Behind the new study changing how doctors view depression

You’ve seen the pharma ads saying depression may be caused by a chemical imbalance in the brain.

For years, that’s what the public was led to believe about how antidepressants work.

That they corrected a serotonin imbalance in the brain. But a big, new study debunks that theory.

It’s not that antidepressants don’t work — for millions of people, they do. It’s just that:

“Doctors don’t know exactly how they work. Patients do want to know that there is an explanation out there,” Daniel Carlat says. “And there are times when we do have to give them a shorthand explanation, even if it’s not entirely accurate.”

Today, On Point: Inside the new study changing how doctors view depression.


Daniel Carlat, chair of psychiatry at Melrose Wakefield hospital and publisher of the Carlat Psychiatry Report, part of the TuftsMedicine network. Author of Unhinged: The Trouble with Psychiatry. (@CarlatPsych)

Also Featured

Joanna Moncrieff, professor of psychiatry at University College, London. Co-author of a new metastudy confirming that the ‘serotonin theory’ of depression is wrong. (@joannamoncrieff)

Anne Harrington, professor of the history of science at Harvard University. Author of Mind Fixers: Psychiatry’s Troubled Search for the Biology of Mental Illness.

Interview Highlights

How many psychiatric drugs can we say, with confidence, we know exactly how the drugs work?   

Daniel Carlat: “That’s a good question. I mean, there are relatively few psychiatric drugs where we say we really know how they work. And those would be drugs that, for example, are used for alcoholism, for opiate use disorder, some of the anti-anxiety drugs, some of the insomnia drugs, which is to be sure, that’s a minority of the psychiatric drugs. It is true that while the drugs do work and you know, I certainly as a practicing psychiatrist, I see them working all the time. It is true that we are humbled when it comes to our actual knowledge of the mechanisms, especially of the antidepressants.”

On the study confirming the ‘serotonin theory’ of depression is wrong

Carlat: “I think it’s a very nice paper that she and her colleagues created. I mean, it’s nice to see all of this information pulled together in one place in a way that gets people talking about my favorite topic, psychiatry. So I applaud her group. I mean, why is this causing such a stir? You know, it’s kind of hard to know. I think that, yes, people have been led to believe that there is a chemical imbalance theory of depression, that they are convinced is real and that it has to do with serotonin.

“But the fact is that for years now, and you mentioned the book that I wrote, I mean, so when I was doing research for that book, I remember reading the same studies that I’m sure Dr. Moncrieff and her colleagues read, which were basically saying that there’s no direct evidence of a serotonin deficiency. So it’s not really new. I think, again, they were able to pull the data together in a nice way. That makes it very clear. So maybe that’s why it’s caused such a reaction.”

On major findings about depression from the study

Carlat: “The finding is really an artifact in a sense of how complicated the brain is. I mean, we have a brain with about 100 billion neurons and with many connections between them. And it really isn’t possible to just put a syringe in the brain and pull out fluid. So they had to use indirect measures, such as spinal fluid. Some of the studies that she reviewed actually were post autopsy studies, where kind of gruesomely they would take brains out of people who had depression in their lifetime and do those analyses. So there were a lot of findings.

“But the fact is that, you know, in psychiatry in general, the medications that we use were really discovered by accident, usually in the 1940 and 1950s. And those antidepressants were based on looking for a better antihistamine. They were tried on various patients. They were found to be extremely effective. And it was after the fact that researchers then went into the lab and tried to figure out how old drugs like imipramine or amitriptyline worked.

“And they found out, hey, you know, these drugs do, in fact, increase levels of serotonin, and norepinephrine and several other neurotransmitters. So the natural conclusion of that would be, if these drugs work and if this is what the drugs do, then depression may be related to a chemical imbalance. And I don’t think that’s a wrongheaded, you know, sort of conclusion that they made. The fact is that it really hasn’t panned out, that we’ve been able to come up with the direct evidence that we need.”

On a history of our understanding of the serotonin theory of depression

Carlat: “The 1950s and 1960s were a time when these medications that we knew were very helpful were brought into the lab, and they were able to do experiments to show that they did seem to operate on neurotransmitters. That didn’t mean that we understood that depression was caused by low serotonin, but we knew that the drugs seemed to work that way. So therefore, they thought there must be a chemical imbalance.

“But I remember I did my residency at Mass General in the early 1990s, and I remember being in seminars with really the top figures in psychopharmacology at the time. And we were all extremely skeptical of this theory. And one of the reasons is that when you give an antidepressant, and anybody who’s been on one knows this, famously there’s a delay of about two weeks before the medication works. And so if it were a simple matter of a chemical imbalance and righting that imbalance, you would think it would work pretty much right away, but it doesn’t.

“So we knew that there were some downstream effects that we knew nothing about. And more recently, you know, there’s been newer research on brain derived neurotropic factor, and changing the architecture of the brain, and changing connections between brain structures. And we’re thinking that that may have something to do with how these drugs work, but you never know. It’s such a complicated research topic, that in ten years we could be having this conversation about another paper, debunking all of those theories as well.”

On decreasing the stigma around depression

Carlat: “Biochemically, we do not know what the cause of depression is. I mean, I think one of the things that I do talk to some of my patients about and I’ve been very, very honest in my writing, is that I, too, have suffered from depression. And I remember having a very, very amazing experience taking some of these SSRI’s.

“And that two week gap that I talked about, I remember waking up two weeks after I started. I think in this case, it was Celexa many years ago, actually feeling better. And sort of the weight of the world was lifted from my shoulders. So when people wonder to me whether these medications really work, one of the things I do is, you know, to decrease stigma, and to let people know that I have had the actual experience, is to tell them that story.”

For those who haven’t received help, or are unable to receive help, what should they do?

Carlat: “They should be encouraged by the fact that there’s a lot of research going on in other modalities. So I talked about the ketamine and the psychedelics, but there’s also brain modulation techniques like transcranial magnetic stimulation, that is also very helpful. And a number of therapies. You mentioned insomnia in adolescents.

“One of the big success stories in psychotherapy is cognitive behavioral therapy for chronic insomnia. And that can be delivered actually just as effectively via an app and online as it can in person. So we’re using the newer technologies to augment the already effective methods that we’re using to help people.”

Science leaders demand crackdown on medical research fraudsters after allegations that pivotal Alzheimer’s study contained manipulated data – giving false hope to families and slowing the development of effective treatments

  • Science leaders say medical research fraudsters pose a threat to public health
  • It comes after allegations a key Alzheimer’s study contained manipulated results
  • Some have said the paper in question has led scientists down a blind alley
  • However, some neuroscientists say good researchers by far outnumber the bad 


Science leaders are demanding a crackdown on medical research fraudsters, warning that the worst offenders pose a threat to public health and should be handed prison sentences.

And they have also called for academic journals that publish dodgy data to be slapped with hefty fines if they fail to act swiftly when fakes are exposed.

The demands come after bombshell allegations that a pivotal study on the cause of Alzheimer’s disease contained manipulated results, potentially leading other scientists down a blind alley, hindering the development of effective treatments and giving false hope to patients and their families. 

It is just the latest in a string of revelations in recent months that have rocked the field of dementia research, and may see top neuroscientists face US government investigations, probes by financial authorities for misuse of public funds and deceiving shareholders, and criminal charges.

In one of the most egregious examples, allegedly falsified data led to patients on a trial risking the side effects of experimental drugs with no chance of seeing any benefit.

Some neuroscientists insist that, while deeply concerning, these problems are outweighed by the large amount of well-conducted research in the field. But others believe corruption will have significantly set back the search for an effective dementia treatment.

Importantly, doubts about some of these studies were raised almost a decade ago, The Mail on Sunday has learnt, leading many to ask why has it taken so long for problems to come to light.

The most recent study to fall under scrutiny, published in 2006, was the first to identify a protein named amyloid beta star 56 as the cause of memory loss in lab mice. 

Authored by Dr Sylvain Lesné, a rising star in Alzheimer’s research at the University of Minnesota, Minneapolis, along with his boss Professor Karen Ashe and colleagues, it went on to be cited in more than 2,000 subsequent studies carried out by other researchers looking for a drug treatment for the devastating illness. 

But some experts expressed concern that they were unable to replicate the study – a vital part of the scientific process that helps confirm findings.

More worryingly, others warned on numerous occasions that images used in the report appeared to have been faked. They alerted the journals that published the studies, yet it wasn’t until June that a warning was put on the suspect paper.

These issues were finally made public a fortnight ago when the highly respected Science magazine published a report highlighting the issues. 

The article was based on findings made by neuroscientist Dr Matthew Schrag, who had analysed Dr Lesné’s work and uncovered manipulation. The key query is around lab tests, called western blots, that feature in the papers.

 The technique is a way to detect proteins in samples of tissue or blood, and the results are presented visually, in digital photographs, as a series of parallel bars or bands.

The suspicious paper was authored by  Dr Sylvain Lesné (pictured), a rising star in Alzheimer’s research at the University of Minnesota, Minneapolis, along with his boss Professor Karen Ashe and colleagues

The suspicious paper was authored by  Dr Sylvain Lesné (pictured), a rising star in Alzheimer’s research at the University of Minnesota, Minneapolis, along with his boss Professor Karen Ashe and colleagues

In Dr Lesné’s study the tests seem to show higher levels of amyloid beta star 56 in the brains of mice that were older, with signs of memory loss. Yet critics say that scores of these images look as if they have been doctored.

Top Alzheimer’s researchers and forensic image analysis backed Dr Schrag’s findings. Some appeared to be ‘shockingly blatant’ examples of image tampering, said Professor Donna Wilcock, a dementia expert at the University of Kentucky.

Others, however, are less optimistic. 

Prominent neuroscientist Baroness Greenfield has long voiced doubts over amyloid drugs, saying the build-up of the protein in the brain is a symptom, not a cause of Alzheimer’s.

Prof Greenfield adds: ‘This study was framed as the be-all-and-end-all by scientists who believed amyloid plaque causes Alzheimer’s. People built the whole amyloid story around it. Whenever I argued that theory made no sense, multiple scientists pointed at this paper as proof I was wrong. So while my heart goes out to the researchers who spent years trying to develop this study, I also feel vindicated.’

Professor Robert Howard, a trustee of Alzheimer’s Research UK, says: ‘We mustn’t throw the baby out with the bathwater. We are only going to beat this disease through scientific study and it is vital this continues as there are a lot of people doing good work out there.’

At present there are no drugs that can fight Alzheimer’s. The first company to invent one would no doubt have a billion-dollar blockbuster on its hands – and this, says Adrian Heilbut, has incentivised misconduct. 

He agrees that ‘too much focus on amyloid’ has held back the search for other effective treatments.

Dr Bik agrees that research into other promising avenues of dementia treatment might have missed out on funding after Dr Lesné’s studies were published. 

‘It’s a setback, for sure. We should all be mad about wasted research money, but this really isn’t a unique case.’

The biggest problem, she says, is just how frighteningly common research fraud is. Which begs the question: what can be done to stop it happening in the first place?

Cardiff University neuroscientist Professor Chris Chambers agrees with Dr Bik and Richard Smith. ‘We need to levy fines at academic publishers for every instance of published fraud within their records. Fining them would motivate them to check results before publication.’

Prof Chambers also suggests journals approve studies for publication before they are carried out, on the basis of a proposal. He explains: ‘The main reason researchers fake results is because beautiful results are more likely to be published than boring results. We can solve this problem if journals evaluate study plans and then accept papers based on the quality of the plan rather than the sexiness of the results.

‘Some journals do this, but others fear that publishing science based on quality rather than flashiness will reduce their journal’s newsworthiness. The price for their arrogance is the kind of fraud we see in this case. Until we hold them accountable, it will be the public that suffers the consequences of fraud.’

Dr Elisabeth Bik, a research fraud expert who also reviewed Dr Lesne’s western blots, adds: ‘It’s quite easy to spot. Manipulating images like these is simple to do with Photoshop. You can edit out parts you don’t want.

‘Both of these things appear to have been done in this case.’

Dr Bik has now identified 14 other studies by Dr Lesné that also appear suspicious. Despite this, in the majority of cases, no action has been taken against the journals that published them. The University of Minnesota declined a request to comment by The Mail on Sunday.

Prof Ashe, a neuroscientist who runs the lab in which Dr Lesné performed his work and who is co-author of the paper, issued a statement saying: ‘Having worked for decades to understand the cause of Alzheimer’s disease, so that better treatments can be found for patients, it is devastating to discover a co-worker may have misled me and the scientific community through the doctoring of images.’

However, she went on to accuse Science magazine of misrepresenting their work and claimed that, despite the problems, the findings were valid.

Richard Smith, a former editor-in-chief of the British Medical Journal (BMJ), who has warned that research fraud is a ‘major threat to public health’, said that the case was ‘shocking but not surprising’. 

He cites research that suggests up to one in five of the estimated two million medical studies published each year could contain invented or plagiarised results, details of patients who never existed and trials that did not actually take place. He adds the problem is ‘well known about’ in science circles, yet there is a reluctance within the establishment to accept the scale of the problem.

In light of the recent debacle, he renewed calls for major changes, saying: ‘Scientific journals make vast amounts of money. If they publish fraudulent work and fail to swiftly put things right, it’s a very serious matter and they need to be held accountable. I would support fines. There also needs to be some sort of global regulator, and criminal prosecutions against those found to have carried out fraudulent research – just like there is with financial fraud.’

Dr Bik agrees that publishers seem reluctant to take responsibility. She says: ‘We need a regulator with teeth. I’ve flagged more than 6,000 studies as potentially fraudulent, but just one in six have been retracted by publishers. Without penalties and the threat of punishment, nothing will change.

‘We know if we break the speed limit in our car we’ll get fined and points on our licence, so we don’t do it. Without these rules, it would be like the Wild West on the roads.

‘The same principles apply here – publishers act with impunity because they can.’

Perhaps even more troubling is that the recent incident isn’t an isolated one.

Biotech firm Cassava Sciences has come under fire for alleged irregularities in research behind its dementia drug simufilam. The medication initially showed great promise. In early studies, two-thirds of patients who took simufilam showed improvement after a year – news that sent Texas-based Cassava’s stock soaring. The company was worth more than £4 billion last summer, according to reports.

It subsequently launched two large-scale trials, which are ongoing and aim to recruit and treat roughly 1,000 dementia patients.

Despite this, many scientists were sceptical about the results presented, claiming the studies were flawed and results ‘cherry-picked’ to show the best possible outcome. Some went further, accusing two researchers, Dr Hoau-Yan Wang of City University New York, and Cassava’s own Dr Lindsay Burns, of tampering with western blots.

Cassava hit back, claiming critics had financial conflicts of interest. Some of those making allegations have also been involved in short selling Cassava stock, a financial practice that involves betting that a company’s value will fall.

But in December the Journal Of Neuroscience issued an ‘expression of concern’ regarding one key study by the pair. 

In March another study they authored was hit with a similar warning from the journal Neurobiology Of Aging. The editors ‘did not find compelling evidence of data manipulation intended to misrepresent the results’, but admitted there were methodological errors on the paper.

The same month, journal PLOS One retracted five papers by Dr Wang, citing ‘serious concerns about the integrity and reliability of the results’.

Two of these studies, co-authored by Dr Burns, focused on the brain protein that simufilam targets. In June, science journal Alzheimer’s Research & Therapy retracted a 2017 study by Dr Wang due to concerns over some western blot images. Yet others, including the prestigious Journal Of Neuroscience, claimed they found no evidence of data manipulation.

More than a dozen journals have failed to respond in any way to concerns raised about papers by Dr Wang and colleagues.

On Wednesday the US Department of Justice launched an investigation into Cassava, looking at whether it may have defrauded investors or government agencies that funded the research. 

A Cassava spokesman said: ‘Cassava Sciences vehemently denies any and all allegations of wrongdoing,’ adding that the company ‘has never been charged with a crime, and for good reason – Cassava Sciences has never engaged in criminal conduct’.

However, scientist Adrian Heilbut, who has been tracking the case and is among the short-sellers, says that if the claims of fabrication were proved correct, then the patients on the current trial ‘are being treated with an imaginary drug that does nothing’. He adds: ‘We expect some of the researchers involved to face criminal charges.’ 

He adds: ‘We expect some of the researchers involved to face criminal charges.’

Meanwhile, another dementia medication, aducanumab, sold under the brand name Aduhelm, has also become mired in controversy.

In June last year it became the first anti-amyloid dementia treatment to be approved by US drug watchdog the Food and Drug Administration (FDA).

It was hailed as a watershed moment by the Alzheimer’s Association, America’s biggest dementia campaign group, which has pressed for the medicine to be given the green light. But three members of the FDA advisory committee subsequently resigned in protest and the regulator was accused of collaborating too closely with the drug’s maker, Biogen, sparking an internal investigation, which is ongoing.

Dr Hoau-Yan Wang (pictured), an Alzheimer's researcher, has had five papers retracted journal PLOS One over 'serious concerns about the integrity and reliability of the results’

Dr Hoau-Yan Wang (pictured), an Alzheimer’s researcher, has had five papers retracted journal PLOS One over ‘serious concerns about the integrity and reliability of the results’

One of the committee members who stepped down, Harvard professor of medicine Aaron Kesselheim, branded aducanumab ‘probably the worst drug approval decision in recent US history’. 

NHS chiefs and UK dementia charities have so far refused to back the £40,000-a-year treatment, saying more research is needed.

The key concern was that, despite early studies showing promise, in clinical trials it failed to work.

Biogen re-evaluated the data a number of times and eventually suggested there was an improvement in mental capacity among dementia sufferers – of less than one per cent. 

Professor Robert Howard, a dementia expert at University College London, says: ‘They broke the rules of how you analyse clinical trial results to make it look like there was a benefit when there wasn’t. I see this as fraudulent.’

Worryingly, safety data published in November showed that 41 per cent of patients who took the drug suffered major side effects. The most serious of these include a type of swelling and bleeding in the brain known as ARIA-E. An FDA Adverse Event Reporting System case report shows that at least one woman died from this complication. 

‘Patients have been harmed and some have died as a direct result of taking a drug that didn’t even work,’ says Prof Howard.

Despite this, Biogen is pressing on with a trial into another amyloid drug, lecanemab, while pharmaceutical giants Roche and Eli Lilly continue to develop their versions, gantenerumab and solanezumab.

All the experts we spoke to agree the controversies that have emerged in dementia research are troubling. Both Dr Lesné’s and Dr Wang’s studies were carried out in collaboration with numerous other leading names in neuroscience, and although the degree of their involvement in the alleged fraud isn’t clear, it raises questions about all of their integrity.

‘Could there be a problem with the culture in these labs? We just don’t know. That’s why it’s so concerning,’ says Professor Malcolm MacLeod, a neuroscientist at the University of Edinburgh. 

‘These things cast doubts over everyone involved.’

Prof MacLeod and other experts still hold out hope that amyloid drugs may prove beneficial. ‘There is a lot of good research in this field,’ he adds.

Alzheimer’s Research in Turmoil as Sleuths Cast Doubt on Field-Defining Paper


Sylvain Lesné Karen Ashe

  • A 2006 study published in Nature set the stage for years’ and millions of dollars’ worth of Alzheimer’s research. The paper’s images may have been doctored.
  • The findings were led by the work of neurologist Matthew Schrag and were checked by multiple experts who agreed that the images contained signs of manipulation.
  • Science magazine reported the findings in a deep-diving report, which also considered whether a compound implicated by the 2006 paper in the disease really exists.

The dominant theory about what causes Alzheimer’s disease may have been driven by data derived from falsified results and “shockingly blatant” image tampering, an in-depth investigation by Science has found.

For nearly 16 years, clinical trials on how to cure Alzheimer’s – a neurodegenerative disease that can cause memory loss, dementia and behavioural issues – have been influenced by a study published in 2006 in the journal Nature. It said that deposits of a species of amyloid beta (Aβ) – a protein – in brain tissues were the primary cause of cognitive decline, a hallmark of Alzheimer’s disease.

Alois Alzheimer, who first detected the disease in 1906, found plaques and other protein deposits in the brain of a deceased dementia patient. Several decades later, in 1984, researchers identified Aβ to be the main component of the plaques.

But the Nature paper was significant because one researcher from the group that conducted the study claimed that Aβ*56 – a previously unknown type of compounds called oligomers – was “the first substance ever identified in brain tissue in Alzheimer’s research that has been shown to cause memory impairment.”

The researchers claimed to have isolated Aβ*56 and injected it into young rats. They wrote that subsequently, the rats’ capacity to “recall simple, previously learned information – such as the location of a hidden platform in a maze – plummeted”.

The findings were described as a “smoking gun” for the amyloid theory and received widespread acclaim.

Since publication, the Nature paper has been cited in about 2,300 scholarly articles – putting it in the top five Alzheimer’s-related reports published since 2006, according to Science.

“Since then, annual [government] support for studies labelled ‘amyloid, oligomer, and Alzheimer’s’ has risen from near zero to $287 million in 2021,” the magazine said.

As the theory became more dominant and received billions of dollars in funding from the US National Institutes of Health (NIH), proponents of other potential causes of Alzheimer’s – such as immune dysfunction and inflammation – were “sidelined”.

John Forsayeth of the University of California, an expert on Alzheimer’s, told Science that the amyloid hypothesis became “the scientific equivalent of the Ptolemaic model of the Solar System”, with Earth at the centre of the universe.

Now, Science‘s investigation has found evidence suggesting that at least 70 images published by the first author of that influential 2006 paper, Sylvain Lesné, a neuroscientist at the University of Minnesota, may have been manipulated. More than 100 images related to the amyloid theory in all have been cast in doubt, the magazine reported.

These manipulations were allegedly made to show that Aβ*56 played a role in causing Alzheimer’s, the evidence suggests – whereas it may not have.

Science wrote that an independent image analyst and several top Alzheimer’s researchers reviewed the findings and concurred that the images had been tampered with.

“Some look like shockingly blatant examples of image tampering,” Science quoted Donna Wilcock, an Alzheimer’s expert at the University of Kentucky, as saying.

How was manipulation identified?

In July 2021, neurologist Matthew Schrag was a high-profile opponent of the US Food and Drug Administration (FDA)’s decision to approve a drug to treat Alzheimer’s. The drug was based on the amyloid hypothesis and Schrag felt there was “scant evidence the treatment worked”, according to a Washington Post report.

He told the newspaper then that “years of testing drugs that target amyloid had yielded a string of failures”.

“We had been hoping for a recalibration of the field,” Schrag, currently a researcher at the Vanderbilt University Medical Centre, Tennessee, said.

Soon after, Schrag was hired by an attorney who was investigating another experimental drug for Alzheimer’s, called Simufilam. This drug’s developer, Cassava Sciences, also claimed it improved cognition by targeting the amyloid deposits.

The Schrag applied his expertise to “interrogate published images about the drug and its underlying science – for which the attorney paid him $18,000”, according to Science. He was able to identify images that could have been altered or duplicated in dozens of journal articles.

The attorney, whose clients were two neuroscientists who were betting that Cassava’s shares would fall, used Schrag’s findings in a citizen petition submitted to the FDA to call into question the veracity of data in Simufilam trials. Even though the FDA ultimately rejected the petition, Cassava’s shares plummeted.

Schrag continued his investigation and found discrepancies in Lesné’s work, including in the important 2006 Nature paper.

He shared his findings with the NIH, saying his “dossier is a fraction of the anomalies easily visible on review of the publicly accessible data”. The suspect work “not only represents a substantial investment in [NIH] research support, but has been cited … thousands of times and thus has the potential to mislead an entire field of research,” he added.

He also shared his findings with Science.

A week ago, after Schrag had alerted Nature about possible manipulation in the 2006 paper, the journal added a note on the paper’s page saying it had been “alerted to concerns regarding some of the figures” in it. “Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein,” it said.

Schrag hesitated to describe Lesné’s work and the Cassava-related studies as “fraud” or misconduct. Science reported that to prove fraud, he required access to original, complete, unpublished images and raw numerical data.

“I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he said.

Elizabeth Bik, the noted science integrity consultant, told Science that the authors “appear to have pieced together pieces of photographs from different experiments.”

“The experimental results obtained may not have been consistent with the desired results, and these data may have been modified to … better fit the hypothesis,” she said.

Cassava denied wrongdoing while Lesné didn’t respond to requests for comments.

Karen Ashe, another senior author of the 2006 paper, declined via email to be interviewed or to answer written questions posed by Science. However, she posted portions of a few original, unpublished versions of photos used in the 2006 paper that don’t show the “digital cut marks Schrag had detected in the published images”.

“That suggests the markings were harmless digital artifacts,” Science wrote. “Yet the original images reveal something that Schrag and Selkoe find even more incriminating: unequivocal evidence that, despite the lack of obvious cut marks, multiple bands were copied and pasted from adjacent areas,” Science said.

Does Aβ*56 even exist?

Additionally, Science reported that there are doubts if Aβ*56 even exists. Dennis Selkoe, a Harvard University professor, said in two papers published in 2008 that he could not find Aβ*56 in human fluids or tissues. There is also scarce independent confirmation about the Aβ*56 claims.

“In science, once you publish your data, if it’s not readily replicated, then there is real concern that it’s not correct or true,” Selkoe told Science. “There’s precious little clear-cut evidence that Aβ*56 exists, or if it exists, correlates in a reproducible fashion with features of Alzheimer’s – even in animal models.”

According to Hindustan Times, a research article published in Nature Neuroscience on June 2 questioned the amyloid hypothesis entirely. Researchers found that mice that had been given a form of Alzheimer’s disease “showed damage inside neurons of the brain which occurred prior to the formation of amyloid-containing plaques”.

The paper suggested, according to the newspaper, that while researchers had assumed that amyloid plaques are a cause of Alzheimer’s disease, “it’s possible that they are a consequence of disease progression in certain cases or even coincidental”.

But Schrag and Selkoe said that the doubts about Aβ*56’s role in causing Alzheimer’s shouldn’t call the broader amyloid hypothesis into question – yet. Selkoe added, “I hope that people will not become faint-hearted as a result of what really looks like a very egregious example of malfeasance that’s squarely in the Aβ oligomer field.”

If phase 3 clinical trials of drugs targeting amyloid oligomers fail, then the hypothesis would be “very much under duress.”

But Selkoe also worried that “the Lesné episode might further undercut public trust in science during a time of increasing skepticism and attacks”. Scientists must show they can find and correct rare cases of apparent misconduct, he said.

Psilocybin may effectively treat addiction


She watched herself from the corner. She saw herself pull a pack of cigarettes from the pocket of her favorite red coat. As she lit the cigarette, she watched as the smoking silhouette broke like shattered glass. She saw a thousand versions of herself staring back at her, inhaling and exhaling cigarette smoke. In that moment, she realized that smoking just one cigarette was committing to smoking a thousand more. When the psilocybin-induced trip subsided, she vowed to never smoke again.

This is just one experience amongst participants in a clinical study at Johns Hopkins University. Researchers conducting the study planned to determine if psilocybin, a substance that induces hallucinations, could help smokers break the habit (1). 

Long before they turned their sights to addiction, the research team wondered if psilocybin could provide meaningful, spiritual experiences. In 2006, the team published that under expert supervision, psilocybin-induced mystical experiences could have long-term positive effects. Eighty percent of participants reported increased well-being two months after the study completed (2). 

“I think [that psilocybin] has an ability to change behavior in the long-term and allow people to see things through a new lens,” said Matthew Johnson, a psychiatric researcher at the Center for Psychedelic and Consciousness Research at Johns Hopkins University. “It seems that the models that people have used to define how they behave in the world can be changed.”

Studies from the 1950s and 1960s indicated that psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin were promising candidates for addiction treatment, but further study was halted in the United States when the Controlled Substances Act was passed in 1970. The act classified psychedelic substances as schedule one substances, meaning that they were considered high risk for abuse and lacked any accepted medical applications. But after the Johns Hopkins study in 2006, psychedelics research entered a renaissance. 

In 2009, Johnson and his colleagues recruited fifteen smokers to participate in a fifteen-week trial to test if psilocybin could help smokers quit (1). Participants went through a month of preparation, where a psychiatric researcher developed a strong working relationship with the participant so that they became comfortable sharing formative and difficult life experiences. They employed cognitive behavioral therapy (CBT) to get a sense of the relationship between a participant and their smoking habit, why they want to stop, and any roadblocks preventing them from quitting. 

“They also keep a smoking diary, which is used as a tool to start contemplating the situations that prompt their smoking and the effect it has on them. It raises their awareness around the role that smoking plays in their life, and we can work out methods to replace smoking with alternate activities,” said Johnson.

After the initial CBT sessions, participants had three, seven-hour, medically supervised psilocybin-induced experiences spaced out over several weeks. The participants continued CBT every week before and after their experiences with psilocybin. More than 60% of the participants were non-smokers a year later (3).

Johnson and his team later reviewed the psilocybin-induced experiences the patients had to look for any commonalities (4). While the CBT employed beforehand seemed to influence their hallucinations to center around smoking, others had more general mystical experiences like those observed in the initial 2006 study conducted at Johns Hopkins University. Whether or not the hallucinations directly addressed the participant’s smoking habit, however, did not impact smoking cessation.

“We’ve had a lot of experiences where people have spiritual or unitive type qualitative features in their experiences,” said Albert Garcia-Romeu, a psychiatric researcher at the Center for Psychedelic and Consciousness Research at Johns Hopkins University, who also contributed to this study. “Those people are also having very positive effects, even in the absence of any kind of narrative, image, or memory related to smoking. That’s consistent with biological changes we’re seeing in the brain and the way that the brain is working, not only when people are under the influence of the drug.”

Alex Kwan, a neuroscientist from Yale University who was not involved in the smoking trials, recently reported that psilocybin “rewired” neurons in mouse brains within 24 hours of taking the drug, and these changes persisted for a month (5). Researchers previously hypothesized that psilocybin’s effects are mediated by serotonin, a hormone that regulates mood. Serotonin helps send messages between neurons through spine like extensions called synapses. 

Kwan found significantly increased growth in dendritic spines, which receive messages from synapses, after exposure to psylocibin. Researchers imaged the mouse brains every day for a month, and found that spine density and length increased by about 5% in just 24 hours, and capped out at about 10% increase over the course of two weeks. This increased growth persisted 34 days after the initial treatment with psilocybin.

“In addition to the immediate effect on the brain, maybe [psilocybin] changes the plasticity in the brain, which means it can change the brain’s architecture and function in a way that then sustains and mediates prolonged changes in behavior,” said Kwan. “This is strong evidence that this drug can promote plasticity in the brain.”

Psilocybin isn’t the only psychedelic shown to change neuroplasticity. 3,4-methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, also enhances synaptic growth. The pharmaceutical company Awakn is using MDMA and derivatives they are developing in house to treat addictions to alcohol, opioids, and tobacco. 

David Nutt, chief research officer of Awakn, said that since MDMA doesn’t have the same intense, hallucinatory effect that psilocybin does, psychotherapy can be conducted while the person experiences the drug’s effect.

“That’s what makes MDMA rather different and interesting because when the brain is more malleable and most receptive, you can actually begin to get the person to engage in and think differently,” said Nutt. “It could be that MDMA turns out to be better than [psilocybin] in therapy because it actually allows you better engage with the therapist.”

Overall, Nutt thinks that psychedelics have the potential to treat the true cause of addiction: thinking patterns.

“Addiction has many different roots, but a single trunk. Cutting off one root isn’t going to cure the problem. You’ve got to cut the tree down. This approach of disrupting the kind of core phenomenology is not only novel, but it might also be better,” said Nutt.


  1. Johnson, M.W. et al. Pilot study of the 5HT2AR agonist psilocybin in the treatment of tobacco addiction. J. Psychopharmacol., 28, 983-982 (2014).
  2. Griffiths, R.R. et al. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (2006).
  3. Johnson, M.W. et al. Long-term follow-up of psilocybin-facilitated smoking cessation. Am. J. Drug Alcohol Abuse43, 55-60 (2017).
  4. Noorani, N. et al, Psychedelic therapy for smoking cessation: Qualitative analysis of participant accounts. J. Psychopharmacol., 32, 756-769 (2018).  
  5. Shao, L-X. et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo109, 2535-2544 (2021).

Giant Study Finds Viagra Is Linked to Almost 70% Lower Risk of Alzheimer’s


Usage of the medication sildenafil – better known to most as the brand-name drug Viagra – is associated with dramatically reduced incidence of Alzheimer’s disease, new research suggests.

According to a study led by researchers at the Cleveland Clinic, taking sildenafil is tied to a nearly 70 percent lower risk of developing Alzheimer’s compared to non-users.

That’s based on an analysis of health insurance claim data from over 7.2 million people, in which records showed that claimants who took the medication were much less likely to develop Alzheimer’s over the next six years of follow up, compared to matched control patients who didn’t use sildenafil.

It’s important to note that observed associations like this – even on a huge scale – are not the same as proof of a causative effect. For example, it’s possible that the people in the cohort who took sildenafil might have something else to thank for their improved chances of not developing Alzheimer’s.

Nonetheless, the researchers say the correlation shown here – in addition to other indicators in the study – is enough to identify sildenafil as a promising candidate drug for Alzheimer’s disease, the viability of which can be explored in future randomized clinical trials designed to test whether causality does indeed exist.

“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” explains computational biologist and senior author of the study, Feixiong Cheng from the Cleveland Clinic.

It’s not the first time sildenafil use has been linked with better health outcomes, with the drug previously showing promise in a range of different scientific contexts, including cancer and malaria research among others.

Here, Cheng’s team began by building over a dozen endophenotype modules, using computational techniques to map genetic factors that could hypothetically govern the manifestation of Alzheimer’s disease.

With 13 of these modules in hand, the researchers then looked at what kinds of FDA-approved drugs might hypothetically help against the identified phenotypes.

Out of over 1,600 such medications already approved by the FDA, sildenafil turned out to be one of the most promising candidates.

That might sound baffling – given the drug is so far used in the main only for treating erectile dysfunction and pulmonary hypertension – in the research community, there were already signs the sildenafil compound might have other kinds of health benefits, given its interactions with the amyloid and tau proteins implicated in Alzheimer’s pathology.

“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” Cheng says.

“We hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success… Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate.”

The hypothesis appears to be borne out by the health insurance data, with the team finding sildenafil users had a 69 percent reduced risk of Alzheimer’s disease compared to non-users – a reduction that was notably stronger than other kinds of medications also investigated in the study, including losartan, metformin, diltiazem, and glimepiride.

Of course, the researchers emphasize that none of this establishes causality, but on that front there may be other promising leads.

In separate experiments studying human brain cells in vitro to explore how sildenafil might confer protection against Alzheimer’s cognitive decline, the researchers observed that neurons treated with the drug showed elevated growth and reduced tau accumulation.

It’s early days, but those effects could well have something to do with the reduced chances of developing Alzheimer’s in the insurance cohort. To that end, it’s important to follow these leads further, the team says.

“We are now planning a mechanistic trial and a phase II randomized clinical trial to test causality and confirm sildenafil’s clinical benefits for Alzheimer’s patients,” Cheng says.

“We also foresee our approach being applied to other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis, to accelerate the drug discovery process.”

The findings are reported in Nature Aging.

Taking new aim at COVID-19

The coronavirus’s tangled strands of RNA could offer new ways to treat people who get infected.

To the untrained eye, the loops, kinks and folds in the single strand of RNA that makes up the coronavirus genome look like a jumble of spaghetti or tangled yarn. But to researchers like Amanda Hargrove, a chemistry professor at Duke University, the complex shapes that RNA takes on as it folds upon itself could have untapped therapeutic potential in the fight against COVID-19.

In a study to appear Nov. 26 in the journal Science Advances, Hargrove and colleagues have identified chemical compounds that can latch onto these 3D structures and block the virus’s ability to replicate.

“These are the first molecules with antiviral activity that target the virus’s RNA specifically, so it’s a totally new mechanism in that sense,” Hargrove said.

Even more than 18 months into the pandemic, that’s good news. We have vaccines to prevent COVID-19, but effective, easy-to-administer drugs to help people survive and recover once they’ve been infected remain limited.

The virus is receding in some parts of the world, but cases are still surging in others where vaccines are in short supply. And even in regions with easy access to vaccines, COVID-19 vaccine hesitancy means many of the world’s eight billion people remain vulnerable to infection.

To infect your cells, the coronavirus must break in, deliver its genetic instructions in the form of RNA, and hijack the body’s molecular machinery to build new copies of itself. The infected cell becomes a virus factory, reading the 30,000 nucleotide “letters” of the virus’s genetic code and churning out the proteins the virus needs to replicate and spread.

Most antivirals — including remdesivir, molnupiravir and Paxlovid, the only antiviral drugs for COVID-19 that have been FDA-approved or are in line for approval — work by binding to these proteins. But Hargrove and colleagues are taking a different approach. They’ve identified the first molecules that take aim at the viral genome itself — and not just the linear sequence of A’s, C’s, G’s and U’s, but the complex three-dimensional structures the RNA strand folds into.

When the first terrifying hints of the pandemic started to make headlines, the team including Hargrove, Blanton Tolbert from Case Western Reserve University and Gary Brewer and Mei-Ling Li from Rutgers were already investigating potential drug candidates to fight another RNA virus — Enterovirus 71, a common cause of hand, foot and mouth disease in children.

They had identified a class of small molecules called amilorides that can bind to hairpin-like folds in the virus’s genetic material and throw a wrench in the virus’s replication.

To see if the same compounds could work against coronaviruses too, first they tested 23 amiloride-based molecules against another, far less deadly coronavirus responsible for many common colds. They identified three compounds that, when added to infected monkey cells, reduced the amount of virus within 24 hours of infection without causing collateral damage to their host cells. They also showed greater effects at higher doses. The researchers got similar results when they tested the molecules on cells infected with SARS-CoV-2, the virus that causes COVID-19.

Further work showed that the molecules stopped the virus from building up by binding to a site in the first 800 letters of the viral genome. Most of this stretch of RNA doesn’t code for proteins itself but drives their production.

The region folds in on itself to form multiple bulges and hairpin-like structures. Using computer modeling and a technique called nuclear magnetic resonance spectroscopy, the researchers were able to analyze these 3D RNA structures and pinpoint where the chemical compounds were binding.

The researchers are still trying to figure out exactly how these compounds stop the virus from multiplying, once they’re bound to its genome.

When it comes to using RNA as a drug target, Hargrove says the field is still in its early stages. Part of the reason is that RNA structures are unstable. They bounce around a lot more than their protein counterparts, which makes it hard to design molecules that can interact with them in specific ways.

“The binding pocket that you’re looking for may not even be present most of the time,” Hargrove said.

What’s more, 85% of the RNA in an infected cell doesn’t belong to the virus, but to the ribosomes — cellular particles made of RNA and protein — of its human host. “There’s a sea of competition,” Hargrove said.

But Hargrove is hopeful. The first small-molecule drug that works by binding to non-ribosomal RNA directly, rather than proteins, was just approved by the FDA last August, to treat people with a devastating disease called spinal muscular atrophy. “So while there are lots of challenges, it’s not impossible,” Hargrove said.

The researchers have a patent pending on their method. They want to modify the compounds to make them more potent, and then test them in mice “to see if this could be a viable drug candidate,” Hargrove said.

This isn’t the first time that coronaviruses have caused an outbreak, and it likely won’t be the last, the researchers say. In the last two decades, the same family of viruses was responsible for SARS, which emerged in China and spread to more than two dozen countries in 2002, and MERS, first reported in Saudi Arabia in 2012.

The researchers determined that the loops and bulges of RNA they identified have remained essentially unchanged by evolution across related coronaviruses in bats, rats and humans, including the ones that caused the SARS and MERS outbreaks. That means their method might be able to fight more than just SARS-CoV-2, the virus that causes COVID-19.

Clearly, more antivirals would be valuable weapons to have, so when the next pandemic hits we’ll be better prepared. Having more drugs on hand would have another benefit: fighting resistance. Viruses mutate over time. Being able to combine drugs with different mechanisms of action would make it less likely that the virus could develop resistance to all of them simultaneously and become impossible to treat, Hargrove said.

“This is a new way to think about antivirals for RNA viruses,” Hargrove said.


The researchers collaborated across seven institutions for this study, including Rutgers University, Case Western Reserve University, Washington University School of Medicine in St. Louis, University of Nebraska-Lincoln, University of Glasgow and the University of Michigan.

This research was supported by the National Institute of General Medical Sciences (R35GM124785, GM126833), Tobacco Settlement Fund (21-5734-0010), Medical Research Council of the United Kingdom (MC_UU_12014/12), and Duke University.

CITATION: “Amilorides Inhibit SARS-CoV-2 Replication in vitro by Targeting RNA Structures,” Martina Zafferani, Christina Haddad, Le Luo, Jesse Davila-Calderon, Liang Yuan-Chiu, Christian Shema Mugisha, Adeline Monaghan, Andrew Kennedy, Joseph Yesselman, Robert Gifford, Andrew Tai, Sebla Kutluay, Mei-Ling Li, Gary Brewer, Blanton Tolbert, Amanda Hargrove. Science Advances, Nov. 26, 2021. DOI: 10.1126/sciadv.abl6096


Science Advances



Alzheimer’s nasal vaccine to enter human trials for the first time, spurring renewed hope for preventing the disease

An Alzheimer's Nasal Spray Vaccine Is About to Enter Human Trials For The  First Time - The Worldzz News

by Aria Bendix

Wed, November 24, 2021, 3:08 PM

Alzheimer’s treatments seemed like an unlikely prospect just months ago.

Drug trials tried and failed for 20 years to produce treatments that would stop the progression of the disease, and several large pharmaceutical companies abandoned the mission of developing Alzheimer’s treatments altogether. So patients’ only hopes of improvement were drugs that lessened Alzheimer’s symptoms — such as memory loss, insomnia, and loss of language or reasoning skills — for a limited time.

Now, the field of Alzheimer’s treatments may finally be opening up.

Last week, Brigham and Women’s Hospital announced it would spearhead the first human trial of a nasal vaccine for Alzheimer’s, designed to prevent or slow the disease’s progression.

The trial is small — 16 people between ages 60 and 85 with Alzheimer’s symptoms will receive two doses of the vaccine one week apart. But it builds on decades of research suggesting that stimulating the immune system can help clear out beta-amyloid plaques in the brain. The sticky plaques are a hallmark of Alzheimer’s disease. They form when pieces of the beta-amyloid protein accumulate between nerve cells, which could disrupt a person’s ability to think or recall information.

The vaccine sprays a drug called Protollin directly into the nasal passage, with the goal of activating immune cells to remove the plaque.

The concept isn’t entirely new, but it’s particularly promising now that scientists better understand how to treat the disease, Jeffrey Cummings, a brain-science professor at the University of Nevada, Las Vegas, told Insider.

“The idea of activating immune cells is becoming more and more central to the idea of treating Alzheimer’s disease,” Cummings said. He added that a nasal spray could be better at delivering Protollin to immune cells than an infusion or inhaler.

The trial results could tell us more about how to thwart the disease’s progression, since participants must be at an early stage in their illness and otherwise in good health. Before the nasal vaccine can advance to larger trials, though, researchers must demonstrate that it’s safe and determine which dose to give.

The nasal-vaccine trial comes during a prolific year for Alzheimer’s treatments.

In June, the Food and Drug Administration approved the first new Alzheimer’s drug in nearly 20 years, an antibody infusion called Aduhelm. But that approval quickly became controversial: Many scientists questioned whether the drug warranted the FDA’s green light, since it didn’t definitively improve memory or cognition in clinical trials.

Aduhelm was shown to lower the levels of sticky plaque on the brains of Alzheimer’s patients, but an FDA advisory committee determined that there wasn’t enough evidence to confirm it worked as a treatment. Part of the skepticism stemmed from the fact that the drug’s maker, Biogen, discontinued late-stage clinical trials in 2019, as it assumed the drug would fail. Then, roughly six months later, a small group of participants started to show positive results.

“Biogen stopped the trial thinking that it was futile, then followed the patients, and it turned out not to be futile — but, of course, that created a lot of controversy in the interpretation of the data,” Cummings said.

The FDA voted to approve the drug under a special accelerated pathway, which green-lights drugs that are likely to benefit patients even when there’s uncertainty about how well they work.

As many as 5.8 million Americans are living with Alzheimer’s — a leading cause of death among US adults. Nearly 122,000 Americans died of the disease in 2019, according to the latest available data.

Alzheimer’s deaths are also becoming more frequent as more Americans reach old age. From 1999 to 2019, the US mortality rate for Alzheimer’s rose 88% — from 16 deaths per 100,000 people to 30 deaths per 100,000 people. That death rate may be an underestimate, since people with cognitive decline sometimes have difficulty seeking an Alzheimer’s diagnosis or suffer from other health conditions.

But in the past five years or so, Cummings said, new technologies such as brain scans and blood tests have made it easier to confirm Alzheimer’s diagnoses and measure how well treatments are working.

“It just feels like we have turned a corner,” Cummings said.

In addition to Aduhelm, he said, a few other antibody drugs have shown promise. The pharmaceutical company Eli Lilly plans to submit data for its Alzheimer’s drug, donanemab, to the FDA by the end of the year, which puts it on track for approval in 2022. Two more companies, Biogen and Eisai, are jointly completing an FDA application for their antibody drug, lecanemab.

“These other drugs that are very like” Aduhelm appear to produce a “clinical benefit,” Cummings said.

He added: “That’s the key: Are patients better, or at least losing their cognitive capacity less rapidly, if they are treated? That seems to be true across this whole class of drugs.”

Read the original article on Business Insider

University Hospital Cleveland Medical Center Doctors Successfully Reattach Woman’s Nearly Severed Leg

n August 2020, Caroline Rarick, 18, experienced a horrific trauma. Celebrating the summer with her volleyball team on Lake Roaming Rock in Roaming Shores, Ohio, Caroline enjoyed the day jet skiing and tubing. Toward the end of the afternoon, her friend took off on the jet ski as Caroline stood on the back. A tubing rope got caught around Caroline’s right leg, just below the knee. She was yanked into the water and pulled by her leg for a short distance. After her friend stopped the jet ski, Caroline looked down and saw bone with muscle hanging from her leg.

“When I first saw it I was extremely scared,” said Caroline. “I remember seeing my bone, but I think I was in shock and didn’t completely comprehend what was going on. I didn’t feel any pain initially, but I saw the injury and I knew it was bad.”

“In case I pass out, hold me up!” Caroline told her friend as she bobbed in the water, thankfully wearing a life vest. The pair flagged down another jet skier who pulled Caroline onto his jet ski. None of them had cell phones with them on the water. As they drove toward shore, Caroline’s friend recognized a boat passing by. She knew the owner – a doctor.

They got to the boat and discovered two doctors on board – one pediatrician and one anesthesiologist. They transferred Caroline to the boat, applied a tourniquet and called 911. The doctors detected a slight pulse in Caroline’s leg, but it was growing faint because of so much bleeding.

Fighting To Save Her Leg

An ambulance arrived and rushed Caroline to UH Geauga Medical Center, about 30 miles away. That’s where Caroline’s parents met her. “The color in her leg was gone, it looked dead,” her mother Jennifer said. It was decided Caroline would be transported to UH Cleveland Medical Center, where a trauma team was already assembling. When she arrived, the the trauma team confirmed her artery was completely severed and her tibia suffered a fracture as well.

“Caroline’s injury was extremely severe. Nearly all of the tissue and muscle were pulled from her bone, called a degloving injury,” said vascular surgeon Vikram Kashyap, MD, Division Chief, Vascular Surgery, UH Harrington Heart & Vascular Institute; Alan H. Markowitz, MD Chair for Cardiac and Vascular Surgery. “She had lost a lot of blood, there was no pulse below the injury, and she could barely move her foot indicating either nerve damage or severe ischemia. The injury was severe enough that we were even considering amputation as the best course of action.”

Her team of vascular, orthopedic and plastic surgeons headed into the operating room at 10 p.m., five hours after the initial accident. “Heading into the procedure I was really scared, because I finally understood how serious it was. I was terrified I was going to wake up without a leg. I asked my dad if I was going to lose my leg and he didn’t know what to say. There was a pause and that’s when Dr. Kashyap said, ’We’re not scheduled for an amputation tonight.’ That calmed my nerves,” Caroline said.

During the initial operation, Dr. Kashyap and his team explored the wound, and performed a bypass of the severed artery in the right leg using a vein from the mid-thigh of her left leg. They released the fascia (thin casing of connective tissue) in the lower leg muscle compartments to relieve pressure. Then, pediatric plastic surgery specialist Edward Davidson, MD and the plastic surgery team performed a debridement (removal of damaged tissue or foreign objects from a wound) with coverage of the bypass.

The color returned in Caroline’s leg and her pulse strengthened. Even though the initial operation appeared successful, the odds were against Caroline returning to normal function.

The Long Road to Recovery

Caroline was in the trauma intensive care unit for four days. She was released from the hospital after 12 days. But she faced a long road to normalcy: multiple debridements, fasciotomy, a wound vac, a skin graft, she fought an infection and faced several more surgeries along the way. Her leg atrophied and most of her remaining muscle disappeared.

For months, Caroline worked with determination and dedication during physical therapy and at-home exercises. Over time, she built strength and graduated from a wheelchair to crutches and was walking independently by Christmas. In April 2021, she was cleared to attempt jogging.

Caroline missed her senior year of volleyball at Gilmour Academy, but she never lost her positivity. “Everyone always asks me how I’ve remained so positive. Honestly, when I woke up from the initial surgery and I still had my leg I was just so happy. I was just so thankful to have a leg in the first place. That has kept me going,” said Caroline. “I don’t think it would have been the same outcome if I would have gone anywhere else. I’m so thankful to the doctors and everyone at University Hospitals.”

“2020 was a devastating year for so many people due to the pandemic,” said Dr. Kashyap. “We have seen our share of challenges at UH and many caregivers have witnessed depressing outcomes in patients. I can’t tell you how gratifying it is to see Caroline recover from a life-threatening and limb-threatening accident. She has had a miraculous outcome. She has returned to essentially a normal functional state and is ready to run and participate in competitive sports! Her resilience, positive attitude and mental fortitude should be a shining example for all of us.”

Caroline is thankful to the team of doctors who saved her leg as she prepares to walk onto the campus of Indiana University in fall 2021.

UH Harrington Heart & Vascular Institute

Nationally recognized for heart and vascular care, University Hospitals Harrington Heart & Vascular Institute offers a Limb Salvage Program, one of a select number of such centers in the United States. Thanks to the limb salvage program, patients like Caroline are able to receive life-saving care.

Study identifies mechanisms by which COVID-19 can lead to Alzheimer’s disease-like dementia

A new Cleveland Clinic-led study has identified mechanisms by which COVID-19 can lead to Alzheimer’s disease-like dementia. The findings, published in Alzheimer’s Research & Therapy, indicate an overlap between COVID-19 and brain changes common in Alzheimer’s, and may help inform risk management and therapeutic strategies for COVID-19-associated cognitive impairment.

Reports of neurological complications in COVID-19 patients and “long-hauler” patients whose symptoms persist after the infection clears are becoming more common, suggesting that SARS-CoV-2 (the virus that causes COVID-19) may have lasting effects on brain function. However, it is not yet well understood how the virus leads to neurological issues.

While some studies suggest that SARS-CoV-2 infects brain cells directly, others found no evidence of the virus in the brain. Identifying how COVID-19 and neurological problems are linked will be critical for developing effective preventive and therapeutic strategies to address the surge in neurocognitive impairments that we expect to see in the near future.”

– Feixiong Cheng, PhD, Study Lead Author and Assistant Staff, Cleveland Clinic, Genomic Medicine Institute

In the study, the researchers harnessed artificial intelligence using existing datasets of patients with Alzheimer’s and COVID-19. They measured the proximity between SARS-CoV-2 host genes/proteins and those associated with several neurological diseases where closer proximity suggests related or shared disease pathways. The researchers also analyzed the genetic factors that enabled SARS-COV-2 to infect brain tissues and cells.

While researchers found little evidence that the virus targets the brain directly, they discovered close network relationships between the virus and genes/proteins associated with several neurological diseases, most notably Alzheimer’s, pointing to pathways by which COVID-19 could lead to AD-like dementia. To explore this further, they investigated potential associations between COVID-19 and neuroinflammation and brain microvascular injury, which are both hallmarks of Alzheimer’s.

“We discovered that SARS-CoV-2 infection significantly altered Alzheimer’s markers implicated in brain inflammation and that certain viral entry factors are highly expressed in cells in the blood-brain barrier,” explained Dr. Cheng. “These findings indicate that the virus may impact several genes or pathways involved in neuroinflammation and brain microvascular injury, which could lead to Alzehimer’s disease-like cognitive impairment.”

The researchers also found that individuals with the allele APOE E4/E4, the greatest genetic risk factor for Alzheimer’s, had decreased expression of antiviral defense genes, which could make these patients more susceptible to COVID-19.

“Ultimately, we hope to have paved the way for research that leads to testable and measurable biomarkers that can identify patients at the highest risk for neurological complications with COVID-19,” said Dr. Cheng.

Dr. Cheng and his team are now working to identify actionable biomarkers and new therapeutic targets for COVID-19-associated neurological issues in COVID long-haulers using cutting-edge network medicine and artificial intelligence technologies.


Cleveland ClinicJournal reference:

Zhou, Y., et al. (2021) Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimer’s Research and

Broken Heart Syndrome Linked to the Brain

A chronically stressed amygdala can prime the heart to overreact to acute stress events, a new study shows.

The paper
A. Radfar et al., “Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome,” Eur Heart J, ehab029, 2021

Takotsubo syndrome, also known as broken heart syndrome, is a rare, reversible condition with symptoms mimicking a mild heart attack. A disease that disproportionately affects women, TTS is triggered by stressful events such as bankruptcy, the death of a loved one, or divorce, and results in a weakening of the heart’s left ventricle such that it becomes temporarily misshapen.

Previous work has shown that TTS patients have elevated activity in their amygdala, a brain region involved in stress response. What has never been clear, however, is whether “this activity in the brain happens as a result of the syndrome or whether it began many years before,” says Shady Abohashem, a nuclear cardiologist at Harvard Medical School.

Abohashem and his colleagues retrospectively analyzed full-body PET/CT scans from 104 patients, most of whom had cancer and 41 of whom had developed TTS since first being scanned, and 63 individually matched controls. The team calculated ratios of the activity in each person’s amygdala to that of two brain regions that attenuate the stress response, the temporal lobe and the prefrontal cortex. Higher amygdala activity was associated with an increased risk for TTS, and among those with the condition, patients with higher ratios had developed TTS roughly two years earlier following the imaging than those with lower ratios. “We can now show that this syndrome happens as a result of chronic stress over years that makes you vulnerable to developing the syndrome more easily and sooner than [less stressed] people,” Abohashem says.

“This study confirms our suspicion that there’s a relationship between amygdala activity and future risk of Takotsubo,” says Janet Wei, a cardiologist at Cedars-Sinai Medical Center who was not involved in the work. The results, she adds, “necessitate further study to see why these patients have higher amygdala activity and how it actually regulates the acute response.”