Tag Archives: swelling

Swelling Along Brain’s Axons May Be True Culprit in Alzheimer’s Disease

Summary: The formation of plaques can cause the accumulation of spheroid-shaped swellings along axons near the amyloid plaque deposits. The swellings are caused by lysosomes, which digest cellular waste. As the swelling enlarges, it can block the transmission of signals from one area of the brain to another.

Source: Yale

The formation of amyloid plaques in the brain is a hallmark of Alzheimer’s disease. But drugs designed to reduce accumulations of these plaques have so far yielded, at best, mixed results in clinical trials.

Yale researchers have found, however, that swelling caused by a byproduct of these plaques may be the true cause of the disease’s debilitating symptoms, they report Nov. 30 in the journal Nature. And they identified a biomarker that may help physicians better diagnose Alzheimer’s and provide a target for future therapies.

According to their findings, each formation of plaque can cause an accumulation of spheroid-shaped swellings along hundreds of axons—the thin cellular wires that connect the brain’s neurons—near amyloid plaque deposits.

The swellings are caused by the gradual accumulation of organelles within cells known as lysosomes, which are known to digest cellular waste, researchers found. As the swellings enlarge, researchers say, they can blunt the transmission of normal electrical signals from one region of the brain to another.

This pileup of lysosomes, the researchers say, causes swelling along axons, which in turn triggers the devasting effects of dementia.

The swellings are caused by the gradual accumulation of organelles within cells known as lysosomes, which are known to digest cellular waste, researchers found. Image is in the public domain

“We have identified a potential signature of Alzheimer’s which has functional repercussions on brain circuitry, with each spheroid having the potential to disrupt activity in hundreds of neuronal axons and thousands of interconnected neurons,” said Dr. Jaime Grutzendler, the Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience at the Yale School of Medicine and senior author of the study.

Further, the researchers discovered that a protein in lysosomes called PLD3 caused these organelles to grow and clump together along axons, eventually leading to the swelling of axons and the breakdown of electrical conduction.

When they used gene therapy to remove PLD3 from neurons in mice with a condition resembling Alzheimer’s disease, they found that this led to a dramatic reduction of axonal swelling. This, in turn, normalized the electrical conduction of axons and improved the function of neurons in the brain regions linked by these axons.

The researchers say PLD3 may be used as a marker in diagnosing the risk of Alzheimer’s disease and provide a target for future therapies.

“It may be possible to eliminate this breakdown of the electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, independent of the presence of plaques,” Grutzendler said.

About this Alzheimer’s disease research news

Author: Bill Hathaway
Source: Yale
Contact: Bill Hathaway – Yale
Image: The image is in the public domain

Original Research: Open access.
“PLD3 affects axonal spheroids and network defects in Alzheimer’s disease” by Peng Yuan et al. Nature Communications

See also


Abstract

PLD3 affects axonal spheroids and network defects in Alzheimer’s disease

The precise mechanisms that lead to cognitive decline in Alzheimer’s disease are unknown. Here we identify amyloid-plaque-associated axonal spheroids as prominent contributors to neural network dysfunction.

Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting as electric current sinks in a size-dependent manner.

Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3—a potential Alzheimer’s-disease-associated risk gene that encodes a lysosomal protein that is highly enriched in axonal spheroids.

Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function.

Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independent of amyloid removal.

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Easton Oliverson: Little League World Series player faces swelling limiting his ability to see

Doctors told the parents that swelling in 12-year-old Easton “Tank” Oliverson’s face has increased, according to an Instagram account set up to provide updates on his recovery.

“The swelling in his face has gone up, and the doctors have told his parents that it will get worse,” the post reads. “This has limited Easton’s ability to see, creating a unique challenge for him. While we have seen a countless amount of miracles in Easton’s journey (and still are), he is still going to have hard moments like today.”

“Through it all, he still makes sure to tell everyone he talks to that he loves them. Instead of complaining, he chooses to express his love. That’s truly the kind of kid that Easton is, which is why we know he will come out of this with so much strength. Please keep praying for our buddy. We love you all!!”

The post also said that Oliverson, dressed in his Mountain Region gear, was able to watch Friday’s game between his team and Tennessee’s Nolensville Little League from his hospital room.

“This was a very emotional afternoon for him,” the post stated.

Oliverson suffered a fractured skull after falling from a bunk bed at the players’ dormitory in Williamsport, Pennsylvania, early Monday morning. His team, Utah’s Snow Canyon Little League, earned a trip to Williamsport after winning a regional championship in California.

The young athlete was airlifted to a children’s hospital in critical condition. His father told CNN that he was “fighting for his life,” with doctors saying he was just 30 minutes from death. He underwent surgery and was placed in a medically induced coma.

In the days since, Oliverson has made impressive strides toward recovery, as documented on the “miraclesfortank” Instagram account. By Wednesday, he was no longer sedated, and on Thursday, he moved out of an intensive care unit and was able to feed himself.

The Little Leaguer has received an outpouring of support from around the nation. On Saturday, Kevin Cash, the manager of the Major League Baseball’s Tampa Bay Rays, sent a heartfelt message to Oliverson.

“We’ve been keeping up with your progress and just want to let you know that you have fans that you have never met in Florida who are really rooting for you,” Cash said in an Instagram video posted to @miraclesfortank. “I remember how excited I was to have a chance to play in the Little League World Series. There’s something about baseball that brings people together. It’s like an extended family.”

“We’re here for each other to celebrate the wins and we encourage each other during challenging times. Tank, we are sending positive thoughts and well-wishes to you and the Snow Canyon Little League … Let’s do this for Tank.”

The post thanked the Rays for the message. “Thank you to the @raysbaseball for sending over this heartfelt message. The support means the world and more for Easton and his family!”

CNN’s Jason Hanna, Jason Carroll, and Carolyn Sung contributed to this report.



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Bay Area COVID cases keep swelling as pandemic persists

There’s no relief for Bay Area counties on the COVID-19 front, as the latest numbers from the state show new cases and hospitalizations driven by subvariants of the coronavirus continuing their steady climb.

The Bay Area reported about 42 new daily cases per 100,000 residents on Tuesday, up from 35 a week ago. Eight of the nine counties in the region are among those that have the highest infection rate in California, with San Francisco reporting 54 daily cases per 100,000 residents. Health officials say the actual number of infections is probably much higher because of people testing at home or not getting tested at all.

The rising count of Bay Area cases came on the same day that the death toll from COVID in the U.S. officially topped 1 million, according to data compiled by Johns Hopkins University.

The number of people hospitalized in the city with COVID-19 climbed to 76, up from 61 last week. Across the Bay Area, there were 456 people with COVID in hospitals, a number that has steadily been rising since a lull in mid-April. Alameda, Contra Costa, Santa Clara, San Mateo and Marin counties have all seen substantial increases during that time.

San Francisco’s coronavirus positive test rate is now at 11%. That’s more than twice California’s overall rate of 5%, which is the threshold infectious disease experts consider acceptable for controlling the spread of the virus and represents a dramatic increase over the low of 2.4% the city sank to after the winter omicron surge.

Dr. Susan Philip, San Francisco’s health officer, told The Chronicle last week that it’s not clear why the Bay Area is experiencing substantially higher case rates than the rest of the state, though officials think it might have to do with more infectious variants or higher levels of testing.

San Francisco public school students and staff reported 320 coronavirus cases last week, including 303 exposures where those infected were on a school site within 48 hours of showing symptoms or testing positive for the coronavirus. That is the highest figure since late January, at the tail end of the midwinter omicron surge. It also marks a 15% increase in cases at schools from the previous week.

On Friday, health officers from around the Bay Area issued a joint statement strongly urging but not requiring that residents once again mask up indoors amid the swell of COVID-19 cases and hospitalizations.

Since then, public health officials in New York City, Los Angeles County and other parts of the nation have released similar recommendations.

The BA.2 subvariant of the omicron coronavirus variant is being crowded out by its sublineage BA.2.12.1, which accounted for 47.5% of new cases in the U.S. last week, according to genomic sequencing by the Centers for Disease Control and Prevention. BA.2 made up the other half of last week’s cases, a drop from its nearly 60% proportion the previous week.

The hyper-transmissible BA.2.12.1 is believed to be behind the swell of cases causing a sharp uptick of infections in the Bay Area and other U.S. regions. Each new subvariant is 20% to 30% more infectious than its parent, experts say.

Two other subvariants — BA.4 and BA.5 — are looming on the horizon, fueling outbreaks in other parts of the world and showing signs of increased ability to evade immunity. They were recently labeled “variants of concern” by the European Centre for Disease Prevention and Control.

“The bunk that cases are not important is preposterous,” Dr. Eric Topol, executive vice president of Scripps Research, wrote in an analysis of virus variants. “They are infections that beget more cases, they beget long COVID, they beget sickness, hospitalizations and deaths.”

More than 90,000 people in California have died from COVID-19 since the start of the pandemic, with the state reporting an average of 40 new deaths a day for the past six weeks.

Deaths, a lagging indicator of pandemic trends, have leveled off in the Bay Area since the surge, in part because of increased access to treatments such as the antiviral pill Paxlovid, which is now available at most pharmacies. The figures now are a far cry from the death and devastation documented during the first two years of the pandemic.

Aidin Vaziri (he/him) is a San Francisco Chronicle staff writer. Email: avaziri@sfchronicle.com

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Mammograms pick up swelling related to the Covid-19 vaccine, study says

Then the Moderna vaccine became available to health care professionals in the city. She received her first Covid-19 shot about a week before her scheduled mammogram.

Quasha didn’t notice much of a reaction to the vaccine at first, but a couple of days before her appointment her left arm began to hurt.

Tender, swollen lumps developed under her left armpit, along with a large swelling above her collarbone — all areas where the body has lymph nodes, the body’s filters for germs.

“You have lymph nodes above and below your collarbone,” Quasha said. “You don’t want to feel those. It was scary when I felt it.”

Lymph nodes contain immune cells that help fight invaders. That’s why it made sense to Quasha that the nodes were reacting to the vaccine, building antibodies as they were designed to do. But she couldn’t be sure.

The swelling was only on the left side where she had gotten the shot — the same side as the worrisome lump. Was it a reaction to the vaccine or another sign of breast cancer?

‘It was like a wildfire’

After the ultrasound, Quasha’s radiologist was concerned. She told Quasha she considered the lump she had felt in her breast to be of little significance, but the lymph nodes that showed up as white blobs on her mammogram were another matter.

In non-pandemic times, that finding would set off alarm bells, requiring the need for further investigation, even an immediate biopsy. Yet Quasha had just had the vaccine. After talking it over with her, Quasha said her doctor decided not to do a biopsy at that time. Instead she told Quasha to come back for a follow-up ultrasound in six weeks.

Similar scenarios had been happening in mammogram centers around the country. As radiologists compared notes with colleagues, word began to spread.

“We all started talking about it, and it was like a wildfire,” said Dr. Connie Lehman, chief of breast imaging in Massachusetts General’s department of radiology.

“I cannot tell you how many women are showing nodes on mammograms and people thought it was going to be not that common,” said Lehman, who is also a professor of radiology at Harvard Medical School.

Tales of unnecessary biopsies spurred the patient care committee of the Society of Breast Imaging (SBI) to put out an advisory in January: Ask your patients about their Covid-19 status, and record the date and which arm received the vaccine. Consider that before automatically scheduling a biopsy.

“We wanted to advocate that women don’t always need to have a biopsy,” said Dr. Lars Grimm, associate professor of radiology at Duke University School of Medicine and one of the authors of the SBI advisory. “Because oftentimes the default if you see swollen lymph nodes in a patient would actually be to recommend doing a biopsy.”

Mass General’s Lehman agreed. “When you hear hoofbeats, don’t think zebra,” she said. “If a woman had a vaccine in the arm on the same side, and the lymph nodes are swollen, this is a normal biological response. It’s totally expected. It just doesn’t make sense to start imaging.”

That does not mean that women who wish to be sure about their cancer status cannot have a biopsy, Grimm stressed.

“You actually have some women who want to biopsy,” he said. “You might tell them, ‘Hey, I think this is due to your Covid vaccine, and I’m sure that it’s going to resolve in a few weeks on its own and you’re going to be fine.’ But that patient tells you, ‘I’m not going to be comfortable waiting, I want to know now.’ “

Focus on screening to save lives

For Quasha, the knowledge that many women were experiencing the same type of reaction to the vaccine was a welcome relief from worry. After a discussion with her doctor, she said she no longer needs the follow-up screening.

“I was very reassured,” Quasha said. “The point here is that there are a number of side effects from the vaccine which are not dangerous but can sometimes increase patient anxiety.”

Instead of bringing women back in for an unnecessary ultrasound, radiology centers should be focused on scheduling women who have missed or are overdue on their mammogram, Lehman said.

“We need to take care of the large percentage of women who didn’t get screened because of the shutdowns during Covid,” she said. “At Mass General alone, we failed to screen 15,000 women because of Covid, and we’re still trying to get them back in.

“This isn’t where I need to start doing axillary ultrasounds, because someone had a vaccine and the node swelled. It’s just not being practical or pragmatic or putting our patient’s needs first,” she said.

It’s not just breast cancer, Lehman stressed. Lymph nodes in other parts of the body are also reacting to the Covid-19 vaccines, causing people with other forms of cancer to undergo unnecessary procedures.

“There have been some false scares and some unnecessary biopsies because people didn’t think to ask, and they assume that the node was the cancer coming back,” she said.

What to do?

To avoid unnecessary worry, SBI recommends women schedule any routine, annual breast screening before getting the Covid-19 vaccine. If a woman has already had the vaccine, or is soon scheduled to do so, the society suggests waiting at least four to six weeks after the second dose before scheduling your appointment.

At Mass General, Lehman and her team have gone a step further. They are screening all women regardless of vaccine status, but telling those with no history of cancer that any swelling in the lymph nodes that might be connected to a Covid-19 vaccine is benign — meaning not cancerous.

“This follows the American College of Radiology recommendations that if you have a known inflammatory cause you can say it’s benign,” said Lehman, who recently published a paper on the hospital’s procedures.

“If their concern is a swelling or tenderness after the vaccine in their armpit, we suggest that they wait four to six weeks, talk to their doctor, and if it persists, then we have them come in to do an evaluation of it,” she said.

Whatever you do, experts stress, don’t skip getting your breast cancer screening when it is recommended. A study published Tuesday in the journal Radiology that followed over half a million women made the point clearly: Women who skip even one scheduled mammography screening before they are diagnosed with breast cancer have a significantly higher risk of dying.

In fact, the risk of having a fatal breast cancer within 10 years of diagnosis was 50% lower for women who had regular breast screenings, the study said.

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