Tag: neurodegeneration

Sleep apnea severity tied to greater buildup of Alzheimer’s brain plaques

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Stephen Robinson, Ph.D.

n a research first, Alzheimer’s-like amyloid plaques have been found in the brains of people with clinically verified obstructive sleep apnea, according to the results of a small study published last week in the journal Sleep.

Sleep apnea and Alzheimer’s are thought to be related, but the reasons for the connection remains unclear, the researchers said. In the new study, plaques were found to develop in the same place (the hippocampus) and spread in the same way in the brains of people with obstructive sleep apnea as they do in Alzheimer’s. In addition, the severity of sleep apnea was linked with greater plaque build-up.

Notably, the use of continuous positive airway pressure (the standard treatment for moderate to severe sleep apnea) made no difference in the amount of plaques found, reported Stephen Robinson, Ph.D., of RMIT University, Melbourne, Australia.

The study participants had no clinical symptoms of dementia before they died. This suggests that they may have been in an early pre-dementia stage of disease, the authors concluded.

“While some people may have had mild cognitive impairment or undiagnosed dementia, none had symptoms that were strong enough for an official diagnosis, even though some had a density of plaques and tangles that were sufficiently high to qualify as Alzheimer’s disease,” Robinson said.

The authors hope to conduct a larger clinical trial of the study, and plan to further analyze the current samples for additional understanding of how the participants’ brains had changed.

Sleep apnea severity tied to greater buildup of Alzheimer’s brain plaques

2 College Students Dreamed Up an A.L.S. Treatment. The Results Are In.

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Amylyx co-founders Joshua Cohen, left, and Justin Klee in their company’s new Cambridge offices.


Mike Teal, who lives in Tallahassee, began developing symptoms of A.L.S. in 2016. He takes an experimental drug called AMX0035 which aims to slow the progression of the disease.

Seven years ago, Joshua Cohen, then a junior at Brown University majoring in biomedical engineering, was captivated by the question of why people develop brain disorders. “How does a neuron die?” he wondered.

After poring over scientific studies, he sketched out his ideas for a way to treat them. “I was sitting in my dorm room and I had kind of written out the research on these crazy-looking diagrams,” he recalled.

A study published on Wednesday in the New England Journal of Medicine reported that the experimental treatment he and another Brown student, Justin Klee, conceived might hold promise for slowing progression of amyotrophic lateral sclerosis, the ruthless disease that robs people of their ability to move, speak, eat and ultimately breathe.

More than 50 clinical trials over 25 years have failed to find effective treatments for A.L.S., also called Lou Gehrig’s disease, which often causes death within two to five years. But now, scientific advances and an influx of funding are driving clinical trials for many potential therapies, generating hope and intense discussion among patients, doctors and researchers.

The new study reported that a two-drug combination slowed progression of A.L.S. paralysis by about six weeks over about six months, approximately 25 percent more than a placebo. On average, patients on a placebo declined in 18 weeks to a level that patients receiving the treatment didn’t reach until 24 weeks, said the principal investigator, Dr. Sabrina Paganoni, a neuromuscular medicine specialist at Massachusetts General Hospital’s Healey & AMG Center for A.L.S.

“It’s such a terrible disease and as you can imagine, for the folks who have it or the family members, it’s just desperation that something’s going to work,” said Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, who wasn’t involved in the new study. “Any kind of slowing of progression for a patient with A.L.S. might be valuable even though it’s not a big effect.”

He and other experts were careful not to overstate the results and noted that the drug wasn’t shown to improve patients’ condition or halt decline. The study evaluated safety and efficacy in a Phase 2 trial with 137 participants, not as large and long as many Phase 3 trials often required for regulatory approval. Experts and the authors themselves said further trials were necessary.

Still, doctors and advocates said the relentlessness of the illness and the availability of only two approved A.L.S. medications, neither significantly effective, gives urgency to finding additional treatments. The A.L.S. Association, an advocacy group, said that since the study found the drug to be safe and patients can die waiting for other trials, it should be made available to people with the disease as soon as possible.

“That can mean the difference between being able to feed yourself versus being fed or not needing a wheelchair versus needing a wheelchair, and if we can delay that level of disability, that’s a big deal for our community,” said Neil Thakur, chief mission officer of the association, which helped finance the study.

The association will urge the Food and Drug Administration to grant approval as soon as the company applies for it, and then require rigorous follow-up studies. The group will also urge the company, Amylyx, a Massachusetts start-up the students founded, to seek the agency’s permission to provide the drug for compassionate use while it is still being evaluated.

A.L.S., the most common motor neuron disorder, diagnosed in about 6,000 people worldwide each year, has drawn greater attention of late, bolstered by prominent people with the disease, like Stephen Hawking, the astrophysicist who died in 2018; Steve Gleason, a former professional football player; and Ady Barkan, a health care activist who used a computer-generated voice at this year’s Democratic National Convention because he can no longer speak.

There is now legislation in Congress to accelerate A.L.S. therapy access and a $25 million federal research program. The Ice Bucket Challenge, a 2014 fund-raising juggernaut featuring celebrities and others dumping icy water on their heads, generated about $220 million. More than 20 treatments are being tested, including stem cells, immunotherapy and genetic therapies for the 10 percent of cases caused by known mutations. Results from other trials are expected soon.

“This is a really exciting time,” said Dr. Robert Miller, director of clinical research at Forbes Norris MDA/A.L.S. Research Center at California Pacific Medical Center, who is involved in several trials, but not the new study.

Most of the study’s participants were already taking one or both of the approved A.L.S. medications: riluzole, which can extend survival by several months, and edaravone, which can slow progression by about 33 percent. It’s possible the new drug, AMX0035, provided additional benefit. Dr. Merit Cudkowicz, the Healey Center’s director and the study’s senior author, said she envisioned the new drug combination would be taken alongside existing medications.

The study is the first clinical trial supported by Ice Bucket Challenge money to publish results, said the A.L.S. Association. Amylyx financed the bulk of the study and agreed to use a percentage of income from sales of the drug to repay 150 percent of the association’s grant to fund more research.

Mr. Cohen’s idea in 2013 was that a combination of taurursodiol, a supplement, and sodium phenylbutyrate, a medication for a pediatric urea disorder, could safeguard neurons by preventing dysfunction of two structures in cells, mitochondria and the endoplasmic reticulum.

He quickly involved Mr. Klee, a senior neuroscience major who was a fraternity brother and fellow player on the university’s club tennis team. Over cheap sparkling wine, “we both said ‘let’s start a company,’” Mr. Klee said. “We had no idea what we were doing.”

They heard skepticism from several experts they consulted until they met with Rudolph Tanzi, a prominent Alzheimer’s expert who had belonged to their fraternity.

Dr. Tanzi told them to test whether the drug combination protected rat neurons from a bleach-like chemical that kills them. With $8,000 from a university grant, their parents (two of whom are physicians) and savings, they hired a professional lab, which found that their combination salvaged 90 percent of neurons, Dr. Tanzi said.

“’That’s impossible,’” he said he told them, urging more tests, which showed 95 percent of neurons were saved.

“Guys, you got something here,” Dr. Tanzi told them. He became an Amylyx co-founder and leads its scientific advisory board.

The combination was christened AMX0035 because 3 and 5 are the favorite numbers of Mr. Cohen’s fiancée. During YMCA basketball sessions with Dr. Tanzi, they discussed trying it for Alzheimer’s. But investors weren’t interested.

Dr. Tanzi introduced the young men to Dr. Cudkowicz, who had once studied sodium phenylbutyrate and convinced them to test it for A.L.S. It’s now also in an Alzheimer’s trial.

The A.L.S. study, called Centaur, conducted across the country by leading A.L.S. researchers, involved patients who developed symptoms within 18 months before the trial and were affected in at least three body regions, generally signs of fast-progressing disease. Two-thirds received AMX0035, a bitter-tasting powder they mixed with water to drink or ingest through a feeding tube twice daily.

The primary goal was slowing decline on a 48-point A.L.S. scale rating 12 physical abilities, including walking, speech, swallowing, dressing, handwriting and breathing. Over 24 weeks, patients on placebo declined 2.32 points more than those taking the drug combination. Fine motor skills benefited most.

“The data that we see here indicates there may be some beneficial effect but it doesn’t look like what you’d call a home run,” Dr. Koroshetz said.

Some patients experienced gastrointestinal side effects like nausea and diarrhea, but after three weeks those effects largely subsided, and overall, the drug was safe, researchers said.

In most secondary measures, including muscle strength, respiratory ability and whether patients were hospitalized, AMX0035 appeared better than placebo, although it wasn’t statistically significant. Another measure, a biomarker of neurodegeneration, didn’t seem significantly affected. A few patients died in both groups, but experts said identifying the impact on mortality would require evaluation over a longer period.

“This is very encouraging,” said Dr. Neil Shneider, director of the Eleanor and Lou Gehrig A.L.S. Center at Columbia University, who was not involved. “The question is, is the effect on function sustained beyond the six-month trial period and does it have an effect on survival?”

Researchers said they would soon publish longer-term data because most participants opted to take the drug combination after the trial, and some have now taken it for over two years.

Experts were torn about whether F.D.A. approval should be granted, since Phase 3 results are often required.

“From my heart, I’d say we are so desperate for meaningful treatment for A.L.S. that something that looks as promising as this might well be approved,” Dr. Miller said. “From my head, I’d say it could be chance. We’ve seen that before where Phase 2 looked really good.”

Dr. Shneider noted that some patients have already been obtaining one or both components from Europe or Asia and taking it themselves. “There’ll be a lot of interest from patients and families to get out this drug,” he said.

But experts also said that making the drug available soon might make it difficult to recruit patients for subsequent trials. And insurers may not cover drugs approved based on Phase 2 results, Dr. Koroshetz said. Some patients have had difficulty getting insurance coverage for edaravone, which costs about $148,000 a year and was approved after a Phase 3 trial of the same size and duration as Centaur. Amylyx officials declined to provide a price estimate for their treatment.

In interviews, two trial participants said they believed AMX0035 was beneficial. Given the unpredictable trajectory of the disease, they said any specific effects were hard to describe. Neither knows if they received the drug or placebo during the trial, but they’ve received the treatment since.

Mike Teal, 52, of Tallahassee, Fla., began having symptoms in 2016 and has taken the drug since at least the spring of 2018, when his trial ended. Soon after, he also started edaravone.

He currently has limited speech, needs a feeding tube, often uses a wheelchair and requires a breathing machine every few hours. Last year, he had to stop working at the gift and accessories store he owns with his wife, Lauren.

He said he’s had no negative side effects and believes the drug may have eased cramps in his neck, abdomen and legs.

“I’m confident it has slowed my progression,” he wrote in an email. “But it’s difficult to measure.”

Jeff Derby, 61, a retired forest products company manager in Cloverdale, British Columbia, said that when he was diagnosed in July 2018, doctors described his disease as relatively slow-progressing. He thinks his decline has become more gradual in the 18 months he’s been taking the drug since his trial ended. Mr. Derby, who also takes the two approved medications, said weakness in his left hand isn’t worsening as quickly.

“I think AMX0035 will ultimately be part of a treatment cocktail like there is for other diseases where you’ll take three, four or five different things, and as a group, they will help slow the progression to the point where you can live a somewhat normal life,” he said.

Long-term usage of antidepressant medications may protect from dementia

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Long-term treatment with certain antidepressants appeared associated with reduced dementia incidence, according to results of a case-control study published in Journal of Clinical Psychiatry.

“Depression could represent one of these potentially modifiable risk factors for all-cause dementia,” Claudia Bartels, PhD, of the department of psychiatry and psychotherapy at University Medical Center Goettingen in Germany, and colleagues wrote. “Numerous studies have concordantly demonstrated a strong association between depression and an increased risk [for] subsequent dementia. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depressive symptoms in [Alzheimer’s disease] dementia.

“Preclinical research in recent years has suggested that SSRIs reduce amyloid plaque burden in transgenic mouse models of [Alzheimer’s disease] and in cognitively healthy humans, attenuate amyloid-[beta]1-42–induced tau hyperphosphorylation in cell culture and improve cognition in mice.”

However, the effects of SSRIs on cognition in Alzheimer’s disease dementia were linked mostly to negative results in randomized clinical trials; research is sparse regarding which antidepressants may influence risk for developing dementia; and evidence is particularly rare for treatment duration effects on this risk. Thus, Bartels and colleagues sought to determine the effects of antidepressant drug classes and individual compounds with various treatment durations on the risk for developing dementia. The researchers analyzed data of 62,317 individuals with an incident dementia diagnosis who were included in the German Disease Analyzer database, and they compared outcomes to those of controls matched by age, sex and physician. They conducted logistic regression analyses, which were adjusted for health insurance status and comorbid diseases linked to dementia or antidepressant use, to evaluate the association between dementia incidence and treatment with four major classes of antidepressant drug, as well as 14 of the most commonly prescribed individual antidepressants.

Results showed an association between treatment for 2 years or longer with any antidepressant and a lower risk for dementia vs. short-term treatment among 17 of 18 comparison. Particularly for long-term treatment, herbal and tricyclic antidepressants were linked to a decrease in incidence of dementia. Long-term treatment with escitalopram (OR = 0.66; 95% CI, 0.5-0.89) and Hypericum perforatum (OR = 0.6; 95% CI, 0.51-0.7) were associated with the lowest risks for dementia on an individual antidepressant basis.

“Clinical trials — although well acknowledged as the gold standard procedure — have debunked numerous promising compounds and become increasingly challenging with longer treatment durations,” Bartels and colleagues wrote. “Thus, and in awareness of the controversy of this suggestion, analyzing data from registries in a naturalistic setting may be an attractive and feasible alternative. If individual datasets could be combined in a multinational effort, even more powerful analyses of merged big databases could be performed and an additive contribution with naturalistic data could be made.”

https://www.healio.com/news/psychiatry/20200828/longterm-treatment-with-certain-antidepressants-may-reduce-dementia-incidence

Case Western Reserve University-led team develops new approach to treat certain neurological diseases

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Paul Tesar, professor of genetics and genome sciences, School of Medicine


Regeneration of myelin in the brain, shown in blue, after ASO drug treatment

A team led by Case Western Reserve University medical researchers has developed a potential treatment method for Pelizaeus-Merzbacher disease (PMD), a fatal neurological disorder that produces severe movement, motor and cognitive dysfunction in children. It results from genetic mutations that prevent the body from properly making myelin, the protective insulation around nerve cells.

Using mouse models, the researchers identified and validated a new treatment target—a toxic protein resulting from the genetic mutation. Next, they successfully used a family of drugs known as ASOs (antisense oligonucleotides) to target the ribonucleic acid (RNA) strands that created the abnormal protein to stop its production. This treatment reduced PMD’s hallmark symptoms and extended lifespan, establishing the clinical potential of this approach.

By demonstrating effective delivery of the ASOs to myelin-producing cells in the nervous system, researchers raised the prospect for using this method to treat other myelin disorders that result from dysfunction within these cells, including multiple sclerosis (MS).

Their research was published online July 1 in the journal Nature.

“The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment,” said Paul Tesar, principal investigator on the research, a professor in the Department of Genetics and Genome Sciences at the School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics. “Our results open the door for the development of the first treatment for PMD as well as a new therapeutic approach for other myelin disorders.”

Study co-authors include an interdisciplinary team of researchers from the medical school, Ionis Pharmaceuticals Inc., a Carlsbad, California-based pioneer developer of RNA-targeted therapies, and Cleveland Clinic. First author Matthew Elitt worked in Tesar’s lab as a Case Western Reserve medical and graduate student.

PMD attacks the young

PMD is a rare, genetic condition involving the brain and spinal cord that primarily affects boys. Symptoms can appear in early infancy and begin with jerky eye movements and abnormal head movements. Over time, children develop severe muscle weakness and stiffness, cognitive dysfunction, difficulty walking and fail to reach developmental milestones such as speaking. The disease shortens life-expectancy, and people with the most severe cases die in childhood.

The disease results from errors in a gene called proteolipid protein 1 (PLP1). Normally, this gene produces proteolipid protein (PLP) a major component of myelin, which wraps and insulates nerve fibers to allow proper transmission of electrical signals in the nervous system. But a faulty PLP1 gene produces toxic proteins that kill myelin producing cells and prevent myelin from developing and functioning properly—resulting in the severe neurological dysfunction in PMD patients.

PMD impacts a few thousand people around the world. So far, no therapy has lessened symptoms or extended lifespans.

For nearly a decade, Tesar and his team have worked to better understand and develop new therapies for myelin disorders. They have had a series of successes, and their myelin-regenerating drugs for MS are now in commercial development.

Latest research

In the current laboratory work, the researchers found that suppressing mutant PLP1 and its toxic protein restored myelin-producing cells, produced functioning myelin, reduced disease symptoms and extended lifespans.

After validating that PLP1 was their therapeutic target, the researchers pursued pre-clinical treatment options. They knew mutations in the PLP1 gene produced faulty RNA strands that, in turn, created the toxic PLP protein.

So they teamed with Ionis Pharmaceuticals, a leader in RNA-targeted therapeutics and pioneer of ASOs. These short strings of chemically modified DNA can be designed to bind to a specific RNA target and block production of its protein product.

And that’s exactly what happened in their studies. The result was improved myelin and locomotion, and substantial extension of lifespan. “ASOs provided an opportunity to cut the disease-causing protein off at its source,” Elitt said.

The successful clinical use of ASOs is relatively new, yet recent developments seem promising. In 2016, the U.S. Food and Drug Administration approved the first ASO drug for a neurological disorder, spinal muscular atrophy. The drug, Spinraza, was developed by Ionis and commercialized by Biogen Inc. More ASO therapies are in development, and clinical trials and hold promise for addressing many neurological diseases that as of now have no effective treatment options.

Tesar said that ongoing and planned experiments in his laboratory will help guide future clinical development of ASO therapy for PMD. For example, researchers want to understand more about how well the treatment works after the onset of symptoms, how long it lasts, how often treatment needs to be given and whether it might be effective for all PMD patients, regardless of their specific form of the disease.

“While important research questions remain, I’m cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients,” Tesar said. “I truly hope our work can make a difference for PMD patients and families.”

Case Western Reserve University-led team develops new approach to treat certain neurological diseases

For The First Time, Scientists Have Captured Video of Brains Clearing Out Dead Neurons

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by DAVID NIELD

We already know that our brains have a waste disposal system that keeps dead and toxic neurons from clogging up our biological pathways. Now, scientists have managed to capture a video of the process for the first time, in laboratory tests on mice.

There’s still a lot we don’t know about how dead neurons are cleared out, and how the brain reacts to them, so the new research could be a significant step forward in figuring some of that out – even if we’ve not yet confirmed that human brains work in the exact same way.

“This is the first time the process has ever been seen in a live mammalian brain,” says neurologist Jaime Grutzendler from the Yale School of Medicine in Connecticut.

Further down the line, these findings might even inform treatments for age-related brain decline and neurological disorders – once we know more about how brain clean-up is supposed to work, scientists can better diagnose what happens when something goes wrong.

The team focussed in on the glial cells responsible for doing the clean-up work in the brain; they used a technique called 2Phatal to target a single brain cell for apoptosis (cell death) in a mouse and then followed the route of glial cells using fluorescent markers.

“Rather than hitting the brain with a hammer and causing thousands of deaths, inducing a single cell to die allows us to study what is happening right after the cells start to die and watch the many other cells involved,” says Grutzendler.

“This was not possible before. We are able to show with great clarity what exactly is going on and understand the process.”

Three types of glial cells – microglia, astrocytes, and NG2 cells – were shown to be involved in a highly coordinated cell removal process, which removed both the dead neuron and any connecting pathways to the rest of the brain. The researchers observed one microglia engulf the neuron body and its main branches (dendrites), while astrocytes targeted smaller connecting dendrites for removal. They suspect NG2 may help prevent the dead cell debris from spreading.

The researchers also demonstrated that if one type of glial cell missed the dead neuron for whatever reason, other types of cells would take over their role in the waste removal process – suggesting some sort of communication is occurring between the glial cells.

Another interesting finding from the research was that older mouse brains were less efficient at clearing out dead neural cells, even though the garbage removal cells seemed to be just as aware that a dying cell was there.

This is a good opportunity for future research, and could give experts insight into how older brains start to fail in various ways, as the garbage disposal service starts to slow down or even breaks.

New treatments might one day be developed that can take over this clearing process on the brain’s behalf – not just in elderly people, but also those who have suffered trauma to the head, for example.

“Cell death is very common in diseases of the brain,” says neurologist Eyiyemisi Damisah, from the Yale School of Medicine.

“Understanding the process might yield insights on how to address cell death in an injured brain from head trauma to stroke and other conditions.”

The research has been published in Science Advances.

https://www.sciencealert.com/for-the-first-time-scientists-capture-video-of-brains-clearing-out-dead-neurons

Oleh Hornykiewicz, Who Discovered Parkinson’s Treatment, Dies at 93

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Oleh Hornykiewicz in his Vienna office in 2009 He helped identify low dopamine levels as a cause of Parkinson’s disease, a finding that led to an effective treatment.

Oleh Hornykiewicz, a Polish-born pharmacologist whose breakthrough research on Parkinson’s disease has spared millions of patients the tremors and other physical impairments it can cause, died on May 27 in Vienna. He was 93.

His death was confirmed by his longtime colleague, Professor Stephen J. Kish of the University of Toronto, where Professor Hornykiewicz (pronounced whor-nee-KEE-eh-vitch) taught from 1967 until his retirement in 1992.

Professor Hornykiewicz was among several scientists who were considered instrumental in first identifying a deficiency of the neurotransmitter dopamine as a cause of Parkinson’s disease, and then in perfecting its treatment with L-dopa, an amino acid found in fava beans.

The Nobel laureate Dr. Arvid Carlsson and his colleagues had earlier shown that dopamine played a role in motor function. Drawing on that research, Professor Hornykiewicz and his assistant, Herbert Ehringer, discovered in 1960 that the brains of patients who had died of Parkinson’s had very low levels of dopamine.

He persuaded another one of his collaborators, the neurologist Walther Birkmayer, to inject Parkinson’s patients with L-dopa, the precursor of dopamine, which could cross the barrier between blood vessels and the brain and be converted into dopamine by enzymes in the body, thus replenishing those depleted levels. The treatment alleviated symptoms of the disease, and patients who had been bedridden started walking.

The initial results of this research were published in 1961 and presented at a meeting of the Medical Society of Vienna. The “L-dopa Miracle,” as it was called, inspired Dr. Oliver Sacks’s memoir “Awakenings” (1973) and the fictionalized movie of the same name in 1990.
As a therapy for Parkinson’s, L-dopa was further refined by other scientists, including George C. Cotzias and Melvin D. Yahr. But it was Professor Hornykiewicz, defying colleagues who had argued that post-mortem brain studies were worthless, who is credited with the critical breakthroughs.

His findings spurred the establishment of human brain tissue banks, research into dopamine and treatments of other diseases caused by low levels of neurotransmitters.

“Today, it is generally agreed that the initiation of the treatment of Parkinson’s disease with L-dopa represented one of the triumphs of pharmacology of our time,” Professor Hornykiewicz wrote in “The History of Neuroscience in Autobiography, Volume IV” (2004). “This provided, apart from the benefit to the patients, a stimulus for analogous studies of many other brain disorders, both neurological and psychiatric.”

He received several distinguished awards, including the Wolf Prize in Medicine in 1979 and the Ludwig Wittgenstein Prize of the Austrian Research Foundation in 1993.

In 2000, when Dr. Carlsson, of Sweden, and others were awarded the Nobel Prize in Physiology or Medicine for discovering dopamine and “allowing for the development of drugs for the disease,” as the Nobel committee wrote, more than 200 scientists signed a petition protesting that the prize had not also been awarded to Professor Hornykiewicz.

Oleh Hornykiewicz was born on Nov. 17, 1926, in the village of Sychow, near Lviv, in what was then southeastern Poland and is now western Ukraine. His was a fourth-generation family of Eastern Orthodox Catholic priests. His father, Theophil Hornykiewicz, ministered to the village’s several dozen parishioners and taught religion; his mother, Anna (Sas-Jaworsky) Hornykiewicz, managed the affairs of the village’s 300-year-old wooden church.

When the Soviet Union invaded in 1939, the family fled to Austria, his mother’s ancestral home, with whatever belongings they could carry. Oleh knew no German but learned it by reading Hitler’s “Mein Kampf,” which was readily available in Vienna. He suffered from tuberculosis and, when the war ended, decided to follow his eldest brother and become a doctor.

He received his medical degree from the University of Vienna in 1951 and began his academic and research career in its pharmacology department. He held a British Council Research Scholarship at the University of Oxford from 1956 to 1958. Beginning in 1967, he headed the psychopharmacology department at the Clarke Institute of Psychiatry in Toronto (now the Center for Addiction and Mental Health), where he established the Human Brain Laboratory in 1978.

He was named a full professor of pharmacology and psychiatry at the University of Toronto in 1973 and, in 1976, appointed to head the newly-founded Institute of Biochemical Pharmacology of the University of Vienna. He held both posts concurrently.

He is survived by his daughter, Maria Hentosz; three sons, Nicholas, Stephen and Joseph; six grandchildren; and one great-grandchild. His wife, Christina (Prus-Jablonowski) Hornykiewicz, had died.

“He was a pharmacologist, biochemist and neurologist who wanted to find out how the brain works and how dopamine was involved,” Professor Kish said. “And he wanted to be known also as a philosopher.”

Despite being snubbed by the Nobel committee, Professor Hornykiewicz was philosophical about what he had accomplished and the degree to which it had been credited.

“I am surprised to see that I have achieved everything I could have wished for,” he wrote in 2004. “The support and recognition I received for my work, I have accepted with gratitude, as a charming reminder to do more and better.”

Professor Kish, who heads the Human Brain Laboratory at the University of Toronto’s Centre for Addiction and Mental Health, said L-dopa, or Levodopa, as it is also called, is today “the mainstay treatment for Parkinson’s disease — no drug is more efficacious.”

“Hornykiewicz,” he added, “reminds us that before L-dopa, persons with Parkinson’s disease were bedridden, crowding chronic hospital wards, and the doctors were powerless to do anything. His discovery changed all that —- it was a miracle.”

https://bioreports.net/oleh-hornykiewicz-who-discovered-parkinsons-treatment-dies-at-93/

“Hero” Proteins May Shield Other Proteins from Harm in Neurodegenerative Disease

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by Emma Yasinski

Researchers at RIKEN and the University of Tokyo report the existence of a new class of proteins in Drosophila and human cell extracts that may serve as shields that protect other proteins from becoming damaged and causing disease. An excess of the proteins, known as Hero proteins, was associated with a 30 percent increase in the lifespan of Drosophila, according to the study, which was published last week (March 12) in PLOS Biology.

“The discovery of Hero proteins has far-reaching implications,” says Caitlin Davis, a chemist at Yale University who was not involved in the study, “and should be considered both at a basic science level in biochemistry assays and for applications as a potential stabilizer in protein-based pharmaceuticals.”

Nearly 10 years ago, Shintaro Iwasaki, then a graduate student studying biochemistry at the University of Tokyo, discovered a strangely heat-resistant protein in Drosophila that seemed to help stabilize another protein, Argonaute, in the face of high temperatures that would denature most proteins. Although he didn’t publish the work at the time, Iwasaki called the new type of protein a Heat-resistant obscure (Hero) protein—not because of their ability to rescue Argonaute from destruction, but because in Japan, the term “hero” means “weak or not rigid,” and Hero proteins don’t have stiff 3-D structures like other proteins do.
But recognition of a more widespread role for Hero proteins in protecting other molecules in the cell gives the name new meaning.

“It is generally assumed that proteins are folded into three-dimensional structures, which determine their functions,” says Kotaro Tsuboyama, a biochemist at the University of Tokyo and the lead author of the new study. But these 3-D structures are disrupted when the proteins are exposed to extreme conditions. When proteins are denatured, they lose the ability to function normally, and sometimes begin to aggregate, forming pathologic clumps that can lead to disease.

Hero proteins can survive these biologically challenging conditions. Heat-resistant proteins have been found in extremophiles—organisms known to live in extreme environments—but were thought to be rare in other organisms. In the new study, Tsuboyama and his team boiled lysates from Drosophila and human cell lines, identifying hundreds of Hero proteins that withstood the temperature.

The researchers selected six of these proteins and mixed them with “client” proteins—other functional proteins that on their own would be denatured by extreme conditions—before exposing them to high temperatures, drying, chemicals, and other harsh treatments. The Hero proteins prevented certain clients from losing their shape and function.

Next, the team tested the effects of Hero proteins in cellular models of two neurodegenerative disorders characterized by pathologic protein clumps: Huntington’s disease and amyotrophic lateral sclerosis (ALS). When the Hero proteins were present, there was a significant reduction in protein clumping in both models.

“This is an extremely important finding as it may pave new therapeutic and preventive strategies for neurodegenerative diseases, such as Alzheimer and Parkinson diseases,” Morteza Mahmoudi, who studies regenerative medicine at Michigan State University and was not involved in the research, writes in an email to The Scientist.

Lastly, the team genetically engineered Drosophila to produce an excess of Hero proteins. These flies lived up to 30 percent longer than their wildtype counterparts.

Not everyone is convinced that the Hero proteins play a major protective role. “Although they show these proteins help their proven targets remain folded/shielded etc, I don’t think there’s a broader application at all,” Nihal Korkmaz, who designs proteins at the University of Washington Institute of Protein Design and also did not participate in the study, tells The Scientist in an email. She adds that many proteins she works with can withstand high temperatures and the researchers “don’t mention at all if [Hero proteins] are found throughout the brain or in CSF [cerebrospinal fluid],” where they’d be able to protect against Huntington’s or ALS.

The authors emphasized that there is a lot left to learn about the proteins. Each Hero protein seems able to protect some client proteins, but not all of them. Moreover, amino acid sequences differ considerably between Hero proteins, making it difficult to predict their functions. The researchers write in the study that they hope future studies will help them identify which clients each Hero might work with.

Whatever discoveries future work might hold, Tsuboyama says, the scientific community’s reaction to the team’s new study has been consistent: “Almost everyone says that Hero proteins are interesting but mysterious.”

K. Tsuboyama et al., “A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation,” PLOS Biol, doi:10.1371/journal.pbio.3000632, 2020.

https://www.the-scientist.com/news-opinion/hero-proteins-may-shield-other-proteins-from-harm-67293?utm_campaign=TS_OTC_2020&utm_source=hs_email&utm_medium=email&utm_content=86341663&_hsenc=p2ANqtz–kkYtO3Wn5lK7HmDq3SWf1KLtul94Crlb2ELPzvFBQWGep0tFzWAy3UdVi_w7ml_E1bn1g9HU_2SVNp–jib-1JCCU_w&_hsmi=86341663

Molecule Offers Hope For Halting Parkinson’s

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A promising molecule has offered hope for a new treatment that could stop or slow Parkinson’s, something no treatment can currently do.

Researchers from the University of Helsinki found that molecule BT13 has the potential to both boost levels of dopamine, the chemical that is lost in Parkinson’s, as well as protect the dopamine-producing brain cells from dying.

The results from the study, co-funded by Parkinson’s UK and published online today in the journal Movement Disorders, showed an increase in dopamine levels in the brains of mice following the injection of the molecule. BT13 also activated a specific receptor in the mouse brains to protect the cells.

Typically, by the time people are diagnosed with Parkinson’s, they have already lost 70-80 per cent of their dopamine-producing cells, which are involved in coordinating movement.

While current treatments mask the symptoms, there is nothing that can slow down its progression or prevent more brain cells from being lost, and as dopamine levels continue to fall, symptoms get worse and new symptoms can appear.

Researchers are now working on improving the properties of BT13 to make it more effective as a potential treatment which, if successful, could benefit the 145,000 people living with Parkinson’s in the UK.

The study builds on previous research on another molecule that targets the same receptors in the brain, glial cell line-derived neurotrophic factor (GDNF), an experimental treatment for Parkinson’s which was the subject of a BBC documentary in February 2019. While the results were not clear cut, GDNF has shown promise to restore damaged cells in Parkinson’s.

However, the GDNF protein requires complex surgery to deliver the treatment to the brain because it’s a large molecule that cannot cross the blood-brain barrier – a protective barrier that prevents some drugs from getting into the brain.

BT13, a smaller molecule, is able to cross the blood-brain barrier – and therefore could be more easily administered as a treatment, if shown to be beneficial in further clinical trials.

Professor David Dexter, Deputy Director of Research at Parkinson’s UK, said:

“People with Parkinson’s desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms.

“One of the biggest challenges for Parkinson’s research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson’s.

“More research is needed to turn BT13 into a treatment to be tested in clinical trials, to see if it really could transform the lives of people living with Parkinson’s.”

Dr Yulia Sidorova, lead researcher on the study, said: “We are constantly working on improving the effectiveness of BT13. We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

“Our ultimate goal is to progress these compounds to clinical trials in a few coming years.”

Molecule offers hope for halting Parkinson’s

Drinking alcohol every day can speed up brain aging by one week per session, according to a study of more than 17,000 people

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Researchers at the University of Southern California looked at more than 17,000 brain scans to see if daily smoking and drinking advanced brain age. The study found that every gram of alcohol consumed a day aged the brain by 11 days. Smoking a pack of cigarettes a day for a year aged the brain by 11 days. It is one of the largest studies ever done on brain aging and alcohol, making the findings quite robust.

by Shira Feder

Over time, drinking a little bit more alcohol than recommended could accelerate the brain’s aging process, according to a new study.

Though previous studies have found the same, most were tentative findings based on small groups of people or large groups of mice.

The new study, from researchers at the University of Southern California, offers a more robust estimate, reached by examining 17,308 human brain scans from the UK Biobank — one of the biggest sample sizes ever seen.

The team found that for every gram of alcohol consumed a day, the brain aged 0.02 years — or, seven-and-a-half days. (The average can of beer or small glass of wine contains 14 grams of alcohol). People who reported drinking every day had brains which were, on average, 0.4 years older than people who didn’t drink daily.

Smoking had even stronger effect: the team found that those who smoke a pack of cigarettes a day for a year age their brains by 0.03 years (11 days).

The researchers took 30% of the brain scans in their study, all from people aged 45 to 81, and used them to train a computer, which scanned each brain to see how old or young they looked.

They then compared the computer’s estimates of each brain’s age with the person’s real age, and their self-reports of how much alcohol and tobacco they consume daily, in order to see if consuming alcohol or tobacco regularly aged the brain.

Comparing those results with the other 70% of their brain scans, they found that the more you drank and smoke, the more likely you were to have a brain aged beyond your actual age.

Lucina Uddin, director of the Cognitive and Behavioral Neuroscience Division at the University of Miami, who was not involved in the study, told Insider that the use of an algorithm is what makes this study’s findings so compelling.

“Back in the day we’d scan 20 or 40 subjects, if we were lucky, for neuroimaging studies,” Uddin said. “Now we’re getting bigger numbers like 200 or 300 individuals. But this is the biggest sample we’ve ever seen.”

Because the sample size is so big, scientists can ask questions that apply to the entire population, rather than just a few people.

Brain age is essentially a measure of brain health, says Uddin, who was not surprised by the study’s findings.

“Looking at brain age is a way of checking how well you’ve been taking care of your brain,” she told Insider. “My age is 40, but does my brain look more like a 50-year-old brain or a 60-year-old brain? Do you look younger than your age or older than your age?”

The lead author of the study, Arthur Toga, told Inverse: “The 0.4 years of difference was statistically significant. We suggest that daily or almost daily alcohol consumption can be detrimental to the brain.”

However, many super-agers — people who live well beyond 100 years old, and often appear resistant to the dementia gene — report drinking alcohol now and then.

What’s more, a recent Harvard study found drinking in moderation can have some benefits, particularly for the heart.

Dr. Qi Sun, a co-author of the Harvard study, previously told Insider: “If you drink alcohol, it’s very important that you drink responsibly, not in excess, and that you also focus on eating a healthy diet, maintaining a healthy body weight, not smoking, and exercising. If you don’t drink you don’t need to start drinking.”

https://www.insider.com/alcohol-every-day-ages-your-brain-quicker-17000-brain-scans-2020-1

Robert Moir, 58, Dies; His Research Changed Views on Alzheimer’s disease

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Dr. Moir’s radical and iconoclastic theories defied conventional views of the disease. But some scientists were ultimately won over.

By Gina Kolata

Robert D. Moir, a Harvard scientist whose radical theories of the brain plaques in Alzheimer’s defied conventional views of the disease, but whose research ultimately led to important proposals for how to treat it, died on Friday at a hospice in Milton, Mass. He was 58.

His wife, Julie Alperen, said the cause was glioblastoma, a type of brain cancer.

Dr. Moir, who grew up on a farm in Donnybrook, a small town in Western Australia, had a track record for confounding expectations. He did not learn to read or write until he was nearly 12; Ms. Alperen said he had told her that the teacher at his one-room schoolhouse was “a demented nun.” Yet, she said, he also knew from age 7 that he wanted to be a scientist.

Dr. Moir succeeded in becoming a researcher who was modest and careful, said his Ph.D. adviser, Dr. Colin Masters, a neuropathologist at the University of Melbourne. So Dr. Masters was surprised when Dr. Moir began publishing papers proposing an iconoclastic rethinking of the pathology of Alzheimer’s disease.

Dr. Moir’s hypothesis “was and is a really novel and controversial idea that he alone developed,” Dr. Masters said.

“I never expected this to come from this quiet achiever,” he said.

Dr. Moir’s theory involved the protein beta amyloid, which forms plaques in the brains of Alzheimer’s patients.

Conventional wisdom held that beta amyloid accumulation was a central part of the disease, and that clearing the brain of beta amyloid would be a good thing for patients.

Dr. Moir proposed instead that beta amyloid is there for a reason: It is the way the brain defends itself against infections. Beta amyloid, he said, forms a sticky web that can trap microbes. The problem is that sometimes the brain goes overboard producing it, and when that happens the brain is damaged.

The implication is that treatments designed to clear the brain of amyloid could be detrimental. The goal would be to remove some of the sticky substance, but not all of it.

The idea, which Dr. Moir first proposed 12 years ago, was met with skepticism. But he kept at it, producing a string of papers with findings that supported the hypothesis. Increasingly, some of the doubters have been won over, said Rudolph Tanzi, a close friend and fellow Alzheimer’s researcher at Harvard.

Dr. Moir’s unconventional ideas made it difficult for him to get federal grants. Nearly every time he submitted a grant proposal to the National Institutes of Health, Dr. Tanzi said in a phone interview, two out of three reviewers would be enthusiastic, while a third would simply not believe it. The proposal would not be funded.

But Dr. Moir took those rejections in stride.

“He’d make a joke about it,” Dr. Tanzi said. “He never got angry. I never saw Rob angry in my life. He’d say, ‘What do we have to do next?’ He was always upbeat, always optimistic.”

Dr. Moir was supported by the Cure Alzheimer’s Fund, and he eventually secured some N.I.H. grants.

Dr. Moir first came to the United States in 1994, when Dr. Tanzi was looking for an Alzheimer’s biochemist to work in his lab. Working with the lab as a postdoctoral fellow and later as a faculty member with his own lab, Dr. Moir made a string of major discoveries about Alzheimer’s disease.

For example, Dr. Moir and Dr. Tanzi found that people naturally make antibodies to specific forms of amyloid. These antibodies protect the brain from Alzheimer’s but do not wipe out amyloid completely. The more antibodies a person makes, the greater the protection against Alzheimer’s.

That finding, Dr. Tanzi said, inspired the development of an experimental drug, which its manufacturer, Biogen, says is helping to treat some people with Alzheimer’s disease. Biogen plans to file for approval from the Food and Drug Administration.

Robert David Moir was born on April 2, 1961, in Kojonup, Australia, to Mary and Terrence Moir, who were farmers. He studied the biochemistry of Alzheimer’s disease at the University of Western Australia before joining Dr. Tanzi’s lab.

Once he learned to read, Ms. Alperen said, he never stopped — he read science fiction, the British magazine New Scientist and even PubMed, the federal database of scientific publications.

“Rob had an encyclopedic knowledge of the natural world,” she said.

He shared that love with his family, on frequent hikes and on trips with his young children to look for rocks, insects and fossils. He also played Australian-rules football, which has elements of rugby as well as American football, and helped form the Boston Demons Australian Rules Football Team in 1997, his wife said.

In addition to his wife, with whom he lived in Sharon, Mass., Dr. Moir’s survivors include three children, Alexander, Maxwell and Holly Moir; a brother, Andrew; and a sister, Catherine Moir. His marriage to Elena Vaillancourt ended in divorce.