Investigational New Drug for Alzheimer’s Scheduled for First Study in Humans--Vanderbilt Scientists Take Investigational Drug Product From Bench To Clinical Trials in Humans

Newswise, February 13, 2017 — Vanderbilt University scientists have received notification from the U.S. Food and Drug Administration (FDA) that testing in humans may proceed for an investigational new drug after more than 10 years of research by scientists at Vanderbilt University and Vanderbilt University Medical Center.

It is relatively uncharted territory for an academic drug discovery group to take a molecule from the laboratory setting to the clinical trials stage.

“The movement to the clinical phase of the research is the result of tireless colleagues reaching across disciplines in pursuit of the shared goal of hoping to someday improve the lives of individuals with Alzheimer’s disease and possibly other brain disorders, such as schizophrenia,” Provost and Vice Chancellor for Academic Affairs Susan R. Wente, Ph.D. said.

“This work exactly illustrates the critical role that basic science conducted in partnership with a world-class medical center can play in advancing knowledge in an attempt to fight a devastating disease.”

For Alzheimer’s disease, the aim is for the investigational drug to target major pathologies of the disease and selectively activate a key receptor in the brain. The Vanderbilt researchers believe that the current standard of care for Alzheimer’s disease, cholinesterase inhibitors, has a different mechanism of action.

They are hoping to establish through future clinical testing that the molecule is broadly effective across a number of cognitive and neuropsychiatric disorders, including schizophrenia.

“This is the first instance I am aware of where an academic drug discovery group moved a molecule designed to hopefully treat a chronic brain disorder all the way from early discovery to human trials without there being, at some point along the way, a pharmaceutical partner,” said P. Jeffrey Conn, Ph.D., Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine and director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). 

“And that really is crossing what people refer to all of the time as the ‘Valley of Death,’ where good research discoveries have a hard time moving into the clinical testing phase due to lack of funding,” he said.

“Importantly, at this early stage, the FDA has only granted permission to assess potential safety of this investigational new drug in healthy volunteers” said Conn.

“We cannot predict the outcome, but if these studies are successful in demonstrating that the investigational drug can be safely administered to humans, this would pave the way to allow filing of additional applications with the FDA to seek permission to advance to testing for efficacy in improving cognitive function in patients suffering from Alzheimer’s disease, and possibly schizophrenia or other brain disorders.

“While we cannot predict the outcome of any future safety or efficacy studies, this decision by FDA allowing clinical research to begin represents a major milestone in allowing us to hopefully provide answers to those critical questions in the future,” Conn said.

VCNDD Co-Director Craig W. Lindsley, Ph.D., director of Medicinal Chemistry and William K. Warren, Jr. Professor of Medicine, said phase I testing will assess drug safety and tolerability in healthy volunteer participants, a process that could take a year.

If successful, the phase II and III studies would include efficacy assessments in patients with Alzheimer’s disease and could take 3-5 years to complete.

“We are hoping to address what we see as an unmet medical need,” Lindsley said.

“For Alzheimer’s patients, the standard of care for symptomatic treatment remains cholinesterase inhibitors, which are 25 years old at this point. There hasn’t been any real scientific advancement in this field in a long time.”

Lindsley and Conn credit The William K. Warren Foundation for its philanthropic investments along the way to make clinical trials for this investigational drug a reality.

“One of the most challenging things about doing this in an academic environment is funding,” Lindsley said.

“Every step requires funding and if there is a delay or break in funding, then everything sits idle and potentially innovative approaches for patient care do not advance.”

“Being matched with the Warrens happened serendipitously. They have invested so much in our programs, and it is wonderful to show them progress on their investments,” he said.

“Without the financial support from the Warrens, this investigational drug would not be poised to enter human clinical trials.”

The William K. Warren Foundation Chief Executive Officer John-Kelly Warren said he is gratified that FDA has allowed for the investigational drug to proceed to testing in human beings.

“Although this is an important sequential milestone, the only milestone that matters to us is the hope that one day we will learn that this investigational new drug has positively and safely changed the life of a patient suffering from a brain disorder such as schizophrenia or Alzheimer’s disease,” Warren said. 

“That day will warrant a celebration felt in the heavens. Until then, we are prepared to support the VCNDD research team until they can deliver the necessary results,” he said.

A NIH National Cooperative Drug Discovery/Development grant funded the early basic science and discovery of this investigational drug and the Alzheimer’s Drug Discovery Foundation and Harrington Discovery Institute helped support some of the key toxicity studies that FDA required, Conn said.

“The investigational new drug has the potential to improve cognitive functions with fewer unwanted side effects.

“This could someday be an important advance for the treatment of cognitive deficits in psychiatric disorders and Alzheimer’s disease,” said Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, which co-funded the research. 

Conn and Lindsley said Vanderbilt’s “team science” approach included contributions from the director of Translational Pharmacology and Development for the VCNDD and Assistant Professor Carrie K. Jones, Ph.D., who coordinated the IND drafting, submission, and subsequent development into Phase I, director of Molecular Pharmacology for the VCNDD and Research Associate Professor of Pharmacology Colleen Niswender, Ph.D., for the molecular pharmacology; Research Assistant Professor of Pharmacology Jerri Rook, Ph.D., for the behavioral studies; and Research Assistant Professor of Pharmacology Thomas Bridges, Ph.D., and Research Assistant Professor of Pharmacology Anna Blobaum, Ph.D., for drug metabolism and pharmacokinetic profiling.

Paul Newhouse, M.D., director of the Center for Cognitive Medicine at VUMC and Jim Turner Professor in Cognitive Disorders, is expected to lead the upcoming clinical study funded in part by the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation.

Study Details Molecular Roots of Alzheimer’s

Credit: Daniel L. Kober

A new study at Washington University School of Medicine in St. Louis details the structure of TREM2, a protein involved in Alzheimer's disease and other neurodegenerative disorders

Cellular 'housekeeping' molecule’s structure linked to neurodegeneration

Newswise, January 3, 2017 — Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer’s disease.

Knowing the shape of the molecule — and how that shape may be disrupted by certain genetic mutations — can help in understanding how Alzheimer’s and other neurodegenerative diseases develop and how to prevent and treat them.

The idea that the molecule TREM2 is involved in cognitive decline — the hallmark of neurodegenerative diseases, including Alzheimer’s — has gained considerable support in recent years.

Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer’s, frontal temporal dementia, Parkinson’s disease and sporadic amyotrophic lateral sclerosis (ALS).

Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50.

“We don’t know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions,” said senior author Thomas J. Brett, PhD, an assistant professor of medicine.

“Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it.”

The analysis of TREM2 structure, completed by first author, Daniel L. Kober, a doctoral student in Brett’s lab, revealed that the mutations associated with Alzheimer’s alter the surface of the protein, while those linked to Nasu-Hakola influence the “guts” of the protein. The difference in location could explain the severity of Nasu-Hakula, in which signs of dementia begin in young adulthood.

The internal mutations totally disrupt the structure of TREM2, resulting in fewer TREM2 molecules. The surface mutations, in contrast, leave TREM2 intact but likely make it harder for the molecule to connect to proteins or send signals as normal TREM2 molecules would.

TREM2 lies on the surface of immune cells called microglia, which are thought to be important “housekeeping” cells. Via a process called phagocytosis, such cells are responsible for engulfing and cleaning up cellular waste, including the amyloid beta that is known to accumulate in Alzheimer’s disease.

 If the microglia lack TREM2, or the TREM2 that is present doesn’t function properly, the cellular housekeepers can’t perform their cleanup tasks.

“Exactly what TREM2 does is still an open question,” Brett said. “We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology. Now that we have these structures, we can study how TREM2 works, or doesn’t work, in these neurodegenerative diseases.”

TREM2 also has been implicated in other inflammatory conditions, including chronic obstructive pulmonary disease and stroke, making the structure of TREM2 important for understanding chronic and degenerative diseases throughout the body, he added.

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This work was supported by the National Institutes of Health (NIH), grant numbers R01-HL119813, R01-AG044546, R01-AG051485, R01-HL120153, R01-HL121791, K01-AG046374, T32-GM007067, K08-HL121168, and P50-AG005681-30.1; the Burroughs-Wellcome Fund; the Alzheimer’s Association, grant number AARG-16-441560; and the American Heart Association, grant number PRE22110004. Results were derived from work performed at Argonne National Laboratory (ANL) Structural Biology Center. ANL is operated by U. Chicago Argonne, LLC, for the U.S. DOE, Office of Biological and Environmental Research, supported by grant number DE-AC02-06CH11357.

Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. Dec. 20, 2016.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

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

Credit: Ping Yan and Jin-Moo Lee

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, 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.

Newswise, November 7, 2016 — 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, of neurology and of biomedical engineering, and the study’s senior author.

“Using this compound, I think we can reduce false negatives, potentially do a better job of identifying people in the earliest stages of Alzheimer’s disease and assess the effects of treatments.”

Amyloid plaques are one of the most telltale findings in the brains of people with Alzheimer’s disease. The neurons near such plaques are often dead or damaged, and this loss of brain cells is thought to account for difficulty with thinking, memory loss and confusion experienced by Alzheimer’s patients.

Amyloid plaques can be either diffuse or compact. The compact kind has long been associated with the disease, but conventional wisdom has held that diffuse plaques are benign, since they can be found in the brains of elderly people without any symptoms of Alzheimer’s disease, as well as the brains of those with Alzheimer’s. Sharma believes that diffuse plaques may mark the earliest stages of the disease.

“It is a relatively underexplored area in the development of Alzheimer’s pathology,” Sharma said.

“Since current approved agents don’t detect diffuse plaques, there is no reliable noninvasive imaging tool to investigate this aspect in animal models or in patients. Our compound could be used to study the role of diffuse plaques.”

Using human amyloid beta proteins, Sharma and colleagues showed that Fluselenamyl bound to such proteins two to 10 times better than each of the three FDA-approved imaging agents for detecting amyloid beta.

In other words, Fluselenamyl detected much smaller clumps of the protein, indicating that it may be able to detect the brain changes associated with Alzheimer’s disease earlier.

To determine whether Fluselenamyl can detect plaques in the brain, the researchers used the compound to stain brain slices from people who had died of Alzheimer’s disease and, as controls, people of similar ages who had died of other causes.

The brain slices from the Alzheimer’s patients, but not the controls, were identified as containing plaques.

When a radioactive atom was incorporated into the compound, the researchers found very little interaction between Fluselenamyl and the healthy white matter in the human brain slices.

“A huge obstacle with existing state-of-the-art PET agents approved for plaque detection is that they tend to bind indiscriminately to the brain’s white matter, which creates false positives on the scans,” Sharma said.

Nonspecific binding to other parts of the brain creates “noise,” which makes it difficult to distinguish samples with plaques from those without.

A similar experiment comparing mice genetically predisposed to develop amyloid plaques with normal control mice showed the same pattern of high sensitivity for amyloid beta and low binding to healthy white matter.

Furthermore, Sharma and colleagues showed that when Fluselenamyl with the radioactive atom is injected intravenously into mice, the compound can cross the blood-brain barrier, bind to any plaques in their brains and be detected by PET scan.

In mice without plaques, the compound is quickly flushed from the brain and then excreted from the body.

The next step is to move to testing in patients. Sharma already has submitted an application to the National Institutes of Health (NIH) for a phase 0 trial, to establish whether Fluselenamyl is safe for use in humans and behaves in the human body the same way it behaves in mice.

Phase 0 trials involve a low dose given to a small number of people to learn how a molecule is processed in the body and how it affects the body.

“Ideally, we’d like to look at patients with very mild symptoms who are negative for Alzheimer’s by PET scan to see if we can identify them using Fluselenamyl,” Sharma said.

 “One day, we may be able to use Fluselenamyl as part of a screening test to identify segments of the population that are going to be at risk for development of Alzheimer’s disease. That’s the long-term goal.”

Natural Compound Reduces Signs Of Aging In Healthy Mice

Safety of NMN being tested in small clinical trial in Japan

Newswise, October 31, 2016 — Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells’ ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body’s energy supply chain is a key driver of the aging process.

Now, scientists at Washington University School of Medicine in St. Louis have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity.

The study is published Oct. 27 in the journal Cell Metabolism

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“We have shown a way to slow the physiologic decline that we see in aging mice,” said Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine.

“This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age.”

Imai is working with researchers conducting a clinical trial to test the safety of NMN in healthy people. The phase 1 trial began earlier this year at Keio University School of Medicine in Tokyo.

With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work by Imai and co-senior author Jun Yoshino, MD, PhD, an assistant professor of medicine, has shown that NAD levels decrease in multiple tissues as mice age.

Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide).

NMN can be given safely to mice and is found naturally in a number of foods, including broccoli, cabbage, cucumber, edamame and avocado.

The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues.

“We wanted to make sure that when we give NMN through drinking water, it actually goes into the blood circulation and into tissues,” Imai said. “Our data show that NMN absorption happens very rapidly.”

To determine the long-term effects of giving NMN, Imai, Yoshino and their colleagues studied three groups of healthy male mice fed regular mouse chow diets.

Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN.

The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years.

The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice.

“When we give NMN to the young mice, they do not become healthier young mice,” Yoshino said.

“NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body’s ability to make NMN and, by extension, NAD.”

In skeletal muscle, the investigators — including the study’s first author, Kathryn Mills, the research supervisor in Imai’s lab — found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants.

They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity.

The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight.

In a paper published earlier this year in Cell Reports, Yoshino and his colleagues revealed more details of how NAD works in influencing glucose metabolism and the body’s fat tissue.

In that study, the mice had a defect in the ability to manufacture NAD only in the body’s fat tissue. The rest of their tissues and organs were normal.

“Even though NAD synthesis was stopped only in the fat tissue, we saw metabolic dysfunction throughout the body, including the skeletal muscle, the heart muscle, the liver and in measures of the blood lipids,” Yoshino said.

“When we gave NMN to these mice, these dysfunctions were reversed. That means NAD in adipose tissue is a critical regulator of whole body metabolism.”

Added Imai, “This is important because Jun showed that if you mess up NAD synthesis only in fat tissue, you see insulin resistance everywhere. Adipose tissue must be doing something remarkable to control whole body insulin sensitivity.”

During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.

“Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence,” Imai said. “But we have not seen any differences in cancer rates between the groups.”

The phase 1 trial in Japan is using NMN manufactured by Oriental Yeast Co., which also provided the NMN used in these mouse studies. Outside of this clinical trial, high-grade NMN for human consumption is not commercially available. But there’s always broccoli.

Alzheimer’s Detected Before Symptoms via New Eye Technology

Human clinical trials scheduled

Newswise, July 22, 2016. — Scientists may have overcome a major roadblock in the development of Alzheimer’s therapies by creating a new technology to observe ― in the back of the eye ― progression of the disease before the onset of symptoms. Clinical trials are to start in July to test the technology in humans according to a paper recently published in Investigative Ophthalmology & Visual Science (IOVS). 

The paper, titled Early detection of amyloidopathy in Alzheimer’s mice by hyperspectral endoscopy, builds upon previous work in cells by detecting changes in the retina of mice predisposed to develop Alzheimer’s.

Early detection of Alzheimer’s is critical for two reasons. “First, effective treatments need to be administered well before patients show actual neurological signs,” said author Robert Vince, PhD, of the Center for Drug Design at the University of Minnesota (UMN).

“Second, since there are no available early detection techniques, drugs currently cannot be tested to determine if they are effective against early Alzheimer’s disease. An early diagnostic tool like ours could help the development of drugs as well.”

Looking through the eye to see the brain is a key advantage of the new technology. “The retina of the eye is not just ‘connected’ to the brain — it is part of the central nervous system,” said author Swati More, PhD, also of the Center for Drug Design at UMN. While the brain and retina undergo similar changes due to Alzheimer’s disease, “unlike the brain, the retina is easily accessible to us, making changes in the retina easier to observe.” 

“We saw changes in the retinas of Alzheimer’s mice before the typical age at which neurological signs are observed,” said More. “The results are close to our best-case scenario for outcomes of this project.”

For more information on participating in the clinical trial, please visit the trial website.

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The ARVO peer-reviewed open access journal Investigative Ophthalmology & Visual Science (IOVS) publishes results from original hypothesis-based clinical and laboratory research studies, as well as Reviews,Perspectives, and special issues. IOVSranks No. 1 among 58 ophthalmology journals for number of citations and its 2015 Impact Factor places it at No. 6. The journal is online-only (iovs.arvojournals.org) and articles are published daily. ARVO, an organization of nearly 12,000 researchers from over 75 countries, advances research worldwide into understanding the visual system and preventing, treating and curing its disorders. In addition to IOVS, ARVO publishes the Journal of Vision and Translational Vision Science & Technology.

Understanding How Chemical Changes in the Brain Affect Alzheimer's Disease

Newswise, June 24, 2016 — A new study from Western University is helping to explain why the long-term use of common anticholinergic drugs used to treat conditions like allergies and overactive bladder lead to an increased risk of developing dementia later in life. The findings show that long-term suppression of the neurotransmitter acetylcholine - a target for anticholinergic drugs - results in dementia-like changes in the brain.

"There have been several epidemiological studies showing that people who use these drugs for a long period of time increase their risk of developing dementia," said Marco Prado, PhD, a Scientist at the Robarts Research Institute and Professor in the departments of Physiology and Pharmacology and Anatomy & Cell Biology at Western's Schulich School of Medicine & Dentistry. "So the question we asked is 'why?'"

For this study, published in the journalCerebral Cortex, the researchers used genetically modified mouse models to block acetylcholine in order to mimic the action of the drugs in the brain. Neurons that use acetylcholine are known to be affected in Alzheimer's disease; and the researchers were able to show a causal relationship between blocking acetylcholine and Alzheimer's-like pathology in mice.

"We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer's pathology," said Prado.

Prado and his partner Dr. Vania Prado, DDS, PhD, along with PhD candidates Ben Kolisnyk and Mohammed Al-Onaizi, have shown that blocking acetylcholine-mediated signals in neurons causes a change in approximately 10 per cent of the Messenger RNAs in a region of the brain responsible for declarative memory.

Messenger RNA encodes for specific amino acids which are the building blocks for proteins and several of the changes they uncovered in the brains of mutant mice are similar to those observed in Alzheimer's disease.

"We demonstrated that in order to keep neurons healthy you need acetylcholine," said Prado. "So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer's disease."

Importantly, by targeting one of the messenger RNA pathways they uncovered, the researchers improved pathology in the mutant mice.

The study, conducted at Western's Robarts Research Institute, used human tissue samples to validate the mouse data and mouse models to show not only the physical changes in the brain, but also behavioral and memory changes.

The researchers were able to show that long-term suppression of acetylcholine caused brain cell to die and as a consequence decrease memory in the aging mice.

"When the mutant mice were old, memory tasks they mastered at young age were almost impossible for them, whereas normal mice still performed well," said Kolisnyk.

The researchers hope their findings will have an impact on reducing the burden of dementia by providing new ways to reverse the loss of acetylcholine.

The researchers were supported by CIHR, Brain Canada and NSERC and the work was done in collaboration with researchers at the UCL Institute of Neurology, The Hebrew University of Jerusalem and McMaster University.

Why Do People with Alzheimer's Stop Recognizing Their Loved Ones?

 New findings from face perception research

Newswise, April 14, 2016– Alzheimer’s not only steals people’s memories but also their ability to recognize faces, which widens the gulf between people with this disease and their loved ones.

A recent study has demonstrated that, beyond causing memory problems, Alzheimer’s disease also impairs visual face perception.

This finding may help families better understand their loved one's inevitable difficulties and lead to new avenues to postpone this painful aspect of the disease.

Research in this area by the team of Dr. Sven Joubert, PhD, a researcher at the Centre de recherche de l'Institut universitaire de gériatrie de Montréal and a professor with the Department of Psychology at Université de Montréal, will be published tomorrow in the Journal of Alzheimer’s Disease. 

Face perception plays a fundamental role in human communication, which is why humans have evolved into experts at quickly detecting and identifying faces.

This faculty is thought to depend on the ability to perceive a face as a whole. Also known as “holistic perception,” this ability is in contrast to the local and detailed analysis required to perceive individual facial features, such as the eyes, nose or mouth. Dr. Joubert’s study has demonstrated that the holistic ability to perceive faces is impaired by Alzheimer’s disease. 

For the study, the Montreal team recruited people with Alzheimer’s along with healthy seniors to study their ability to perceive faces and cars in photos that were either upright or upside down. Dr. Joubert explains the team's findings: “The results for people with Alzheimer's were similar to those in the control group in terms of answer accuracy and the time to process the upside-down faces and cars.

“To perform these tasks, the brain must perform a local analysis of the various image components perceived by the eye.

“ However, with the upright faces, people with Alzheimer’s were much slower and made more mistakes than the healthy individuals. This leads us to believe that holistic face recognition in particular becomes impaired.

“Subjects with Alzheimer’s disease also demonstrated normal recognition of the upright cars, a task that in theory does not require holistic processing. This suggests that Alzheimer's leads to visual perception problems specifically with faces.”

What's also surprising about this impairment is that it is observed in the early stages of the disease.

Overall, Dr. Joubert’s study better explains the mechanism involved in the problem that people with Alzheimer’s have with recognizing the faces of family members or celebrities.

The fact that impaired facial recognition might stem from a holistic perception problem—and not just a general memory problem—opens the door to different strategies (such as the recognition of particular facial traits or voice recognition) to help patients recognize their loved ones for longer. 

Alzheimer’s Plaques Found in Middle-Aged People with Brain Injuries

Newswise, February 5, 2016--A new study suggests that people with brain injuries following head trauma may have buildup of the plaques related to Alzheimer’s disease in their brains. The research is published in the February 3, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

A corresponding editorial states that over the past decade the rate of emergency department visits related to traumatic brain injury (TBI) has increased by 70 percent. The editorial also says an estimated three to five million Americans live with a TBI-related disability.

“The study is small and the findings preliminary, however, we did find an increased buildup of amyloid plaques in people who had previously sustained a traumatic brain injury,” said study author Professor David Sharp, MD, of Imperial College London, in the United Kingdom. 

“The areas of the brain affected by plaques overlapped those areas affected in Alzheimer’s disease, but other areas were involved. People after a head injury are more likely to develop dementia, but it isn’t clear why. Our findings suggest TBI leads to the development of the plaques which are a well-known feature of Alzheimer’s disease.”

For the study, nine people with an average age of 44 who had a single moderate to severe TBI had PET and MRI brain scans. The brain injuries occurred between 11 months and up to 17 years before the start of the study. The participants were compared to 10 people with Alzheimer’s disease and nine healthy participants.

The PET scans used a marker that detects plaques in the brain. The MRI scans used diffusion tensor imaging to detect damage to brain cells that occurs after TBI. Both the people with brain injuries and the people with Alzheimer’s disease had plaques in the posterior cingulate cortex, which is affected early in Alzheimer’s, but only those with brain injuries had plaques in the cerebellum. The researchers also found that plaques were increased in patients with more damage to the brain’s white matter.

“It suggests that plaques are triggered by a different mechanism after a traumatic brain injury,” Sharp said. “The damage to the brain’s white matter at the time of the injury may act as a trigger for plaque production.”

“If a link between brain injury and later Alzheimer’s disease is confirmed in larger studies, neurologists may be able to find prevention and treatment strategies to stave off the disease earlier,” said Sharp.

The study was supported by the Imperial College Healthcare Trust Biomedical Research Center.

To learn more about Alzheimer’s disease, please visit www.aan.com/patients.

The American Academy of Neurology, an association of 30,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

Jet Lag-Like Sleep Disruptions Spur Alzheimer’s Memory, Learning Loss

Results suggest greater emphasis on managing slumber habits of people with AD risk

Newswise, October 29, 2015 — Chemical changes in brain cells caused by disturbances in the body’s day-night cycle may be a key underlying cause of the learning and memory loss associated with Alzheimer’s disease, according to a University of California, Irvine study.

The research on mice, led by UCI biomedical engineering professor Gregory Brewer, provides the first evidence that circadian rhythm-altering sleep disruptions similar to jet lag promote memory problems and chemical alterations in the brain.

Clinical application of this finding may lead to more emphasis on managing the sleep habits of people at risk for Alzheimer’s disease and those with mild cognitive impairment. Study results appear online in the Journal of Alzheimer’s Disease.

People with Alzheimer’s often have problems with sleeping or may experience changes in their slumber schedule. Scientists do not completely understand why these disturbances occur.

“The issue is whether poor sleep accelerates the development of Alzheimer’s disease or vice versa,” said Brewer, who’s affiliated with UCI’s Institute for Memory Impairments and Neurological Disorders. “It’s a chicken-or-egg dilemma, but our research points to disruption of sleep as the accelerator of memory loss.”

In order to examine the link between learning and memory and circadian disturbances, his team altered normal light-dark patterns with an eight-hour shortening of the dark period every three days for young mouse models of Alzheimer’s disease and normal mice.

The resulting jet lag greatly reduced activity in both sets of mice, and the researchers found that in water maze tests, the AD mouse models had significant learning impairments absent in the AD mouse models not exposed to light-dark variations and in normal mice with jet lag.

In follow-up tissue studies, they saw that jet lag caused a decrease in glutathione levels in the brain cells of all the mice. But these levels were much lower in the AD mouse models and corresponded to poor performance in the water maze tests. Glutathione is a major antioxidant that helps prevent damage to essential cellular components.

Glutathione deficiencies produce redox changes in brain cells. Redox reactions involve the transfer of electrons, which leads to alterations in the oxidation state of atoms and may affect brain metabolism and inflammation.

Brewer pointed to the accelerated oxidative stress as a vital component in Alzheimer’s-related learning and memory loss and noted that potential drug treatments could target these changes in redox reactions.

“This study suggests that clinicians and caregivers should add good sleep habits to regular exercise and a healthy diet to maximize good memory,” he said.

Kelsey LeVault and Shelley Tischkau of the Southern Illinois University School of Medicine contributed to the research, which received support from the National Institutes of Health (grant R01 AG032431).

About the University of California, Irvine: Currently celebrating its 50th anniversary, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot.

Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $4.8 billion annually to the local economy. For more on UCI, visit www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UC Irvine faculty and experts, subject to availability and university approval. For more UC Irvine news, visit news.uci.edu..

Dementia-Staying Safe At Home

 Follow this checklist on making the home a safe environment for those with dementia.

ATLANTA, Aug. 26, 2015 /PRNewswire/ -- Home can be a scary place for someone who has been diagnosed with dementia or Alzheimer's.  The possibility of wandering into unsafe areas or disappearing outside the home is a constant worry for loved ones.  

Environment is so important to a person with dementia.  It is critical to address factors such as noise, color, lighting, as well as these other safety precautions:    

         

• Lighting – Dementia can cause susceptibility to glare, sudden changes in light levels and hallucination. Make sure rooms are evenly lit and that your loved one is not going from an overly lit room to a dark one.  Glare-free lighting works best.  If there is a lot of glare on a table or on a surface it can distort visual perception.  Installing automatic lighting can also be very helpful.          
• Disguise Doors – Disguising a door can prevent wandering into a dangerous place.  Hang a curtain or turn the door into a mural.  Studies have shown that a large red stop sign sends an understandable message to even those with severe memory loss. Install multiple locks on a door, each at varying heights out of direct sight and supplement with an alarm.                    
• Flood Alarms – Flood Alarms are inexpensive insurance in any room where a water leak or overflow might be possible.  Also install faucets with anti-scald devices. 
• Handrails – Mobility issues are common with dementia.  Handrails increase the ability to function.  Grab bars are also helpful for getting on and off the toilet safely. 
• Color Contrast – Depth perception is a serious problem and climbing the stairs can be a big issue.  Use 2 inch color tape or paint stripes going up and down the stairs.                       
• "Baby Proof" – Install latches higher or lower than eye level.  Use gates to deny access to unsafe areas.  Use motion sensor devices that sound an alarm or turn on a light to alert you to someone wandering where it may not be safe.  
• Clear Clutter – People with dementia can develop a shuffling walk and may not pick up their feet.  Remove area rugs and door sills.  Make the home easy to navigate through.      

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