Parkinson’s disease is a slowly progressive chronic neurologic condition, causing a gradual loss of the nerve cells producing the neurotransmitter dopamine in the brain. While there are no standard diagnostic tests for Parkinson’s, the diagnosis is clinical and based on findings of a neurological exam and information provided by the patient. Tremors occur in about 70% of those living with Parkinson’s, typically appearing on one side of the body, in a hand or a foot, while relaxed or at rest.*

The primary and most potent medication used to treat Parkinson’s disease is Levodopa, which helps restore balance, reduce shaking, and manage other motor issues patients experience. Overall, this treatment is radically helpful for those suffering, but erratic involuntary movements often emerge as a side effect of this drug over time.

“Levodopa is amazing, it works like magic, but it has side effects. If we can eliminate these side effects, it could change the life of patients with Parkinson’s,” says Marcel Daadi, Ph.D., an associate professor at Texas Biomed and lead paper author.

Dyskinesia is a common side effect in patients with Parkinson’s disease. It is not a symptom of the disease itself. Still, it typically emerges about five years into taking Levodopa. And like human patients, primates develop Dyskinesia after receiving Levodopa.

A study commenced at Texas Biomedical Research Institute (Texas Biomed) to help make strides in the reduction of Dyskinesia in humans. During this time, Daadi and collaborators administered the compound PD13R (created by medicinal chemists at Temple University) to the marmoset animal model of Parkinson’s. When treated with PD13R, primates experienced relief from uncontrolled movements as their Dyskinesia dropped by more than 85%, a measurement made by with the help of wearable activity monitors.

*https://parkinsonrockies.org/live-well/diagnosis-and-symptoms/?gclid=Cj0KCQiA8vSOBhCkARIsAGdp6RTNBEB0jvY01T0sel6voKUxEkV3GrikEtZbWVghPiKl5jk1CToebVQaAvtIEALw_wcB

Pelizaeus-Merzbacher disease is an inherited condition involving the brain and spinal cord, resulting in reduced neurological function. Those affected by the disease (an estimated 1 in 100,000 people) typically experience weak muscle tone, involuntary movements of the eyes, and delayed motor skill development.

In 2016 the Oregon National Primate Research Center (ONPRC)  received a $4 million grant from the National Institutes of Health (NIH) to develop a genomic database for rhesus macaques. Today, the database contains the genomic sequences of over 2,000 monkeys, which has enabled researchers to identify thousands of genetic variants identical to those known to cause human disorders.

Anne Lewis, D.V.M., Ph.D., head of pathology services at ONPRC, observed three young rhesus macaques displaying symptoms, including tremors and motor dysfunction, which were similar to those seen in  human  Pelizaeus-Merzbacher patients. Scientists at ONPRC were able to match her observations with data in the rhesus macaque genome database, helping other scientists to apply therapies to an animal model that closely matches the disease impacting humans. Additional research, led by scientists at Oregon Health & Science University (ONPRCs affiliated institution), could help develop new therapies to treat Pelizaeus-Merzbacher disease.

 “This really sets us up for the possibility of doing gene therapies, or neural stem cell-based therapies in the developing brain,” said Larry Sherman, Ph.D., professor in the Division of Neuroscience at the ONPRC.

To learn more about genome sequencing at the NPRCs, please visit here.

About 30 percent of people who have severe anxiety and depression do not find sufficient relief in available medications and psychotherapy, causing them chronic, debilitating symptoms and a significant risk of suicide. To help end this debilitation, University of Wisconsin–Madison researcher Ned Kalin, MD, and his team are studying how to dial down overactive responses to potential threats.

The researchers are using an established method, called DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), in monkeys at the Wisconsin National Primate Research Center (WiNPRC) to make small changes to genes in targeted cells to alter cell behavior. The idea is to coax neurons to produce a unique version of a protein, called a receptor. These “designer receptors” can receive chemical signals that regulate the cells’ function and affect how they communicate with other cells. Unlike other receptors in the brain that respond to naturally occurring chemical signals, the DREADDs only respond to a chemical not naturally present — a “designer” drug matched to the designer receptor.

“When such a drug interacts with DREADDs, you have the possibility of ‘fine-tuning’ the function of the brain cell that is now expressing this receptor,” says Patrick Roseboom, PhD, senior scientist and a lead study author.

The researchers injected a low dose of a psychiatric medication, Clozapine, in five monkeys to activate DREADDs in cells in the amygdala, the brain region responsible for regulating emotions. The researchers then tested the monkeys in a mildly stressful situation, placing them near an unfamiliar human, which is similar to how healthcare professionals assess anxiety levels in children. The researchers’ observations of the monkeys’ behavior and levels of stress hormones showed the most anxious monkeys freeze — becoming quiet and very still.

When the researchers gave the Clozapine before the stressful situation, the monkeys with the DREADDs experienced a significant reduction in freezing, while a control group without the DREADDS showed no change in behavior. 

The success of this proof-of-concept study is providing hope for using gene therapy and methods, such as DREADDs, to treat the millions of people who live with severe and treatment-resistant psychiatric illnesses. Read more about the NPRCs’ anxiety and depression research here.

Each year in the U.S., millions of people receive general anesthesia, and a small proportion of those patients actually regain some awareness during their medical procedures.

A recently published study about brain activity representing consciousness could help prevent that potential trauma as well as help scientists define which parts of the brain are key to the conscious mind. Such information could lead to more accurate measurements of patients undergoing anesthesia, improve treatment outcomes for people who have consciousness disorders and help people in comas maintain a continuous level of consciousness.

Yuri Saalmann, a University of Wisconsin-Madison psychology and neuroscience professor, and his research team recorded electrical activity in about 1,000 neurons surrounding each of 100 sites throughout the brains of a pair of monkeys at the Wisconsin National Primate Research Center (WiNPRC). The researchers recorded activity during several states of consciousness: under drug-induced anesthesia, light sleep, resting wakefulness and roused from anesthesia into a waking state through electrical stimulation of a spot deep in the brain.

To sift out characteristics that best indicate whether the monkeys were conscious or unconscious, the researchers used machine learning. They input their large pool of data into a computer, told the computer which state of consciousness had produced each pattern of brain activity and asked the computer which areas of the brain and patterns of electrical activity corresponded most strongly with consciousness.

Surprisingly, the results pointed away from the frontal cortex, which is the part of the brain healthcare professionals typically monitor to maintain patient safety while under general anesthesia and the part most likely to exhibit slow waves of activity long considered typical of unconsciousness.

“In the clinic now, they may put electrodes on the patient’s forehead,” says Mohsen Afrasiabi, an assistant scientist in Saalmann’s lab. “We propose that the back of the head is a more important place for those electrodes because we’ve learned the back of the brain and the deep brain areas are more predictive of state of consciousness than the front.”

And while both low- and high-frequency activity can be present in unconscious states, complexity best indicates a waking mind. “You need more complexity to convey more information, which is why it’s related to consciousness,” says graduate student Michelle Redinbaugh. “If you have less complexity across these important brain areas, they can’t convey very much information. You’re looking at an unconscious brain.”

Read more about our consciousness research and how monkeys are helping improve patient care here.

Promising results from the Wisconsin National Primate Research Center (WiNPRC) are giving hope to the millions of people who live with Parkinson’s disease (PD). By grafting neurons from monkeys, WiNPRC researchers relieved the debilitating movement and depression symptoms associated with the disease.

The researchers used induced pluripotent stem cells from the monkeys’ own bodies to make dopaminergic neurons. which produce dopamine, a chemical that transmits signals between nerve cells. PD damages these neurons and disrupts the signals, making it progressively harder for people who have PD to coordinate their muscles for even simple movements and causing rigidity, slowness and tremors, which are the disease’s hallmark symptoms. Patients — especially those in earlier stages of Parkinson’s — are typically treated with drugs, such as L-DOPA, to increase dopamine production.

“Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at WiNPRC. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”

To develop additional treatment options, the researchers used real-time magnetic resonance imaging (MRI)  to inject millions of dopamine-producing neurons and supporting cells into each monkey’s striatum, an area of the brain that is depleted of dopamine as a consequence of the ravaging effects of Parkinson’s.

Half the monkeys received cells from other monkeys (an allogenic transplant), and the other half received grafts made from their own induced pluripotent stem cells (called an autologous transplant). The allogeneic monkeys’ symptoms remained unchanged or worsened, but the autologous monkeys began making significant improvements within six months and even more within a year — dopamine levels doubled for some and tripled for others.

Emborg says examples of the improvements included the autologous animals moving more and grabbing food much faster and easier. She adds, “Although Parkinson’s is typically classified as a movement disorder, anxiety and depression are typical, too. Symptoms that resemble depression and anxiety — pacing, disinterest in others and even in favorite treats — abated after the autologous grafts grew in.”

These promising results add to the growing body of NPRC research into improving lives for people who live with PD. Read more about our PD research here.

Alzheimer’s disease (AD) affects more than 5.5 million Americans per year. This staggering prevalence makes it a high-priority disease for researchers to develop better treatments and even a cure. Researchers at California’s National Primate Research Center (CNPRC) are among those pursuing answers and believe the disease actually begins decades before the first signs of cognitive decline are triggered. 

Until recently, testing has primarily been done on transgenic mice that express a human version of amyloid or tau proteins, but these studies have proven to be difficult to translate into new medications for the human population. In contrast, nonhuman primate (NHP) models may yield new treatments by providing a closer biological link between the laboratory and clinic. 

“Humans and monkeys have two forms of the tau protein in their brains, but rodents only have one,” said Danielle Beckman, postdoctoral researcher at the CNPRC and first author on the paper. “We think the macaque is a better model, because it expresses the same versions of tau in the brain as humans do.”

Beckman and her team recommend adding an intermediate step for translational research: “If we can test therapies that work in mouse models prior to investing millions or billions of dollars into clinical trials, we really think it’s going to make an impact in having a new drug on the market. I think we really need to be open about new animal models for diseases.”

Visualization of biomarkers in the brain of NHP models may provide the key into the progression of Alzheimer’s disease. So far, teams have monitored signs of neuron death and performed positron emission tomography imaging. The effects of neurodegeneration were observed rapidly; within three months, end-stage tangles were present. And within 6 months, the progress of neurodegeneration increases markedly.

While it is still unknown whether the treated animals will present the full spectrum of Alzheimer’s Disease, including severe cognitive impairment, the initial observations have set the stage for the next steps in testing tau‐based therapeutics for AD patients. Research with monkeys is again proving critical to finding answers that can improve millions of lives worldwide. 

To learn more about the work happening at our research centers around the country, visit this link. 

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.