Landmark Alzheimer’s prevention trial to evaluate third drug

Effort to study drug's ability to prevent, delay the disease By Tamara Bhandari December 19, 2016 Washington University School of Medicine's Randall J. Bateman, MD, talks with DIAN-TU trial participant Natalie Shriver, of Omaha, about a study to test drugs that may prevent or delay Alzheimer's disease. (Photo: Robert Boston/Washington University School of Medicine) An international team led by Washington University School of Medicine in St. Louis has selected a third investigational drug to be tested in a worldwide clinical trial — already underway — aimed at finding treatments to prevent Alzheimer’s disease. The third drug is being developed by Janssen Research & Development, LLC, in New Jersey. It is designed to lower production of amyloid beta, a protein that clumps together into plaques and damages neurons in the brain, leading to memory loss, cognitive problems and confusion. The drug is designed to block the enzyme beta secretase — which produces amyloid beta — with a goal of reducing the amount of amyloid beta available to clump and cause neurodegeneration. This investigational drug joins two others already being evaluated in the Dominantly Inherited Alzheimer’s Network Trial Unit (DIAN-TU) study, which involves people with an inherited predisposition to develop Alzheimer’s at a young age, usually in their 30s, 40s or 50s. Participants already enrolled will continue on their existing drug regimens, and additional volunteers with no or mild symptoms of cognitive impairment will be enrolled to evaluate the third drug. “We are delighted with the new collaboration with Janssen Research & Development to expand the number of novel therapeutic targets we are testing,” said Washington University Alzheimer’s specialist Randall J. Bateman, MD, director of the DIAN-TU, a public-private-philanthropic research partnership. “Testing a beta secretase inhibitor in [...]

Earlier Alzheimer’s diagnosis may be possible with new imaging compound

New tool detects Alzheimer’s protein, may help identify brain changes, assess treatment effects By Tamara Bhandari November 2, 2016 Researchers at Washington University School of Medicine in St. Louis have developed a chemical compound that detects the Alzheimer’s protein amyloid beta better than current FDA-approved agents. The compound potentially may be used in brain scans to identify people in the earliest stages of Alzheimer’s disease. In the image above, the compound has passed from the bloodstream of a living mouse into its brain, where it is detected by a positron emission tomography (PET) scan. Arrows indicate clumps of amyloid beta. (Image: Ping Yan and Jin-Moo Lee) By the time unambiguous signs of memory loss and cognitive decline appear in people with Alzheimer’s disease, their brains already are significantly damaged, dotted with clumps of a destructive protein known as amyloid beta. For years, scientists have sought methods and clues to help identify brain changes associated with Alzheimer’s earlier in the disease process, so they can try to stop or even reverse the changes before they severely affect people’s lives. Now, researchers at Washington University School of Medicine in St. Louis have developed a chemical compound, named Fluselenamyl, that detects amyloid clumps better than current FDA-approved compounds. If a radioactive atom is incorporated into the compound, its location in a living brain can be monitored using positron emission tomography (PET) scans. The compound, described in a paper published Nov. 2 in Scientific Reports, one of the Nature journals, potentially could be used in brain scans to identify the signs of early-stage Alzheimer’s disease or to monitor response to treatment. “Fluselenamyl is both more sensitive and likely more specific than current agents,” said Vijay Sharma, PhD, a professor of radiology, [...]

From labs to lives: Self-replicating cells help treat neuro disorders

July 27, 2016 Scientists estimate that human bodies contain anywhere from 75 to 100 trillion cells. And of these cells, there are hundreds of different types. Yet, one cell type in particular has captured the fascination of assistant professor David Brafman: the human pluripotent stem cell (hPSC).Assistant professor David Brafman mentoring biomedical engineering junior Lexi Bounds, who plans to pursue a career in stem cell research. Photographer: Jessica Hochreiter/ASU As self-replicating cells — capable of dividing and forming new cells — hPSCs offer immense research potential. They are able to provide the raw material needed to generate the hundreds of different cell types that comprise the human body. Think of it as a reverse e pluribus unum. Something like out of one, come many. Brafman has received a $420,000 grant from the National Institutes of Health to take discoveries related to hPSCs out of the research lab and into the clinical setting where they can transform, even save, lives. In particular, his research focuses on using the remarkable qualities of hPSCs to generate large quantities of hPSC-derived neurons, which are instrumental in advances toward the study and treatment of Alzheimer’s disease, ALS, spinal cord injuries and other neurodegenerative disorders. “Neurodegenerative diseases and disorders remain some of the leading causes of mortality and morbidity in the United States,” said Brafman, a biomedical engineering faculty member in ASU’s Ira A. Fulton Schools of Engineering. According to the Alzheimer’s Association, the disease affects more than 130,000 individuals statewide and is the fifth leading cause of death in Arizona. “Several bottlenecks limit the translation of hPSCs and their derivatives from bench to bedside,” said Brafman, referring to the need to take this research from the laboratory bench to the clinical [...]

$4 million grant expands major study to find Alzheimer’s prevention treatments

Investigators will accelerate drug testing, develop new diagnostic measures by Tamara Bhandari • June 21, 2016 JUDY MARTIN FINCH Dean DeMoe, a participant in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) study at Washington University, receives AV1451 — a radiopharmaceutical — from imaging technologist Holly Karsch. AV1451 binds to tau protein in the brain. Washington University School of Medicine in St. Louis has received a $4.3 million award from the Alzheimer’s Association to expand a major international clinical trial evaluating whether drugs can prevent Alzheimer’s disease in patients genetically predisposed to develop the devastating disease at a young age. The funding will accelerate testing of new drugs against early-onset Alzheimer’s and builds on the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) study, which is led by Washington University. The DIAN-TU, which got underway in 2012, is the first trial aimed at identifying drugs to prevent or slow Alzheimer’s in people who are certain to develop the disease but do not yet show symptoms. The new phase of the trial is known as the DIAN-TU Next Generation Prevention Trial (NexGen). As part of the trial’s expansion, multiple sites worldwide will be added to the study. “New funding for the DIAN-TU NexGen is helping us move forward with the trial and is critical to finding a way to slow or stop the progression of Alzheimer’s,” said the DIAN-TU program director and principal investigator, Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University. “We hope to be able to intervene before symptoms of the disease, such as memory loss and cognitive decline, become apparent. The expansion of the trial will let us start quickly with novel trial approaches, which will test [...]

Regenerating memory with neural stem cells

Researchers look for better ways to reduce memory loss in people with age-related disorders June 13, 2016 Although brains—even adult brains—are far more malleable than we used to think, they are eventually subject to age-related illnesses, like dementia, and loss of cognitive function. Someday, though, we may actually be able to replace brain cells and restore memory. Recent work by Ashok K. Shetty, Ph.D., a professor in the Department of Molecular and Cellular Medicine, associate director of the Institute for Regenerative Medicine, and research career scientist at the Central Texas Veterans Health Care System, and his team at the Texas A&M Health Science Center College of Medicine hints at this possibility with a new technique of preparing donor neural stem cells and grafting them into an aged brain. Shetty and his team took neural stem cells and implanted them into the hippocampus—which plays an important role in making new memories and connecting them to emotions—of an animal model, essentially enabling them to regenerate tissue. Findings were published in the journal Stem Cells Translational Medicine. “We chose the hippocampus because it’s so important in learning, memory and mood function,” Shetty said. “We’re interested in understanding aging in the brain, especially in the hippocampus, which seems particularly vulnerable to age-related changes.” The volume of this part of the brain seems to decrease during the aging process, and this decrease may be related to age-related decline in neurogenesis (production of new neurons) and the memory deficits some people experience as they grow older. The aged hippocampus also exhibits signs of age-related degenerative changes in the brain, such chronic low-grade inflammation and increased reactive oxygen species. “We’re very excited to see that the aged hippocampus can accept grafted neural [...]

Research, research, research: 8 undergraduate projects underway at UMSL

MAY/26/2016 | POSTED BY MARISOL RAMIREZ Senior psychology major Beth Wiese (left) and fellow researcher and recent psychology alumnus Tom Mauer present one of the many research projects Wiese is involved with at UMSL during the Undergraduate Research Symposium this spring. (Photo by Marisol Ramirez) Alzheimer’s Disease, stone lithography and plant hormones are just a few of the research topics undergraduate students are pursuing this year at the University of Missouri–St. Louis. As the largest public research university in eastern Missouri, it’s not surprising that UMSL offers such diverse research opportunities for undergraduates, getting them in the lab and writing formal papers early in their academic careers. Building on that tradition, the College of Arts and Sciences awarded eight undergraduate students the CAS Undergraduate Research Award, which funds them up to $1000 each for their proposed projects. It’s an annual and competitive award. “My research gave me the chance to dig into an area of interest that hadn’t been as heavily covered in the classroom,” said Beth Wiese, a senior psychology major whose project on alcoholism in relation to the Greek economy received funding. “It helped foster a passion for an area that I may have never found without the opportunity to do the research. I also get a hands-on understanding of the scientific method.” In addition to the CAS Undergraduate Research Award, Wiese got the chance to present one of her projects earlier this month at the Undergraduate Research Symposium, organized and run by UMSL students in the Golden Key International Honour Society. “URS is great for undergraduate researchers looking to practice presenting their research,” she said. “Plus, it’s an affordable way to do so if they can’t fit a conference into their schedule.” [...]

Brain imaging links Alzheimer’s decline to tau protein

Tau is better marker of progression to Alzheimer’s disease than amyloid beta By Julia Evangelou Strait May 11, 2016 Washington University in St. Louis, the SOURCE A study using a new PET imaging agent shows that measures of tau protein in the brain more closely track cognitive decline due to Alzheimer’s disease compared with long-studied measures of amyloid beta. More red color indicates more tau protein. The image on the left shows the average tau accumulation in the brains of cognitively normal people, averaged over many individuals. The image on the right shows the average amount of tau buildup in the brains of multiple people with mild Alzheimer’s symptoms. Scanning multiple individuals shows that the intensity of tau deposits correlates with the severity of cognitive dysfunction. (Image: Matthew R. Brier) A buildup of plaque and dysfunctional proteins in the brain are hallmarks of Alzheimer’s disease. While much Alzheimer’s research has focused on accumulation of the protein amyloid beta, researchers have begun to pay closer attention to another protein, tau, long associated with this disease but not studied as thoroughly, in part, because scientists only recently have developed effective ways to image tau. Using a new imaging agent that binds to tau protein and makes it visible in positron emission tomography (PET) scans, scientists at Washington University School of Medicine in St. Louis have shown that measures of tau are better markers of the cognitive decline characteristic of Alzheimer’s than measures of amyloid beta seen in PET scans. The new study is published May 11 in the journal Science Translational Medicine. Comparing brain images of people who are cognitively normal to patients with mild Alzheimer’s disease, the researchers found that measures of tau better predict symptoms [...]

Problems finding your way around may be earliest sign of Alzheimer’s disease, study suggests

Navigation skill test could diagnose brain changes long before memory fails By Gerry Everding, April 19, 2016 Long before Alzheimer’s disease can be diagnosed clinically, increasing difficulties building cognitive maps of new surroundings may herald the eventual clinical onset of the disorder, finds new research from Washington University in St. Louis. Denise Head“These findings suggest that navigational tasks designed to assess a cognitive mapping strategy could represent a powerful new tool for detecting the very earliest Alzheimer’s disease-related changes in cognition,” said senior author Denise Head, associate professor of psychological and brain sciences in Arts & Sciences. “The spatial navigation task used in this study to assess cognitive map skills was more sensitive at detecting preclinical Alzheimer’s disease than the standard psychometric task of episodic memory,” she said. Preclinical Alzheimer’s disease denotes the presence of Alzheimer-related changes in the brain that occur prior to the development of symptoms that lead to the diagnosis. The hippocampus (shown in red) is associated with cognitive mapping skills. (Credit: Life Science Databases via Wikimedia Commons)The caudate (shown in red) is more associated with route learning. (Credit: Life Science Databases via Wikimedia Commons)The cognitive findings from this study, published in the April issue of the Journal of Alzheimer’s Disease, are consistent with where in the brain the ill effects of Alzheimer’s disease first surface, as well as with the progression of the disease to other brain regions. Previous research has shown that navigation problems crop up early in individuals with Alzheimer’s disease. These deficits may be associated with the build up of amyloid plaques and tau tangles and other signs of deterioration and shrinkage in the brain’s prefrontal cortex, hippocampus and caudate. The hippocampus, which is associated with long-term memory storage, the [...]

Longer-lived imaging agents could hasten Alzheimer’s research

Chemist hopes to force Alzheimer's to show its hand By Diana Lutz Feb. 29, 2016 In the past few years, despite the best efforts of scientists and medical researchers, drug after drug designed to slow or stop the progression of Alzheimer’s disease has failed in clinical trials. Some had no effect on the progression of the disease, others made patients’ symptoms worse and yet others produced results so equivocal it was difficult to interpret them. Given this ongoing challenge, some scientists have begun to question the model of the disease many of the drugs assume. Known as the amyloid cascade hypothesis, it posits that the cognitive decline in Alzheimer’s is caused by the accumulation in the brain of plaques, or aggregates, of thousands of copies of a peptide called amyloid beta.  Instead of being neurotoxic, the plaques may actually be protective, said Liviu Mirica, associate professor of chemistry in Arts & Sciences at Washington University in St. Louis. Recent work suggests small aggregates of amyloid-beta peptide, called soluble oligomers, rather than the insoluble plaques may be the neurotoxic form of amyloid beta. This might explain why the disease process seems to start 10-15 years before the plaques become prominent in the brain, he said. Mirica, who specializes in the design of chemical agents that contain metal ions, called metal complexes, has a clever idea he hopes might help the scores of scientists and research physicians who are struggling to unravel the mechanism of this disease. A representative bifunctional compound has sites (the left and right arms) that interact with the amyloid beta peptide and another site that binds metal ions such as Cu2+(shown in the center as an orange sphere). (Image: Liviu Mirica)He wants to design bifunctional chemical agents [...]

Body’s immune system may play larger role in Alzheimer’s disease than thought

UCI mouse study finds dramatic increase in brain plaques when key cells are lacking ON FEBRUARY 23, 2016 Irvine, Calif., Feb. 23, 2016 — Immune cells that normally help us fight off bacterial and viral infections may play a far greater role in Alzheimer’s disease than originally thought, according to University of California, Irvine neurobiologists with the Sue & Bill Gross Stem Cell Research Center and the Institute for Memory Impairments and Neurological Disorders. The researchers discovered this when Alzheimer’s disease mice genetically modified to lack these key immune cells in their blood developed the distinctive brain plaques associated with the neurodegenerative disorder much more quickly. According to Mathew Blurton-Jones, assistant professor of neurobiology & behavior, and doctoral student Samuel Marsh, their findings could lead to the creation of new techniques to help identify, or perhaps even treat, individuals at risk of developing the disease. Alzheimer’s is the leading cause of age-related dementia and is thought to be driven by the accumulation of a protein called beta-amyloid that aggregates to form amyloid plaques in the brain. Microglia, immune cells that reside in the brain, attempt to clear this buildup, but in Alzheimer’s, they appear to be fighting a losing battle. While many studies have explored the role of microglia in Alzheimer’s, very few researchers have asked whether a different set of immune cells called T-cells and B-cells that reside outside the brain and play a large part in autoimmune diseases might also impact Alzheimer’s. To test this idea, Blurton-Jones and Marsh bred genetically modified Alzheimer’s disease mice to lack three key immune cell types: T-cells, B-cells and NK-cells. Six months later, when the brains of these mice were compared to those of Alzheimer’s mice with [...]