Parkinson’s disease (PD) is characterized by motor-related symptoms, including tremors, rigidity and stooping posture. Lesser known is damage to nerves in the heart, which progresses over time, is independent of motor symptoms and is not responsive to current therapies.

Marina Emborg, senior scientist at the Wisconsin National Primate Research Center and University of Wisconsin–Madison professor of medical physics, has been working on preclinical models for treating PD for the past three decades. She says by the time patients are diagnosed, about 60 percent have serious damage to nerve connections in the heart.

“When healthy, these nerves stimulate the heart to accelerate its pumping to rapidly respond to changes in activity and blood pressure. Loss of this control causes patients to be less responsive to exercise, subject to intense lightheadedness upon standing and at high risk of falling.”

Emborg’s team, which includes scientists Valerie Joers, Jeanette Metzger, UW–Madison cardiovascular medicine professor Timothy Kamp and neurology professor Catherine Gallagher, had not been able to look at exactly what was causing the heart damage until now.

They mimicked PD cardiac neurodegeneration in adult rhesus macaques and then used positron emission tomography (PET) imaging to follow nerves within the monkeys’ hearts after they administered new-generation radiolabeled biomarkers (i.e., radioligands). The researchers were successful in detecting inflammation and signs of oxidative stress as nerves were deteriorating in real time.

The study suggests cardiac PET imaging combined with new-generation radioligands will be useful in detecting heart disease and evaluating new therapies that specifically target nerve disease within the human heart.

“Many doctors are not aware of this condition, which significantly affects PD patients’ health,” said Emborg. After the study results had been published, several people who have PD reached out to thank her for studying this aspect of the disease. She realized this study gave patients the evidence and confidence they need to talk with their doctors about treatments.

Other diseases share this problem as well, Emborg said. Diabetes, heart attacks and other disorders cause similar damage to nerves in the heart. People who have these health issues could potentially benefit from therapies tested with visualization models. 

Emborg envisions the day when this technique is credited with developing new therapies as well as predicting heart damage in those who have PD.

Alzheimer’s disease is far too common. In fact, the Alzheimer’s Association estimates that more than 5 million Americans are living with it, and one in three seniors die from the disease or something related. Patients experience a gradual decline of memory and other important brain functions, which can cause great difficulty in older age. Unfortunately, early detection of age-associated cognitive dysfunction—although crucial—remains a challenge for scientists and medical professionals. 

Scientists at Texas Biomedical Research Institute’s (Texas Biomed) Southwest National Primate Research Center (SNPRC) recently made progress in this regard when they published findings indicating the baboon could be a relevant model to test therapeutics and interventions for neurodegenerative diseases, such as early-stage Alzheimer’s and others. 

The scientists observed a steep age-related cognitive decline in baboons about 20 years old, which is the equivalent of a 60-year-old human.  

“This is the first time a naturally-occurring model for early-stage Alzheimer’s has been reported,” explained Dr. Marcel Daadi, Associate Professor at Texas Biomed’s SNPRC. “(The baboon) model could be relevant to test promising drugs, to better understand how and why the disease develops and to study the areas of the brain affected in order to determine how can we impact these pathways.” 

Neurodegenerative diseases are related to the aging of brain cells and synaptic loss, which is a loss of the lines of communications inside the brain. Previous studies have pinpointed the prefrontal cortex (PFC) of the brain as one of the regions most affected by age. The PFC plays a key role in working memory function as well as self-regulatory and goal-directed behaviors, which are all vulnerable to aging.  

To observe whether these functions are impacted by aging in baboons and determine whether the baboons at varying ages could discern and learn new tasks, Dr. Daadi and his team separated the baboons into two groups based on age (adult group and aged group) and performed a series of cognitive tests. 

“What we found is that aged baboons lagged significantly in performance among all four tests for attention, learning and memory,” Dr. Daadi said.  

The researchers noted that a delay or inability to collect rewards increased in older baboons, suggesting a decline in motivation and/or motor skills. The team also demonstrated that aged subjects show deficiencies in attention, learning and memory. The findings are consistent with human studies that have suggested a sharp decline in brain systems function and cognition around 60 years. 

Until now, rodents have been the primary lab model to test therapeutic interventions for neurodegenerative diseases. But mice don’t always reflect human processes, so a nonhuman primate like the baboon could prove to be a more effective model for testing. 

“The failure rate in clinical trials of Alzheimer’s disease therapeutics is extremely high at about 99.6%, and we need to change that,” said Dr. Daadi. 

He indicated that the next steps would include performing imaging and examining biomarkers to better understand the origins and nature of the disease. 

The fight against Alzheimer’s is ongoing, and NPRC scientists are on the front lines. To learn more about the work happening at our locations around the country, visit this link. 

Autism Spectrum Disorder (ASD), which impacts communication and interaction abilities, affects 1 in every 54 children in the United States. In order to understand the biological basis of these types of human disorders, scientists must turn to translational animal models—research with animals that closely reflects the same processes in humans.    

Until now, there hasn’t been an effective way to identify which animals were ideal candidates for ASD research. But Kate Talbot, PhD, and her colleagues in the Neuroscience and Behavior Unit at the California National Primate Research Center (CNPRC) have optimized a screening tool—based on an ASD diagnostic tool used in humans—to do just that.  

ASD is classified by the National Institute of Mental Health as a developmental disorder that affects communication and behavior. It is a spectrum disorder, which means autism can present differently in symptoms and severity across individuals. This variability is part of what makes treatment of ASD more complicated. Rather than a primary treatment for ASD, doctors and patients have to work together to develop specific treatment programs.  

Talbot pointed out that studying disease biology directly in ASD patients is difficult in other animal models because they fundamentally lack the complex social cognitive abilities that are impaired in people with autism. But there is a subset of rhesus monkeys within the natural population illustrating low-social behavior similar to what is observed in humans with ASD. The difficult part is identifying enough of these animals early in their development to conduct the necessary translational research. 

Talbot and her team made a breakthrough in that area. The original macaque social responsiveness scale (mSRS) was a 36-item observation-based instrument similar to the Social Responsiveness Scale originally developed for human children. The mSRS was developed using a relatively small sample mostly composed of females, but due to the sample size and the fact that ASD is a particularly male-biased disorder (four males for every one female), the mSRS was difficult to translate to the human screening tool.  

Talbot and colleagues refined the mSRS by applying it to hundreds of male rhesus macaques across their development. They could then compare experimenter responses to the questionnaire directly to behavioral data collected on the animals throughout their lives. Now, the revised tool can determine with 96% accuracy which monkeys qualify as particularly low-social animals compared to their peers.   

“This instrument will be indispensable for advancing the field’s understanding of the developmental trajectory of core autistic symptomology in rhesus and other macaque monkeys, and it can be used as a primary outcome measure in fast-fail preclinical therapeutic testing efforts,” Talbot explained. 

Understanding autism and other neurological conditions is a primary goal of NPRC research. Find out more about our ASD-related studies by visiting this link.  

Researchers at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW) recently made a discovery that moves the scientific community one step closer to understanding and treating Parkinson’s disease. 

Parkinson’s, which affects more than 10 million people worldwide, progressively degrades the nervous system, causing tremors, loss of muscle control, cardiac and gastrointestinal dysfunction and other issues. The group at WiNPRC used gene-editing tools to introduce the disease’s most common genetic mutation into marmoset monkey stem cells and successfully reduce flaws in cellular chemistry. 

“We know now how to insert a single mutation, a point mutation, into the marmoset stem cell,” said Marina Emborg, professor of medical physics at UW. “This is an exquisite model of Parkinson’s. For testing therapies, this is the perfect platform.” 

The researchers used a version of the gene-editing technology CRISPR to change a single nucleotide—among more than 2.8 billion pairs—in the genetic code of the cells and give them a mutation called G2019S. 

In human Parkinson’s patients, G2019S causes over-activity of an enzyme called LRRK2, which is involved in a cell’s metabolism. Other gene-editing studies have seen cells produce both normal and mutated enzymes at the same time.  

This new study, however, is the first to result in cells that make only enzymes with the G2019S mutation, which makes it easier to study what role this mutation plays in the disease. 

“The metabolism inside our stem cells with the mutation was not as efficient as a normal cell, just as we see in Parkinson’s,” said Emborg. “Our cells had a shorter life in a dish. And when they were exposed to oxidative stress, they were less resilient to that.” 

The mutated cells had shorter life and were less resilient to oxidative stress. They also showed lackluster connections to other cells. Stem cells can develop into many different types of cells found throughout the body. But when the researchers spurred the mutated stem cells to differentiate into neurons, they developed fewer branches to connect and communicate with neighboring neurons. 

“We can see the impact of these mutations on the cells in the dish, and that gives us a glimpse of what we could see if we used the same genetic principles to introduce the mutation into a marmoset,” says Jenna Kropp Schmidt, a WiNPRC scientist and co-author of the study.  

The researchers also used marmoset stem cells to test a genetic treatment for Parkinson’s. They shortened part of a gene to block LRRK2 production, which made positive changes in cellular metabolism. 

“We found no differences in viability between (the altered cells) and normal cells, which is a big thing. And when we made neurons from these cells, we actually found an increased number of branches,” Emborg says. “This (particular technique) is a good candidate to explore as a potential Parkinson’s therapy.” 

To learn more about how scientists across the NPRC network are combating Parkinson’s disease and other neurological disorders, visit this link. 

Here’s a sobering statistic: one in every five American women and one in every 10 American men at the age of 45 are at risk of developing Alzheimer’s disease. Moreover, as the rate of the disease continues to increase and promising therapies tested in rodents fail in human subjects, the need for another option has become apparent.

Now, scientists at the California National Primate Research Center (CNPRC) have developed a monkey model of the earliest phase of Alzheimer’s. By selectively infusing protein fragments linked to the disease into the brain of middle-aged female rhesus monkeys, they have induced the earliest of the stages of Alzheimer’s, known as the synaptic phase, without neuron death. The researchers are focusing on middle-aged females, instead of the older populations previously studied, in hopes of identifying a treatment to stop the disease before irreversible degeneration occurs.

Some neurons, like those in the prefrontal cortex and hippocampus, are critically important for learning and memory and are more susceptible to the effects of Alzheimer’s than others. In a healthy brain, there is a delicate balance necessary for the cellular communication and plasticity necessary for learning—but in Alzheimer’s, this balance is compromised, leading to cognitive decline and possible neuron death.

The scientists believe that by instigating the synaptic damage, they have established a model of Alzheimer’s that isolates the synaptic phase before evidence of permanent damage.

Next, the researchers plan to examine ways of stopping Alzheimer’s progression before it reaches the degenerative phase. Primate models of the disease will greatly boost the capacity to outline an effective treatment plan for humans in the earliest phase of Alzheimer’s, prior to the worst symptoms and irreversible damage that results in dementia.

Interested in what else the NPRCs are doing to understand and improve brain health? Take a look at some related studies here.

Scientists have made one more step toward the treatment and cure of multiple sclerosis (MS) by developing a compound that successfully promotes the regeneration of the protective myelin sheath around nerve cells.

In a recent study, scientists at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU) described successfully testing the compound in mice, and they have already started to apply it to a rare population of macaque monkeys who develop a disease that is similar to MS in humans.

“I think we’ll know in about a year if this is the exact right drug to try in human clinical trials,” said senior author Larry Sherman, PhD, an OHSU professor in the Division of Neuroscience at the primate center. “If it’s not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains?” 

The discovery arrives after more than a decade of research following a 2005 breakthrough by Sherman’s lab. In that study, scientists discovered that a molecule called hyaluronic acid (HA), accumulates in the brains of patients with MS. The researchers then linked this accumulation of HA to the failure of cells called oligodendrocytes (which generate myelin) to mature. 

Myelin forms a protective sheath covering each nerve cell’s axon—the threadlike portion of a cell that transmits electrical signals between cells. Damage to myelin is associated with MS, stroke, brain injuries and certain forms of dementia like Alzheimer’s disease. Delay in myelination can also affect infants born prematurely, leading to brain damage or cerebral palsy. 

Other studies led by the Sherman lab have shown that HA is broken down into small fragments in multiple sclerosis lesions by enzymes called hyaluronidases, and these fragments send a signal to immature oligodendrocytes to not turn on their myelin genes. 

There is currently no cure for MS, but an international team of researchers led by OHSU has been working to develop a compound that neutralizes the hyaluronidase in the brains of patients with MS and other neurodegenerative diseases. This will ideally revive the ability of progenitor cells (descendants of stem cells that differentiate, or change, into specific cell types) to mature into myelin-producing oligodendrocytes and regenerate myelin sheath. 

The ONPRC macaque study describes a modified flavonoid—a class of chemicals found in fruits and vegetables—that does just that. The compound, called S3, reverses the effect of HA and promotes functional remyelination in mice. 

“It’s not only showing that the myelin is coming back, but it’s causing the axons to fire at a much higher speed,” Sherman said. “That’s exactly what you want functionally.”

The next phase of research involves testing, and possibly refining, the compound in macaque monkeys who carry a naturally occurring version of MS called Japanese macaque encephalomyelitis. The condition, which causes clinical symptoms similar to multiple sclerosis in people, is the only spontaneously occurring MS-like disease in nonhuman primates in the world. 

Researchers at the ONPRC and other NPRC locations are consistently making breakthrough discoveries to help treat and eradicate MS and other neurological diseases. Learn more about the latest findings here.

Is it possible for consciousness to be controlled through the brain? And if so, what implications could this have for people with serious brain disorders or conditions, like comas?

As it turns out, a small amount of electricity delivered at a specific frequency to a particular point in the brain will wake a nonhuman primate out of deep anesthesia, according to a study by a team led by researchers at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW).

Macaques put to sleep with general anesthetic drugs commonly administered to human surgical patients, propofol and isoflurane, were revived and alert within two or three seconds of applying a low electrical current.

“For as long as you’re stimulating their brain, their behavior — full eye opening, reaching for objects in their vicinity, vital sign changes, bodily movements and facial movements — and their brain activity is that of a waking state,” said Yuri Saalmann, UW-Madison psychology and neuroscience professor. “Then, within a few seconds of switching off the stimulation, their eyes closed again. The animal is right back into an unconscious state.”

Mice have been roused from light anesthesia before with a related method, and humans with severe disorders have improved through electric stimulation applied deep in their brains. The new study, however, is the first to pull primates in and out of a deep unconscious state.

In the study, the scientists focused on a spot deep in the core of the brain called the central lateral thalamus. Lesions in that area of the human brain are linked to severe consciousness disruptions, such as comas.

As the macaques moved from unconscious to conscious states, the researchers observed the central lateral thalamus stimulating parts of the cortex, or the outer folds of the brain. In turn, the cortex influenced the central lateral thalamus to keep it active, forming a loop—or an engine—of sorts.

Achieving this manipulation of consciousness in the brain required precisely stimulating multiple sites as little as 200 millionths of a meter apart simultaneously, as well as applying bursts of electricity 50 times per second. The researchers noted that designing and delivering electrical stimulation with such precision gives them hope that their approach could be used to help patients dealing with many types of abnormal brain activity.

 “We can now point to crucial parts of the brain that keep this engine running and drive changes in the cerebral cortex that affect your awareness, the richness of your conscious experience,” explained Saalmann.

The inner workings of the brain are complex and have yet to be fully unraveled, but scientists at the NPRCs are making daily progress in helping us to understand this fascinating and crucial organ. You can learn more about the other NPRC neuroscience studies here.

Could increasing just a single type of molecule in the brain alleviate anxiety? According to researchers at the California National Primate Research Center (CNPRC), it could indeed.

Anxiety disorders often emerge around adolescence and can continue to affect people for most of their lives. Researchers can now identify children who display an extreme anxious or inhibited temperament and determine that they are at risk to develop stress-related conditions as they transition to adulthood. However, little is known about how to effectively alleviate anxious symptoms.

CNPRC scientists recently conducted a study examining “dispositional anxiety”—the tendency to perceive many situations as threatening—in nonhuman primates. Researchers used an altered virus to boost levels of a molecule called neurotrophin-3 in the dorsal amygdala of juvenile rhesus macaques.

They found that this increase led to a decrease in anxiety-related behaviors, particularly behaviors associated with inhibition, a core part of the early-life risk for developing anxiety disorders in humans. Brain imaging studies of these animals found that neurotrophin-3 changed activity throughout the brain that contributes to anxiety.

Because current treatments work for only a subset of people and often only partially relieve symptoms, this finding provides hope for new methods of early-life intervention to treat people at risk for anxiety disorders, depression and related substance abuse.

Andrew Fox, an assistant professor in the UC Davis Department of Psychology and a researcher at the CNPRC, hopes that other scientists can further build on their research. The research team included a list of additional promising molecules for future investigation.

“We’re only just beginning,” noted Fox. “Neurotrophin-3 is the first molecule that we’ve been able to show in a nonhuman primate to be causally related to anxiety. It’s one of potentially many molecules that could have this effect. There could be hundreds or even thousands more.”

People who suffer from post-traumatic stress disorder (PTSD) and other stress- and anxiety-related conditions experience debilitating bouts of fear when they encounter certain environmental cues. In some cases, these bouts of fear come about when cues that merely resemble those that were directly associated with a traumatic or stressful episode are encountered. As a result, individuals find themselves becoming paralyzed with fear when they encounter harmless cues in their environment.

This is called fear generalization, and it can significantly hamper one’s quality of life. The major question for researchers is: What happens in the brain to cause this generalized fear? 

Previous research has focused on the amygdala, prefrontal cortex and hippocampus, all brain regions that monitor and detect threatening stimuli. However, a new study from the Yerkes National Primate Research Center (YNPRC) has demonstrated the zona incerta (ZI), a brain region previously thought insignificant, may play an important role.

Scientists at the YNPRC mapped and manipulated brain activity in the ZI of mice that demonstrated fear toward neutral stimuli of which they should not have been fearful.

Review of the neural activity in the mice’s brains revealed the ZI was less active in mice that showed fear generalization, and stimulating specific cells in the ZI dramatically reduced fear generalization. This suggests the ZI might serve to halt exaggerated fear responses.

These findings could hold therapeutic value for suppressing debilitating fear generalization and helping thousands of people with stress- and anxiety-related disorders live calmer, happier lives.

It has been known that a widely-used attention-deficit/hyperactivity disorder (ADHD) drug affected the brain—but the specifics of those effects hadn’t been fully understood until now.

Luis Populin, PhD, professor of neuroscience in the School of Medicine and Public Health at the University of Wisconsin-Madison, and colleagues at the Wisconsin National Primate Research Center (WiNPRC) have demonstrated for the first time the complete actions of Ritalin (methylphenidate, or MPH) on various regions and chemicals in the brain.

Ritalin can increase dopamine, a brain chemical associated with reward-motivated behavior, and is typically prescribed to children with ADHD. This increase changes the way the brain makes connections among its various networks, including those that affect attention, learning and motor processes.

In the study, the scientists used positron-emission tomography (PET) imaging to study the brains of three conscious adult male rhesus monkeys. Using simultaneous functional magnetic resonance imaging (fMRI), the researchers were able to directly link increases in dopamine from MPH to changes in functional connections between the caudate—the part of the brain critical to learning through storing and processing memories—and the prefrontal, hippocampal and motor regions.

Studies in humans using fMRI have explored how MPH alters the brain, but some of those studies have reported increases in dopamine after MPH administration, while others have reported decreases. The researchers noted that this may be because most studies used a single dose of the drug and different experimental conditions.

In this study, they “bridged the gap” between neurochemistry and functional organization by simultaneously measuring changes in extracellular dopamine using PET. Additionally, the doses given to the monkeys were comparable to those resulting in equivalent blood levels of the medication when used therapeutically in children.

“Our study sheds much needed light on understanding the mechanisms underlying the effects of therapeutically relevant doses of MPH,” said Populin, adding that future studies may go even further to understand how the drug works in the context of cognition. “We hope we can expand on this research to better understand how the drug works in the brain while it’s actually processing different things.”

Populin noted that the more scientists discover about the processes, the more effective doctors can be in prescribing ADHD medications for children.