“Aging is not inevitable; it is an opportunity. Not everyone has the chance to grow old,” said Robert Friedland, professor of neurology at the University of Louisville and an expert on aging. “How well we age depends on what we do.”

Inspired by his grandfather’s struggle with dementia, Friedland has spent nearly five decades as a neurologist and researcher, studying the causes of neurological diseases and seeking new ways to treat and prevent them. In addition to seeing patients with a focus on cognitive, behavioral and geriatric neurology, his ongoing research investigates the connection between microbes in the gut and mouth and the development of Alzheimer’s and Parkinson’s disease and other neurodegenerative conditions.

Based on this work, Friedland says it is possible for people to preserve health into later years by stockpiling reserves in cognitive, physical, psychological and social health.

Although Friedland admits that certain physical declines are inevitable with age and that genetics can predispose a person to certain diseases, he believes in many cases these reserves can prevent diseases or lessen their effects, delay age-related declines and allow an older person to recover from accidents and illness.

“Genetics do have a role in our health but they are not the whole story. Choices we make throughout life affect whether diseases develop and how much they reduce our health when they do,” Friedland said. “We can do things that delay or mitigate heart disease, diabetes and cognitive and neurological diseases and allow us to recover from life events that otherwise may cause permanent declines in health.”

Each of Friedland’s four factors, described below, is dependent on the others. Friedland provides tips on increasing reserves of each area. By developing habits that add to these reserves, you can maximize your opportunity to remain active and healthy as you get older.

Cognitive reserve – The ability of the brain to work effectively, solve problems and make decisions.

Since the brain controls every system in the body, it makes sense that a healthy brain will support other reserve factors (physical, psychological, social).

Keep the brain healthy by seeking opportunities to learn new things and challenge your ways of thinking throughout life. Learn a new language or a new skill, such as playing a musical instrument or crochet. Play chess or other games. Any activity that involves learning and strategy will strengthen your brain.

“Watching television is not a good activity since it is completely passive and does not require participation. Reading is a better choice as it demands involvement,” Friedland said. “Telling stories is good for your memory and attention skills.”

Physical reserve – The health of the body’s cardiovascular, neurological, musculoskeletal and other systems.

These reserves depend on eating the right food, engaging in physical activity every day and receiving regular health care.

A diverse diet of healthy foods supports both your body and your microbiota, the microorganisms that live in and on the body and are essential to your overall health. Friedland recommends a diet that is mostly plants, high in fiber and low in sugar, salt and saturated fat. When you improve your diet, you also can improve the health of your microbes which aids your own health.

“I call it gene therapy in the kitchen,” Friedland said. “By making the best choices in your food, you can alter the genetic makeup of your microbiota and improve your overall health in as little as two weeks.”

Exercising for 30 minutes each day, regardless of weather or circumstance, is enough to improve physical health, Friedland says. More is better, of course, and when you combine physical activity with social interactions and cognitive activity by playing a sport such as golf or tennis, the benefits multiply.

Taking steps to protect yourself from injury or illness also is important. Wear a helmet when you are riding a bike, wash your hands and avoid exposure to toxins.

It also is important to get enough quality sleep each night, practice good dental hygiene, avoid excess alcohol and have regular medical checkups.

Polypharmacy is another problem to avoid. Friedland said that as people age, they may accumulate prescriptions for multiple health concerns that can interact or alter the effectiveness of each other. If you are taking several prescriptions, regularly evaluate all of them with your health care provider.

Psychological reserve – A healthy mental state that is free of agitation, anxiety and depression.

Poor mental health can affect your ability to interact with others or maintain your physical health. Practice a positive mental attitude, engage in activities that are meaningful to you and manage stress with meditation or other measures.

“Depression is common in older people, and that can lead to memory problems,” Friedland said. “Physical factors can contribute to depression, such as poor sleep or vitamin deficiency. A lack of social interactions and physical activity also can cause or aggravate depression.”

Social reserve – Personal relationships and the ability to function in society.

The company of others can motivate people to take care of themselves and encourage them to maintain healthful behaviors. Positive relationships can be with a spouse, a group of friends or professional colleagues.

“Studies indicate that dementia is more common among people whose social activity declines later in life,” Friedland said. “Humans need relationships with others in order to maintain good health.”  

Social engagement can go hand in hand with the other types of activity by including friends in physical exercise, games, a craft or work. Involvement in community or religious activities also can increase a sense of belonging and a desire to stay active.

Ideally, you will begin developing habits that contribute to these reserves early in life, but Friedland says it is possible to add to reserves and improve your health at any age – even once you reach an age when you experience the effects of deficits.

“Aging is not inevitable,” Friedland said. “The chance to be alive should be recognized as an opportunity – an opportunity to manage our lifestyle factors to maximize survival, health, fitness and meaning as we age.”

More detailed advice from Friedland that may help people live longer, healthier lives and a deeper discussion of the reasons he makes these recommendations are available in his book, “.” Published in October by Cambridge University Press, the book was cited by the Wall Street Journal as one of the five best books on aging and retirement published in 2022.

Friedland has studied Alzheimer’s disease, dementia and related conditions for more than 30 years. His previous work has uncovered the such as Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease), Alzheimer’s disease and Parkinson’s disease. Previously, Friedland worked with researchers at the National Cerebral and Cardiovascular Center in Osaka to reveal the important influence of oral bacteria on the development of hemorrhagic stroke.

In Kyoto, Friedland will further investigate the influence of the microbiota on neurodegenerative disease models in fruit flies. He plans tests to determine the influence of functional bacterial amyloid proteins on the aggregation of brain proteins, a key element of neurodegenerative diseases. Friedland will collaborate in this research with Toshiki Mizuno, PhD, of the KPUM Division of Neurology and Gerontology, one of several Japanese researchers with whom Friedland has worked for several decades.

He also will conduct research with collaborators at the Kyoto Institute of Technology.

“I am excited to have the opportunity to collaborate further with my Japanese colleagues and to conduct this research in Kyoto,” Friedland said.

JSPS awards fellowships to select international researchers to conduct collaborative work with researchers in Japan. Long-term fellowships for 2020 have been awarded in agriculture, engineering, chemistry, math, humanities and medicine. Friedland received one of four fellowships in the field of medicine.

After his year in Kyoto, Friedland will continue his research and clinical work at UofL, where his collaborators in the lab of Levi Beverly, PhD, currently are finishing data analysis on a study of the influence of bacterial amyloid on ALS in mice.

A paper published today in details how researchers identified Pg in the brains of patients with AD.��

University of Louisville researcher Jan Potempa, PhD, Department of Oral Immunology and Infectious Diseases in the School of Dentistry, was part of the team of international scientists led by , a privately held, clinical-stage pharmaceutical company.

According to Potempa, although infectious agents have been implicated in the development and progression of Alzheimer’s disease, the evidence of causation hasn’t been convincing.

However, “we now have strong evidence connecting P. gingivalis and Alzheimer’s pathogenesis, but more research needs to be done.

“An even more notable aspect of this study is demonstration of the potential for a class of molecule therapies targeting major virulence factors to change the trajectory of AD, which seems to be epidemiologically and clinically associated with periodontitis,” Potempa said.

In animal models, oral Pg infection led to brain colonization and increased production of amyloid beta (Aβ), a component of the amyloid plaques commonly associated with AD.

The study team also found the organism’s toxic enzymes, or gingipains, in the neurons of patients with AD. Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of Pg in a variety of cells. The team correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein tag that marks damaged proteins.

Seeking to block Pg-driven neurotoxicity, Cortexyme set out to design a series of small molecule therapies targeting Pg gingipains. In preclinical experiments detailed in the paper, researchers demonstrated that by inhibiting the compound COR388, there was reduced bacterial load of an established Pg brain infection, blocked Aβ42 production, reduced neuroinflammation and protected neurons in the hippocampus –  the part of the brain that mediates memory and frequently atrophies early in the development of AD.

In October 2018, Cortexyme announced results from its Phase 1b clinical trial of COR388 at the 11^th Clinical Trials in Alzheimer’s Disease Conference. COR388 showed positive trends across several cognitive tests in patients suffering from AD, and Cortexyme plans to initiate a Phase 2 and 3 clinical trial of COR388 in mild to moderate AD in 2019.

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To generate new ideas in Alzheimer’s disease research, the National Institute on Aging, one of the National Institutes of Health, has offered researchers in other fields already funded by the NIH additional money to explore links between their current field of research and Alzheimer’s disease. Beverly, a UofL cancer researcher, has received one of the first rounds of these $385,000 awards.

“They are hoping to spark some new directions, uncovering potential new areas for research,” said Beverly, PhD, associate professor of medicine at UofL. “This will get more people involved in the work and develop some preliminary seed data.”

Alzheimer’s and other neurodegenerative diseases affect more than 5 million people in the United States. As the population ages, this number is increasing.

Beverly’s primary research grant from the National Cancer Institute is to study ubiquilin proteins in cancer. Ubiquilin proteins are critical adapters that appear to be central to signaling pathways driving Alzheimer’s disease as well as cancer.

“The protein ubiquilin is lost in both cancer and Alzheimer’s and other neurodegenerative diseases,” Beverly said. “What we hope to discover is how this protein, which is associated with aberrant cell growth in cancer, also is associated with aberrant cell death in neurodegenerative diseases.”

Beverly plans to use the new funding to determine whether and how ubiquilin regulates contradictory signaling pathways in neuronal cells and epithelial cells, and how the loss of ubiquilin affects multiple types of tissues.

Robert Friedland, MD, professor of neurology at UofL who has conducted research in Alzheimer’s disease for more than three decades, is collaborating with Beverly on the project.  

“We have known for many years that protein folding patterns are critical to neuronal damage in Alzheimer’s,” Friedland said. “The work Dr. Beverly has done with ubiquilin has uncovered pathways that may be involved in key mechanisms of both Alzheimer’s disease and cancer. We anticipate that the interaction of researchers in cancer and neurodegeneration will help advance both fields.”

With combined annual national expenditures of approximately $300 billion for cancer and Alzheimer’s diseases in the U.S., these conditions represent two of the largest burdens on the health care system. Beverly believes the laboratory research conducted in this project will facilitate the development of therapeutic interventions for these diseases.

“Only by understanding the basic molecular, biochemical and genetic causes of these diseases will we be able to make significant progress in treating these patients,” Beverly said.

These unique graphic characters may prove to be valuable tools in detecting signs of Alzheimer’s disease decades before symptoms become apparent.

In an article published online last week in , Emily Mason, PhD, a postdoctoral associate in the Department of Neurological Surgery at UofL, reported research showing that cognitively normal people who have a genetic predisposition for Alzheimer’s disease have more difficulty distinguishing among novel figures called Greebles than individuals without genetic predisposition.

Alzheimer’s disease is a progressive, irreversible neurodegenerative disease characterized by declining memory, cognition and behavior. AD is the most prevalent form of dementia, affecting an estimated 5.5 million individuals in the United States and accounting for 60 to 80 percent of dementia cases. The ability to detect the disease earlier may allow researchers to develop treatments to combat the disease.

“Right now, by the time we can detect the disease, it would be very difficult to restore function because so much damage has been done to the brain,” Mason said. “We want to be able to look at really early, really subtle changes that are going on in the brain. One way we can do that is with cognitive testing that is directed at a very specific area of the brain.”

AD is characterized by the presence of beta amyloid plaques and tau neurofibrillary tangles in the brain. Tau tangles predictably develop first in the perirhinal and entorhinal cortices of the brain, areas that play a role in visual recognition and memory. Mason and her colleagues developed cognitive tests designed to detect subtle deficiencies in these cognitive functions. They hoped to determine whether changes in these functions would indicate the presence of tau tangles before they could be detected through imaging or general cognitive testing.

Working in her previous position at Vanderbilt University, Mason identified test subjects age 40 to 60 who were considered at-risk for AD due to having at least one biological parent diagnosed with the disease. She also tested a control group of individuals in the same age range whose immediate family history did not include AD.

The subjects completed a series of “odd-man-out” tasks in which they were shown sets of four images depicting real-world objects, human faces, scenes and Greebles in which one image was slightly different than the other three. The subjects were asked to identify the image that was different.

The at-risk and control groups performed at similar levels for the objects, faces and scenes. For the Greebles, however, the at-risk group scored lower in their ability to identify differences in the images. Individuals in the at-risk group correctly identified the distinct Greeble 78 percent of the time, whereas the control group correctly identified the odd Greeble 87 percent of the time.

“Most people have never seen a Greeble and Greebles are highly similar, so they are by far the toughest objects to differentiate,” Mason said. “What we found is that using this task, we were able to find a significant difference between the at-risk group and the control group. Both groups did get better with practice, but the at-risk group lagged behind the control group throughout the process.”

Mason would like to see further research to determine whether the individuals who performed poorly on the test actually developed AD in the future.

“The best thing we could do is have people take this test in their 40s and 50s, and track them for the next 10 or 20 years to see who eventually develops the disease and who doesn’t,” Mason said.

In recent years, a great deal of research has focused on identifying early biomarkers of Alzheimer’s disease. However, not everyone who has an individual biomarker ultimately develops the disease. Brandon Ally, PhD, assistant professor of neurological surgery at UofL and senior author of the publication, said the tests with Greebles can provide a cost-effective way to identify individuals who may be in the early stages of AD, as well as a tool for following those individuals over time.

“We are not proposing that the identification of novel objects such as Greebles is a definitive marker of the disease, but when paired with some of the novel biomarkers and a solid clinical history, it may improve our diagnostic acumen in early high-risk individuals,” Ally said. “As prevention methods, vaccines or disease modifying drugs become available, markers like novel object detection may help to identify the high priority candidates.”

professor and Mason and Mary Rudd Endowed Chair in Neurology at UofL, has studied clinical and biological issues in Alzheimer’s disease and related disorders for 35 years. He believes that early detection will enhance the ability of patients and physicians to employ lifestyle and therapeutic interventions.

“This work shows that the effects of Alzheimer’s disease on cognition can be measured decades before the onset of dementia,” Friedland said. “The fact that the disease takes so long to develop provides us with an opportunity to slow its progression through attention to the many factors that are linked to the disease, such as a sedentary lifestyle, a high fat diet, obesity, head injury, smoking, and a lack of mental and social engagement.”

The article, “,” will appear in the Journal of Alzheimer’s Disease, Volume 57, Issue 2.

ANSWER: Greeble No. 4 is different.

The number of individuals with AD and related disorders in the region is rising due to the rapidly aging population and public health systems have not kept pace with recent developments in treatment.

“There is little awareness of dementia in the region because of prevailing biases about the loss of function in healthy aging,” Friedland said. “People in the Middle East need to know that it is never normal for a person at any age to be demented.”

Friedland, the Mason and Mary Rudd Endowed Chair in Neurology at UofL and an organizer for the previous six ICAD-ME meetings, will discuss his research into the relationship between gut microbiota and neurodegeneration, and provide information on potential preventative measures to delay the onset of AD. In addition, he hopes to learn about special features and needs of the region’s population.

The conference will cover topics including the history of Alzheimer’s disease and its basic pathophysiology, pharmacological and non-pharmacological therapies, ethical and legal issues, and aging as it is addressed in the Koran and the Bible.

The event, sponsored by the United States National Institutes of Health/National Institute on Aging and Biogen, is Feb. 23-25, 2017 in Abu Dhabi, United Arab Emirates. Additional organizers are Changiz Geula, PhD, professor at Northwestern University, Marwan Sabbagh, MD, professor at Barrow Neurological Institute of Phoenix, and Abdu Adem, PhD, professor at United Arab Emirates University.

Robert P. Friedland, MD, the Mason C. and Mary D. Rudd Endowed Chair and professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid, that have structural similarity to brain proteins, leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by , involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, PhD, of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

Friedland is the corresponding author of the article, , published online Oct. 6 in Scientific Reports, a journal of the Nature Publishing Group. UofL researchers involved in the publication in addition to Friedland include Vilius Stribinskis, PhD, Madhavi J. Rane, PhD, Donald Demuth, PhD, Evelyne Gozal, PhD, Andrew M. Roberts, PhD, Rekha Jagadapillai, Ruolan Liu, MD, PhD, and Richard Kerber, PhD.��

This work supports recent studies indicating that the microbiota may have a role in disease processes in age-related brain degenerations.��It is part of Friedland’s ongoing research on the relationship between the microbiota and age-related brain disorders, which involves collaborations with researchers in Ireland and Japan.

“We are pursuing studies in humans and animals to further evaluate the mechanisms of the effects we have observed and are exploring the potential for the development of preventive and therapeutic strategies,” Friedland said.