Tag: Alzheimers

Stanford chemists produce chemical — originally from marine creature — needed for new drugs

Photo by Fitzgerald Marine Reserve Docent

One person’s weed is another’s flower. A good example of this is spiral-tufted bryozoan, an invasive marine organism that fouls up marine environments. Although considered a pest by many, spiral-tufted bryozoan is much sought after by researchers since it can produce biostatin 1 — a chemical critical to the development of promising new drugs to treat HIV/AIDS, Alzheimer’s disease and cancer.

Although this bryozoan is abundant, bryostatin 1 is very scarce because it’s difficult to harvest from the sea creature and complex to synthesize. In fact, the National Cancer Institute’s stock of bryostatin 1 is nearly depleted from supplying over 40 clinical trials. So Stanford chemists have developed a new, easier way to synthesize bryostatin 1, as recently reported in Science.

Paul Wender, PhD, a professor of chemistry and of chemical and systems biology at Stanford, has been working for years to develop bryostatin analogs that are more effective for drug development. However, the dwindling supply of bryostatin 1 inspired him to synthesize the drug itself.

“Ordinarily, we’re in the business of making chemicals that are better than the natural products,” Wender said in a recent Stanford news release. “But when we started to realize that clinical trials a lot of people were thinking about were not being done because they didn’t have enough material, we decided, ‘That’s it, we’re going to roll up our sleeves and make bryostatin because it is now in demand.’”

The researchers devised a much simpler synthesize process, cutting the steps down from 57 to 29. They also dramatically increased the yield, making it tens of thousands of times more efficient than extracting bryostatin from spiral-tufted bryozoan and significantly more efficient than the previous synthetic approaches. And they confirmed with a wide range of tests that their synthetic bryostatin was identical to a natural sample supplied by NCI.

So far, the team has produced over two grams of bryostatin 1, and a single gram can treat about 1000 cancer patients or 2000 Alzheimer’s patients, according to their paper. After scaling up production, they expect manufacturers to produce about 20 grams per year to meet clinical and research needs, Wender said in the news release.

They also expect their work could facilitate research using bryostatin analogs derived from their synthesis process. The paper explains that these analogs “are proving to be more effective and better tolerated in comparative studies with cells, disease models in animals, and ex vivo samples taken from HIV-positive patients.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Artificial Intelligence can help predict who will develop dementia, a new study finds

 

Photo by Lukas Budimaier

If you could find out years ahead that you were likely to develop Alzheimer’s, would you want to know?

Researchers from McGill University argue that patients and their families could better plan and manage care given this extra time. So the team has developed new artificial intelligence software that uses positron emission tomography (PET) scans to predict whether at-risk patients will develop Alzheimer’s within two years.

They retrospectively studied 273 individuals with mild cognitive impairment who participated in the Alzheimer’s Disease Neuroimaging Initiative, a global research study that collects imaging, genetics, cognitive, cerebrospinal fluid and blood data to help define the progression of Alzheimer’s disease.

Patients with mild cognitive impairment have noticeable problems with memory and thinking tasks that are not severe enough to interfere with daily life. Scientists know these patients have abnormal amounts of tau and beta-amyloid proteins in specific brain regions involved in memory, and this protein accumulation occurs years before the patients have dementia symptoms.

However, not everyone with mild cognitive impairment will go on to develop dementia, and the McGill researchers aimed to predict which ones will.

First, the team trained their artificial intelligence software to identify patients who would develop Alzheimer’s, by identifying key features in the amyloid PET scans of the ADNI participants. Next, they assessed the performance of the trained AI using an independent set of ADNI amyloid PET scans. It predicted Alzheimer’s progression with an accuracy of 84 percent before symptom onset, as reported in a recent paper in Neurobiology of Aging.

The researchers hope their new AI tool will help improve patient care, as well as accelerate research to find a treatment for Alzheimer’s disease by identifying which patients to select for clinical trials.

“By using this tool, clinical trials could focus only on individuals with a higher likelihood of progressing to dementia within the time frame of the study. This will greatly reduce the cost and time necessary to conduct these studies,” said Serge Gauthier, MD, a senior author and professor of neurology and neurosurgery and of psychiatry at McGill, in a recent news release.

The new AI tool is now available to scientists and students, but the McGill researchers need to conduct further testing before it will be approved and available to clinicians.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Head injuries alter genes linked to serious brain disorders, new study shows

Photo by geralt

Traumatic brain injuries, like those caused by concussions, are common. But suffering even a mild brain injury boosts the likelihood of developing neurological and psychiatric disorders, such as Alzheimer’s disease and posttraumatic stress disorder, years later. Exactly how and why that happens remains a mystery.

“Very little is known about how people with brain trauma — like football players and soldiers — develop neurological disorders later in life,” said Fernando Gomez-Pinilla, PhD, a University of California, Los Angeles professor of neurosurgery and of integrative biology and physiology, in a recent news release.

Now, Gomez-Pinilla and his colleagues have discovered that a brain injury harms “master” genes that control other genes throughout the body. This triggers the alteration of hundreds of genes, which are linked to disorders like Alzheimer’s disease, Parkinson’s disease, PTSD, attention deficit hyperactivity disorder and depression. Their study was recently published in EBioMedicine.

In the study, the researchers trained 20 rats to navigate through a maze. They then injected a fluid into the brain of half the rats to simulate a concussion-like brain injury. When all the rats were retested in the maze, the rats with a brain injury took about 25 percent longer than the controls to solve the maze — indicating a change in basic cognitive function.

Next, the team investigated how the brain injuries altered the rats’ genes. They analyzed RNA samples from the rats’ white blood cells and hippocampi, the part of the brain that plays a central role in memory processes. In the injured rats, they found almost 300 genes had been altered in the hippocampus and over 1200 genes in the white blood cells.

More than 100 of these altered genes have counterparts in humans that are linked to neurological and psychiatric disorders. The researchers concluded that concussive brain injury reprograms key genes and this reprogramming could make neurological and psychiatric disorders more likely.

In addition, almost two dozen of the altered genes occurred in both the hippocampus and white blood cells. The researchers hope this genetic signature can be used to develop a gene-based blood test that determines whether a brain injury has occurred and whether future neurological disorders are likely.

They also hope their identification of master genes can give scientists new targets to develop better pharmaceuticals for brain disorders. However, more research is needed to fully understand the role of these master genes. Gomez-Pinilla said he now plans to study the phenomenon in people who have suffered a traumatic brain injury.

This is a reposing of my Scope blog story, courtesy of Stanford School of Medicine.

Alzheimer’s researchers call on citizen scientists to play an online game

Image by geralt
Image by geralt

Many people, like me, have helplessly watched a loved one suffer and die from dementia. Now there is something you can do to help accelerate Alzheimer’s research — play a game.

The game, called Stall Catchers, is part of the EyesOnALZ project that uses citizen scientists to analyze Alzheimer’s research data. The game was developed by the Human Computation Institute, in collaboration with scientists from Cornell University, MIT and the University of California, Berkeley. The research team is trying to understand the association between reduced blood flow in the brain and Alzheimer’s disease.

The game features movies of real blood vessels in live mouse brains. Players must search for clogged vessels where blood flow is blocked, or stalled. Each movie is seen by many citizen scientists and then checked by a research scientist in order to quickly and accurately identify the stalls.

Past research has shown that Alzheimer’s is associated with the accumulation of beta amyloid proteins that clump together into sticky, neurotoxic aggregates called amyloid plaques. These proteins are normally cleared by the blood stream, but the formation of amyloid plaques slows down this clearance process.

Recent animal studies, performed by the Schaffer-Nishimura Lab at Cornell, suggest that improving blood flow in the brain may help reduce the devastating effects of amyloid accumulation. The researchers discovered that up to two percent of capillaries in the brains of Alzhiemer’s-affected mice were clogged — 10 times more than usual — and this caused up to a 30 percent decrease in overall blood flow in the brain.

“Advanced optical techniques have allowed us to peer into the brain of mice affected by Alzheimer’s disease,” said Chris Schaffer, PhD, the principal investigator in the Schaffer-Nishimura Lab, in a recent news release. “For the first time, we were able to identify the mechanism that is responsible for the significant blood flow reduction in Alzheimer’s, and were even able to reverse some of the cognitive symptoms typical to the disease.”

Now the main challenge for the Cornell researchers is the time-consuming process of manually analyzing all the brain movies to identify the stalled vessels. They need to study up to a thousand vessels for each animal. That’s why they collaborated with the experienced citizen teams at UC Berkeley and MIT to create the Stall Catchers game to get help from the public.

“Today, we have a handful of lab experts putting their eyes on the research data,” said Pietro Michelucci, PhD, the EyesOnALZ principal investigator, in a news story. “If we can enlist thousands of people to do that same analysis by playing an online game, then we have created a huge force multiplier in our fight against this dreadful disease.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

 

Hope for Alzheimer’s Patients?

PET image of brain using PIB
Courtesy of Dr. Jagust Lab, UC Berkeley

My mother died of Alzheimer’s at the age of 69, so I can personally attest to the horror of this disease. I can think of few things worse than slowly watching your cognitive abilities decline, particularly if you are aware of the progressive deterioration as my mother was. So I’m keeping a close watch on the latest Alzheimer’s research, including the research of my colleague William Jagust who is a neuroscientist at UC Berkeley.

Dr. Jagust is participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which is large multicenter project supported by NIH, private pharmaceutical companies and nonprofit organizations. The primary goal of ADNI is to discover indicators (biomarkers) that can track disease progression and hopefully diagnose Alzheimer’s early on. Basically, they want to help speed up and streamline drug and clinical trials by developing biomarkers that track Alzheimer’s more reliably.

The initial ADNI five-year research project completed last fall. It studied cognition, function, brain structure and biomarkers for 800 subjects (200 elderly controls, 400 subjects with mild cognitive impairment, and 200 subjects with Alzheimer’s). The clinical data from the patients went into a large database, including MRI scans, PET scans, blood tests, neuropsychological tests, and genetic tests. The truly unique thing is that this database can be accessed by the public through a website. Basically the raw data (with patient personal information removed) is made available for everyone to use, in hopes that this will help scientists more rapidly understand and treat Alzheimer’s. This ADNI project just received the second phase of funding, so the studies will be expanded.

Although the cause and progression of Alzheimer’s disease is not fully understood, current research indicates that the disease is associated with the formation of “amyloid plaques” and “neurofibrillary tangles” in the brain that damage nerve cells. What does this mean? Amyloid plaques are protein fragments that the body produces naturally. In a healthy brain, these protein fragments are broken down and eliminated. In a brain with Alzheimer’s, the fragments instead accumulate to form hard, insoluble plaques between nerve cells. This excess amyloid buildup occurs before clinical Alzheimer’s symptoms, so it may be used as a predictor of disease. Neurofibrillary tangles are insoluble twisted fibers found inside the brain’s cells. These  tangles mainly consist of a protein called tau, which helps form microtubules that transport nutrients from one part of the nerve cell to another. In an Alzheimer’s brain, the tau protein is abnormal and the tangles collapse this important transport system.

Dr. Jagust and other researchers are studying this beta-amyloid buildup using medical imaging, including PET imaging with a new drug called [11C]Pittsburg Compound B. This new PET drug binds to beta-amyloid plaques and indicates their size and position. “With PET, we’re able to study the biochemistry of the brain, and with MRI we can study both the anatomy and structure of the brain,” Jagust said. “We can also study some of the function of the brain to see what parts of the brain are active during different cognitive tests. So when you put all this information together, you can get a very detailed picture of how the brain is functioning and how function and structure might change with age.” Last fall Jagust published an article on the relationships between biomarkers in aging and dementia. The group found that the confluence of three factors — beta-amyloid deposition, atrophy of the hippocampus (part of the brain that stores and sorts memories), and episodic memory loss — signals early stage of Alzheimer’s. Hopefully this new understanding will ultimately provide early and more accurate diagnosis.

I don’t have room here to summarize all the results from the Jagust lab, let alone all the other labs doing Alzheimer’s research. But I must say that I’m optimistic given the recent progress they have made in understanding the disease. There are also many clinical trials underway for new Alzheimer’s drugs, including ones that hope to stop cognitive deterioration instead of just reducing symptoms. I’m encouraged but I still tell my friends who are doing the research that they need to find a cure within the next 10 years, because I do not want to suffer through this frightening disease like my mother did.

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