Insights into Parkinson's balance problems

In PD, disorganized sensorimotor signals cause muscles in the limbs to contract, such that both a muscle promoting a motion and its antagonist muscle are Read more

Cajoling brain cells to dance

“Flicker” treatment is a striking non-pharmaceutical approach aimed at slowing or reversing Alzheimer’s disease. It represents a reversal of EEG: not only recording brain waves, but reaching into the brain and cajoling cells to dance. One neuroscientist commentator called the process "almost too fantastic to believe." With flashing lights and buzzing sounds, researchers think they can get immune cells in the brain to gobble up more amyloid plaques, the characteristic clumps of protein seen in Read more

Insights into Parkinson’s balance problems

Loss of balance and falls are big concerns for people living with Parkinson’s disease and their caregivers. Researchers at Emory and Georgia Tech recently published a paper in PLOS ONE providing insights into how sensory and motor information are misrouted when people with Parkinson’s are attempting to adjust their balance.

When the researchers examined 44 people with Parkinson’s, their history of recent falls correlated with the presence and severity of abnormal muscle reactions. This could help clinicians predict whether someone is at high risk of falling and possibly monitor responses to therapeutic interventions.

People with Parkinson’s tend to lose their balance in situations when they are actively trying to control their center of mass, like when they are getting up from a chair or turning around. Disorganized sensorimotor signals cause muscles in the limbs to contract, such that both a muscle promoting a motion and its antagonist muscle are recruited. It’s like stepping on the gas and the brake at the same time, says J. Lucas McKay, who is first author of the paper.

Physical therapists are sometimes taught that balance reactions in Parkinson’s patients are slower than they should be.

“We show this is not true,” McKay says. “The reactions are on-time but disorganized.”

The paper extends groundbreaking work on how muscles maintain balance, conducted by co-author Lena Ting in animals and healthy young humans, to people with Parkinson’s. Co-authors of the PLOS One paper include Ting and Parkinson’s specialists Madeleine Hackney and Stewart Factor, director of Emory’s movement disorders program. McKay is assistant professor of neurology and biomedical informatics.

McKay says that sensorimotor problems may be a result of degeneration of regions of the brain, outside of and after the dopaminergic cells in the basal ganglia.

“We have to speculate, but the sensory misrouting would be occurring in brain regions like the thalamus — not usually the ones we think about in Parkinson’s, such as the basal ganglia,” he says. “This suggests that future therapies involving these areas could reduce falls.”

The set-up that researchers used to measure balance reactions resembles an earthquake simulator, and was designed and customized by Ting. The photo shows one of the Parkinson’s study participants, being watched by a physical therapy student.

The apparatus can produce around 1 g of acceleration inside of 12 inches of travel, which is “definitely enough to knock someone over,” McKay says.

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Cajoling brain cells to dance

“Flicker” treatment is a striking non-pharmaceutical approach aimed at slowing or reversing Alzheimer’s disease. It represents a reversal of EEG: not only recording brain waves, but reaching into the brain and cajoling cells to dance. One neuroscientist commentator called the process “almost too fantastic to believe.”

With flashing lights and buzzing sounds, researchers think they can get immune cells in the brain to gobble up more amyloid plaques, the characteristic clumps of protein seen in Alzheimer’s. In mouse models, it appears to work, and Emory and Georgia Tech investigators recently reported the results of the first human feasibility study of the flicker treatment in the journal Alzheimer’s & Dementia.

“So far, this is very preliminary, and we’re nowhere close to drawing conclusions about the clinical benefit of this treatment,” said neurologist James Lah, who supervised the Flicker study at Emory Brain Health Center. “But we now have some very good arguments for a larger, longer study with more people.”

The good news: most participants in the study could tolerate the lights and sounds, and almost all stuck with the eight-week regimen of experimental treatment. (Some even joined an optional extension.) In addition, researchers observed that brain cells were dancing to the tunes they piped in, at least in the short term, and saw signs of a reduction in markers of inflammation. Whether the approach can have a long-term effect on neurodegeneration in humans is still to be determined.

Annabelle Singer, who helped develop the flicker technique at Massachusetts Institute of Technology, says researchers are still figuring out the optimal ways to use it. Recent studies have been assessing how long and how often people should experience the lights and sounds, and more are underway.

“We need to collect all the information we have about how to measure someone’s progress,” says Singer, who is now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

In the feasibility study, ten people diagnosed with mild cognitive impairment used goggles and headphones that provided light/sound stimulation at home for an hour every day. This video from Georgia Public Broadcasting’s Your Fantastic Mind series demonstrates what that was like.

“To me — It’s not painfully loud. And the lights are not as bright as you would think they are… I don’t find them to be annoying,” says retired psychotherapist Jackie Spierman in the video.

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Natural killer cells can help control virus in primate model of HIV/AIDS

A combination immunotherapy of IL-21 and IFN-alpha, when added to antiviral therapy, is effective in generating highly functional natural killer cells that can help control and reduce SIV (simian immunodeficiency virus) in animal models. This finding, from Yerkes National Primate Research Center scientists in collaboration with Institut Pasteur, could be key for developing additional treatment options to control HIV/AIDS.

The results were published in Nature Communications.

Antiviral therapy (ART) is the current leading treatment for HIV/AIDS, and is capable of reducing the virus to undetectable levels, but is not a cure and is hampered by issues such as cost, adherence to medication treatment plan and social stigma.

To reduce reliance on ART, the Yerkes, Emory and Institut Pasteur research team worked with 16 SIV-positive, ART-treated rhesus macaques. In most nonhuman primates (NHPs), including rhesus macaques, untreated SIV infection progresses to AIDS-like disease and generates natural killer (NK) cells with impaired functionality. In contrast, natural primate hosts of SIV do not progress to AIDS-like disease. Determining why natural hosts do not progress or how to stop the progression is a critical step in halting HIV in humans.

The researchers compared ART-only treated animals with animals that received ART, IL-21 and IFN-alpha to evaluate how the ART plus combination immunotherapy affected the amount of virus in the animals’ tissues.  

“Our results indicate ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says first author Justin Harper, PhD, a senior research specialist and manager of the Paiardini research lab. “These robust NK cell responses helped clear cells in the lymph nodes, which are known for harboring the virus and enabling its replication and, therefore, the virus’ persistence. Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV.”

HIV treatment has historically focused on the role of T cells in immunity, so harnessing NK cells opens up different avenues.

Mirko Paiardini, PhD

“This proof-of-concept study in rhesus monkeys, which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activities can contribute to controlling the virus,” says Mirko Paiardini, PhD, an associate professor of pathology and laboratory Medicine at Emory University and a researcher at Yerkes. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission in the absence of ART, and, ultimately, reducing the burden HIV is to individuals, families and the world.”

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More evidence for autoantibodies in severe COVID-19

A recent paper from Emory pathologist Cheryl Maier and colleagues provides more evidence for autoantibodies in critically ill COVID-19 patients. Autoantibodies are signs that the immune system attacking the body itself, and are features of diseases such as lupus and rheumatoid arthritis. They have been proposed as an explanation for the severity of some acute COVID-19 cases, as well as continued symptoms in long COVID.

Generally, antibodies are a good thing, and a major goal of COVID-19 vaccination is to drive the immune system to generate protective antibodies against the coronavirus. With autoantibodies and COVID, the idea is that intense inflammation coming from viral infection is causing immune cells to become confused. Not every COVID-19 patient’s immune system goes off the rails, but the train wreck seems to happen more often in COVID-19.

Last year, immunologist Ignacio Sanz’s lab at Emory demonstrated that patients with severe COVID-19 display signs of immune dysregulation similar to those seen in lupus. A follow-up preprint found the suspected autoantibodies, and several other labs have observed autoantibodies in COVID-19 that may be sabotaging antiviral responses or perturbing blood clotting. Now, an active topic of investigation is whether the autoantibodies last longer or don’t diminish as quickly in long COVID. Stay tuned.

This image has an empty alt attribute; its file name is MaierC.jpg
Cheryl Maier, MD, PhD

However, in the current paper in Cell Reports Medicine, autoantibodies were also found in most control samples from intensive care unit patients with pneumonia or sepsis, who are experiencing a state of systemic inflammation comparable to severe COVID-19.

“It’s a reminder that autoantibodies are not necessarily unique to COVID,” Maier says. “They may be more dramatic in COVID, but we see autoantibodies associated with other severe diseases too.”

Maier is medical director for Emory’s Special Coagulation Laboratory, and her team came to the autoimmunity question from a side angle. They were investigating blood clots and hyperviscosity in COVID-19 patients, and wanted to check whether high concentrations of antibodies might be an explanation. Antibodies are proteins, after all, and if someone’s blood is full of them, they thicken it.

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Fly model of repetitive head trauma speeds up time

Tap tap tap ka-CHUNK! That was the sound of fruit flies being given concussions in an Emory laboratory recently.

Emory MD/PhD student Joe Behnke, working with neuroscientist James Zheng, has developed a model for studying repetitive head trauma in the fruit fly Drosophila melanogaster – analogous to CTE (chronic traumatic encephalopathy) in humans. The results were published in Scientific Reports.

CTE is a term for neurodegeneration linked to repeated concussions or blows to the head, which has been observed in athletes and military veterans. Head trauma has also been linked to other neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS (amyotrophic lateral sclerosis).

What’s critical about using fruit flies is that it speeds up time. It can take years or decades for CTE or other neurodegenerative conditions to appear in humans, but Behnke and Zheng can experiment with a mutant fly strain or other interventions in a few weeks. They describe their model as a platform for future studies, in which they can unleash all of the genetic tools fruit flies have to offer.

MD/PhD student Joe Behnke with the apparatus for delivering Drosophila head injuries

To begin with, Behnke worked out a system for giving flies controlled blows to the head. He says that it exploits the climbing instinct flies have when startled, called negative geotaxis. When he taps a vial with flies in it three times, they reorient themselves and begin climbing up. Then a stronger blow, delivered in a crash test-like apparatus, gives flies the desired head injury. Previous models in flies hadn’t really focused on the head, but gave them injuries all over their bodies.

Already, Behnke and Zheng have been able to demonstrate that female fruit flies are more vulnerable to repeated head injuries than males. Repeated head injury results in locomotor deficits and shortened lifespan and accelerates age-related degeneration.

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Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth.

The results were published in the journal Cell Reports.

“The beauty of using organoids is that they allow us to trace back what could happen at the molecular level in early developmental stages,” says lead author Bing Yao, PhD, assistant professor of human genetics at Emory University School of Medicine. “A lot of epigenetic studies on Alzheimer’s use postmortem brains, which only represent the end point of the disease, in terms of molecular signatures.”

Photos of brain organoid cultures courtesy of Zhexing Wen

The brain organoid model allows scientists to probe human fetal brain development without poking into any babies; they have also been used to study schizophrenia, fragile X syndrome and susceptibility to Zika virus.

Co-author Zhexing Wen helped develop the model, in which human pluripotent stem cells recapitulate early stages of brain development, corresponding to 17-20 weeks after conception. The stem cell lines were obtained from both healthy donors and from people with mutations in PSEN1 or APP genes, which lead to early-onset Alzheimer’s.

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The earliest spot for Alzheimer’s blues

The Emory laboratories of Keqiang Ye and David Weinshenker recently published a paper on ApoE, the most common genetic risk factor for late-onset Alzheimer’s. The findings, published in Acta Neuropathologica, suggest how the risk-conferring form of ApoE (ApoE4) may exacerbate pathology in the locus coeruleus.

The LC, part of the brainstem, is thought to be the first region of the brain where pathological signs predicting future cellular degeneration show up. The LC (“blue spot”) gets its name from its blue color; it regulates attention, arousal, stress responses and cognition. The LC is also the major site for production of the neurotransmitter norepinephrine.

ApoE, which packages and transports cholesterol, was known to modulate the buildup of the toxic protein fragment beta-amyloid, but this proposed mechanism goes through Tau. Tau is the other pesky protein in Alzheimer’s, forming neurofibrillary tangles that are the earliest signs of degeneration in the brain. Tau pathology correlates better with dementia and cognitive impairments than beta-amyloid, which several proposed Alzheimer’s therapeutics act on.

The new paper shows that ApoE4 inhibits the enzyme VMAT2, which packages norepinephrine into vesicles. As a result, free/unpackaged norepinephrine lingers in the cytoplasm, and forms a harmful oxidative byproduct that triggers enzymatic degradation of Tau. Thus, norepinephrine may have a “too hot to handle” role in Alzheimer’s – with respect to the LC — somewhat analogous to dopamine in Parkinson’s, which has also been observed to form harmful byproducts. Dopamine and norepinephrine are similar chemically and both are substrates of VMAT2, so this relationship is not a stretch.

Model of how norepinephrine byproduct DOPEGAL triggers locus coeruleus degeneration through Tau

The Emory results make the case for inhibiting the enzyme AEP (asparagine endopeptidase), also known as delta-secretase, as an approach for heading off Alzheimer’s. AEP is the Tau-munching troublemaker, and is activated by the norepinephrine byproduct DOPEGAL

An alternative approach may be to inhibit monoamine oxidase (MAO-A above) enzymes — several old-school antidepressants are available that accomplish this.

At Emory, Ye’s lab has been tracing connections for AEP/delta-secretase in the last few years, and Weinshenker’s group is expert on all things norepinephrine, so the collaboration makes sense.

Delta-secretase’s name positions it in relation to beta- and gamma-secretase, enzymes for processing APP (amyloid precursor protein) into beta-amyloid, but AEP/delta-secretase has the distinction of having its fingers in both the beta-amyloid and Tau pies.

We have to caution that most of the recent research on delta-secretase has been in mouse models. Ye’s collaborators in China have been testing an inhibitor of delta-secretase in animals but it has not reached human studies yet, he reports. That said, this work has been oriented toward figuring out the web of interactions between known players such as ApoE and Tau, whose importance has been well-established in studies of humans with Alzheimer’s.

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Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus.

Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the bacteria?

The answer is neutrophils, one of the most abundant types of immune cells and foot soldiers against bacterial infections. When neutrophils get into the lungs in people with CF, they change behavior and shut off the expression of genes that would be important for them to combat bacteria. They stay around in the lungs, and release harmful proteins that interfere with other cells’ ability to clean up the bacteria.

Tirouvanziam’s lab has developed a culture system for studying neutrophil behavior, a model for how they act in the lungs. The system makes the neutrophils pass through a layer of lung epithelial cells. Under the influence of lung fluids obtained from CF patients, neutrophils turn what Tirouvanziam calls GRIM (Granule Release, Immunomodulatory, Metabolic). They’re feeding but not fighting: highly metabolically active, but not producing the molecules needed for bactericidal activity.

In a recent paper published in Cell Reports Medicine, researchers show that they can reverse the GRIM fate by applying alpha-amanitin, which blocks RNA transcription, and bring back bactericidal activity. This is a sledgehammer approach, because alpha-amanitin shuts down everything – it’s the toxic ingredient in destroying angel/death cap mushrooms.

Thus, alpha-amanitin would not be appropriate as a therapeutic medication. But it is a tantalizing hint of more specific approaches to come – related papers are on the way, Tirovanziam says. Reviving the anti-bacterial ability of neutrophils should be applicable regardless of the pathogen, and independent of antibiotic resistance, he adds.

“We can steer them in the right direction,” he says. “We are starting to realize that neutrophils have multiple programs and pathways – sort of like T cells. And we can show that it is being exposed to CF lung fluid that makes them go wrong – it’s not intrinsic to the neutrophils.”

The paper also says that scientists in his lab have been separating lung fluids from CF patients into fractions, in order to isolate the molecular entities responsible for steering neutrophils down the wrong path.

The first author of the Cell Reports Medicine paper was former graduate student Camila Margaroli, currently a postdoc at UAB. Tirouvanziam’s lab is part of Emory’s Department of Pediatrics and the Emory-Children’s Healthcare Center for Cystic Fibrosis and Airways Disease Research.

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“Trojan horse” antibiotic underperforms; does heteroresistance explain?

A stealthy form of antibiotic resistance may be limiting the effectiveness of a new weapon against bacterial infections, research from Emory’s Antibiotic Resistance Center suggests.

The antibiotic cefiderocol (Fetroja) was developed by the Japanese company Shionogi, and was FDA-approved for the treatment of complicated urinary tract infections in 2019 and for hospital-acquired bacterial pneumonia in 2020.

In a recent international clinical trial testing cefiderocol in patients with serious infections resistant to carbapenems (CREDIBLE-CR), outcomes weren’t significantly better for cefiderocol, compared to patients who received the best available therapy otherwise. In addition, mortality was actually higher for patients treated with cefiderocol.

Resistance to carbapenems, a common class of antibiotics, is a major problem and precisely what cefiderocol was meant to circumvent. These results have had infectious disease experts asking why cefiderocol didn’t perform better, and wondering what place it should take in physicians’ tool boxes.

Cefiderocol has been touted as a “Trojan horse” antibiotic

Emory scientists think that cefiderocol’s effectiveness may have been undermined by heteroresistance, in which a small subpopulation of bacteria is already resistant to a given antibiotic before it is applied. Heteroresistance is often missed by standard tests.

Researchers led by David Weiss, director of Emory’s Antibiotic Resistance Center, surveyed bacterial samples from the Georgia Emerging Infections program, reporting their findings in Lancet Infectious Diseases.

Postdoc Jacob Choby and senior research specialist Tugba Ozturk were the primary surveyors.

They discovered that heteroresistance to cefiderocol was widespread in samples from Georgia, ranging from 9 to 59 percent, depending on the type of bacteria. Weiss acknowledges that he and his colleagues are making indirect inferences about the bacterial infections from the CREDIBLE-CR trial; they would like to test such strains directly in the future.

Still, the prevalence of cefiderocol heteroresistance is similar between bacteria isolated from different countries. Also, the prevalence among various kinds of bacteria in Georgia roughly matches up with mortality rates in the CREDIBLE-CR trial – particularly among the kinds that were the most troublesome (Acinetobacter).

“We’ve shown that heteroresistance can cause treatment failure in animal models, but these data suggest that it may be contributing to treatment failure in hospitals right now,” Weiss says.

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Revealing brain temperature via MR imaging and biophysical modeling

Magnetic resonance (MR) imaging technology and biophysical modeling being developed at Emory and Georgia Tech could provide more accurate predictions of brain temperature, which is difficult for doctors to directly assess. The temperature of the brain is critical information after someone has experienced a stroke or cardiac arrest, and even more important during treatment. 

The results of a pilot study were published today in the journal Communications Physics.

The project grew out of a collaboration between Candace Fleischer, PhD, an assistant professor of radiology and imaging sciences at Emory, and Andrei Fedorov, PhD, a world expert on thermodynamics and biophysical modeling and a professor of mechanical engineering at Georgia Tech. The first author of the paper is Georgia Tech/Emory biomedical engineering graduate student Dongsuk Sung.

The researchers developed a biophysical model based on heat transfer, using data acquired by imaging individuals’ brain tissue and blood vessel structure. As predicted and in agreement with MR whole brain measurements, brain temperature is slightly higher than core body temperature – about 1 degree C; there are “hot” spots in the brain domains with high rate of metabolism; and the regions of the brain that are closer to the scalp are also slightly cooler than the midbrain.

“We find that every subject’s brain temperature and spatial temperature patterns are different, setting the stage for a personalized approach to managing brain temperature,” says Fleischer, who is also a faculty member in the Wallace H. Coulter Department of Biomedical Engineering and Georgia Tech at Emory.

Metabolic heat, cerebral blood flow, and model-predicted brain temperature maps for three healthy volunteers. From Sung et al (2021), via Creative Commons 4.0

Researchers then compared the predictions of their model with measurements based on the magnetic resonance properties of water, which change with temperature, and the temperature-insensitive brain metabolite N-acetylaspartate. The Communications Physics paper shows temperature modeling and MR-based measurements for three healthy volunteers.

Fleischer recently received a three-year, $400,000 Trailblazer grant from the National Institute of Biomedical Imaging and Bioengineering to monitor brain temperature while patients are undergoing therapeutic hypothermia after cardiac arrest. More information about that here.

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