer T cells lurking in the older mice’s subventricular zone.

The healthy brain is by no means devoid of immune cells. In fact, it boasts its own unique version of them, called microglia. But a much greater variety of immune cells abounding in the blood, spleen, gut and elsewhere in the body are ordinarily denied entry to the brain, as the blood vessels pervading the brain have tightly sealed walls. The resulting so-called blood-brain barrier renders a healthy brain safe from the intrusion of potentially harmful immune cells on an inflammatory tear as the result of a systemic illness or injury.

“We did find an extremely sparse population of killer T cells in the subventricular zone of young mice,” said Brunet, who is the Michele and Timothy Barakett Endowed Professor. “But in the older mice, their numbers were expanded by 16-fold.”

That dovetailed with reduced numbers of proliferation-enabled neural stem cells in the older mice’s subventricular zone. Further experiments demonstrated several aspects of the killer T cells’ not-so-mellow interaction with neural stem cells. For one thing, tests in laboratory dishware and in living animals indicated that killer T cells isolated from old mice’s subventricular zone were far more disposed than those from the same mice’s blood to pump out an inflammation-promoting substance that stopped neural stem cells from generating new nerve cells.

Second, killer T cells were seen nestled next to neural stem cells in old mice’s subventricular zones and in tissue taken from the corresponding neurogenic niche in autopsied brains of old humans; where this was the case, the neural stem cells were less geared up to proliferate.

Possible brain-based antigens

A third finding was especially intriguing. Killer T cells’ job is to roam through the body probing the surfaces of cells for biochemical signs of a pathogen’s presence or of the possibility that a cell is becoming, or already is, cancerous. Such telltale biochemical features are called antigens. The tens of billions of killer T cells in a human body are able to recognize a gigantic range of antigens by means of receptors on their own surfaces. That’s because every unexposed, or naïve, killer T cell has its own unique receptor shape.

When an initially naïve killer T cell is exposed to an unfamiliar antigen that fits its uniquely shaped receptor, it reacts by undergoing multiple successive rounds of replication, culminating in a large set of warlike cells all sharing the same receptor and all poised to destroy any cells bearing the offending antigen. This process is called clonal expansion.

The killer T cells found in old mice’s brains had undergone clonal expansion, indicating likely exposure to triggering antigens. But the receptors on those killer T cells differed from the ones found in the old mice’s blood, suggesting that the brain-localized killer T cells hadn’t just traipsed through a disrupted blood-brain barrier via passive diffusion but were, rather, reacting to different, possibly brain-based, antigens.

Brunet’s group is now trying to determine what those antigens are. “They may bear some responsibility for the disruption of new neuron production in the aging brain’s neurogenic niches,” she said.

Single cell analysis reveals T cell infiltration in old neurogenic niches, Nature (2019). DOI: 10.1038/s41586-019-1362-5 , https://www.nature.com/articles/s41586-019-1362-5

https://medicalxpress.com/news/2019-07-immune-cells-invade-aging-brains.html

In a pilot study of 14 older adults with mild cognitive problems suggestive of early Alzheimer’s disease, Johns Hopkins Medicine researchers report that a high-fat, low-carbohydrate diet may improve brain function and memory.

Although the researchers say that finding participants willing to undertake restrictive diets for the three-month study—or partners willing to help them stick to those diets—was challenging, those who adhered to a modified Atkins diet (very low carbohydrates and extra fat) had small but measurable improvements on standardized tests of memory compared with those on a low-fat diet.

The short-term results, published in the April issue of the Journal of Alzheimer’s Disease, are far from proof that the modified Atkins diet has the potential to stave off progression from mild cognitive impairment to Alzheimer’s disease or other dementias. However, they are promising enough, the researchers say, to warrant larger, longer-term studies of dietary impact on brain function.

“Our early findings suggest that perhaps we don’t need to cut carbs as strictly as we initially tried. We may eventually see the same beneficial effects by adding a ketone supplement that would make the diet easier to follow,” says Jason Brandt, Ph.D., professor of psychiatry and behavioral sciences and neurology at the Johns Hopkins University School of Medicine. “Most of all, if we can confirm these preliminary findings, using dietary changes to mitigate cognitive loss in early-stage dementia would be a real game-changer. It’s something that 400-plus experimental drugs haven’t been able to do in clinical trials.”

Brandt explains that, typically, the brain uses the sugar glucose—a product of carbohydrate breakdown—as a primary fuel. However, research has shown that in the early stage of Alzheimer’s disease the brain isn’t able to efficiently use glucose as an energy source. Some experts, he says, even refer to Alzheimer’s as “type 3 diabetes.”

Using brain scans that show energy use, researchers have also found that ketones—chemicals formed during the breakdown of dietary fat—can be used as an alternative energy source in the brains of healthy people and those with mild cognitive impairment. For example, when a person is on a ketogenic diet, consisting of lots of fat and very few sugars and starches, the brain and body use ketones as an energy source instead of carbs.

For the current study, the researchers wanted to see if people with mild cognitive impairment, often an indicator of developing Alzheimer’s disease, would benefit from a diet that forced the brain to use ketones instead of carbohydrates for fuel.

After 2 1/2 years of recruitment efforts, the researchers were able to enroll 27 people in the 12-week diet study. There were a few dropouts, and so far, 14 participants have completed the study. The participants were an average age of 71. Half were women, and all but one were white.

To enroll, each participant required a study partner (typically a spouse) who was responsible for ensuring that the participant followed one of two diets for the full 12 weeks. Nine participants followed a modified Atkins diet meant to restrict carbs to 20 grams per day or less, with no restriction on calories. The typical American consumes between 200 and 300 grams of carbs a day. The other five participants followed a National Institute of Aging diet, similar to the Mediterranean diet, that doesn’t restrict carbohydrates, but favors fruits, vegetables, low- or fat-free dairy, whole grains and lean proteins such as seafood or chicken.

The participants and their partners were also asked to keep food diaries. Prior to starting the diets, those assigned to the modified Atkins diet were consuming about 158 grams of carbs per day. By week six of the diet, they had cut back to an average of 38.5 grams of carbs per day and continued dropping at nine weeks, but still short of the 20-gram target, before rising to an average of 53 grams of carbs by week 12. Participants on the National Institute of Aging diet continued to eat well over 100 grams of carbs per day.

Each participant also gave urine samples at the start of the dietary regimens and every three weeks up to the end of the study, which were used to track ketone levels. More than half of the participants on the modified Atkins diet had at least some ketones in their urine by six weeks into the diet until the end; as expected, none of the participants on the National Institute of Aging control diet had any detectable ketones.

Participants completed the Montreal Cognitive Assessment, the Mini-Mental State Examination and the Clinical Dementia Rating Scale at the start of the study. They were tested with a brief collection of neuropsychological memory tests before starting their diets and at six weeks and 12 weeks on the diet. At the six-week mark, the researchers found a significant improvement on memory tests, which coincided with the highest levels of ketones and lowest carb intakes.

When comparing the results of tests of delayed recall—the ability to recollect something they were told or shown a few minutes earlier—those who stuck to the modified Atkins diet improved by a couple of points on average (about 15% of the total score), whereas those who didn’t follow the diet on average dropped a couple of points.

The researchers say the biggest hurdle for researchers was finding people willing to make drastic changes to their eating habits and partners willing to enforce the diets. The increase in carbohydrate intake later in the study period, they said, suggests that the diet becomes unpalatable over long periods.

“Many people would rather take a pill that causes them all kinds of nasty side effects than change their diet,” says Brandt. “Older people often say that eating the foods they love is one of the few pleasures they still enjoy in life, and they aren’t willing to give that up.”

But, because Brandt’s team observed promising results even in those lax with the diet, they believe that a milder version of the high-fat/low-carb diet, perhaps in conjunction with ketone supplement drinks, is worth further study. As this study also depended on caregivers/partners to do most of the work preparing and implementing the diet, the group also wants to see if participants with less severe mild cognitive impairment can make their own dietary choices and be more apt to stick to a ketogenic diet.

A standardized modified Atkins diet was created and tested at Johns Hopkins Medicine in 2002, initially to treat some seizure disorders. It’s still used very successfully for this purpose.

According to the Alzheimer’s Association, about 5.8 million Americans have Alzheimer’s disease, and by 2050 the number is projected to increase to 14 million people.

Jason Brandt et al. Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer’s Disease, Journal of Alzheimer’s Disease (2019). DOI: 10.3233/JAD-180995

https://medicalxpress.com/news/2019-06-low-carb-keto-diet-atkins-style-modestly.html

by Bob Yirka

A team of researchers from the University of California and Stanford University has found that the tendency to see people from different racial groups as interchangeable has a neuronal basis. In their paper published in Proceedings of the National Academy of Sciences, the group describes studies they conducted with volunteers and what they found.

One often-heard phrase connected with racial profiling is “they all look the same to me,” a phrase usually perceived as racist. It implies that people of one race have difficulty discerning the facial characteristics of people of another race. In this new effort, the researchers conducted experiments to find out if this is valid—at least among one small group of young, white men.

In the first experiment, young, white male volunteers looked at photographs of human faces, some depicting black people, others white, while undergoing an fMRI scan. Afterward, the researchers found that the part of the brain involved in facial recognition activated more for white faces than it did for black faces.

In the second experiment, the same volunteers looked at photographs of faces that had been doctored to make the subjects appear more alike, regardless of skin color. The researchers report that the brains of the volunteers activated when dissimilarities were spotted, regardless of skin color, though it was more pronounced when the photo was of a white face.

In a third series of experiments, the volunteers rated how different they found faces in a series of photographs or whether they had seen a given face before. The researchers report that the volunteers had a tendency to rate the black faces as more similar to one another than the white faces. And they found it easier to tell if they had seen a particular white face before.

The researchers suggest that the results of their experiments indicate a neural basis that makes it more difficult for people to see differences between individuals of other races. They note that they did account for social contexts such as whether the volunteers had friends and/or associates of other races. They suggest that more work is required to determine if such neuronal biases can be changed based on social behavior.

Brent L. Hughes et al. Neural adaptation to faces reveals racial outgroup homogeneity effects in early perception, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1822084116

https://medicalxpress.com/news/2019-07-neuronal-alike.html

by KERRY GRENS

In mice whose sense of smell has been disabled, a squirt of stem cells into the nose can restore olfaction, researchers report today (May 30) in Stem Cell Reports. The introduced “globose basal cells,” which are precursors to smell-sensing neurons, engrafted in the nose, matured into nerve cells, and sent axons to the mice’s olfactory bulbs in the brain.

“We were a bit surprised to find that cells could engraft fairly robustly with a simple nose drop delivery,” senior author Bradley Goldstein of the University of Miami Miller School of Medicine says in a press release. “To be potentially useful in humans, the main hurdle would be to identify a source of cells capable of engrafting, differentiating into olfactory neurons, and properly connecting to the olfactory bulbs of the brain. Further, one would need to define what clinical situations might be appropriate, rather than the animal model of acute olfactory injury.”

Goldstein and others have independently tried stem cell therapies to restore olfaction in animals previously, but he and his coauthors note in their study that it’s been difficult to determine whether the regained function came from the transplant or from endogenous repair stimulated by the experimental injury to induce a loss of olfaction. So his team developed a mouse whose resident globose basal cells only made nonfunctional neurons, and any restoration of smell would be attributed to the introduced cells.
The team developed the stem cell transplant by engineering mice that produce easily traceable green fluorescent cells. The researchers then harvested glowing green globose basal cells (as identified by the presence of a receptor called c-kit) and delivered them into the noses of the genetically engineered, smell-impaired mice. Four weeks later, the team observed the green cells in the nasal epithelium, with axons working their way into the olfactory bulb.

Behaviorally, the mice appeared to have a functioning sense of smell after the stem cell treatment. Unlike untreated animals, they avoided an area of an enclosure that had a bad smell to normal mice.

To move this technology into humans suffering from a loss of olfaction, more experiments in animals are necessary, says James Schwob, an olfactory researcher at Tufts University who has collaborated with Goldstein but was not involved in the latest study, in an interview with Gizmodo. “The challenge is going to be trying to [engraft analogous cells] in humans in a way . . . that [would] not make things worse.”

https://www.the-scientist.com/news-opinion/stem-cells-delivered-to-the-nose-restore-mices-ability-to-smell-65953


Brains of individuals with PTSD and suicidal thoughts (top) show higher levels of mGluR5 compared to healthy controls (bottom).

By Bill Hathawaymay

The risk of suicide among individuals with post-traumatic stress disorder (PTSD) is much higher than the general population, but identifying those individuals at greatest risk has been difficult. However, a team at Yale has discovered a biological marker linked to individuals with PTSD who are most likely to think about suicide, the researchers report May 13 in the journal Proceedings of the National Academy of Sciences.

Researchers used PET imaging to measure levels of metabotropic glutamatergic receptor 5 (mGluR5) — which has been implicated in anxiety and mood disorders — in individuals with PTSD and major depressive disorder. They found high levels of mGluR5 in the PTSD group with current suicidal thoughts. They found no such elevated levels in the PTSD group with no suicidal thoughts or in those with depression, with or without current suicidal thoughts.

There are two FDA approved treatments for PTSD, both of which are anti-depressants. It can take weeks or months to determine whether they are effective. That can be too late for those who are suicidal, note the researchers.

“If you have people who suffer from high blood pressure, you want to reduce those levels right away,” said Irina Esterlis, associate professor of psychiatry at Yale and senior author of the study. “We don’t have that option with PTSD.”

Esterlis said testing for levels of mGluR5 in people who have experienced severe trauma might help identify those at greatest risk of harming themselves and prompt psychiatric interventions. Also, researchers might investigate ways to regulate levels mGluR5 with hopes of minimizing suicide risk in PTSD patients, she said.

https://news.yale.edu/2019/05/13/biomarker-reveals-ptsd-sufferers-risk-suicide