Posts Tagged ‘neurodegeneration’


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

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 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.”

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

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

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

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


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.

Pioneering aerosol writer Lonny Wood, better known by his moniker, Phase 2, has died. He is remembered for his invaluable, media-spanning contributions to hip-hop and is acknowledged as the first artist to perfect the “softie” style of aerosol calligraphy, characterized by its marshmallow-like bubbled lettering.

Born in the Bronx, New York, Phase 2 began tagging subway trains in the early 1970s, becoming one of the most widely emulated stylists of that moment. As his work matured, he progressively abstracted and complicated his calligraphy, “deconstructing the letter”—in the words of hip-hop journalist Jeff Chang—“into hard lines, third eyes, horns, drills, spikes, arches, Egyptian pharos and dogs, pure geometrics.” Phase 2 was an early member of United Graffiti Artists (UGA), a collective of train painters credited with mounting the first gallery show of so-called graffiti art, a term Wood rejected for devaluing and criminalizing his work and that of his peers.

In addition to his calligraphic work, Phase 2 rapped, DJ’ed, and was a member of the New York City Breakers, a pioneering break-dancing crew. As a graphic artist, he lent his hard-edge geometric style—influenced by the Bronx’s many Art Deco theaters—to flyers promoting significant parties and shows like 1982’s Kool Lady Blue at the Roxy nightclub in Chelsea, which established a rapport between hip-hop and New York’s contemporaneous punk and New Wave scenes. In the mid-’80s, he served as the art director of the underground zine International Graffiti Times, often cited as the first publication devoted to street and subway art. In 1996, he and International Graffiti Times editor David Schmidlapp copublished the book Style: Writing from the Underground, a history of aerosol art. In recent decades, his work has been featured in numerous exhibitions of urban art.

“I’m absorbing and devouring language,” Phase 2 said of his work “and creating something else with it. . . . The English language isn’t much, especially in its current state. By comparison (to Chinese and Japanese) it’s like a dot. Why not go beyond that and just create an alphabet or language? You can’t put a limit on communication or how one can communicate, you’ve always got to look further, that’s how style expanded in the first place.”

https://www.artforum.com/news/phase-2-1955-2019-81607

Young carriers of the APOE4 allele have brains that are more connected (left, red lines illustrate connections between brain areas) and active (right, yellow indicates activity) than the brains of those without the allele.
KRISHNA SINGH, ELIFE, 8:E36011, 2019.

A growing body of evidence supports the theory that neural hyperactivity and hyperconnectivity precede the pathological changes that lead to neurodegeneration.

DIANA KWON

There are approximately 5.6 million people over the age of 65 living with Alzheimer’s disease in the United States. With the population aging, that number is projected to grow to 7.1 million by 2025. Researchers know that age, a family history of the disease, and carrying a genetic variant known as APOE4 are all associated with a higher chance of developing the condition. But the biological mechanisms leading to Alzheimer’s are still largely a mystery.

Over the last decade, scientists have amassed evidence for a hypothesis that, prior to developing full-blown Alzheimer’s disease, patients experience a period of hyperactivity and hyperconnectivity in the brain. Several functional magnetic resonance imaging studies have reported that people with mild cognitive impairment (MCI), a condition that often precedes Alzheimer’s, appear to have higher brain activity levels than their age-matched counterparts. Researchers have also found signs of such changes in healthy people carrying the APOE4 allele, as well as in presymptomatic stages of Alzheimer’s in rodent models of the disease.

Krishna Singh, a physicist and imaging neuroscientist at the Cardiff University Brain Research Imaging Center (CUBRIC) in the UK, and his colleagues wanted to investigate this theory further. Previous studies of brain activity in young APOE4 carriers were mostly conducted using small sample sizes, according to Singh. But by the mid-2010s, his team had access to neuroimaging data from close to 200 participants studied at CUBRIC as part of an effort to build a massive dataset of healthy brains. So the researchers decided to use the data to search for signs of unusual brain activity and connectivity in people with the APOE4 allele.

Using magnetoencephalography (MEG), a neuroimaging technique that records the magnetic fields generated by electrical activity in the brain, Singh and his colleagues had measured resting-state brain activity in a group of 183 healthy adults, which included 51 individuals who carried at least one copy of APOE4. The average age of the participants was 24 years old, although ages ranged from 18 to 65 years old.

Analysis of the imaging data revealed that, compared with controls, young APOE4 carriers displayed greater activity in several regions in the right side of the brain, including parts of what’s known as the default mode network, which is active when a person is not focused on a specific task. A similar set of brain regions also showed an overall increase in connectivity.

The researchers next compared the results to brain activity and connectivity data from a previous neuro­imaging study they had conducted, which found that elderly people with early-stage Alzheimer’s disease had decreased neuronal activity and connectivity compared with that of age-matched controls. The network of brain areas that displayed increased connectivity in young APOE4 carriers, the team found, partially overlapped with the brain regions that exhibited a decrease in connectivity in people with early-stage Alzheimer’s. These findings are intriguing, Singh says, because they suggest that brain areas that end up getting impaired in Alzheimer’s may be highly active and connected early in life—long before symptoms of the disease appear.

“This study adds further evidence that hyperactivity and hyperconnectivity may play an influential role in Alzheimer’s disease,” says Tal Nuriel, a professor of pathology and cell biology at the Columbia University Medical Center who wasn’t involved in the work. Because this was an observational study, the findings can only establish a correlation between brain activity and Alzheimer’s, Nuriel adds, so it’s still unclear whether the hyperactivity and hyperconnectivity observed during the early stages of the disease are a cause or a consequence of pathological changes that lead to neurodegeneration.

Scientists used to think that increased activity was simply a compensatory effect—the brain trying to make up for a loss of neurons and synapses, says Willem de Haan, a neurologist at the Amsterdam University Medical Center who was not involved in the latest study. “But I think there’s overwhelming evidence that this may actually be pathological hyperactivity.”

Much of that evidence comes from animal experiments conducted over the last decade or so. In rodents, researchers have found that hyperactivity can increase the production and spread of amyloid-ß, the peptide that accumulates into plaques found in the brains of people with Alzheimer’s—and that amyloid-ß can in turn induce neuronal hyperactivity. These findings have led some scientists to speculate that there might be a self-amplifying loop, where a progressive hyperactivity and build-up of amyloid-ß drives pathological changes associated with the neurodegenerative disease.

Research in humans also supports the idea that hyperactivity could play a causal role in Alzheimer’s disease. In 2012, researchers at Johns Hopkins University treated individuals with MCI with the anti-epileptic drug levetiracetam and found that the therapy suppressed activity in the hippocampus and led to improved memory performance. The team is currently testing levetiracetam for MCI in clinical trials. “I think this is one of the most interesting results,” says de Haan. “It seems to show that by correcting hyperactivity we can actually find some improvements in patients that might point to a completely new type of therapy for [Alzheimer’s disease].”

For the current study, Singh’s team also trained a machine-learning algorithm to distinguish APOE4 carriers from non-carriers based on their MEG data and tested whether it would be able to predict cases of Alzheimer’s. They found that while the program was able to perform above chance, the effect was not significant. “In a way, that was kind of encouraging,” Singh says. “Because I don’t think anybody would predict that we could find a signature [for Alzheimer’s] in 20- and 30-year-olds.”

For now, Singh says, his team’s findings simply shed light on what might be going on in the brains of people with the APOE4 allele. There are still a number of unanswered questions—such as when the transition from hyper- to hypoconnectivity and activity happens, what changes occur in the largely understudied middle-aged cohort, and whether there are differences between APOE4 carriers who go on to develop Alzheimer’s and those who don’t. Ultimately, to understand how disruptions in neuronal activity lead to behavioral and cognitive deficits, scientists need to decipher what’s going on inside a healthy brain, Singh says. “[We] require a model of how the brain works—and those are still in their infancy.”

https://www.the-scientist.com/notebook/genetic-risk-for-alzheimers-disease-linked-to-highly-active-brains-66483?utm_campaign=TS_DAILY%20NEWSLETTER_2019&utm_source=hs_email&utm_medium=email&utm_content=78081371&_hsenc=p2ANqtz-98aZf5axxCqtPYITNqfIVWKM6xuk3ni-QSpgTS4gFXzeQcntecrOf6DFFXjrf5qcktWTUz2M3xnAEJlvXTaS7WDQEKNg&_hsmi=78081371

A technology that originated at the University of Minnesota is well on its way to commercialization thanks to an investment award from Alzheimer’s Drug Discovery Foundation (ADDF).

The investment of up to $500,000 was awarded through the ADDF’s Diagnostics Accelerator initiative. Toronto, Ontario-based RetiSpec licensed through the University of Minnesota’s Technology Commercialization program. The technology harnesses hyperspectral imaging and machine learning.

“We are focused on bringing to market a noninvasive, easy-to-use, screening technology that can change when and how we detect Alzheimer’s disease at its earliest stages including before a patient presents with symptoms,” said Eliav Shaked, CEO of RetiSpec. “Early detection provides an important window of opportunity for timely therapeutic interventions that can slow or even prevent the progression of Alzheimer’s disease. ADDF’s investment represents another point of external validation of the promise of our technology.”

In preclinical studies and a pilot human study, the retinal imaging technology was effective in detecting small changes in biomarkers associated with elevated cerebral amyloid beta levels early in the disease process including before the onset of clinical symptoms.

RetiSpec is currently collaborating with Toronto Memory Program, Canada’s largest Alzheimer’s clinical trial site, to validate the accuracy and usability of the technology in patients.

“We believe that RetiSpec’s retinal scanner stands out and shows promise as a unique diagnostic tool among a range of technologies in development,” said Howard Fillit , MD, founding executive director and chief science officer of ADDF The technology has the potential to facilitate early diagnosis, improve the lives of patients and their loved ones and save the healthcare system money and resources. The technology will also be useful in making clinical trials for Alzheimer’s disease more efficient.”

https://www.mddionline.com/feast-your-eyes-new-technology-early-alzheimers-screening