ALZHEIMER'S | +80 articles

[mr peabody]

Deep sleep helps the brain to remove waste and toxic proteins linked to Alzheimer’s.

Taking out the protein garbage becomes more difficult as neurons age*

Neuroscience News | Jul 19 2019

Cells dispose of harmful “trash” through autophagy, a normal and necessary process in which aggregated proteins and dysfunctional structures are handled. If any part of this fails, waste builds up inside cells, eventually killing them. According to a new study from the Perelman School of Medicine at the University of Pennsylvania, as cells age, their ability to shed harmful refuse declines. The findings suggest that the deterioration of autophagy in aged neurons—cells that never replicate and are as old as the bodies they inhabit—could be a risk factor for a suite of neurodegenerative diseases such as ALS, Alzheimer’s, and Parkinson’s.

Using live-cell imaging of neurons from young and aged mice, Erika Holzbaur, Ph.D., a professor of Physiology, and first author Andrea Stavoe, Ph.D., a postdoctoral fellow in Holzbaur’s lab, published their study this week in eLife. The importance of autophagy was recognized in 2016 with the Nobel Prize in Physiology or Medicine.

“The current thinking among scientists is that a decline in autophagy makes neurons more vulnerable to genetic or environmental risks,” Holzbaur said. “What motivates our line of research is that most neurodegenerative diseases in which a deterioration of autophagy has been implicated, such as ALS, and Alzheimer’s, Huntington’s and Parkinson’s diseases, are also disorders of aging,”

At the start of autophagy, a component within the cell called an autophagosome, engulfs misfolded proteins or damaged structures to be degraded, essentially sequestering this waste in a biological trash bag. The autophagosome then fuses with a second cellular structure, called a lysosome, that contains the enzymes needed to breakdown the garbage, allowing the components to be recycled and reused. This elegant waste-removal stream is what keeps neurons healthy, but in its absence, neurons eventually die due to the buildup of unattended refuse.

“Think of city streets during a sanitation workers strike,” Stavoe said.

The team assessed rates of autophagy in mouse neurons during aging and identified a significant decrease in the number of autophagosomes produced, along with pronounced defects in the structure of autophagosomes produced by neurons from aged mice.

While early stages of autophagosome formation were unaffected, they found frequent stalling in their formation in aged mice, while the ones that did form were misshapen. These defects may allow the trash to accumulate at neuronal synapses. Stavoe notes that in other studies autophagosomes with misformed membranes have been observed in deceased human brain tissue from donors with neurodegenerative disease.

Importantly, turning on the protein WIPI2B in aged mice restores autophagosome formation in aged neurons, bringing the autophagy garbage-hauling process back online. This rescue is dependent on the level of activation of WIPI2B, providing insight into the biological regulation of autophagosome formation.

On the other hand, when researchers took WIPI2B out of young neurons, autophagosome formation stalled. “This stunning and complete rescue of autophagy using one protein suggests a novel therapeutic target for age-associated neurodegeneration,” Stavoe said.

*From the article here: https://neurosciencenews.com/autophagy-aging-14529/​

 

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Promising results for Focused Ultrasound Treatment of Alzheimer’s

West Virginia University | Neuroscience News | 25 Feb 2021

Focused Ultrasound targeting the hippocampus may induce an immunological healing response for those with Alzheimer’s disease.

West Virginia University scientists used MRI scans to show what happens when ultrasound waves target a specific area of Alzheimer’s patient’s brains. They concluded that this treatment may induce an immunological healing response, a potential breakthrough for a disease that accounts for up to 80% of all dementia cases.

Rashi Mehta, a researcher with the WVU School of Medicine and Rockefeller Neuroscience Institute, led the study that appears in the journal Radiology.

“Focused ultrasound is an innovative technique and new way of approaching brain diseases, including Alzheimer’s disease,” said Mehta, an associate professor in the Departments of Radiology, Neuroscience and Neuroradiology. “Novel techniques are needed for Alzheimer’s disease since traditional approaches have not proven effective.”

In 2018, WVU launched a first-of-its-kind clinical trial to explore the use of focused ultrasound to open the blood-brain barrier in early-stage Alzheimer’s patients.

“The blood-brain barrier has long presented a challenge in treating the most pressing neurological disorders,” said Ali Rezai, the executive chair of RNI and principal investigator of the clinical trial. “The ability to noninvasively and reversibly open the blood-brain barrier in deep brain areas, such as the hippocampus, offers a new potential in developing treatments for Alzheimer’s disease.”

The ultrasound targeted the hippocampus in particular because it plays a large role in learning and memory.

Mehta used MRI with contrast-enhancement dye to observe the changes that took place in the brains of three early-stage Alzheimer’s patients–ages 61, 72 and 73–who underwent the ultrasound treatment.

She observed that the dye moved along the course of draining veins following the procedure.

“This imaging pattern was unexpected and enhances our understanding of brain physiology,” she said. “The glymphatic system, which is a fluid-movement and waste-clearance system that’s unique to the brain, has been studied in animals, but there is controversy about whether this system truly exists in humans. The imaging pattern that we discuss in the paper offers evidence not only to support that the system does likely exist in humans but that focused ultrasound may modulate fluid movement patterns and immunological responses along this system.”

Mehta and her colleagues’ analysis of the MRI scans suggests that an immunological healing response may occur around the draining veins following the procedure.

Her research team included Rezai; RNI researchers Jeffrey Carpenter, Marc Haut, Manish Ranjan, Umer Najib, Paul Lockman, Peng Wang and Pierre-Francois D’haese; and Rupal Mehta from the Rush University Alzheimer’s Disease Center.

“This observation may be an important clue in understanding the physiological mechanism by which the focused ultrasound procedure modifies brain amyloid levels and might be used to treat patients with Alzheimer’s disease and other brain disorders,” she said.

Why are amyloid levels important? Unusually high amounts of this protein tend to clump together in the brains of Alzheimer’s patients, forming plaques between nerve cells and sabotaging their function. The ongoing clinical trial aims to assess whether focused ultrasound can reduce amyloid plaques in patients with Alzheimer’s disease.

This project did not involve any medications. The ultrasound itself was enough to elicit a probable immunological response. In the future, however, the treatment may make it easier to medicate the brain with more precision, even in people who don’t have Alzheimer’s disease.

“The blood brain barrier limits our ability to deliver drugs and therapeutic agents directly to the brain,” Mehta said. “Therefore, opening this barrier in patients would allow focal delivery of medications in select brain regions targeted by the procedure.”

The clinical trial–sponsored by INSIGHTEC, the manufacturer of the ultrasound device–continues.

As Mehta and her team enroll more participants, they plan to examine the treatment’s long-term effects. They want to know whether it is safe and effective for slowing–or even reversing–the progression of Alzheimer’s dementia.

So far, the results are promising. The treatment has not harmed any of the participants who have completed it.

“We are thankful to the patients who have volunteered for this trial,” Mehta said. “They are brave to undergo this procedure, which if proven effective may benefit patients with Alzheimer’s disease in the future.”

Alzheimer’s disease is the nation’s most common form of dementia, and it’s on the rise. The Alzheimer’s Association reports that 5.8 million Americans age 65 and older had Alzheimer’s dementia in 2020. By 2050, that number could rise to 13.8 million.

The focused ultrasound team at RNI is committed to improving the lives of patients with Alzheimer’s disease by pioneering advances using a truly integrated approach and the latest technologies.

Promising Results for Focused Ultrasound Treatment of Alzheimer's - Neuroscience News

Focused ultrasound targeting the hippocampus may induce an immunological healing response for those with Alzheimer's disease.

neurosciencenews.com

 

[mr peabody]

Experimental Alzheimer's drug could slow cognitive decline*

by Lauren Mascarenhas | CNN | 13 Mar 2021

Eli Lilly and Company's experimental intravenous drug Donanemab could slow the cognitive decline of patients with Alzheimer's disease, according to early clinical trial results, published in The New England Journal of Medicine on Saturday.

The study included 257 patients with early symptomatic Alzheimer's disease; 131 received Donanemab, while 126 received a placebo. The researchers found Donanemab slowed the decline of cognition and daily function in Alzheimer's patients by 32% after 76 weeks, compared to those who received a placebo.

"Taken over 18 months, that 32% slowing of decline could be noticeably impactful for Alzheimer's patients," noted Maria Carrillo, chief science officer at the Alzheimer's Association, who was not involved in the study.

'Six more months of better cognition'

"Out of 18 months, in comparison to the people that did not get the drug, these folks were declining six months slower," Carrillo said. "That's six more months of better cognition, better memories, better enjoyable times with your family."

Decline was measured using the Integrated Alzheimer's Disease Rating Scale, which measures both cognitive and functional ability, like memory and the ability to perform daily tasks.

Carrillo said the Phase 2 trial results are early but promising, and represent some of the most robust data on a single drug's ability to slow the progression of Alzheimer's disease.

"This has a lot of potential," Carrillo added. "It could be a first step towards slowing more significantly, or stopping, cognitive decline in these earlier stages, which would really be transformational for our field."

The researchers also looked at the drug's impact on the buildup of amyloid beta plaque and tau proteins, which are considered hallmarks of Alzheimer's disease.

At 52 weeks, almost 60% of participants had reached amyloid-negative status, meaning their levels were at those of otherwise healthy people. At 76 weeks, amyloid plaque levels -- measured in centiloids -- decreased by 85 centiloids more than in those who received the placebo, the researchers reported.

Patients who reached these low levels of amyloid beta plaque were taken off of Donanemab and given the placebo.

Slowing down disease

"Once these participants were cleared of amyloid in the brain, the drug was taken away, and that slowing still continued," Carrillo. "That is important because then you don't have the continued monitoring of any safety or adverse events."

Participants who received Donanemab also showed a greater reduction in the overall tau load than those who received the placebo.

Carrillo said this study was unique in that it screened participants for the presence of both amyloid beta plaque and tau before they entered the trial.

Some researchers in the field believe that "if you stop amyloid early enough, and you slow down that tau, you might be able to slow Alzheimer's," said Carrillo. "That's what this paper is trying to show, and it is one of the very first times we've seen this."

The research on Donanemab is still early, and the researchers say that longer and larger trials are needed to determine the safety and efficacy of the drug.

"We are extremely pleased about these positive findings for Donanemab as a potential therapy for people living with Alzheimer's disease, the only leading cause of death without a treatment that slows disease progression," Dr. Mark Mintun, Eli Lilly's vice president of pain and neurodegeneration, said in a January statement announcing the trial results. Mintun said additional, ongoing research would aim to replicate the findings.

No new approved treatments since 2004

The US Food and Drug Administration has not approved a new Alzheimer's drug since 2004. The experimental Alzheimer's drug aducanumab, developed by the pharmaceutical company Biogen and its Japanese partner Eisai, is currently under review by the FDA.

Many of the most promising Alzheimer's drug candidates aim to target amyloid beta plaques and tau proteins, since the buildup of these correlates with the progression of Alzheimer's disease. The goal with drugs such as Donanemab isn't to cure the disease, but to preserve a person's memory and cognition for longer.

Alzheimer's disease is the most common form of dementia, and currently affects 6.2 million Americans age 65 and older, according to the Alzheimer's Association. The US Centers for Disease Control and Prevention says that number is expected to rise to at least 14 million people by 2060.

*From the article here :

Experimental Alzheimer's drug could slow cognitive decline in patients, early results suggest

Eli Lilly and Company's experimental intravenous drug donanemab could slow the cognitive decline of patients with Alzheimer's disease, according to early clinical trial results, published in The New England Journal of Medicine on Saturday.

www.cnn.com

 

[mr peabody]

An artist's impression of amyloid plaques forming in the brain.

Novel Alzheimer's treatment clears brain plaques with light and oxygen

by Nick Lavars | New Atlas | 13 Apr 2021

Research into what causes Alzheimer's and how it might be treated involves a number of possibilities, but one scientists are continually coming back to is brain plaques playing a central role in driving the disease. It follows that researchers are investigating ways to destroy these plaques or prevent them from forming, and scientists at the University of Tokyo have come up with a novel approach to this problem involving injectable, oxygenated atoms that are activated by infrared light.

The brain plaques at the center of this study are formed by abnormal accumulations of amyloid protein, and many see these as the primary pathological cause of Alzheimer's disease. Many drugs have been designed to target the plaques, some that use antibodies to clear away the amyloid proteins and others originally developed to treat stroke.

Despite these wide-ranging efforts, many of the promising therapies have fallen short in late-stage human trials. Nonetheless, tackling amyloid in the brain is still seen as a worthwhile pursuit by many, the University of Tokyo scientists included.

The team has developed a small molecule described as a photo-oxygenation catalyst. Part of the reasoning for this descriptor is that the molecule contains oxygen atoms that can alter the chemical bonds that hold molecules together, in the same way oxygen bleach can be used for stain removal in the laundry. But instead of spilled wine, the catalyst is designed to target the folded structure of amyloid and dismantle the plaques.

But only when instructed to do so. The molecule remains inert until it is activated by near-infrared light. And once it has been kicked into action and the amyloid has been picked apart, the brain's immune cells, known as the microglia, come along and clean up the mess, clearing away the debris and leaving healthy cells behind.

The technique was studied in live mice with Alzheimer's, with the scientists injecting their molecule directly into the brains of the rodents and using a probe to shine light into their brains for half an hour each day, over the course of a week. Their brain tissue was then examined through chemical analysis which revealed a significant reduction in amyloid protein. As part of separate experiments on mouse cells grown in a dish, the microglia could be seen engulfing and breaking down the oxygenated amyloid.

With a view to one day translating their technique to human patients, the scientists also carried out additional experiments on brains donated by Alzheimer's patients, with promising results. They note that one of the problems still to overcome is refining the design of the catalyst so it can be triggered by shining light from outside the skull.

The research was published in the journal Brain.

Novel Alzheimer's treatment clears brain plaques with light and oxygen

Research into what causes Alzheimer's and how it might be treated involves a number of possibilities, but one scientists are continually coming back to is brain plaques playing a central role in driving the disease. It follows that researchers are investigating ways to destroy these plaques or…

newatlas.com

 

[mr peabody]

First report that CBD reduces plaque, improves cognition.

CBD found to reduce plaque and improve cognition in familial Alzheimer’s*

Dental College of Georgia | Neuroscience News | 9 Mar 2021

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report.

The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.

"The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s," says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia and the study’s corresponding author.

There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia investigators write in the Journal of Alzheimer’s Disease.

“Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. “But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. "There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment," Baban says. "In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system."

That up and down expression in health and disease could make IL-33 both a good biomarker and treatment target for disease, the investigators say.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Low levels of TREM2 and rare variations in TREM2 are associated with Alzheimer’s, and in their mouse model TREM2 and IL-33 were both low.

Both are essential to a natural, ongoing housekeeping process in the brain called phagocytosis, in which microglial cells regularly consume beta amyloid, which is regularly produced in the brain, the result of the breakdown of amyloid-beta precursor protein, which is important to the synapses, or connection points, between neurons, and which the plaque interrupts.

They found CBD treatment increased levels of IL-33 and TREM2 — sevenfold and tenfold respectively.

CBD’s impact on brain function in the mouse model of early onset Alzheimer’s was assessed by methods like the ability to differentiate between a familiar item and a new one, as well as observing the rodents’ movement.

"People with Alzheimer’s may experience movement problems like stiffness and an impaired gait," says Dr. Hesam Khodadadi, a graduate student working in Baban’s lab. Mice with the disease run in an endless tight circle, behavior which stopped with CBD treatment, says Khodadadi, the study’s first author.

Next steps include determining optimal doses and giving CBD earlier in the disease process. "The compound was given in the late stages for the published study, and now the investigators are using it at the first signs of cognitive decline," Khodadadi says. They also are exploring delivery systems including the use of an inhaler that should help deliver the CBD more directly to the brain. For the published studies, CBD was put into the belly of the mice every other day for two weeks.

A company has developed both animal and human inhalers for the investigators who also have been exploring CBD’s effect on adult respiratory distress syndrome, or ARDS, a buildup of fluid in the lungs that is a major and deadly complication of COVID-19, as well as other serious illnesses like sepsis and major trauma. The CBD doses used for the Alzheimer’s study were the same the investigators successfully used to reduce the “cytokine storm” of ARDS, which can irrevocably damage the lungs.

Familial disease is an inherited version of Alzheimer’s in which symptoms typically surface in the 30s and 40s and occurs in about 10-15% of patients.

CBD should be at least equally effective in the more common, nonfamilial type Alzheimer’s, which likely have more targets for CBD, Baban notes. They already are looking at its potential in a model of this more common type and moving forward to establish a clinical trial.

"Plaques as well as neurofibrillary tangles, a collection of the protein tau inside neurons, are the main components of Alzheimer’s," Morgan says. Beta-amyloid generally appears in the brain 15-20 years or more before dementia, he says, and the appearance of tau tangles, which can occur up to 10 years afterward, correlates with the onset of dementia. "There is some interplay between beta amyloid and tau that decrease the dysfunction of each," Morgan notes.

"The Food and Drug Administration is scheduled to make a ruling by early June on a new drug aducanumab, which would be the first to attack and help clear beta" amyloid, Morgan says.

*From the article here :

CBD Reduces Plaque and Improves Cognition in Model of Familial Alzheimer's - Neuroscience News

A two-week course of CBD helps normalize and restore the function of two proteins associated with reducing amyloid-beta accumulation in mouse models of familial Alzheimer's disease. CBD also reduces levels of IL-6, an immune protein associated with inflammation in Alzheimer's patients.

neurosciencenews.com

 

[mr peabody]

High doses of radiation are known to have harmful effects on our health. However, low doses,
such as those used for diagnostic CT scans, can help the body protect and repair itself.

Low doses of radiation may improve quality of life for those with severe Alzheimer’s

Baycrest’s Rotman Research Institute | Neuroscience News | 3 May 2021

Summary: Patients with severe Alzheimer’s disease experienced remarkable improvements in both behavior and cognition within days of receiving low-dose radiation treatment.

Individuals living with severe Alzheimer’s disease showed remarkable improvements in behaviour and cognition within days of receiving an innovative new treatment that delivered low doses of radiation, a recent Baycrest-Sunnybrook pilot study found.

“The primary goal of a therapy for Alzheimer’s disease should be to improve the patient’s quality of life. We want to optimize their well-being and restore communication with family and friends to avoid social isolation, loneliness and under-stimulation. Although the study was a small pilot and should be interpreted with caution, our results suggest that low-dose radiation therapy may successfully achieve this,” says Dr. Morris Freedman, scientist at Baycrest’s Rotman Research Institute, head of the division of neurology at Baycrest and senior author of the study.

The study was a clinical follow-up to a 2015 case report about a patient in hospice with Alzheimer’s disease. After being treated several times with radiation to her brain, she showed such significant improvements in cognition, speech, movement and appetite that she was discharged from the hospice to a long-term care home for older adults.

High doses of radiation are known to have harmful effects on our health. However, low doses, such as those used for diagnostic CT scans, can help the body protect and repair itself.

“Numerous neurological disorders, including Alzheimer’s disease, are thought to be caused in part by oxidative stress that damages all cells, including those in the brain. We have natural protection systems to combat the damage, but they become less effective as we get older. Each dose of radiation stimulates our natural protection systems to work harder – to produce more antioxidants that prevent oxidative damage, to repair more DNA damage and to destroy more mutated cells,” says Dr. Jerry Cuttler, a retired Atomic Energy of Canada scientist. He has been researching the effects of radiation on health for more than 25 years and is the lead author of the study.

In this study, published in the Journal of Alzheimer’s Disease, four individuals living with severe Alzheimer’s disease were given three treatments of low-dose radiation, each spaced two weeks apart. A CT scanner at Sunnybrook Health Sciences Centre was employed to provide the treatments, with the supervision and support of Dr. Sandra Black, senior scientist and neurologist, and Dr. Sean Symons, radiologist-in-chief, both at Sunnybrook.

The researchers used standardized tests and observation to record changes in the patients’ communication and behaviour after the treatment. Most importantly, they collected information (descriptions, photos and videos) from the patients’ spouse, children and caregivers.

Remarkably, three of the four individuals showed improvements within one day of the first treatment, with their relatives reporting increased alertness and responsiveness, recognition of loved ones, mobility, social engagement, mood and more.

Two days after the first treatment, the son of one of the patients reported, “When I said hello, she looked at me and said, ‘Hello dear.’ She hadn’t said this to me in years!”

The daughter of another patient noted: “I had an amazing visit with my dad this evening. I’m speechless from last night. He was excited to see me – he spoke to me right away and gave me multiple kisses – real kisses like years ago. He was clapping his hands to the music. My mom agreed it’s been years since he has done this. Everyone is amazed.”

The results of this study offer hope for those with severe Alzheimer’s disease and their loved ones. However, it is important to note that this was a small pilot study with some limitations, including missing a placebo group. Future research is needed to examine the effects of this novel therapy in larger clinical trials.

Low Doses of Radiation May Improve Quality of Life for Those With Severe Alzheimer's - Neuroscience News

Patients with severe Alzheimer's disease experienced remarkable improvements in both behavior and cognition within days of receiving low-dose radiation treatment.

neurosciencenews.com

 

[mr peabody]

‘Rejuvenating’ the Alzheimer’s Brain

KNAW | Neuroscience News | 25 May 2021

MicroRNA-132 regulates neurogenesis in the hippocampus, according to both mouse and human tissue studies. Restoring levels of microRNA-132 in mouse models of Alzheimer’s disease reduces neurogenetic deficits and restores cognitive abilities, researchers say.

Alzheimer’s disease is the main cause of dementia and current therapeutic strategies cannot prevent, slow down or cure the pathology. The disease is characterized by memory loss, caused by the degeneration and death of neuronal cells in several regions of the brain, including the hippocampus, which is where memories are initially formed.

Researchers from the Netherlands Institute for Neuroscience (NIN) have identified a small molecule that can be used to rejuvenate the brain and counteract the memory loss.

New cells in old brains

The presence of adult-born cells in the hippocampus of old people was recently demonstrated in scientific studies. It suggests that, generally speaking, the so-called process of adult neurogenesis is sustained throughout adulthood.

Adult neurogenesis is linked to several aspects of cognition and memory in both animal models and humans, and it was reported to sharply decrease in the brains of patients with Alzheimer’s disease.

Researchers also found that higher levels of adult neurogenesis in these patients seem to correlate with better cognitive performance before death.

“This could suggest that the adult-born neurons in our brain may contribute to a sort of cognitive reserve that could later on provide higher resilience to memory loss,” says Evgenia Salta, group leader at the NIN.

Therefore, researchers from the NIN investigated if giving a boost to adult neurogenesis could help prevent or improve dementia in Alzheimer’s disease.

A small molecule with big potential

Salta said, “Seven years ago, while studying a small RNA molecule that is expressed in our brain, called microRNA-132, we came across a rather unexpected observation. This molecule, which we had previously found to be decreased in the brain of Alzheimer’s patients, seemed to regulate homeostasis of neural stem cells in the central nervous system.”

Back then, Alzheimer’s was thought to be a disease affecting only mature neuronal cells, so at first glance this finding did not seem to explain a possible role of microRNA-132 in the progression of Alzheimer’s.

In this study, the researchers set out to address whether microRNA-132 can regulate adult hippocampal neurogenesis in healthy and Alzheimer’s brains. Using distinct Alzheimer’s mouse models, cultured human neural stem cells and post-mortem human brain tissue, they discovered that this RNA molecule is required for the neurogenic process in the adult hippocampus.

“Decreasing the levels of microRNA-132 in the adult mouse brain or in human neural stem cells in a dish impairs the generation of new neurons. However, restoring the levels of microRNA-132 in Alzheimer’s mice rescues neurogenic deficits and counteracts memory impairment related to adult neurogenesis,” Sarah Snoeck, technician in the group of Salta, explains.

These results provide a proof-of-concept regarding the putative therapeutic potential of bringing about adult neurogenesis in Alzheimer’s. Salta: “Our next goal is to systematically assess the efficacy and safety of targeting microRNA-132 as a therapeutic strategy in Alzheimer’s disease.”

'Rejuvenating' the Alzheimer's Brain - Neuroscience News

MicroRNA-132 regulates neurogenesis in the hippocampus, according to both mouse and human tissue studies. Restoring levels of microRNA-132 in mouse models of Alzheimer's disease reduces neurogenetic deficits and restores cognitive abilities, researchers say.

neurosciencenews.com

 

[mr peabody]

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Brain cell membranes’ lipids may play a big role in Alzheimer’s progression

American Institute of Physics | Neuroscience News | 15 Jun 2021

Summary: Study reveals the significant role lipids play in regulating the amyloid pathway protein C99 and the progression of Alzheimer’s disease.

Alzheimer’s disease is predominant in elderly people, but the way age-related changes to lipid composition affect the regulation of biological processes is still not well understood. Links between lipid imbalance and disease have been established, in which lipid changes increase the formation of amyloid plaques, a hallmark of Alzheimer’s disease.

This imbalance inspired researchers from Aarhus University in Denmark to explore the role of lipids comprising the cellular membranes of brain cells.

In Biointerphases, by AIP Publishing, the researchers report on the significant role lipids may play in regulating C99, a protein within the amyloid pathway, and disease progression. Lipids have been mostly overlooked from a therapeutic standpoint, likely because their influence in biological function is not yet fully understood.

Toxic amyloid plaques are formed within the brain when a series of enzymes cleave the protein APP, which sits within the neuronal cell membrane, to form C99, which in turn is cleaved to release the amyloid-beta peptide that can form plaques.

Both C99 and APP are able to protect themselves from cleavage by forming homodimers, a protein composed of two polypeptide chains that are identical. The interaction between C99 molecules is regulated by lipids that make up the membrane in which the protein sits.

“We showed that a change in the cholesterol content of the neuronal cell membrane can change how the C99 dimerizes,” said Amanda Dyrholm Stange, one of the authors. “Our work suggests age-related changes to cholesterol content in the membrane weakens the C99-C99 interaction, which consequently decreases the ‘protective’ effect of the dimerization process, leading to the hypothesis of why more toxic amyloid-beta peptides are released in the elderly.”

Links between lipid imbalance and disease have been established, in which lipid changes increase the formation
of amyloid plaques. This inspired researchers to explore the role of lipids in cellular membranes of brain cells.

"Therapeutics for Alzheimer’s disease have a very high failure rate, with no therapeutics developed for a very long period of time, so a novel strategy is desperately needed,” said co-author Nils Anton Berlund. “Attempting to modulate the composition of the lipid membrane would be an entirely new class of Alzheimer’s disease therapeutics but also immensely challenging without side effects.”

The researchers postulate shifting the strategy away from targeting proteins to instead targeting the lipid concentration of membranes may be worthwhile.

“We hope our work will lead the pharmaceutical/biotechnology sector to choose lipid modulation as a means for targeting in drug development, because these changes in lipid composition are linked not just to Alzheimer’s but a large host of diseases — from diabetes to cardiovascular disease,” said co-author Birgit Schiøtt. “We also hope it will lead to more research and funding toward understanding the fundamental science behind the possible regulatory roles of lipids.”​

About this Alzheimer’s disease research news​

Source: American Institute of Physics
Contact: Larry Frum – American Institute of Physics
Image: The image is credited to Amanda Dyrholm Stange, Jenny Pin-Chia Hsu, Lisbeth Ravnkilde, Nils Berglund, and Birgit Schiøtt

Original Research: Open access.
“The effect of cholesterol on the dimerization of C99–a molecular modeling perspective” by Amanda Dyrholm Stange, Jenny Pin-Chia Hsu, Lisbeth Ravnkilde Kjølbye, Nils Anton Berglund, and Birgit Schiøtt. Biointerphases​

 

[mr peabody]

Tiny cannabis capsules could help treat Alzheimer’s, MS, and TBI

Curtin University | Neuroscience News | 18 Jun 2021

A newly developed cannabidiol capsule can be absorbed by the body faster and penetrate the brain more quickly in mouse models of neurological disorders such as Alzheimer’s Disease, Multiple Sclerosis and TBI.

A team of researchers led by Curtin University has discovered a new way to improve the absorption rate of medicinal cannabis when taken orally, which could potentially be used to treat neurological disorders such as Alzheimer’s Disease, Multiple Dclerosis and Traumatic Brain Injuries in the future.

Published in the journal PLOS ONE and funded by industry partner Zelira Therapeutics, the researchers were able to create tiny capsules containing cannabinoids which, when taken orally, were absorbed by the body faster and penetrated the brain quicker in mice models with neurological diseases, than when it was delivered in liquid form.

Lead researcher, Associate Professor Ryu Takechi from the Curtin Health Innovation Research Institute (CHIRI) and the School of Population Health at Curtin University, said there has been a growing interest in the use of cannabidiol to treat various neurological diseases, but there are limitations due its poor absorption and sensitivity to light and stomach acid when consumed orally.

“Cannabidiol is found in medicinal cannabis and is a popular natural remedy for people living with neurological and metabolic diseases. Due to limitations in absorption, we aimed to design and test a new drug delivery method,” Associate Professor Takechi said.

“Our team was able to significantly improve the absorption and brain delivery of cannabidiol by administering it in a novel microcapsule form, in combination with a naturally occurring bile acid."

“With this new capsulated form, we were able to improve the brain delivery of cannabidiol remarkably by 40 times in animal models and we were also able to protect the drug from oxidation and degradation by light, which helps extend product shelf-life.”

Associate Professor Takechi said the findings may be helpful in supporting the clinical use of medicinal cannabis in the treatment of neurological disorders.

“In this study, we were able to show for the first time that a bile acid actually increased the uptake and retention of cannabidiol within the brain. This shows that bile acids, could be used to enhance the delivery of cannabidiol when taken orally, particularly when treating neurological disorders,” Associate Professor Takechi said.

“Further research is needed to test whether this type of drug delivery method could be successful in human studies, but our findings are very promising.”

Zelira CEO Dr Oludare Odumosu said he was delighted with the outcome of the collaboration with Associate Professor Takechi and his team.

“The new encapsulation technology appears to significantly improve the efficiency with which cannabinoid-based drugs can be delivered into the brain. This could lead to improvements in the effectiveness of cannabinoid therapies to treat neurological disorders while reducing cost and enhancing safety,” Dr Oludare Odumosu said.

Tiny Cannabis Capsules Could Help Treat Alzheimer's, MS, and TBI - Neuroscience News

A newly developed cannabidiol capsule can be absorbed by the body faster and penetrate the brain more quickly in mouse models of neurological disorders such as Alzheimer's disease, multiple sclerosis and TBI.

neurosciencenews.com

 

[mr peabody]

Strawberries are a great source of flavonoids.


Eating foods high in flavonoids could slow cognitive decline, study

by Megan Marples | CNN | 28 Jul 2021

Eating a plate full of colorful foods like strawberries and peppers, which include flavonoids, could slow your cognitive decline, a new study found.

People who ate about 600 milligrams (0.02 ounces) of flavonoids per day had a 20% lower risk of cognitive decline than those who ate only 150 milligrams (0.005 ounces) per day, according to the study published Wednesday in the American Academy of Neurology journal.

A 100-gram (3.5-ounce) serving of strawberries has about 180 milligrams (0.006 ounces) of flavonoids, while an apple has about 113 milligrams (0.003 ounces), the study said.

Flavonoids are a series of compounds with strong antioxidant abilities that are commonly found in many fruits and vegetables, said study author Dr. Walter Willett, professor of epidemiology and nutrition at the Harvard T.H. Chan School of Public Health and professor of medicine at Harvard University in Cambridge, Massachusetts.

"Damage to the "blood supply to the brain is an important contributor to cognitive decline," said Willett, adding "the anti-inflammatory properties of flavonoids help protect that blood supply, which in turn slows down the cognitive decline."

"Cognitive decline can lead to diseases like dementia and Alzheimer's," he added.

The study spanned nearly a quarter of a century and had about 75,000 participants. The average age of the participants at the start of the study was 50, and they are now in their 70s and 80s, Willett said.

People's brain functions begin to decline in our 20s and 30s, but we usually don't notice it until we reach our 70s, he said. Eating foods high in flavonoids could make the downward slope less steep, he added.

"After tracking the participants' diets over 20 years, researchers had them answer a questionnaire multiple times over a four-year period to determine cognitive decline," Willett said.

Each person's cognitive decline was calculated with six yes or no questions. Questions included "Do you have more trouble than usual remembering a short list of items, such as a shopping list?" and "Do you have trouble remembering things from one second to the next?"

Because the study took place over decades, the results are much more valid than other studies that occur over a couple years, said Dr. Daniel Potts, a fellow of the American Academy of Neurology and attending neurologist at the US Department of Veterans Affairs in Tuscaloosa, Alabama, who was not involved in the study.

"Cognitive decline is something that takes place slowly, so when you're assessing it, you're able to pick up subtle changes better over a long period of time," he said.

How to eat more flavonoids

Willett said there isn't a specific number of flavonoids people should eat each day, and they shouldn't be counted or measured.

Additionally, eating flavonoids only plays a small role in potentially slowing down cognitive decline, he said. People should live a healthy lifestyle as well, he noted, which includes regular physically activity and not smoking.

The Mediterranean diet has been shown to be effective in the preservation of cognitive function, Potts said, and many of the foods featured in the diet are high in flavonoids.

"Nutrition has a lot to do with our cognitive health, and the choices that we make today concerning the things we consume have a big role to play later in life in protecting our brains," he said.

Some fruits high in flavonoids include strawberries, blueberries and oranges, he said. Peppers and celery are some vegetables with high amounts of the compound, he added.

Current Events, Politics, and Science

Serious discussion of politics, science, and technology

www.bluelight.org

 

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Could psychedelics help treat dementia?

These ancient healing compounds could offer benefits to people with dementia.

by Daniel R. George, Ph.D., M.Sc. & Devon Frye | Psychology Today | 3 Jan 2022​

• Psychedelics and guided therapy may benefit the treatment of depression, anxiety, substance use disorder, and PTSD.​
• Success of preliminary studies have led researchers to imagine a potential role for psychedelics in skilled nursing care settings.​
• Some believe psychedelics may potentially be used in ways that improve cognition, mood, and quality of life for people living with dementia.​
• Ongoing studies must investigate questions regarding proper dosages, safety and supervision, ethics around consent, and other critical issues.​

After being banned internationally in the 1970s, psychedelics have experienced a recent resurgence in Western medical research. What do we know? And could these powerful ancient compounds be integrated into care for people living with dementia?
​

Current research​

A small but growing evidence base suggests that “classical” psychedelics like psilocybin, LSD, DMT, as well as compounds like MDMA and ketamine may be effective therapies in controlled medical settings, with researchers observing preliminary benefits in the treatment of depression, anxiety, substance use disorder, PTSD, and in palliative care for patients facing terminal cancer.

The mechanisms underlying these benefits remain somewhat nebulous. However, the compounds are generally believed to contribute to greater cognitive flexibility and increased communication across brain regions. Given that many mental health conditions are marked by persistently inflexible patterns of thought, feeling, and behavior, treatments that disrupt the neural systems that encode and overdetermine such patterns and provide opportunities for people to “rewire their brains” in ways that provide long-term relief is compelling.

Indeed, research strongly suggests that it is not the mere drug itself that matters as much as the supportive presence of a “guide” who can help the patient interpret and integrate their experience and develop new habits of mind within a therapeutic window of greater openness. (For a deeper dive into the ancient shamanic roots of this dynamic, see this recent paper).
​

New directions for psychedelics—including dementia care​

The success of preliminary studies has served to re-legitimate psychedelic research in Western medicine.

Treatments are now being explored for patients with conditions such as eating disorders, migraine and cluster headaches, and opioid addiction. Some researchers, including our colleagues at Johns Hopkins Center for Psychedelics and Consciousness Research, have begun exploring whether there may be benefits for people living with dementia.

From a cognitive perspective, there is some evidence that the neuroplastic/anti-inflammatory properties of psychedelics can potentially confer benefits for those with progressive neurodegenerative illness. Given the 100 percent fail-rate of anti-Alzheimer’s drugs over the past several decades—especially those narrowly targeting beta-amyloid—such out-of-the-box thinking is welcome.

However, as we have previously addressed, it is unlikely that a heterogeneous, age-related syndrome like Alzheimer’s is itself “curable,” and it is important to not over-inflate the clinical potential for treatments like psychedelics. Instead, we might think more imaginatively about how these treatments could yield benefits adjacent to cognition—for instance, supporting the psychosocial wellbeing of older adults living in long-term care.
​

Helping to treat agitation, behaviors, and delirium?​

Those who work in skilled-care settings are intimately familiar with the limitations of current pharmaceuticals in managing resident behaviors. Our aging Western cultures are facing a massive crisis involving the overuse of anti-psychotics, with 1 in 5 nursing home residents currently subjected to this class of drugs to treat agitation, behaviors, and delirium.

Whereas anti-psychotics have proven largely ineffective and quite dangerous, it has been proposed that micro-doses of psychedelic treatments that disrupt ego and allow temporary unbinding from acute physical/mental suffering (as well as inflexible, habitual patterns of cognitive activity) could theoretically help foster greater calmness in people living with dementia.

In light of the deleterious consequences of anti-psychotics, investigating the potential mood-altering effects of psychedelics—which are generally well-tolerated, non-addictive, and non-hallucinatory at low dosages—would appear a valuable direction for inquiry.
​

Enhancing the benefits of the arts?​

One irony in the dementia field is that while drugs have failed spectacularly despite billions of dollars of investment, one consistently effective “intervention” in long-term care is the arts. Storytelling, music, dance, gardening, pet therapy, and other activities we often jokingly call “socialceuticals” (since they are almost comically superior to current drugs for dementia) connect to the quintessential humanity of the cognitively frail, allowing for rich expression, the forging of bonds with caregivers, and improved QOL.

Psychedelics, of course, are known for their capacity to enhance sensorial experiences, elicit feelings of the sacred, sublime, and numinous, and deepen a sense of unity and inter-connection. It is thus worthwhile considering whether micro-dosages of psychedelic compounds could, in long-term care settings, help deepen the qualitative experience of “socialceuticals” like listening to or singing songs, observing nature, engaging with art works, interacting with animals, or bonding with other residents.
​

The future​

Obviously, in the absence of data, the promise of psychedelics is, at present, mostly speculative or theoretical. Much must be learned about proper dosages, safety and supervision protocols, ethics around consent, how to address adverse reactions, staff training, and other questions that crop up around modern treatment regimens for these ancient compounds.

We must also be cautious of market forces—specifically, companies, entrepreneurs, and bad actors with vested interests who hype treatments as quick-fix commodities. Thankfully, rigorous studies are being undertaken internationally, and what we learn in the next decade should help light the path forward (or not).

In the meantime, we can still, as citizens, bring the arts into long-term care environments—and also to our elder relatives in general—and help provide the “altered states” that we know are protective, enjoyable, and supportive of QOL for all of us.

We have written more extensively about this subject in our latest book, American Dementia: Brain Health in an Unhealthy Society.

Could Psychedelics Help Treat Dementia?

These ancient healing compounds could offer benefits to people with dementia.

www.psychologytoday.com

 

[mr peabody]

Psychedelics and the Treatment of Alzheimer’s

by Haley Noble | Reality Sandwich | 20 Jun 2021

For many, the struggles associated with aging are an inevitable part of life. Similarly, watching loved ones grow old can includes transitioning into the role of caretaker and taking on new responsibilities. Sometimes, part of this journey can include navigating the trials of Alzheimer’s — an incurable disease that tends to worsen over time. The stress that this disease puts on patients and their families has researchers searching for novel treatments. Inspired by psychedelics’ success in treating other neurological disorders, the medical community is beginning to explore the potentials of psychedelics as a treatment for Alzheimer’s.

What is Alzheimer’s?

Alzheimer’s disease is a neurological disorder that damages the brain’s cognitive and memory abilities. Over time, Alzheimer’s progressively affects more and more of a person’s functioning. A feature of Alzheimer’s disease is the presence of dementia. Dementia is a general term for loss of cognitive functioning to the extent that daily activities are affected. People’s range of functioning varies based on their dementia severity. Though Alzheimer’s is not the only cause of dementia, it is the most common — affecting roughly 6 million Americans alone.

Alzheimer’s can begin affecting the brain a decade before cognitive or behavioral symptoms present themselves. This is because Alzheimer’s disease produces an excess of protein deposits — specifically, amyloid proteins and tangles of neurofibrillary proteins. Amyloid proteins are abnormal proteins originating in the bone marrow that cause buildup on organs. In Alzheimer’s patients, the amyloid deposits clump between neurons, stopping their ability to communicate with each other.

The neurofibrillary tangles hijack neuron’s production of tau proteins, causing these proteins to stick together in dense tangles rather than attaching to the structural microtubules within the cell. The tangles disrupt the cell from within, hindering neural transport to and from the synapse.

The specific structural brain changes associated with Alzheimer’s disease are thought to exist because of the unique interplay of these two proteins. The clumps of abnormal amyloid proteins bunch into the synaptic space of neurons in areas of the brain associated with memory. There appears to be a tipping point, where enough blocked synapses trigger rapid production of tau protein tangles within the cells. Eventually, by working together these proteins cause the neuron to die off. Enough dead neurons in one area and the region is unable to function and shrinks.

Brains affected by Alzheimer’s are also unable to execute proper cleaning procedures. The brain has specific glial cells, responsible for clearing out debris and pruning off protein deposits. Researchers are unsure why or how Alzheimer’s hinders the glial cells from performing their cleaning duties, but the result is further neural damage as the glial cells build-up and release inflammatory chemicals. The protein build-ups also affect blood flow to the brain, giving Alzheimer’s patients higher chances for stroke and increased neural death.

The first area of the brain affected by Alzheimer’s is the hippocampus —the seahorse-shaped tube responsible for memory and learning — and the nearby entorhinal cortex — part of the temporal lobe responsible for navigation and perception of time. The initial damage to these areas presents as symptoms of memory loss and confusion characteristic of early-stage Alzheimer’s.

Alzheimer’s disease affects patients differently and changes over time as more areas of the brain atrophy. Usually, people present with Alzheimer’s in their mid-60’s though early-onset cases make up about 10% of diagnoses. Early and mild stages can involve loss of word-finding abilities and general confusion, while more moderate stages often involve delusions and paranoia.

For caregivers and loved ones, Alzheimer’s can be incredibly challenging to manage as the person suffering loses their ability to relate to the world around them. Doctors are desperate for revolutionary treatment approaches, but let’s take a look at what is available now.

Current treatments available

The current treatment approaches aim to help people with Alzheimer’s maintain cognition, behavioral function and hopefully slow down memory loss. The hope is to find treatments addressing the root causes of the disease but at the moment there are no preventative solutions.
FDA approved pharmaceutical medications work to treat Alzheimer’s in two ways: Cholinesterase inhibition and glutamate signaling.

Cholinesterase inhibitors, like Donepizel or Exelon, are commonly prescribed for moderate or mild Alzheimer’s cases. One of the ways that this disease harm’s the brain is by decreasing the production of acetylcholine, a key neurotransmitter for alertness, memory and judgment. By blocking the production of cholinesterase, a protein that breaks down acetylcholine, the medications try to keep acetylcholine available in the synapse. This does not stop the progression of Alzheimer’s, as over time the neurons are unable to produce enough acetylcholine for the medication to be of help.

For late-stage Alzheimer’s, medications containing Memantine, work to balance levels of glutamate in the brain. Glutamate is an important excitatory neurotransmitter, the key to opening many different metabolic pathways in the brain. In Alzheimer’s patients, the glutamate system can be overactive, causing toxicity that damages the brain. However, glutamate is still an essential part of learning and memory so the hope is that by balancing the brain’s glutamate levels, Alzheimer’s patients can retain cognitive function.

Both of these medication options have modest effects at best, making the demand for new Alzheimer’s treatments incredibly high. As researchers work to tackle the many different mechanisms by which Alzheimer’s damages the brain, psychedelics begin to present as a viable treatment option.

Psychedelics as treatment

The schedule one listing of most psychedelic substances at the beginning of the 1970s halted the exploration of psychedelics as treatments for decades. As the culture shifts, respected institutions realize that the legalization of psychedelics may have been more politically motivated than associated with potential risks related to these substances.

Researchers at Johns Hopkins University, believe that psychedelics have the ability to change not only brain function but structure. The human brain comprises more than 10 billion neurons. Psychedelics pose the potential to change how the branches of these neurons structure areas of the brain, promoting adaptive neuroplasticity. Apart from structural change, psychedelics can also influence the way different parts of the brain communicate with each other.

Inspired by these findings and the success of psilocybin in animal trials aiming to improve memory processes, Johns Hopkins researchers are currently conducting a clinical trial of psilocybin treatments for early-stage Alzheimer’s. Their plan — put on hold for a year due to the global pandemic — is to administer 2 large doses of psilocybin to around 20 participants with no placebo. The goal is to look for changes in mood and memory over the following months.

Researchers in the UK identified the commonalities between the success of psychedelic treatments for neurological disorders like depression and its promise as an Alzheimer’s treatment. Psychedelics like psilocybin and LSD have the potential to stimulate neurogenesis, promote neuroplastic change and reduce inflammation. These are all helpful tools in combating the degeneration associated with Alzheimer’s disease.

Aside from treating the disease, many Alzheimer’s patients suffer from depression and anxiety. Not only does this affect their quality of life, but some studies show that both of those cognitive patterns can adversely affect memory down the line. Psychedelics’ ability to treat depression and anxiety may be able to help improve the quality of life and memory retention of Alzheimer’s patients.

There are currently no definitive answers about psychedelics’ ability to treat Alzheimer’s, but researchers are hopeful for answers in the next few years as clinical trials conclude. The demand for new and innovative treatments continues to grow as new generations of people experience the loss of Alzheimer’s. The willingness to see psychedelics as a solution can bring new hope to families around the world.

Psychedelics as a Treatment for Alzheimer's | Reality Sandwich

Inspired by the success in treating neurological disorders, research is now looking into psychedelics as a treatment for Alzheimer's.

realitysandwich.com

 

[mr peabody]

​

Silo Pharma, Columbia University to develop psychedelic therapeutics for Alzheimer’s Disease*

Psilocybin Alpha | 27 Oct 2021

Silo Pharma, a development-stage biopharmaceutical company focused on the use of psychedelics as a therapeutic, today announced that it has entered into a sponsored research agreement with Columbia University pursuant to which Silo has been granted an option to license certain assets currently under development, including Alzheimer’s disease.

This agreement incorporates the work of Dr. Christine Ann Denny, an Associate Professor of Clinical Neurobiology (in Psychiatry) at Columbia University Irving Medical Center. Denny and her team are focusing their efforts on the molecular mechanisms underlying learning and memory, including diseases such as Alzheimer’s disease. An estimated 5.8 million Americans, including one in ten people, age 65 and older, currently live with Alzheimer’s disease. Dr. Denny’s pioneering research into whether ketamine and the novel inventions that may be licensed by Silo may improve memory retrieval, halt, or even reverse, the process of Alzheimer’s disease-related to memory loss or cognitive aging, could have life-altering implications for people suffering with everything from Alzheimer’s disease to post-traumatic stress disorder (PTSD).

Eric Weisblum, CEO of Silo Pharma stated “We are excited to partner with Dr. Denny and Columbia University, a world-renowned institution that is at the forefront of research and development in this area. To be able to bring hope and possibly a therapeutic to patients suffering from Alzheimer’s disease is an exciting proposition for Silo Pharma. The unique compounds being developed at Columbia have shown tremendous promise and we look forward to continuing to explore and develop these therapeutics.”

*From the article here :

Silo Pharma Enters into Sponsored Research Agreement with Columbia University to Develop Psychedelic Therapeutics for Alzheimer’s Disease - Psilocybin Alpha

Agreement Provides for Option to License Alzheimer’s Therapeutic Englewood Cliffs NJ, Oct. 27, 2021 (GLOBE NEWSWIRE) — Silo Pharma, Inc. (OTCQB: SILO), a development-stage biopharmaceutical company…

psilocybinalpha.com

 

[mr peabody]

Why psychedelic research may bring the next big breakthrough in dementia treatment

by Carrie Dagenhard | Psychedelic Spotlight | 20 Dec 2021​

"Psychedelics are well-observed to basically rewire the brain," says Return Health CEO Dr. James Kuo, who is currently working with DMT because it’s shown the most efficacy in neurogenesis.

Anyone who has ever cared for a loved one living with dementia can testify that it’s a horrible condition. First, it attacks a patient’s cognitive functioning, triggering forgetfulness, distorting their reality, and robbing them of precious memories. Later, it kills off brain cells associated with muscle control, gradually limiting a patient’s ability to walk, stand, button a shirt, or even swallow food.

According to CDC estimates, about 5.8 million people have Alzheimer’s and dementia and, by 2060, that number could balloon to more than 14 million. Currently, there is no known cure for dementia or many of the diseases that cause it — but a few dedicated trailblazers believe psychedelics could offer a tremendous breakthrough.

Dr. James Kuo, CEO of Return Health, is one of those people. With a dual background in medicine and business, he’s devoted his career to innovative, out-of-the-box drug development for challenging conditions. And now, he and his team have set their sights on dementia.

“It’s a devastating problem, it’s a costly problem, and, aside from COVID, it’s the epidemic of our time,” he says. “Right now, psychedelics seem to be the most promising option.”

The current state of dementia research

Despite the growing prevalence of dementia worldwide, the past few decades of drug development have delivered dismal results. “It’s known as a graveyard of a lot of drug development programs,” Dr. Kuo says. And that’s primarily because it’s a highly complex issue — multiple diseases lead to dementia, and we don’t know much about their causes.

For example, when a person dies from Alzheimer’s, neuroimaging often shows plaques and tangles on key parts of the brain. Drug development programs have focused on removing those plaques, but it’s still unclear whether they’re the cause or result of the disease. According to Dr. Kuo, if the plaques are the result, then removing them would do little to help the patient. And that could explain why many new Alzheimer’s drugs have only a modest effect on the disease.

And while the medical field is increasingly turning to DNA testing and genome sequencing to clarify the root causes of various diseases, our understanding of dementia is still murky at best.

That’s why Return Health is taking a different approach. “We’re treating the symptoms of dementia using psychedelics,” Dr. Kuo says. “Which means our approach is somewhat agnostic to the particular cause.”

Why psychedelics might be the answer

Of course, psychedelics like psilocybin and LSD are still considered schedule 1 drugs in the US. From a pharmaceutical standpoint, that’s a massive headache. In addition to the usual hurdles for approval, drug companies will also have to go through DEA licensing and institutional review boards.

So, why even bother with psychedelics? Because, in short, there’s a ton of promise.

First, there’s evidence that psychedelics help with treatment-resistant mental illnesses that share symptoms with Alzheimer’s and dementia.

“Preliminary clinical trials with psilocybin show persisting reductions in depressed mood, anxiety, and addictive behaviors,” says Dr. Albert Garcia-Romeu, assistant professor of psychiatry and behavioral sciences at Johns Hopkins. “This suggests psychedelics could have therapeutic benefits in some patients with neurodegenerative disorders, such as Alzheimer’s Disease, that are characterized by neuronal atrophy and are often comorbid with depressed mood.”

Then, there’s the suggestion that psychedelics can help stop or even reverse cognitive decline by decreasing neuroinflammation, inducing neurogenesis (the process of forming new neurons in the brain), and improving neuroplasticity (the brain’s ability to form new neural pathways and remap).

“Psychedelics are well-observed to basically rewire the brain,” Dr. Kuo says. “So if you have damaged a part of the brain — like the hippocampus, which is responsible for short-term memory — we think it’s important to rewire it around those damaged sections.”

Most research on psychedelics for mental illness and neurodegenerative disorders has centered on psilocybin, MDMA, and DMT because they all work through a similar mechanism of action: by hitting the 5HT2A serotonin receptor (which is responsible for the psychedelic effect patients experience).

Return Health, however, is focused on DMT because it’s shown the most efficacy in neurogenesis. The team is currently working with derivatives of the DMT molecule because, as Dr. Kuo says, it’s not perfect and needs to be optimized.

“Things you find in nature are seldom the optimal drug, but they can point you in the right direction,” he says.

What’s next for psychedelics as a treatment for dementia

There’s still a long road ahead in terms of understanding dementia and who would benefit most from psychedelic-based treatments. And there will likely be plenty of regulatory setbacks to slow down the process to drug approval.

Fortunately, Dr. Garcia-Romeu, who is currently working on a study at John Hopkins examining the impact of psilocybin on early-stage Alzheimer’s, says the tides are turning.

“People in the medical and mental healthcare professions seem quite interested in exploring psychedelics as a new direction for developing novel treatments,” he says. “And the enthusiasm has spread to the financial and pharmaceutical sectors as well.”

Dr. Kuo is also encouraged by evidence-based research and his company’s progress. Regardless of the obstacles ahead, he feels the work is worthwhile.

“We’re very optimistic that we’re going to be successful,” Dr. Kuo says. “And if we are successful, I believe we’re going to change the world.”

https://psychedelicspotlight.com/psychedelic-research-dementia-breakthrough/​

 

[mr peabody]

Psychedelics as a treatment for Alzheimer’s Disease Dementia

Simon Andrew Vann Jones and Allison O’Kelly

Cornwall Partnership NHS Foundation Trust, Liskeard, UK

Currently, there are no disease-modifying treatments for Alzheimer’s disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and LSD, coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce neuroinflammation. This inevitably makes them interesting candidates for therapeutics in dementia. This mini-review will look at the basic science and current clinical evidence for the role of psychedelics in treating dementia, especially early AD, with a particular focus on micro-dosing of the classical psychedelics LSD and psilocybin.

Introduction

Globally an estimated 50 million people have a diagnosis of dementia and population prevalence continues to increase. Alzheimer’s disease (AD) accounts for approximately 50–70% of cases.

AD is a progressive neurological disorder characterized by extracellular amyloid protein deposition and intracellular tau protein aggregates (tangles) that, in accumulation, are associated with a variety of pathological processes including microtubular damage, axonal transport disruption and, ultimately, cell death. The hippocampus, a key structure in the ability to learn and retain information and a site for neurogenesis, is particularly vulnerable to AD pathology and one of the earliest parts of the brain to be affected by the disease.

Currently, there is a renaissance of research using psychedelics, potent 5HT2A receptor (5HT2A-R) agonists, in psychiatric and neurological disorders. The 5HT2A-R is found in high concentrations in regions of the brain vulnerable to dementia such as the prefrontal cortex and aforementioned hippocampus. Psychedelics induce brain plasticity and modify connectivity between brain regions and there is considerable anecdotal evidence of cognitive benefits from micro-dosing—a dose that does not cause perceptual change or impair functioning.

This mini-review will explore the role of classical psychedelics psilocybin and LSD in treating AD with a focus on sub-perceptual- or “micro”- dosing. Promoting neuroplasticity and neurogenesis via the 5HT2A-R in regions such as the hippocampus could theoretically help protect this and other brain structures and may, therefore, hold potential for treating AD.

Cognitive effects

High dose psilocybin reduces attention to both clinical and electrophysiological parameters. However, this may be due to an increased awareness of sensory stimuli that are usually filtered out rather than reduced attentional ability per se.

In younger adults, the only controlled studies of micro-dosing LSD to date, both using a within-subjects design, found no effects either positive or negative on the cognitive function of healthy volunteers at different sub-perceptual doses. Participants had all previously experienced psychedelics. The former study used a placebo, 6.5, 13, and 26 μg, and the latter study placebo, 5, 10, or 20 μg. In the latter study, subjects had objective increases in psychomotor vigilance (and subjective happiness and mood scores) coupled with a paradoxical reduction in concentration and reduced set-shifting ability at the highest microdose (20 μg) hours after ingestion. Participants also reported subjectively greater productivity at 10 micrograms and no discernible subjective or objective differences at five micrograms compared to placebo. Importantly, subjects were aware that they were on the active drug at the two higher doses and had the experience of recreational drug use.

A 2018 uncontrolled, open-label naturalistic trial found increased cognitive fluency, flexibility, and originality amongst the 33 participants at various micro-doses of psilocybin. However, results should be interpreted with a degree of caution due to the risk of selection bias, a lack of a placebo control arm, risk of practice effect bias, and no intention-to-treat analysis.

In older adults, a recent double-blind placebo-controlled study in older adults who had not taken LSD for at least the past 5 years found no difference in the number of adverse events (including cognitive impairment) between those taking placebo, 5, 10, or 20 μg doses every 5 days for 28 days. Headaches were reported more often in those taking LSD however the small number of participants and non-linear dose-response makes this difficult to interpret. In general, the medication was well tolerated with no serious adverse events or drop-outs.

Longer-term effects

In rat models, 5HT2A-R activation with mid-dose psilocybin enhances both prospective and retrospective learning with lesser effects at low-dose. Consecutive daily dosing diminished benefits, and older rodents learning was enhanced by an enriched environment.

An observational study of 89 recreational users micro-dosing psychedelics found self-reported improvement across multiple psychological domains, including creativity and attention, with a sustained improvement over 6 weeks. Studies of recreational micro-dosing, highly vulnerable to bias but arguably self-selecting for longer-term users, report improvement in cognitive focus and attention. However only one of these studies reported figures for the duration of use, with 60.5% of respondents using for 3 months of more

There have been no properly controlled studies of micro-dosing in cognitively impaired humans or effects on cognition or mood beyond the acute phase. However, studies of high dose LSD and psilocybin have shown long-term benefits on mood. A study of 16 healthy subjects showed subjective benefits of a single dose of 200 μg LSD 12 months later, with 10 participants rating the experience as one of the top 10 most meaningful of their lives. In 10 patients with a life-threatening disease, LSD-assisted psychotherapy reduced anxiety significantly, an effect that persisted 12-months after therapy in 77.7%. Two-thirds of the respondents also reported that the experience has improved their quality of life.

Similar results have been observed following high dose psilocybin both in patients with anxiety related to life-threatening cancer, and cancer-related depression and anxiety. Both studies reported that approximately 60–80% of participants had a clinically significant response that was sustained some 6 months later. The latter study also followed up 4.5 years later and found that these results were sustained, with 71–100% of participants reporting the experience being one of the most meaningful of their lives.

In treatment-resistant depression, 10 mg and 25 mg of psilocybin given 1 week apart led to clinical response or remission in 14 participants sustained at assessment 5 weeks later. This effect persisted at 6 months follow up despite no further treatment.

These encouraging results have led, in part, to approval for a trial of high-dose psilocybin specifically targeting depression in early AD.

Neurobiological effects

Specific 5HT2A-R polymorphisms impair verbal memory recall and object recognition and reduced 5HT2A-R density in areas of the brain responsible for key memory processes are associated with worse cognitive performance. Pre-task 5HT2A-R activation in mice enhances post-task hippocampal long-term potentiation and enables the re-consolidation of fear conditioning in the amygdala supporting a critical role in neuroplasticity. This effect can be reproduced in rats and rabbits by very low dose psychedelics but is abolished by higher doses.

In rats, 5HT2A-R activation stimulates neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the neocortex but appears to consistently inhibit the same process in the hippocampus. This may be dose-dependent, with higher doses suppressing neurogenesis beyond a certain threshold. In cultured rat neurons, activation also stimulates dendritic spine proliferation and growth. In a mouse model of fear conditioning, both low and high dose psilocybin led to complete resolution of a cued fear response in animals that had been primed for a shock by an auditory tone. This process was more rapid at lower doses where hippocampal neurogenesis was unimpaired. In rat cortical neuron cultures and drosophila larvae, LSD promotes neurogenesis and synaptogenesis in a dose-dependent manner suggesting both an important cross-species evolutionary pathway for this effect and that there may be an optimal dose to which it may be therapeutic for this purpose.

There is also likely to be an optimal dose spacing. Repeated administration of LSD and/or psilocybin leads to rapid tolerance, or tachyphylaxis, of mental effects from 24 h which peaks after just four consecutive daily doses, cannot be overcome even with substantial dose increases or switching to the other substance (cross-tolerance) and is completely reversed by 5 days of abstinence. In rats, high doses of LSD (0.16 mg/kg) given every 2 days for 90 days resulted in hyperactive and asocial symptoms. The aforementioned double-blind placebo-controlled safety study in older adults using a schedule of a dose every fourth day. This may be optimal as tachyphylaxis is unlikely at this infrequency and, importantly, side effects were minimal and not significantly different to those on placebo.

Neurophysiological effects

Human gamma frequency oscillations within neuronal networks are important for communication between brain regions, particularly those involving attention and memory. These networks become disrupted decades before the onset of symptoms in AD, possibly linked to dysfunctional inhibitory interneurons leading to the disruption of the gamma-mediated temporal structure for cortical processing which allows for the coherent packaging of sensory information.

Studies in mild cognitive impairment and AD show contradictory results on levels of gamma activity with some showing an increase and others a decrease in vulnerable brain regions and networks. However, a recent study found that gamma frequency response is slowed in response to stimulus in Alzheimer patients suggesting that the increase in gamma power seen in some studies with AD patients may the greater use of brain resources to maintain resting state. The same researchers found that long-distance gamma-related connectivity was heightened in AD patients compared to controls. It is possible that this increase in gamma activity is an initial response to brain failure but that this process is fatigable.

In recent studies, enhancing gamma frequency oscillations via external stimuli reduced amyloid burden, possibly via increased microglia activity, and improved cognitive function in rodents. 5HT2A-R agonists enhance the power of gamma-frequency recordings suggesting a role for the 5HT2A-R both in mediating long-range projections and reducing focal Alzheimer’s pathology.

Neuroimaging

In AD there is a reduction in global brain glucose metabolism which is marked in frontal and temporal-parietal areas. In the only psilocybin FDG-PET study to date, in healthy volunteers, acute ingestion of a 15 mg or 20 mg dose increased global brain glucose metabolism by approximately 25%, particularly in the frontal and medial temporal cortex.

A 2019 fMRI study showed lasting benefits 4 months after a single dose of 315 μg/kg psilocybin in a group of 38 meditators. Acute MRI changes—reduced connectivity between self-perceiving medial prefrontal and ventral cingulate areas—were associated with positive changes at 4 months. A 2020 fMRI study involving 16 patients with depression who took a single dose of 10 mg of psilocybin and 25 mg a week later, found increased functional connectivity between the ventromedial prefrontal cortex and the default mode network in responders the day following treatment completion, with changes sustained 5 weeks post-dosing. Functional connectivity was increased between regions with high 5HT2A-R density suggesting that reorganizing of dysfunctional neural circuitry is an important component of the neuroplastic effects of 5HT2A-R agonists.

Studies suggest that at least some of the antidepressant effect from psilocybin may be mediated via improved top-down control of the limbic system, which holds significant promise for impulse control and well-being in dementia where this control has diminished. In healthy adults, high-dose psilocybin (16 mg/kg and) has been shown to attenuate amygdala reactivity to emotional stimuli. In 19 adults with treatment-resistant depression, 10 mg and 25 mg psilocybin given a week apart, improved functional connectivity between the cortex and amygdala a day after the higher dose. In another study, also in healthy adults, sub-perceptual doses of LSD (13 μg) was shown to significantly influence functional connectivity between the amygdala and other key regions within the limbic system suggesting 5HT2A-R mediated reorganization of more primitive networks is possible without profound acute perceptual changes, although whether these changes were lasting is unclear.

These imaging studies reveal the potent reorganization of dysfunctional brain networks in affective and anxiety states. Such changes may also yield improvements in cognition, mood, and behavior by ameliorating dysfunctional circuits in cognitive impairment and dementia.

Anti-inflammatory mechanisms

All known genetic and environmental risk factors for AD are associated with increased inflammation, suggesting that reducing inflammation could be a target for preventing AD. Psychedelics have been shown to have potent anti-inflammatory properties and, given their affinity for the 5HT2A-R, may represent a unique anti-inflammatory overwhelmingly targeted to brain tissue.

In a rodent model of AD induced by chronic intracerebral inoculation of streptozotocin, 5HT1A- and 5HT2A-R agonists had a significant independent and synergistic neuroprotective effect in hippocampal neurons at 35 days via anti-apoptotic pathways. This neuroprotection infers activation of anti-inflammatory pathways, the corollary to this being that activation of 5HT2A-R in rodent neurons protects against reactive oxygen species (ROS) via the upregulation of neuroprotective Sirtuin 1 expression. This pathway simultaneously stimulates mitochondrial biogenesis leading to greater availability of adenosine triphosphate and suggesting the potential for psychedelics to address impaired energy metabolism, another key pathological pathway to cognitive dysfunction in AD.

Discussion

After decades of repeated failure of treatments for dementia, there is an urgent need to develop new treatments for AD. The potential for psychedelic compounds to influence and enhance functional neuronal connectivity, stimulate neurogenesis, restore brain plasticity, reduce inflammation and enhance cognition provides a new therapeutic target and compelling argument for further investigation of the potential for psychedelics as a disease-modifying compound in conditions where currently none exists.

Animal models testing the neurobiological effects of psychedelic compounds have demonstrated hippocampal neurogenesis at lower doses and suppression at higher doses and potent neuroprotective properties. Studies in people suffering from depression and anxiety disorders have demonstrated lasting neuroplastic changes following just one or two large doses. This suggests a potential role for both sub-perceptual “micro”- and psychedelic-doses as a strategy for neuroprotection and cognitive enhancement in prodromal AD. For cognitive enhancement, the ideal dose and frequency have yet to be determined however the rapid desensitization of 5HT2A receptors by both psilocybin and LSD suggests that daily dosing is unlikely to be the optimal strategy.

Despite anecdotal evidence of widespread recreational use of micro-dosing for cognitive enhancement, robust scientific studies of the cognitive effects of micro-dosing in humans have so far been limited to acute changes in very small studies in cognitively normal individuals with no reports of persistent cognitive changes, either positive or negative, at psychedelic doses. Studies looking at both micro-dosing and psychedelic doses, longer-term, in cognitively impaired individuals are lacking and urgently needed.

*From the article (including references) here :

Psychedelics as a Treatment for Alzheimer’s Disease Dementia

Currently, there are no disease-modifying treatments for Alzheimer’s disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive...

www.frontiersin.org

 

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Are we on the cusp of psychedelics being used as a treatment for Alzheimer’s?

by Patrick Ryan | The Dales Report | 30 Dec 2021

Psychedelics researchers insist the substances’ microbiological action has the potential to help combat symptoms in Alzheimer’s patients. To be more specific, a growing segment of the medical community believes pyschedelics’ microbiological action has the potential to help offset symptoms within the brains of those who are saddled by this form of dementia in its earliest stages. This is an important development as the population is aging, meaning Alzheimer’s disease is quickly becoming a public health threat.

About the research

The research referenced above is detailed in a paper recently published in Current Topics in Behavioral Sciences. The paper explains how psychedelics might prove helpful in preventing the degenerative brain disease that is Alzheimer’s disease. The research sets the stage for additional research in which psychedelics might be used to treat dementia symptoms. The information contained in the paper is a bullish sign for psychedelics stocks.

In excess of five million adults are living with Alzheimer’s disease in the United States alone. This figure is poised to increase by 300% across the ensuing three decades. Sadly, there is no cure for dementia yet psychedelics certainly provide hope. Dr. Albert Garcia-Romeu and other scientists at Johns Hopkins University insist psychedelics have the potential to mitigate the effects of the mentally deleterious condition on patients as well as society as a whole.

The potential role of psychedelics in treating alzheimer’s

There is a considerable overlap between the impact of psychedelic treatment within the brain and the root causes of dementia such as Alzheimer’s disease. It is possible that a carefully structured regimen of psychedelics will help boost quality of life for those saddled by Alzheimer’s disease.

A UC Davis lab headed by Dr. David Olson has determined psychedelics have a powerful impact on the brain. Olson’s team has determined psychedelics have a significant impact on the brain’s neuroplastic effects. In plain terms this means an elevated dose of psychedelics has the potential to help the brain grow and otherwise change. In particular, the frontal lobe and other areas toward the front of the brain compromised by Alzheimer’s have the potential to grow and improve with the ongoing use of psychedelics.

Researchers have also found psilocybin and LSD have meaningful anti-inflammatory properties. Garcia-Romeu insists psychedelics’ microbiological action has the potential to help combat Alzheimer’s patients’ brain-based symptoms.

The paper’s authors also delve into pyschedelics’ positive impact on mental health as well as memory. The researchers highlight how alterations in autobiographical memory amidst the use of psychedelics suggest psilocybin and LSC have the potential to catalyze memory recall as well as the clarity of patients’ life memories. In plain English, this means the research indicates both LSD and psilocybin have the potential to treat Alzheimer’s disease.

More clinical trials scheduled

Patients battling Alzheimer’s will be encouraged to learn additional clinical trials will be conducted to determine if psychedelics can help treat patients who have Alzheimer’s disease. Research on the subject is currently being conducted at Johns Hopkins University. The research team is administering high and moderate doses of psilocybin across a period of two months and quantifying results in the context of improvement in patient quality of life and mood.

Stay tuned. If the results of the research conducted at Johns Hopkins University reveal psychedelics improve both mood and quality of life by a considerable margin, it might not be long until psychedelics investors make a bundle of money with well-timed trades.

Patrick Ryan
Patrick graduated from Tulane University with degrees in sociology and political science. He also studied economics at Boston University and Tulane University. Patrick holds an ABA-approved paralegal certificate in addition to his undergraduate degrees.

Are We On The Cusp Of Psychedelics Being Used As Treatment for Alzheimer’s?

Psychedelics researchers insist the substances’ microbiological action has the potential to help combat symptoms in Alzheimer’s patients.

thedalesreport.com

 

[mr peabody]

UC Berkeley scientists propose radical new theory that AD memory loss and cognitive
dysfunction are due to a leaky barrier between the blood stream and the brain.

Drugs that quell brain inflammation found to reverse dementia

UC Berkeley | Neuroscience News | Dec 29 2019

Older mice given anti-inflammatory medication were better able to learn new tasks and became almost as adept at learning as mice half their age.

Drugs that tamp down inflammation in the brain could slow or even reverse the cognitive decline that comes with age. In a publication appearing today in the journal Science Translational Medicine, University of California, Berkeley, and Ben-Gurion University scientists report that senile mice given one such drug had fewer signs of brain inflammation and were better able to learn new tasks, becoming almost as adept as mice half their age.

“We tend to think about the aged brain in the same way we think about neurodegeneration: Age involves loss of function and dead cells. But our new data tell a different story about why the aged brain is not functioning well: It is because of this “fog” of inflammatory load,” said Daniela Kaufer, a UC Berkeley professor of integrative biology and a senior author, along with Alon Friedman of Ben-Gurion University of the Negev in Israel and Dalhousie University in Canada. “But when you remove that inflammatory fog, within days the aged brain acts like a young brain. It is a really, really optimistic finding, in terms of the capacity for plasticity that exists in the brain. We can reverse brain aging.”

The successful treatment in mice supports a radical new view of what causes the confusion and dementia that often accompany aging. More and more research shows that, with age, the filtration system that prevents molecules or infectious organisms in the blood from leaking into the brain — the so-called blood-brain barrier — becomes leaky, letting in chemicals that cause inflammation and a cascade of cell death. After age 70, nearly 60% of adults have leaky blood- brain barriers, according to Friedman’s magnetic resonance imaging (MRI) studies.

An accompanying paper by the two researchers and Dan Milikovsky of Ben-Gurion University shows that the inflammatory fog induced by a leaky blood-brain barrier alters the mouse brain’s normal rhythms, causing microseizure-like events — momentary lapses in the normal rhythm within the hippocampus — that could produce some of the symptoms seen in degenerative brain diseases like Alzheimer’s disease. Electroencephalograms (EEGs) revealed similar brain wave disruption, or paroxysmal slow wave events, in humans with epilepsy and with cognitive dysfunction, including Alzheimer’s and mild cognitive impairment (MCI).

Together, the papers give doctors two biomarkers — leaky barriers detectable by MRI and abnormal brain rhythms detectable by EEG — that can be used to flag people with blood-brain barrier problems, as well as a potential drug to slow or reverse the consequences.

“We now have two biomarkers that tell you exactly where the blood-brain barrier is leaking, so you can select patients for treatment and make decisions about how long you give the drug,” said Kaufer, a member of UC Berkeley’s Helen Wills Neuroscience Institute. “You can follow them, and when the blood-brain barrier is healed, you no longer need the drug.”

Blood-brain barrier

Scientists have long suspected that a leaky blood-brain barrier causes at least some of the tissue damage after brain injury and some of the mental decline that comes with age. But no one knew how.

In 2007, however, Friedman and Kaufer linked these problems to a blood protein, albumin. In 2009, they showed that when albumin leaks into the brain after trauma, it binds to the TGF-β (TGF-beta) receptor in brain cells called astrocytes. This triggers a cascade of inflammatory responses that damage other brain cells and neural circuits, leading to decreased inhibition and increased excitation of neurons and a propensity toward seizures.

They also showed in mice that blocking the receptor with an antihypertension drug, losartan, prevented the development of epilepsy after brain trauma. Epilepsy is a frequent consequence of concussions like those sustained by soldiers from roadside bombs.

Subsequent studies revealed leakiness in the barrier after stroke, traumatic brain injury and football concussions, solidly linking albumin and an overexcited TGF-β receptor to the damage resulting from these traumas.

In their new studies, Kaufer and Friedman showed that introducing albumin into the brain can, within a week, make the brains of young mice look like those of old mice, in terms of hyperexcitability and their susceptibility to seizures. These albumin-treated mice also navigated a maze as poorly as aged mice.

“When we infused albumin into the brains of young mice, we recapitulated aging of the brain: the gene expression, the inflammatory response, resilience to induced seizures and mortality after seizures, performance in a maze. And when we recorded their brain activity, we found these paroxysmal slow wave events,” Kaufer said. “And all were specific to the site we infused. So, doing this is sufficient to get an aged phenotype of this very young brain.”

When they genetically engineered mice so that they could knock out the TGF-β receptor in astrocytes after they’d reached old age, the senile mouse brains looked young again. The mice were as resistant to induced seizures as a young mouse, and they learned a maze like a young mouse.

Serendipitously, a Palo Alto, California, medicinal chemist, Barry Hart, offered to synthesize a small-molecule drug that blocks the TGF-β receptor in astrocytes only, and that could traverse the blood-brain barrier. When they gave the drug, called IPW, to mice in doses that lowered the receptor activity level to that found in young mice, the brains of the aged mice looked younger, too. They showed young brain-like gene expression, reduced inflammation and improved rhythms — that is, reduced paroxysmal slow wave events — as well as reduced seizure susceptibility. They also navigated a maze or learned a spatial task like a young mouse.

In analyzing brain tissue from humans, Kaufer found evidence of albumin in aged brains and increased neuroinflammation and TGF-β production with age. Friedman developed a special type of MRI imaging — dynamic contrast-enhanced (DCE) imaging — to detect leakage in the blood-brain barrier and found more leakage in people with greater cognitive dysfunction.

"Altogether, the evidence points to a dysfunction in the brain’s blood filtration system as one of the earliest triggers of neurological aging," Kaufer said.

Kaufer, Friedman and Hart have started a company to develop a drug to heal the blood-brain barrier for clinical treatment and hope that the drug will help reduce brain inflammation — and, thus, permanent damage — after stroke, concussion or traumatic brain injury, and eventually help older adults with dementia or Alzheimer’s disease who have demonstrated leakage of the blood-brain barrier.

“We got to this through the back door — we started with questions about plasticity having to do with the blood-brain barrier, traumatic brain injury and how epilepsy develops,” Kaufer said. “But after we’d learned a lot about the mechanisms, we started thinking that maybe in aging it is the same story. This is new biology, a completely new angle on why neurological function deteriorates as the brain ages.”

Drugs that quell brain inflammation reverse dementia - Neuroscience News

Older mice given anti-inflammatory medication were better able to learn new tasks and became almost as adept at learning as mice half their age.

neurosciencenews.com

 

[mr peabody]

Can Psychedelics treat Alzheimer’s Disease?

by Evan Lewis-Healey | Psychedelic Spotlight | 27 Dec 2021​

Since substances such as LSD and psilocybin have powerful anti-inflammatory properties, researchers argue that the microbiological action of psychedelics may therefore help fight brain-based symptoms in early Alzheimer’s patients.

An aging population is a double-edged sword. On one hand, people living longer demonstrates that modern medicine is working and people are generally living healthier lives. On the other hand, an aging population means that conditions like Alzheimer’s disease are more widespread than ever before.

But the psychedelic movement offers renewed hope.

A recent paper published in Current Topics in Behavioural Sciences highlights that psychedelics may be used as a tool to fight this degenerative brain disease, and paves the way for a new line of research, where psychedelics can be used to treat specific symptoms of this type of dementia.

In the United States, more than five million adults are living with Alzheimer’s, with the figure expected to triple in the next 30 years. This is a rapid cause for concern — there is, of course, no magic bullet for the treatment of Alzheimer’s.

However, Dr. Albert Garcia-Romeu and his colleagues from Johns Hopkins University, argue that psychedelics could soften the blow of this horrendous condition on the individual and society.​

Alzheimer’s in the brain and mind​

Within the paper, the author’s highlight several potential brain-based causes of Alzheimer’s disease. Normal aging is associated with neurodegeneration — the decay of brain cells. However, Alzheimer’s patients display this to a pathological extent. For these patients, the widespread decay of neurons in important brain areas, like the hippocampus, can lead to clinical problems in learning and memory.

Alzheimer’s has also been linked to brain inflammation. Why inflammation occurs in the brain is not so clear, but the effects of inflammation are as dire as neurodegeneration. Inflammation will impact general brain functioning, which can worsen the difficulties in learning and memory.

These two brain-based impacts can also have a significant impact on mental health. According to the authors, more than 40% of Alzheimer’s patients show clinically significant symptoms of depression. These all contribute to a very poor quality-of-life for Alzheimer’s patients.​

Psychedelics and Alzheimer’s​

Remarkably, there is a significant overlap between the effects of psychedelics in the brain, and some of the potential causes of Alzheimer’s disease, highlighting a fruitful exploration to enhance patients’ quality of life.

Psychedelics have an extraordinary effect on the brain. Work at Dr. David Olson’s lab at UC Davis, has found that psychedelics can have huge neuroplastic effects – in other words, a high dose of psychedelics may help the brain to change and grow in these important areas at the front of your brain, implicated in Alzheimer’s.

Moreover, substances such as LSD and psilocybin have powerful anti-inflammatory properties. Garcia-Romeu and his colleagues argue that the microbiological action of psychedelics may therefore help fight brain-based symptoms in early Alzheimer’s patients.

The author’s also highlight that psychedelics have significant positive effects on mental health, and even memory. They write, “acute changes in autobiographical memory during psychedelic effects have also been reported, suggesting LSD and psilocybin can facilitate recall and vividness of salient life memories, a potentially relevant mechanism for treatment of Alzheimer’s disease.”​

Future clinical trials​

Hope is further bolstered for patients suffering from Alzheimer’s — this promising line of research to treat Alzheimer’s with psychedelics is currently being carried out at Johns Hopkins University. Researchers are administering both moderate and high doses of psilocybin over an eight week course, and measuring patients mood and quality of life succeeding the therapy.

The research, however, is a preliminary step forward, simply to establish the exact effects on patients with early effects of the disease.

The author’s conclude, “In sum, three converging biological pathways may be responsible for induced neural plasticity resulting in long-lasting and profound effects following psychedelic administration … In addition, classic psychedelics ’ antidepressant and anxiolytic effects could provide important inroads for promoting psychological benefits in patients struggling with AD and neuropsychiatric comorbidities such as depression and apathy.”

Tying together the biological, the psychological, and the cognitive represents a ground-breaking multi-pronged approach to tackling this devastating condition.

Can Psychedelics Treat Alzheimer's Disease? | Psychedelic Spotlight

Prevalence of Alzheimer's disease in the United States is expected to triple over the next 30 years. Psychedelics may offer renewed hope.

psychedelicspotlight.com

 

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Can psychedelics treat Dementia?*

by Emily Jarvieon | Psychedelic Spotlight | 15 Oct 2021

There is currently no known cure for dementia, but Return Health CEO Dr. James Kuo says psychedelics offer "unprecedented" potential.
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In good news for those suffering from dementia and their loved ones, a new biotechnology company hopes to bring psychedelic medicines that will treat cognitive decline to the market within three to five years.

Return Health wants to introduce new treatments based on psychedelic medicines that can reduce cognitive decline and the behavioral and psychological symptoms of dementia. The company plans to use an AI-assisted drug discovery tool to identify new non-hallucinogenic psychedelic compounds with cognitive benefits.

“The potential of psychedelic drugs to treat cognitive decline from dementia by temporarily inducing a change in growth and reorganization of the brain neural network and moderating neuroinflammation is unprecedented,” says company Co-Founder and CEO Dr. James Kuo. “The industry truly has the unique opportunity to create positive capital returns while helping and healing humanity.”

Return Health Co-Founder and Chief Scientific Officer Dr. Lila Khennouf added: “Using the latest AI-assisted drug discovery technology, we believe we will go to market faster and with higher success rates than ever before. We need to use every tool available to us, the latest technology, and the untapped potential of psychedelic medicine in the fight against dementia. Patients deserve it.”

Dementia is the general term for a decline in a person’s mental ability, which is severe enough to interfere with their daily life. The most common type of dementia is Alzheimer’s Disease, accounting for 60 to 80% of cases. Sadly, the average person lives just four to eight years after receiving a dementia diagnosis, but some may live as long as 20 years post-diagnosis.

According to the Centres for Disease Control and Prevention, 5 million American adults aged 65 and older have dementia, with this number projected to reach 14 million by 2060. Globally, according to the World Health Organization, around 55 million people have dementia, with this number expected to reach 139 million by 2050.

There is currently no known cure for dementia, but there are medications that can help with dementia symptoms such as behavior changes or anxiety. Many companies are carrying out research and clinical trials involving new drugs with the hope of finding a more effective way to treat patients living with dementia and perhaps even prevent cognitive decline pre-diagnosis.

Psychedelic drugs such as psilocybin and LSD have demonstrated the ability to promote neuroplasticity and neurogenesis by way of the 5HT2A-R receptors in the hippocampus—an area of the brain involved in memory and cognition that is progressively shrunk as the result of Alzheimer’s Disease.

A 2020 review on psychedelics as a treatment for Alzheimer’s Disease and other dementia subtypes found: “The potential for psychedelic compounds to influence and enhance functional neuronal connectivity, stimulate neurogenesis, restore brain plasticity, reduce inflammation, and enhance cognition provides a new therapeutic target and compelling argument for further investigation of the potential for psychedelics as a disease-modifying compound in conditions where currently none exists.”

Return Health believes psychedelics can provide a better solution for dementia patients than current medications, leading to an improved quality of life for them, their families, and their caregivers.

*From the article here :

This New Company Plans to Treat Dementia with Psychedelics | Psychedelic Spotlight

Return Health launches with high hopes of treating dementia with psychedelic medicines, which may hit the market within three to five years.

psychedelicspotlight.com

 

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Cannabinol found to protect aging brain cells*

Salk Institute | Neuroscience | 25 Jan 2022

Decades of research on medical cannabis has focused on the compounds THC and CBD in clinical applications. But less is known about the therapeutic properties of cannabinol (CBN). Now, a new study by Salk scientists shows how CBN can protect nerve cells from oxidative damage, a major pathway to cell death.

The findings, published online in the journal Free Radical Biology and Medicine, suggest CBN has the potential for treating age-related neurodegenerative diseases, like Alzheimer’s.

“We’ve found that cannabinol protects neurons from oxidative stress and cell death, two of the major contributors to Alzheimer’s,” says senior author Pamela Maher, a research professor and head of Salk’s Cellular Neurobiology Laboratory. “This discovery could one day lead to the development of new therapeutics for treating this disease and other neurodegenerative disorders, like Parkinson’s disease.”

Derived from the cannabis plant, CBN is molecularly similar to THC, but is not psychoactive. It’s also less heavily regulated by the FDA. Previous research by Maher’s lab found that CBN had neuroprotective properties, but it wasn’t clear how it worked. Now, this new study explains the mechanism through which CBN protects brain cells from damage and death.

Maher’s team looked at the process of oxytosis, also called ferroptosis, which is thought to occur in the aging brain. Growing evidence suggests that oxytosis may be a cause of Alzheimer’s disease. Oxytosis can be triggered by the gradual loss of an antioxidant called glutathione, causing neural cell damage and death via lipid oxidation. In the study, the scientists treated nerve cells with CBN, and then introduced an agent to stimulate oxidative damage.

They further found that the CBN worked by protecting mitochondria, the cell’s powerhouses, within the neurons. In damaged cells, oxidation caused the mitochondria to curl up like donuts—a change that’s also been seen in aging cells taken from the brains of people with Alzheimer’s disease. Treating cells with CBN prevented the mitochondria from curling up and kept them functioning well.

To confirm the interaction between CBN and mitochondria, researchers then replicated the experiment in nerve cells that had the mitochondria removed. In these cells, CBN no longer demonstrated its protective effect.

“We were able to directly show that maintenance of mitochondrial function was specifically required for the protective effects of the compound,” Maher said.

In another key finding, researchers showed that CBN did not activate cannabinoid receptors, which are required for cannabinoids to produce a psychoactive response. Thus, CBN therapeutics would work without causing the individual to become “high.”

“CBN is not a controlled substance like THC, the psychotropic compound in cannabis, and evidence has shown that CBN is safe in animals and humans. And because CBN works independently of cannabinoid receptors, CBN could also work in a wide variety of cells with ample therapeutic potential,” says first author Zhibin Liang, a postdoctoral fellow in the Maher lab.

In addition to Alzheimer’s, the findings have implications for other neurodegenerative diseases, such as Parkinson’s, which is also linked to glutathione loss. “Mitochondrial dysfunction is implicated in changes in various tissues, not just in the brain and aging, so the fact that this compound is able to maintain mitochondrial function suggests it could have more benefits beyond the context of Alzheimer’s disease,” Maher said.

Maher adds that the study shows the need for further research into CBN and other lesser-studied cannabinoids. As a next step, Maher’s team is working to see if they can reproduce their results in a preclinical mouse model.

Other authors on the study are David Soriano-Castell, Devin Kepchia, Antonio Currais and David Schubert from Salk; and Brendan Duggan from the University of California San Diego.

*From the article here :

Active Ingredient in Cannabis Protects Aging Brain Cells - Neuroscience News

Cannabinol, an active ingredient in cannabis, can help protect brain cells from oxidative damage and preserve mitochondrial function.

neurosciencenews.com