TAMPA, Fla. (April 6, 2021) — The National Institutes of Health (NIH) has awarded the University of South Florida (USF) total expected funds of $44.4 million over the next five years to study whether computerized brain training exercises can reduce the risk of mild cognitive impairment (MCI), and dementias like Alzheimer’s disease, in older adults.

The grant from the NIH’s National Institute on Aging, supported under Award Number R01AG070349, expands USF’s Preventing Alzheimer’s with Cognitive Training (PACT) study. PACT will be the largest primary prevention trial to date designed to rigorously test the effectiveness of computer-based training to protect against MCI and dementias. Dementia such as Alzheimer’s disease leads to a loss in thinking, reasoning, memory, and everyday functional abilities.

“We are grateful for the willingness of the Tampa Bay community to support our efforts to prevent Alzheimer’s disease and dementia by participating in the PACT trial,” said USF site principal investigator Jerri Edwards, PhD, a professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine. “Because of their willingness to join us in the fight against Alzheimer’s disease, we can now expand this trial across the U.S. with hope of ultimately reducing dementia incidence.”

No proven treatments yet exist to cure or stop the progression of Alzheimer’s disease, the most common form of dementia. Dementia prevention research like that done by Dr. Edwards and her team takes on increased urgency, because the few Alzheimer’s medications currently on the market primarily provide short-term management of symptoms for those who already have dementia. Alzheimer’s disease afflicts 5.8 million Americans, including one in every 10 people age 65 and older, according to the Alzheimer’s Association. Without effective interventions, the human and economic costs for those living with dementia, their caregivers, and the health care system will continue to rise as the population ages.

“If we can reduce the chances of progressing to Alzheimer’s disease and related dementias with a cognitive training regimen – an inexpensive and safe non-drug intervention – that would be a huge public health advance,” Dr. Edwards said. “Research suggests that delaying the onset of dementia by even one year would result in millions of fewer cases over the next 30 years.”

Jerri Edwards, PhD, professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine, is  USF site principal investigator for the PACT study.

The multisite trial is expected to expand the study to enroll 7,600 healthy adults at various US locations who are ages 65 and older with no signs of cognitive impairment or dementia. People with mild cognitive impairment experience more memory problems than expected for those the same age. MCI can increase the risk for dementia. Within two years, Dr. Edwards said, about 15% of people with MCI progress to dementia with more serious cognitive decline that interferes with everyday tasks, such as preparing a meal, doing laundry, or driving.

Published research by Dr. Edwards and others indicates that targeted computerized training can help maintain mental and physical function. In the breakthrough Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, healthy older adults randomized to receive such training had a 29% lower risk of dementia after 10 years than the untreated control group. Those completing additional training benefited even more; they were 48% less likely to show signs of dementia 10 years later.

“As an academic medical center with a growing Neuroscience Institute and well-established Byrd Alzheimer’s Center, USF Health is at the forefront of the latest research attacking Alzheimer’s disease and related dementias on multiple fronts,” said Charles J. Lockwood, MD, senior vice president of USF Health and dean of the USF Health Morsani College of Medicine. “This pivotal study, based on compelling preliminary evidence, moves us one step closer to answering a critical question: Can computer-based cognitive training prevent dementia and help keep our brains healthy as we age?”

With the PACT study, Dr. Edwards’ team seeks more conclusive evidence about whether and how computerized training can protect against age-related cognitive impairment and dementia. The researchers will identify through comprehensive medical evaluation any study participants who develop MCI or dementia three years after enrollment in the PACT study. They will use brain scans to diagnose dementia such as Alzheimer’s disease and to see if those with amyloid protein in the brain (a hallmark protein of the neurodegenerative disease) benefit from the training.

Dr. Edwards emphasizes the need for more African-American and Hispanic/Latino study volunteers as the Alzheimer’s Association reports they are populations at highest risk for Alzheimer’s disease and other dementias.

USF Health expects to continue enrolling participants across the Tampa Bay region in the PACT study over the next three years. Study participants cannot have dementia or other neurological disorders, but a family history of Alzheimer’s disease does not disqualify an otherwise healthy person. Two initial supervised training sessions will be conducted onsite (with strict adherence to CDC guidelines for COVID-19), and study participants will complete the remaining brain training sessions independently at home over the next two years.

For more information, please visit the PACT study website at pactstudy.org or call (813) 974-6703.

ABOUT USF HEALTH
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Can the community of microbes in our digestive track influence our mental state and, if so, how?

That’s a focus of study by Monica Uddin, PhD, a professor in USF’s College of Public Health, where she contributes to the Genomics Program within the Center for Global Health and Infectious Disease Research, focusing on the genomics of stress-related mental disorders. As part of USF’s ambitious Initiative on Microbiomes, Uddin wants to better understand how gut microbiota is linked to the symptoms of depression.

Monica Uddin, PhD

“Historically, we’ve always thought about our organs as working independently from one another, so it’s a bit hard to wrap your mind around this,’’ said Uddin, whose research just won a $150,000 seed grant from USF.  Her USF Health coprincipal investigators are Glenn Currier, MD, professor and chair of psychiatry, and Adetola Louis-Jacques, MD, assistant professor of obstetrics and gynecology.

“We now know that the gut microbiota can make neurotransmitters that influence mental health in ways that can cross the blood/brain barrier.”          

Monica Uddin, PhD, professor in the USF College of Public Health

Major depressive disorder (MDD) is a disabling mental condition worldwide. Treatment resistant depression (TRD) is a particularly severe form in which antidepressant trials have failed. Resistance occurs at a high rate, with more than 35% failing to respond to two different classes of antidepressant.

Recent research, however, is shedding light on the role of microscopic organisms such as bacteria, fungi and viruses on human health, both physical and mental. Such work reveals that a person’s intestinal florae is strongly associated with depressive symptoms and MDD. Work from animal models indicates that microbiota is causally linked to depressive behaviors.

Currently, very little is known about the relationship between the microbiome and TRD, and how patients respond to treatment depending on their microbiota. Researchers need to know more about how this florae differs in patients who respond to anti-depression treatment versus those who do not respond despite multiple attempts.

Up to one-third of adults with major depression battle symptoms that do not respond to several treatment attempts.

To address this significant health need, Uddin is working with a team that focuses on patients electing a treatment known as transcranial magnetic stimulation (TMS), which has shown some promise in treating TRD. The treatment uses magnetic fields to stimulate brain nerve cells to improve depression symptoms. While it has been effective in treating certain types of depression, it does not provide relief to all patients.

Uddin is studying microbiome-related biomarkers that could one day be used to inform treatment choices and, ultimately, enhance therapy response. Her work is part of a collaboration across professions in which diverse research and solutions can move from the laboratory to the patient bedside.

“The science is at the stage of being more than just descriptive; we’re moving toward function,’’ she said. “And by understanding the function, the hope is 10 or 20 years down the road we can potentially engineer the gut microbiota of people who get depressed.’’

Uddin’s seed grant will help her provide the preliminary results needed to pursue full National Institutes of Health or National Science Foundation grant applications.

-Story by Kurt Loft

The USF Health neuroscientist aims to translate his research on kappa opioid receptors into personalized treatments for alcoholism and other addictive disorders

//www.youtube.com/watch?v=FRU0TCpvsuo

When USF Health neuroscientist Brendan Walker, PhD, was a teen in California at the height of the 1980s crack epidemic, several of his friends who were top intellects and accomplished athletes grew increasingly dependent on cocaine and alcohol. Some died from their addictions.

The painful loss of friends he grew up with started his journey toward a research career seeking to understand the neurobehavioral systems that drive addiction. “I wondered what could be so powerful about drugs of abuse, including alcohol, that would take over someone to the point where they lost their life,” he said.

Dr. Walker, a professor in the Department of Psychiatry and Behavioral Neurosciences, joined the USF Health Morsani College of Medicine in June 2019.

Brendan Walker, PhD, in his laboratory at the USF Health Department of Psychiatry and Behavioral Neurosciences. Dr. Walker’s group focuses on the long-lasting negative reinforcement aspects of heavy alcohol use in the brain, which can make giving up drinking difficult.

Backed by a five-year, $1.79-million R01 grant  from the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, his laboratory primarily studies the role of kappa opioid receptors in the transition to alcohol dependence. His long-term goal is to turn those discoveries into targeted medications and gene therapies for addictive disorders leading to devastating social, occupational and health consequences.

Historically many researchers have paid more attention to the positive reinforcement effects of alcohol and drugs — particularly the interaction in the brain of peptides known as endorphins with the mu opioid receptors. Endorphins are natural “feel good” chemicals (neurotransmitters) that can relieve stress, boost mood and produce a feeling of euphoria.

Excessive drinking takes a toll on society as a whole, costing an estimated $249 billion a year, according to the Centers for Disease Control and Prevention.

Dr. Walker and his USF Health team focus on a less studied opioid receptor called the kappa receptor.

They examine what happens in the brain circuitry when the alcohol-induced release of “feel bad” peptides called dynorphins activate kappa opioid receptors. Their preclinical research has shown that abnormal regulation of this dynorphin/kappa-opioid receptor system through excessive drinking can stimulate dysphoria associated with negative emotional states like depression and anxiety, as well as impaired motivation, judgement and decision-making, Dr. Walker said.

“It’s hard to stop drinking once a person achieves a particular pattern of heavy use,” he said. “By blocking some of the dysphoria that drives excessive alcohol use, we’re incorporating a new modality that may achieve better long-term success in stopping alcoholism.”

Dr. Walker with his research team

Brain changes and maladaptive behaviors

Although Dr. Walker’s research centers on alcohol use disorders, the work has relevance for a wide range of addictions.

“Our group and others have shown that the progressive dysregulation that occurs in the brain can extend to all drugs of abuse, whether it be opiates like heroin, or psychostimulants like cocaine and nicotine,” he said. “Whatever the addictive disorder, many of the exact same physical changes happen in the brain to cause a person to adapt in ways that perpetuate self-harm.”

One example of this “maladaptive behavior” is impulsively choosing to consume more alcohol for instant gratification, rather than abstaining from drinking to attain long-term goals. “All these different drugs of abuse activate brain reward systems 50 to 100 times more (powerfully) than anything natural can,” Dr. Walker added. “Instead of having to go out and achieve a long-term goal to get that feeling of euphoria, an individual can inject, smoke or drink something to quickly activate those systems.”

Senior biological scientist Rong (Jennifer) Wang

Many individuals start using alcohol or drugs to get the euphoric ‘feel good’ effects. But the brain normally prefers a set point that balances the highs and lows of mood, so problems arise with misuse, Dr.  Walker said. “The more you artificially create this euphoria, the more intensely the brain fights back by creating dysphoria to equalize the system.”

As alcohol dependence escalates, those who quit drinking in an attempt to stay sober no longer experience the heightened “up” state of euphoria – but all the negative feelings of dysphoria, the “down” state, remain and become more pronounced, he added.  “So, they frequently end up drinking again to self-medicate the depression and anxiety that occurs during withdrawal.”

A major obstacle to recovery — even months or years after rehabilitation and prolonged abstinence – appears to be physical changes in neurotransmitters and their receptor targets as the brain adapts to drugs of abuse.

“Depending on how long or how intensely someone has used alcohol or other drugs of abuse, the dysregulation of the dynorphin-kappa opioid receptor system can persist long after someone stops using,” Dr. Walker said. “Certain environmental cues, like seeing or smelling something associated with prior misuse, may reactivate the dysphoria and cause a relapse.”

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The “one-two” punch of alcoholism

In a key paper published in Biological Psychiatry (2014) titled “The one-two punch of alcoholism,” Dr. Walker and colleagues demonstrated that the dynorphin-kappa opioid receptor system is dysregulated in the amygdala of rats chronically exposed to alcohol. The brain’s amygdala region is vital for many functions, including regulation of emotional behavior and decision-making.

The researchers discovered that dynorphins and signaling by their target kappa opioid receptors both increased in the amygdala, combining to produce a greater (adverse) effect than normal. This combined upregulation underlies the highly maladaptive behavior that promotes continued drinking to temporarily relieve moodiness, anxiety, depression and other dysphoria symptoms, Dr. Walker said.

In the same study, alcohol-dependent rats in acute alcohol withdrawal started to drink like they were nondependent when pharmacological compounds were administered directly into the amygdala to specifically suppress activation of the kappa opioid receptors. The data contributed by Dr. Walker strongly supported the hypothesis that kappa receptor antagonists (blockers) could be a beneficial treatment target for combatting alcohol dependence — in part by preventing a relapse among patients during and soon after withdrawal.

His preclinical work helped determine that kappa opioid receptors were important for the therapeutic effectiveness of nalmefene, a medicine licensed in the European Union to reduce heavy drinking in alcoholic patients who cannot completely abstain.

Gengze Wei, PhD, scientific researcher

Genetics underlying alcohol dependence

Armed with advanced genetic tools, Dr. Walker’s laboratory has also begun exploring ways that genetic variations may work with environmental cues to regulate the neurobehavior (negative emotions, poor judgement and decision-making) that contributes to excessive drinking and relapse.

His group is comparing changes in kappa-opioid receptor gene expression in various brain regions both in alcohol-dependent rats and in their nondependent counterparts. They expect soon to be able to precisely target subtypes of nerve cells involved in shifting the brain’s circuitry from nondependence to dependence. The USF Health researchers plan to mimic the gene expression changes in nondependent rats to observe if they start drinking like dependent rats. They will also block these genetic variations in dependent rats to try to reverse the alcohol-induced maladaptive behavior.

The ability to safely modify specific genes would treat the underlying neurobehavioral causes of alcohol use disorder – not just its symptoms.

The science isn’t there yet. But, Dr. Walker envisions a time when behavioral screening to identify factors that most motivate a person to abuse alcohol or other drugs could be combined with genotyping to help break the addict’s cycle of dependence.

“If we could profile the major genetic and environmental factors that push an individual to continue excessive use, then we could personalize treatment approaches,” he said. “It could help predict how effective a particular treatment would be for an individual patient — and improve the chances of success.”

Stains of dopamine neurons in the midbrain

A White House early career award 

Dr. Walker came to the University of South Florida from Washington State University, where he was an associate professor of psychology.  He was previously a staff scientist for molecular and integrative neurosciences at the Scripps Research Institute in La Jolla, CA.

Dr. Walker received a PhD in neuroscience and behavior from the University of California, Santa Barbara in 2004, and completed postdoctoral research at the Pearson Center for Alcoholism and Addiction Research at Scripps.

He has received numerous distinguished awards, including the 2011 Presidential Early Career Award for Scientists and Engineers presented by President Barack Obama at the White House. The highly competitive PECASE award recognizes exceptional potential for leadership at the frontiers of scientific knowledge.

Continuously funded by the NIH since 2001, Dr. Walker has authored 36 papers in peer-reviewed journals. He served on editorial boards for Neuropsychopharmacology and Honors in Higher Education and as a grants reviewer for the NIH Molecular Neuropharmacology and Signaling (MNPS) study section. He is a member of the American College of Neuropsychopharmacology, the Research Society on Alcoholism and the Society for Neuroscience. 

The 2011 Presidential Early Career Award for Scientists and Engineers, presented to Dr. Walker at the White House, recognizes exceptional potential for leadership at the frontiers of scientific knowledge.

Some things you may not know about Dr. Walker 

• Walker and his wife Jennifer Walker, an IRB research compliance administrator at USF, are both certified scuba divers. They look forward to combining scuba diving with sailing along Florida’s Gulf Coast on his family’s Irwin Ketch called “Peregrine.”
• As a boy in Los Angeles, Dr. Walker hiked to the landmark Hollywood Hills sign overlooking downtown LA, climbing to the top of its white capital letters to take in the view.

-Video by Allison Long, and photos by Freddie Coleman, USF Health Communications and Marketing

An antagonist that blocks a specific interaction between the protein apoE and amyloid precursor protein appears promising in a preclinical study led by USF Health

TAMPA, Fla. (June 12, 2019) — Apolipoproten E (apoeE) is a major genetic risk factor for the development of Alzheimer’s disease, yet the protein tends to be understudied as a potential druggable target for the mind-robbing neurodegenerative disease.

Study lead author Darrell Sawmiller, PhD (left), and senior author Jun Tan, PhD, MD

Now a research team led by the University of South Florida Health (USF Health) Morsani College of Medicine reports that a novel apoE antagonist blocks apoE interaction with N-terminal amyloid precursor protein (APP). Moreover, this peptide antagonist, known as 6KApoEp, was shown to reduce Alzheimer’s-associated beta amyloid (β-amyloid) accumulation and tau pathologies in the brain, as well as improving learning and memory in mice genetically engineered to mimic symptoms of Alzheimer’s disease.

Many failed anti-amyloid therapies for Alzheimer’s disease have been directed against various forms of the protein β-amyloid, which ultimately forms clumps of sticky plaques in the brain. The presence of these amyloid plaques is one of the major hallmarks of Alzheimer’s disease.

The USF Health research findings suggests that disrupting apoE physical interaction with N-terminal APP may be a new disease-modifying therapeutic strategy for this most common type of dementia.

The preclinical study was published online May 2 in Biological Psychiatry, a journal of Psychiatric Neuroscience and Therapeutics.

Microscopic image shows the merging of APP (red) and apoE (green) in brain cells.  This co-localization (yellow) suggests an age-associated increase in apoE-N-terminal APP interaction and higher production of the toxic amyloid-β (Aβ) protein characteristic of Alzheimer’s disease.

“For the first time, we have direct evidence that the N-terminal section of apoE itself acts as an essential molecule (ligand) to promote the binding of apoeE to the N-terminal region of APP outside the nerve cell,” said the study’s lead author Darrell Sawmiller, PhD, an assistant professor in the USF Health Department of Psychiatry & Behavioral Neurosciences. “This receptor-mediated mechanism plays a role in the development of Alzheimer’s disease. Overstimulation of APP by apoE may be an earlier, upstream event that signals other neurodegenerative processes contributing to the amyloid cascade.”

“Initially we wanted to better understand how apoE pathologically interacts with APP, which leads to the formation of β-amyloid plaques and neuronal loss,” said study senior author Jun Tan, PhD, MD, a professor in the USF Health Department of Psychiatry & Behavioral Neurosciences.  “Our work further discovered an apoE derivative that can modulate structural and functional neuropathology in Alzheimer’s disease mouse models.”

Microscopic image depicts the merging of APP and apoE in cell cultures (above).  Depleting the N-terminal region of apoE reduces APP and apoE physical interaction (below).

Alzheimer’s disease is a global epidemic, afflicting an estimated 50 million people worldwide and 5.8 million in the U.S, according to the Alzheimer’s Association.  With the aging of the Baby Boomer generation, the prevalence of the debilitating disease is expected to increase dramatically in the coming years.  Currently, no treatments exist to prevent, reverse or halt the progression of Alzheimer’s disease, and current medications may only relieve dementia symptoms for a short time.

Dr. Sawmiller, Ahsan Habib, PhD, and Lucy (Hauyan) Hou, MD, of the USF Health Department of Psychiatry and Behavioral Neurosciences (all lead authors) collaborated with colleagues from the Laboratory of Neurosciences at the National Institute on Aging (NIA), the Department of Neuroscience at Johns Hopkins University School of Medicine, the USF Center for Neurosurgery and Brain Repair, and Saitama Medical University in Japan.  Other study authors included Takashi Mori, PhD; Anran Fan, PhD; Jun Tian, BS; Brian Giunta, MD, PhD; Paul R. Sanberg, PhD; and Mark P. Mattson, PhD.

The research was supported by an NIA grant from the National Institutes of Health.

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-Photos by Torie M. Doll, USF Health Communications and Marketing
-Microscopic images courtesy of Drs. Darrell Sawmiller and Jun Tan