Dementia, stem cell, and mental health research

This year has been a very charged one for dementia research. As many as 55 million people around the world live with a form of dementia, the most common form of which is Alzheimer’s disease.

While there are some treatments that target symptoms of dementia, such as memory loss and anxiety, there is currently no cure for Alzheimer’s disease and related neurodegenerative conditions.

One thing that would help researchers find better treatments to prevent or slow down the progression of dementia symptoms would be finding out its true cause and the mechanisms that drive it.

The ‘amyloid hypothesis’ controversy

In 2006, a study that appeared in the journal Nature lent credibility to what is now known as the “amyloid hypothesis,” which holds that an overaccumulation of beta-amyloid protein in the brain — forming sticky amyloid plaques — disrupts the communication between neurons, thus being largely responsible for the main symptoms of dementia, such as memory and thinking problems.

Since its publication, the Nature paper has been cited in over 2,200 other studies, and the amyloid hypothesis has informed the vast majority of the dementia research conducted until now.

Yet in July 2022, an assistant professor of neurology at Vanderbilt University called into question claimed that some of the images in the seminal study had been manipulated, which may affect the credibility of the amyloid theory.

While the 2006 Nature paper has not, at the time of writing, been retracted, the recent claims of scientific misconduct have caused an uproar among dementia experts, and given rise to many questions.

One question is: If the paper truly does build on inaccuracies, will this invalidate some of the findings in dementia research reported until now? Not so, some experts say.

Speaking to Medical News Today, Dr. Sara Imarisio, head of research at Alzheimer’s Research UK, explained that “the findings from the [Nature] paper were very specific and, contrary to some reports, have not significantly affected the progress or direction of research into Alzheimer’s.”

“Even for research groups who work in this particular area, findings that can’t be reproduced will be identified as controversial and lose credibility, while genuine findings will come to predominate and guide the direction of future studies.”

– Dr. Sara Imarisio

Indeed, some findings about amyloid plaques seem to hold true, as a recently developed drug, lecanemab, which attacks the accumulation of beta-amyloid in the brain, has shown clear promise in recent clinical trials, and its developers hope that the drug will be approved for use in people aged 65 years and older in the U.S. as soon as next year.

New research avenues

But scientists were already aware that beta-amyloid plaques are not the be-all and end-all of dementia research. How so? In our June 2022 podcast, we spoke with Dr. Kamar Ameen-Ali, a lecturer in biomedical science at Teesside University in the United Kingdom.

Dr. Ameen-Ali explained that the crux of the matter is this: Beta-amyloid accumulates in the brains of healthy people just as it does in those of people with dementia symptoms. What makes this protein disruptive in some cases but not others remains unclear.

This is one of the reasons why dementia research does not, and has never stopped at the amyloid hypothesis, influential as it may be.

The controversy has also meant that more and more researchers are looking into alternative or additional pathologies in Alzheimer’s disease and other forms of dementia, including the role of tau, another protein implicated in dementia, which, some experts say, may be a better indicator of Alzheimer’s disease progression.

In September, an animal study whose results appeared in PLOS Biology suggested that brain inflammation caused by a dysfunction in the blood-brain barrier may be a likely cause of Alzheimer’s disease.

“These findings may have a significant global impact on the millions of people living with Alzheimer’s disease,” Prof. Warren Harding, chair of Alzheimer’s WA, told MNT about the study.

And in November 2022, a study published in Nature argued that disruptive swelling along axons, which form the link between neurons, may be the true cause of Alzheimer’s symptoms.

One emerging treatment for dementia is stem cell therapy, thanks to the potential of stem cells — which are a kind of “blank slate” cells — to differentiate and “specialize” into cells with different functions, thus providing healthy cells to replace those that have experienced some degree of “damage.”

Stem cell research has made great strides this year, with scientists looking at the potential of stem cell treatment in many incurable or difficult-to-treat diseases.

In April 2022, for instance, a study whose findings appeared in npj Regenerative Medicine showed how implanting induced pluripotent stem cells in rats with Parkinson’s disease-like motor symptoms helped reverse those symptoms by replacing damaged neurons.

Speaking to MNT about the study results, Dr. Jeffrey Kordower, director of the ASU-Banner Neurodegenerative Disease Research Center at Arizona State University, said that they gave him “great confidence” about the treatment’s applicability in human patients in the future.

Another stem cell therapy highlight made the press in summer 2022, when the fourth, and oldest patient yet with HIV and leukemia achieved remission after receiving a stem cell transplant.

The patient, a 66-year-old man, achieved long-term remission of HIV 3 years after receiving a stem cell transplant for leukemia, which is a blood and bone marrow cancer.

“When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence. I never thought I would live to see the day that I no longer have HIV,” the patient declares in a statement for the press.

Creating embryo and brain models from stem cells

Stem cell research has also reached other intriguing and much-debated heights this year. In August 2022, two different research teams reported having successfully created embryo models in the laboratory, using not sperm and egg cells, but stem cells to do so.

The embryo models managed to develop rudimentary structures, including a beating heart, blood stem cell circulation, a head region with folds, and the beginnings of a gut tube.

They are also viable enough to allow researchers to delve deeper into the study of embryonic development. Models like these can also help researchers steer free of experiments with potential ethical implications.

Other researchers managed to create brain organoids — models of brain tissue — from stem cells in the lab. Such models can help scientists learn more about rare neurological conditions, such as microcephaly, where the size of the brain is reduced compared to that of a healthy brain.

More widely, researchers could use models of brain tissue to better understand the way in which viruses, such as SARS-CoV-2, might attack and affect the brain, and to further dementia research.

The importance of stem cell donation

Our own Managing Editor, James McIntosh, donated stem cells earlier this year to help further research on better treatments for people with blood cancers and blood disorders. James talks about his experience at length in a “Through My Eyes” personal perspective article.

When a person donates blood, they can also choose to donate stem cells, which are separated through a process called “apheresis.” It may seem like an unsettling experience, but, James wrote, it was nowhere near as scary as a first-time stem cell donor might think.

In his article, he explains how apheresis works:

“All the heavy lifting was going to be done by a cell-separating machine. The nurse inserted a needle into a vein in my left arm from which my blood was drawn into the machine. The machine then separated the blood into its separate components: red blood cells, white blood cells, plasma, and platelets. Once the blood was separated, the parts containing my precious stem cells were taken away, leaving the rest of the blood to return to me. The nurse inserted another needle into a vein in my right arm, and the blood was able to rejoin my bloodstream here from the machine.”

James encourages everyone who can to donate stem cells for treatment and research: “Stem cells are a vital part of treatment for several serious conditions while also showing a lot of potential in the development of new therapies for currently untreatable diseases. As a result, it is very important for there to be people willing to donate their stem cells. Many will be able to save lives by joining a donation register.”

Our January 2022 podcast on blood donations and transfusions further explains how blood donation works, how to prepare, what the different types of blood donation are, and why this is such a vital part of medical treatment and research.

Another research avenue that has been gaining ground in 2022 is the use of psychedelics in the treatment of anxiety and depression.

Around the world, hundreds of millions of people live with anxiety or depression, which can severely affect their quality of life.

The standard treatments for these mental health conditions include psychotherapy and cognitive behavioral therapy (CBT), as well as medications such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) — also known as “antidepressants” — which are meant to help rebalance the levels of key chemicals in the brain.

However, according to some estimates, up to 30{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of adults living with major depressive disorder have treatment-resistant depression, which does not respond to standard lines of treatment.

And around 50{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of adults with generalized anxiety disorder do not respond to first-line treatments, such as antidepressants.

In a bid to find more effective ways of addressing the symptoms of hard-to-treat depression and anxiety, researchers have turned to a sometimes-controversial line of inquiry, namely psychedelics, particularly ketamine, LSD, and psilocybin, the psychoactive compound in magic mushrooms.

What do psychedelics do?

These drugs are, for the most part, illegal in the U.S. and elsewhere, at least for personal use, but researchers can study their effects in humans under closely supervised, clinical trial conditions, and the results of some of these studies have been intriguing.

In our May 2022 podcast, we spoke to Dr. Adrian Jacques Ambrose, medical director of the Columbia Psychiatry Practice Office.

“For anxiety disorder, as well as panic disorder, there’s hyperactivation of what we call the fear network. [By this] I mean specific parts of the brain that includes the thalamus, the amygdala, the hippocampus, and the striatum,” Dr. Ambrose explained.

And since the human brain has a negativity bias — meaning it tends to hold onto negative memories and emotions — this may exacerbate the negative thinking that occurs in anxiety and depression.

Dr. Ambrose believes that standard treatments such as antidepressants may not always work “because of their lack of specificity.” In contrast, psychopharmacological treatments may be able to “rewire” the parts of the brain involved in this vicious cycle of negative thoughts.

Indeed, a study whose results appeared in JAMA Psychiatry in October 2022 concluded that ketamine can ease depression symptoms in as little as 4 hours by “updating” negative beliefs that people with severe depression hold about themselves and the future.

“We observed each patient before and after ketamine and found an early cognitive effect on beliefs about the future. Notably, patients started to show an optimism bias in belief updating 4 hours after [the] first, single infusion. At one week of treatment, the optimist bias in belief updating correlated to the clinical antidepressant effect,” says study author Dr. Liane Schmidt.

And in November, a study from NEJM found that a single, 25-milligram dose of a synthesized formulation of psilocybin also relieved the symptoms of treatment-resistant depression, although the exact way in which psilocybin acts on the brain remains unclear.

The catch

While studies such as the ones mentioned above seem to indicate that psychedelics may indeed be the way to go when it comes to severe anxiety and depression, they all come with a series of caveats.

In the JAMA Psychiatry study, the participants received ketamine infusions, which is a very specific method of administration. They also received their regular antidepressant treatment throughout the study period.

Speaking to MNT, Dr. Guochuan Emil Tsai, neuropsychiatry expert and CEO of the company SyneuRx, not involved in the study, pointed out that:

“Ketamine infusion is available but not commonly used. It’s usually reserved only for treatment-resistant depression and can only be done in facilities that offer IV infusion and can monitor patients. It would be similar to a dialysis center. Ketamine is also a Schedule III controlled substance with inherent risks.”

The NEJM study came with an even greater caveat: Although psylocibin did help reduce depression symptoms in most of the participants, about a week after the treatment, the most commonly reported side effects were suicidal ideation and intentional self-injury.

“It’s not a recreational process — it”s not like do-it-yourself self-help,” Dr. David A. Merrill, psychiatrist, and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, not involved in the study, told MNT in an interview.

“It really needs to be done with professionally trained, licensed, or certified practitioners who understand the power of these drugs to create a mind-altered state. Dissociation, even at times hallucinations, [are] part of the journey of psychedelics to open the mind to new possibilities, but that journey needs to be supported with professional help,” stressed Dr. Merrill.

So in the course of studying psychopharmacological treatments, a few questions remain: What are the safest doses and delivery methods? Do the benefits outweigh the risks? And who would most benefit from these interventions?

Our editorial team hopes that, in 2023, we may be one step closer to finding the answers to these and other questions that could transform healthcare practices for the better, and that our audience will continue to join us in our exploration of medical innovations.