Tag: Parkinson's Disease

Categories : Gastrointestinal Neurodegenerative DiseasesTags :

Parkinson’s Drug Found to Promote Pathogenic Gut Bacteria

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Fig. 1: Chemical imaging of active gut microbes. After brief incubation with heavy water, culture medium and a drug, various chemical bonds (here C-D and C-H) in the stool sample are shown in yellow and green, their ratio in yellow-purple (left). Selected microbes are detected in the same image section with fluorescence-labelled oligonucleotide probes in cyan. The activity of the detected microbes can be determined based on the amount of C-D bonds. C: Xiaowei Ge (Boston University)

An international team of scientists have revealed that the widely prescribed Parkinson’s disease drug entacapone significantly disrupts the human gut microbiome by inducing iron deficiency. This international study, provides new insights into the often-overlooked impact of human-targeted drugs on the microbial communities that play a critical role in human health. The findings, published in Nature Microbiology, suggest however that iron supplementation can help counteract these impacts.

While it is well established that antibiotics can significantly disrupt the human gut microbiome, emerging research shows that a wide range of human-targeted drugs – particularly those used to treat neurological conditions – can also profoundly affect the microbial communities living in our bodies. Despite their intended therapeutic effects on different organs, these drugs can inadvertently disrupt the balance of gut microbes, leading to potential health consequences. Until now, most studies investigating these interactions relied either on patient cohort analyses affected by many confounding factors or on experiments using isolated gut bacteria, which do not fully capture the complexity of the human microbiome.

Investigating drug–bug interactions

The team, which included some from the University of Vienna, used a novel experimental approach. The researchers studied the effects of two drugs – entacapone and loxapine, a medication for schizophrenia – on faecal samples from healthy human donors. They incubated the samples with therapeutic concentrations of these drugs, then analysed the impact on the microbial communities using advanced molecular and imaging techniques, including heavy water labelling combined with Stimulated Raman Spectroscopy (SRS). The team discovered that loxapine and even more so entacapone severely inhibited many microbiome members, while E. coli dramatically expanded in the presence of entacapone.

“The results were even more striking when we examined microbial activity, rather than just their abundance,” explained Fatima Pereira, lead author of the study and former Postdoctoral researcher at the University of Vienna. “The heavy water-SRS method allowed us to observe the subtle yet significant changes in the gut microbiome, which are often missed in traditional abundance-based measurements.”

Entacapone induces iron starvation, favours pathogenic microbes

The researchers hypothesised that entacapone might interfere with iron availability in the gut, a crucial resource for many microbes. Their experiments confirmed that adding iron to faecal samples containing entacapone counteracted the drug’s microbiome-altering effects. Further investigation revealed that E. coli, which thrived under these conditions, carried a highly efficient iron-uptake system (enterobactin siderophore). This system allowed the bacteria to overcome iron starvation and proliferate, even in the presence of the drug.

“By showing that entacapone induces iron deficiency, we have uncovered a new mechanism of drug-induced gut dysbiosis, in which the drug selects for E. coli and other potentially pathogenic microbes well adapted to iron limiting conditions,” said Michael Wagner, scientific director of the Excellence Cluster and vice-head of the Centre for Microbiology and Environmental Systems Science (CeMESS) at the University of Vienna.

Wider implications for drug–microbiome interactions

This discovery has broader implications for understanding how other human-targeted drugs might affect the gut microbiome. Several drugs, including entacapone, contain metal-binding catechol groups, suggesting that this mechanism could be a more common pathway for drug-induced microbiome alterations.

The findings also present an opportunity to mitigate the side effects of drugs like entacapone. By ensuring sufficient iron availability to the large intestine, it may be possible to reduce dysbiosis and the gastrointestinal issues that often accompany Parkinson’s disease treatment.

“The next step is to explore how we can modify drug treatments to better support the gut microbiome,” said Wagner. “We are looking at strategies to selectively deliver iron to the large intestine, where it can benefit the microbiome without interfering with drug absorption in the small intestine.”

Source: University of Vienna

Categories : Neurodegenerative Diseases NeurologyTags :

Major Discovery for the Understanding of Parkinson’s Disease: New Neurotransmitter

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Neurotransmitters at a synapse. Credit: Scientific Animations CC4.0

The treatment of certain neurodegenerative diseases and the pages of neuroscience textbooks may soon be in need of a major update. A research team has discovered that a molecule in the brain – ophthalmic acid – unexpectedly acts like a neurotransmitter similar to dopamine in regulating motor function, offering a new therapeutic target for Parkinson’s and other movement diseases.

As reported in the journal Brain, researchers observed that ophthalmic acid binds to and activates calcium-sensing receptors in the brain, reversing the movement impairments of Parkinson’s mouse models for more than 20 hours.

Parkinson’s disease (PD) symptoms, which include tremors, shaking and lack of movement, are caused by decreasing levels of dopamine in the brain as those neurons die. L-dopa, the front-line drug for treatment, acts by replacing the lost dopamine and has a duration of two to three hours. While initially successful, the effect of L-dopa fades over time, and its long-term use leads to dyskinesia – involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.

“Our findings present a groundbreaking discovery that possibly opens a new door in neuroscience by challenging the more-than-60-year-old view that dopamine is the exclusive neurotransmitter in motor function control,” said co-corresponding author Amal Alachkar, School of Pharmacy & Pharmaceutical Sciences professor. “Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects. The identification of the ophthalmic acid-calcium-sensing receptor pathway, a previously unrecognised system, opens up promising new avenues for movement disorder research and therapeutic interventions, especially for Parkinson’s disease patients.”

Alachkar began her investigation into the complexities of motor function beyond the confines of dopamine more than two decades ago, when she observed robust motor activity in Parkinson’s mouse models without dopamine. In this study, the team conducted comprehensive metabolic examinations of hundreds of brain molecules to identify which are associated with motor activity in the absence of dopamine. After thorough behavioural, biochemical and pharmacological analyses, ophthalmic acid was confirmed as an alternative neurotransmitter.

“One of the critical hurdles in Parkinson’s treatment is the inability of neurotransmitters to cross the blood-brain barrier, which is why L-DOPA is administered to patients to be converted to dopamine in the brain,” Alachkar said. “We are now developing products that either release ophthalmic acid in the brain or enhance the brain’s ability to synthesise it as we continue to explore the full neurological function of this molecule.”

Source: University of California – Irvine

Categories : Ethics and Law Neurodegenerative DiseasesTags :

Over 100 Key Alzheimer’s Papers Found To Have Suspicious Data

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Photo by National Cancer Institute on Unsplash

An investigation by Science has shown that over 100 key papers on Alzheimer’s research have used falsified data. The papers all have a common author – veteran neuropathologist Eliezer Masliah, a key researcher at the National Institute on Aging (NIA), typically as first or last author.

The investigation has found that scores of Masliah’s lab studies at the University of California San Diego (UCSD) and NIA are riddled with apparently falsified Western blots (images used to show the presence of proteins) and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, under supposedly different experimental conditions.

At UCSD, Masliah had amassed decades of experience researching Alzheimer’s and Parkinson’s disease, amassing 800 papers. Some important topics in them, such as alpha-synuclein (a protein linked to both diseases), continue to have great influence. The US Congress had released a flood of funding for Alzheimer’s research, US$2.6 billion for last year’s budget, far outstripping that for the rest of the NIA, and Masliah was an ideal choice for its neuroscience division director. This was a position which was enormously influential for Alzheimer’s research in the US as well as internationally, allowing him to fund selected research over and above others with better scores form peer-review.

One of the drugs being developed based on his work is prasinezumab, which failed to show benefit over placebo in a trial of 316 Parkinson’s patients – but resulting in a host of adverse effects, though none serious. The drug was based on an idea by Masliah and another scientist (whose papers were also seemingly doctored) that a vaccine-like approach could cause the body to create antibodies against harmful precursors in both Parkinson’s and Alzheimer’s.

Questions began to be raised about his research two years ago. These were assessed by a team of forensic analysts and a neuroscientist, who concluded, “In our opinion, this pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work.” They acknowledge that accidental duplication is a possibility, and that images can acquire artefacts resembling improper manipulation during the publication process.

Columbia University neurobiologist Mu Yang used specialised software to detect similarities and alterations in images. She had previously worked with the team investigating manipulation in Alzheimer’s and stroke data. In her analysis, duplicated sections in certain Western blots that had been “seamlessly blended” quickly floated into view, she said. “It tells me someone put a lot of thought and effort into the image … and usually indicates something is very wrong.”

A team of 11 neuroscientists was less charitable when they viewed the images. Samuel Gandy, a prominent neurologist at the Mount Sinai Alzheimer’s Disease Research Center said that he was “floored” by what he saw, noting that even a “bus driver” could see that two images of a mitochondrion published two years apart were identical. “Hundreds of images,” he said in a video interview. “There had to have been ongoing manipulation for years.”

In response to this latest dossier, the NIH issued a statement stating that there was a finding of “research misconduct” for Masliah over reuse of figures in two papers, further stating that Masliah no longer serves as NIA’s neuroscience division director. The NIH stated that it had started its own investigation in 2023.

Source: Science

Categories : Neurodegenerative DiseasesTags :

Why do Some Parkinson’s Disease Treatments Affect Decision Making?

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Parkinson’s disease, a debilitating nervous system disorder, is treated with medications that sometimes cause impaired decision-making and poor impulse control. Now, researchers from Fujita Health University in Japan have identified a structure in the brain called the external globus pallidus which may be responsible for this side effect, paving the way for new treatments.

Parkinson’s disease (PD), also known simply as Parkinson’s, is a disorder of the nervous system that affects millions of people worldwide. The nerve cell damage associated with Parkinson’s can cause tremors, slowed movements, problems with balance, and many other symptoms which worsen gradually over time. Although there is no cure, there are medications available that can treat PD symptoms. Some of these medications, however, have previously unexplained side effects – including impaired decision-making that leads to potentially harmful behaviours such as pathological gambling, binge eating and compulsive shopping.

Now, in a study published in the International Journal of Molecular Sciences, researchers at Fujita Health University in Japan, led by Assistant Professor Hisayoshi Kubota from the Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, have investigated the mechanism by which a drug called pramipexole or PPX impairs the decision-making process in mice with Parkinson’s disease. The research was co-authored by Professor Taku Nagai from the Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), and Professor Hirohisa Watanabe from the Department of Neurology, School of Medicine, both at Fujita Health University.

To take a closer look at the findings of this study, we first need to understand how PPX works to alleviate PD symptoms. PD mainly results from a loss of nerve cells or neurons that produce a compound called dopamine. Some neurons are dependent on dopamine for their regular functioning – they have structures called ‘dopamine receptors’ which can be thought of as locks which can then be activated using dopamine as the ‘key’. Drugs like PPX can imitate the function of dopamine and bind to these receptors instead, especially in patients with PD who lack dopamine-producing neurons.

To study the effects of PPX on PD, the researchers injected the brains of mice with a toxin called 6-hydroxydopamine (or 6-OHDA). 6-OHDA damages neurons in a very similar manner to that observed in the brains of patients with PD. The mice were treated with PPX and then subjected to a touchscreen-based ‘gambling task’ to test their decision-making skills. Interestingly, these mice picked the high-risk/high-reward option much more often – they opted for a disadvantageous outcome where they received a large reward (of strawberry milkshake), which also comes with an increased risk of a large punishment by exposure to flashing lights.

But which part of the brain is responsible for this behaviour? Investigating the brains of mice treated with PPX revealed that a region deep inside the brain called the external globus pallidus (GPe) was hyperactivated, or showed a much higher level of neuron activity. The researchers then chemically inhibited the neurons in the GPe, which actually reduced disadvantageous risk-taking activity in the mice. This proved that hyperactivation of the GPe was indeed responsible for poor decision-making in the mice treated with PPX.

This study has huge implications for treating patients with Parkinson’s disease. “Our findings could lead to the development of new medications or interventions that specifically target the external globus pallidus,” explains Dr. Kubota. “This would help to prevent or reduce decision-making impairments in Parkinson’s disease patients.“

Besides helping medical professionals develop better treatments for Parkinson’s disease, these findings can also help improve awareness among affected patients, their families, as well as the general public. Dr. Kubota, explains that “Investigating how Parkinson’s disease medications affect decision-making will help the public to better understand the complexity of the disease and its treatment.” He also says “This will benefit patients, their families and carers, and motivate them to consider early care and preventive strategies.”

These findings shed new light on the complex processes in the brain that aid our everyday decision-making skills, and promise to improve quality of life for patients affected by Parkinson’s disease. Maybe we can take away some important lessons from this study as well, and think twice before we indulge in poor decision-making in our daily lives!

Categories : Neurodegenerative DiseasesTags :

SGLT-2 Inhibitors may Lower Risk of Dementia and Parkinson’s Disease

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A class of drugs for diabetes may be associated with a lower risk of dementia and Parkinson’s disease, according to a study published in Neurology®, the medical journal of the American Academy of Neurology. The study looked at sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are also known as gliflozins. They lower blood sugar by causing the kidneys to remove sugar from the body through urine.

“We know that these neurodegenerative diseases like dementia and Parkinson’s disease are common and the number of cases is growing as the population ages, and people with diabetes are at increased risk of cognitive impairment, so it’s encouraging to see that this class of drugs may provide some protection against dementia and Parkinson’s disease,” said study author Minyoung Lee, MD, PhD, of Yonsei University College of Medicine in Seoul, South Korea.

The retrospective study looked at people with type 2 diabetes who started diabetes medication from 2014 to 2019 in South Korea. People taking SGLT2 inhibitors were matched with people taking other oral diabetes drugs, so the two groups had people with similar ages, other health conditions and complications from diabetes.

Then researchers followed the participants to see whether they developed dementia or Parkinson’s disease. Those taking the SGLT2 inhibitors were followed for an average of two years and those taking the other drugs were followed for an average of four years.

Among the 358 862 participants with an average age of 58, a total of 6837 people developed dementia or Parkinson’s disease during the study. For Alzheimer’s disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10 000 person-years, compared to 63.7 cases for those taking other diabetes drugs. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

For vascular dementia, which is dementia caused by vascular disease, the incidence rate for people taking the SGLT2 drugs was 10.6 cases per 10 000, compared to 18.7 for those taking the other drugs. For Parkinson’s disease, the incidence rate for those taking the SGLT2 drugs was 9.3 cases per 10 000, compared to 13.7 for those taking the other drugs.

After researchers adjusted for other factors that could affect the risk of dementia or Parkinson’s disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer’s disease and a 20% reduced risk of Parkinson’s disease. Those taking the drugs had a 30% reduced risk of developing vascular dementia.

“The results are generally consistent even after adjusting for factors like blood pressure, glucose, cholesterol and kidney function,” Lee said. “More research is needed to validate the long-term validity of these findings.” Lee said that since participants were followed for less than five years at the most, it’s possible that some participants would later develop dementia or Parkinson’s disease.

Source: American Academy of Neurology

Categories : Implants and Prostheses Neurodegenerative DiseasesTags :

Taming Parkinson’s Disease with Adaptive Deep Brain Stimulation

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Deep brain stimulation illustration. Credit: NIH

Two new studies from UC San Francisco are pointing the way toward round-the-clock personalised care for people with Parkinson’s disease through an implanted device that can treat movement problems during the day and insomnia at night. 

The approach, called adaptive deep brain stimulation, or aDBS, uses methods derived from AI to monitor a patient’s brain activity for changes in symptoms. 

When it spots them, it intervenes with precisely calibrated pulses of electricity. The therapy complements the medications that Parkinson’s patients take to manage their symptoms, giving less stimulation when the drug is active, to ward off excess movements, and more stimulation as the drug wears off, to prevent stiffness.

It is the first time a so-called “closed loop” brain implant technology has been shown to work in Parkinson’s patients as they go about their daily lives. The device picks up brain signals to create a continuous feedback mechanism that can curtail symptoms as they arise. Users can switch out of the adaptive mode or turn the treatment off entirely with a hand-held device.

For the first study, researchers conducted a clinical trial with four people to test how well the approach worked during the day, comparing it to an earlier brain implant DBS technology known as constant or cDBS. 

To ensure the treatment provided the maximum relief to each participant, the researchers asked them to identify their most bothersome symptom. The new technology reduced them by 50%. Results appear August 19 in Nature Medicine.

“This is the future of deep brain stimulation for Parkinson’s disease,” said senior author Philip Starr, MD, PhD, the Dolores Cakebread Professor of Neurological Surgery, co-director of the UCSF Movement Disorders and Neuromodulation Clinic. 

Starr has been laying the groundwork for this technology for more than a decade. In 2013, he developed a way to detect and then record the abnormal brain rhythms associated with Parkinson’s. In 2021, his team identified specific patterns in those brain rhythms that correspond to motor symptoms.

“There’s been a great deal of interest in improving DBS therapy by making it adaptive and self-regulating, but it’s only been recently that the right tools and methods have been available to allow people to use this long-term in their homes,” said Starr, who was recruited by UCSF in 1998 to start its DBS program.

Earlier this year, UCSF researchers led by Simon Little, MBBS, PhD, demonstrated in Nature Communications that adaptive DBS has the potential to alleviate the insomnia that plagues many patients with Parkinson’s. 

“The big shift we’ve made with adaptive DBS is that we’re able to detect, in real time, where a patient is on the symptom spectrum and match it with the exact amount of stimulation they need,” said Little, associate professor of neurology and a senior author of both studies. Both Little and Starr are members of the UCSF Weill Institute for Neurosciences.

Restoring movement

Parkinson’s disease affects about 10 million people around the world. It arises from the loss of dopamine-producing neurons in deep regions of the brain that are responsible for controlling movement. The lack of those cells can also cause non-motor symptoms, affecting mood, motivation and sleep.

Treatment usually begins with levodopa, a drug that replaces the dopamine these cells are no longer able to make. However, excess dopamine in the brain as the drug takes effect can cause uncontrolled movements, called dyskinesia. As the medication wears off, tremor and stiffness set in again.  

Some patients then opt to have a standard cDBS device implanted, which provides a constant level of electrical stimulation. Constant DBS may reduce the amount of medication needed and partially reduce swings in symptoms. But the device also can over- or undercompensate, causing symptoms to veer from one extreme to the other during the day.

Closing the loop

To develop a DBS system that could adapt to a person’s changing dopamine levels, Starr and Little needed to make the DBS capable of recognising the brain signals that accompany different symptoms. 

Previous research had identified patterns of brain activity related to those symptoms in the subthalamic nucleus, or STN, the deep brain region that coordinates movement. This is the same area that cDBS stimulates, and Starr suspected that stimulation would mute the signals they needed to pick up.

So, he found alternative signals elsewhere in the brain – the motor cortex – that wouldn’t be weakened by the DBS stimulation. 

The next challenge was to work out how to develop a system that could use these dynamic signals to control DBS in an environment outside the lab. 

Building on findings from adaptive DBS studies that he had run at Oxford University a decade earlier, Little worked with Starr and the team to develop an approach for detecting these highly variable signals across different medication and stimulation levels.  

Over the course of many months, postdoctoral scholars Carina Oerhn, PhD, Lauren Hammer, PhD, and Stephanie Cernera, PhD, created a data analysis pipeline that could turn all of this into personalised algorithms to record, analyse and respond to the unique brain activity associated with each patient’s symptom state.

John Ngai, PhD, who directs the Brain Research Through Advancing Innovative Neurotechnologies® initiative (The BRAIN Initiative®) at the National Institutes of Health, said the study promises a marked improvement over current Parkinson’s treatment. 

“This personalised, adaptive DBS embodies The BRAIN Initiative’s core mission to revolutionise our understanding of the human brain,” he said. 

A better night’s sleep

Continuous DBS is aimed at mitigating daytime movement symptoms and doesn’t usually alleviate insomnia.

But in the last decade, there has been a growing recognition of the impact that insomnia, mood disorders and memory problems have on Parkinson’s patients. 

To help fill that gap, Little conducted a separate trial that included four patients with Parkinson’s and one patient with dystonia, a related movement disorder. In their paper published in Nature Communications, first author Fahim Anjum, PhD, a postdoctoral scholar in the Department of Neurology at UCSF, demonstrated that the device could recognise brain activity associated with various states of sleep. He also showed it could recognise other patterns that indicate a person is likely to wake up in the middle of the night. 

Little and Starr’s research teams, including their graduate student Clay Smyth, have started testing new algorithms to help people sleep. Their first sleep aDBS study was published last year in Brain Stimulation.  

Scientists are now developing similar closed-loop DBS treatments for a range of neurological disorders. 

“We see that it has a profound impact on patients, with potential not just in Parkinson’s but probably for psychiatric conditions like depression and obsessive-compulsive disorder as well,” Starr said. “We’re at the beginning of a new era of neurostimulation therapies.”

Source: University of California San Francisco

Categories : Neurodegenerative DiseasesTags :

Antioxidants in Seaweed Could help Prevent Parkinson’s Disease

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Parkinson’s disease is induced by neuronal damage due to excessive production of reactive oxygen species. Suppression of reactive oxygen species generation is essential because it is fatal to dopaminergic neurons that manage dopamine neurotransmitters. Currently, only symptomatic treatment is available, so the development of treatment regimens and prevention methods is necessary.

Fortunately, Associate Professor Akiko Kojima-Yuasa of Osaka Metropolitan University’s Graduate School of Human Life and Ecology led a research group that has verified the physiological effect of Ecklonia cava polyphenols, seaweed antioxidants, on the prevention of Parkinson’s disease.

In this study, published in the journal Nutrients, two types of motor function tests were conducted using Parkinson’s disease model mice that were orally fed the antioxidants daily for one week and then administered rotenone. Results showed that motor function, which was decreased by rotenone, was restored. There was also improvement in intestinal motor function and the colon mucosa structure, a special tissue that covers the colon.

Further, cellular experiments using Parkinson’s disease model cells verified the biochemical interaction of the preventive effect of Ecklonia cava. Validation results showed that the antioxidants activate the AMPK enzyme (adenosine monophosphate-activated protein kinase), an intracellular energy sensor, and inhibit the production of reactive oxygen species that cause neuronal cell death.

“This study suggests that Ecklonia cava antioxidants may reduce neuronal damage by AMPK activation and inhibiting intracellular reactive oxygen species production,” stated Professor Kojima-Yuasa. “It is hoped that Ecklonia cava will be an effective ingredient in the prevention of Parkinson’s disease.”

Source: Osaka Metropolitan University

Categories : Neurodegenerative DiseasesTags :

New Ultrasound and Genetics Combination Precisely Targets Neurons in Diseased Regions

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McKelvey School of Engineering researchers have developed a noninvasive technology combining a holographic acoustic device with genetic engineering that allows them to precisely target affected neurons in the brain, creating the potential to precisely modulate selected cell types in multiple diseased brain regions. (Credit: Yaoheng Yang)

Brain diseases such as Parkinson’s disease involve damage in more than one region of the brain, requiring technology that could precisely and flexibly address all affected regions simultaneously. Researchers have developed a noninvasive technology combining a holographic acoustic device with genetic engineering that allows them to precisely target affected neurons in the brain. This has the potential to precisely modulate selected cell types in multiple diseased brain regions. 

Hong Chen, associate professor of biomedical engineering and neurosurgery at Washington University in St. Louis and her team created AhSonogenetics, or Airy-beam holographic sonogenetics, a technique that uses a noninvasive wearable ultrasound device to alter genetically selected neurons in the brains of mice. Results of the proof-of-concept study were published in Proceedings of the National Academy of Sciences. 

AhSonogenetics brings together several of Chen’s group’s recent advances into one technology. In 2021, she and her team launched Sonogenetics, a method that uses focused ultrasound to deliver a viral construct containing ultrasound-sensitive ion channels to genetically selected neurons in the brain. They use low-intensity focused ultrasound to deliver a small burst of warmth, which opens the ion channels and activates the neurons. Chen’s team was the first to show that sonogenetics could modulate the behaviour of freely moving mice.

In 2022, she and members of her lab designed and 3D-printed a flexible and versatile tool known as an Airy beam-enabled binary acoustic metasurface that allowed them to manipulate ultrasound beams. She also is developing Sonogenetics 2.0, which combines the advantage of ultrasound and genetic engineering to modulate defined neurons noninvasively and precisely in the brains of humans and animals. AhSonogenetics brings them together as a potential method to intervene in neurodegenerative diseases. 

“By enabling precise and flexible cell-type-specific neuromodulation without invasive procedures, AhSonogenetics provides a powerful tool for investigating intact neural circuits and offers promising interventions for neurological disorders,” Chen said. 

Sonogenetics gives researchers a way to precisely control the brains, while airy-beam technology allows researchers to bend or steer the sound waves to generate arbitrary beam patterns inside the brain with a high spatial resolution. Yaoheng (Mack) Yang, a postdoctoral research associate who earned a doctorate in biomedical engineering from McKelvey Engineering in 2022, said the technology gives the researchers three unique advantages.

“Airy beam is the technology that can give us precise targeting of a smaller region than conventional technology, the flexibility to steer to the targeted brain regions, and to target multiple brain regions simultaneously,” Yang said.

Chen and her team, including first authors Zhongtao Hu, a former postdoctoral research associate, and Yang, designed each Airy-beam metasurface individually as the foundation for wearable ultrasound devices that were tailored for different applications and for precise locations in the brain.

Chen’s team tested the technique on a mouse model of Parkinson’s disease. With AhSonogenetics, they were able to stimulate two brain regions simultaneously in a single mouse, eliminating the need for multiple implants or interventions. This stimulation alleviated Parkinson’s-related motor deficits in the mouse model, including slow movements, difficulty walking and freezing behaviours.

The team’s Airy-beam device overcomes some of the limits of sonogenetics, including tailoring the design of the device to target specific brain locations, as well as incorporating the flexibility to adjust target locations in a single brain.

Hu said the device, which costs roughly $50 to make, can be tailored in size to fit various brain sizes, expanding its potential applications. 

“This technology can be used as a research platform to speed neuroscience research because of the capability to flexibly target different brain regions,” Hu said. “The affordability and ease of fabrication lower the barriers to the widespread adoption of our proposed devices by the research community for neuromodulation applications.”

Source: Washington University in St. Louis

Categories : Gastrointestinal Neurodegenerative DiseasesTags :

Gut Bacteria in Parkinson’s Disease Produce Fewer B Vitamins

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In Parkinson’s disease, a reduction in the gut bacteria of genes responsible for synthesising the essential B vitamins B2 and B7 was found. Credit: Reiko Matsushita

A study led by Nagoya University in Japan has revealed a link between gut microbiota and Parkinson’s disease (PD). The researchers found that the gut bacteria genes responsible for synthesising vitamins B2 and B7 were reduced. This gene reduction was also linked to low levels of agents that help maintain the integrity of the intestinal barrier, which when weakened causes the inflammation seen in PD. Their findings, published in npj Parkinson’s Disease, suggest that treatment with B vitamins to address these deficiencies can be used to treat PD. 

PD is characterized by a variety of physical symptoms that hinder daily activities and mobility, such as shaking, slow movement, stiffness, and balance problems. While the frequency of PD may vary between different populations, it is estimated to affect approximately 1-2% of individuals aged 55 years or older. 

Various physiological processes are heavily influenced by the microorganisms found in the gut, which are collectively known as gut microbiota. In ideal conditions, gut microbiota produce SCFAs and polyamines, which maintain the intestinal barrier that prevents toxins entering the bloodstream. Toxins in the blood can be carried to the brain where they cause inflammation and affect neurotransmission processes that are critical for maintaining mental health.

To better understand the relationship between the microbial characteristics of the gut in PD, Hiroshi Nishiwaki and Jun Ueyama from the Nagoya University Graduate School of Medicine conducted a metanalysis of stool samples from patients with PD from Japan, the United States, Germany, China, and Taiwan. They used shotgun sequencing, a technique that sequences all genetic material in a sample. This is an invaluable tool because it offers researchers a better understanding of the microbial community and genetic makeup of the sample.

They observed a decrease in the bacterial genes responsible for the synthesising of riboflavin (vitamin B2) and biotin (vitamin B7) in patients diagnosed with PD. Riboflavin and biotin, derived from both food and gut microbiota, have anti-inflammatory properties, which may counteract the neuroinflammation seen in diseases like PD. 

B vitamins play crucial roles in the metabolic processes that influence the production and functions of short-chain fatty acids (SCFAs) and polyamines, two agents that help maintain the integrity of the intestinal barrier, preventing toxins entering the bloodstream. An examination of fecal metabolites revealed decreases of both in patients with PD. 

The findings indicate a potential explanation for the progression of PD. “Deficiencies in polyamines and SCFAs could lead to thinning of the intestinal mucus layer, increasing intestinal permeability, both of which have been observed in PD,” Nishiwaki explained. “This higher permeability exposes nerves to toxins, contributing to abnormal aggregation of alpha-synuclein, activating the immune cells in the brain, and leading to long-term inflammation.” 

He added, “Supplementation therapy targeting riboflavin and biotin holds promise as a potential therapeutic avenue for alleviating PD symptoms and slowing disease progression.”

The results of the study highlight the importance of understanding the complex relationship among gut microbiota, metabolic pathways, and neurodegeneration. In the coming years, customised therapy could potentially be based on patients’ unique microbiome profiles. By altering bacterial levels in the microbiome, doctors can potentially delay the onset of symptoms associated with diseases like PD.

“We could perform gut microbiota analysis on patients or conduct faecal metabolite analysis,” Nishiwaki said. “Using these findings, we could identify individuals with specific deficiencies and administer oral riboflavin and biotin supplements to those with decreased levels, potentially creating an effective treatment.”

Source: Nagoya University

The study, “Meta-analysis of shotgun sequencing of gut microbiota in Parkinson’s disease,” was published in npj Parkinson’s Disease on May 21, 2024, at DOI:10.1038/s41531-024-00724-z.

Categories : Medical Research & Technology Neurodegenerative DiseasesTags :

Soft Robotic Garments Help Parkinson’s Patients to Walk More Freely

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Freezing is one of the most common and debilitating symptoms of Parkinson’s disease, when they suddenly lose the ability to move their feet, often mid-stride, resulting in a series of staccato stutter steps that get shorter until the person stops altogether. These episodes are one of the biggest contributors to falls among people living with Parkinson’s disease. 

Today, freezing is treated with a range of pharmacological, surgical or behavioural therapies, none of which are particularly effective. What if there was a way to stop freezing altogether?

In a Nature Medicine report, researchers used a soft, wearable robot to help a person living with Parkinson’s walk without freezing. The robotic garment, worn around the hips and thighs, gives a gentle push to the hips as the leg swings, helping the patient achieve a longer stride. The device completely eliminated the participant’s freezing while walking indoors, allowing them to walk faster and further. 

The soft robotic apparel was developed by researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Boston University Sargent College of Health & Rehabilitation Sciences.

“We found that just a small amount of mechanical assistance from our soft robotic apparel delivered instantaneous effects and consistently improved walking across a range of conditions for the individual in our study,” said Conor Walsh, professor at SEAS and co-corresponding author of the study. 

For over a decade, Walsh’s Biodesign Lab at SEAS has been developing assistive and rehabilitative robotic technologies to improve mobility for individuals’ post-stroke and those living with ALS or other diseases that impact mobility. Some of that technology, specifically an exosuit for post-stroke gait retraining, received support to develop and commercialise the technology.

“Leveraging soft wearable robots to prevent freezing of gait in patients with Parkinson’s required a collaboration between engineers, rehabilitation scientists, physical therapists, biomechanists and apparel designers,” said Walsh, whose team collaborated closely with that of Terry Ellis,  Professor and Physical Therapy Department Chair and Director of the Center for Neurorehabilitation at Boston University.

The team spent six months working with a 73-year-old man with Parkinson’s disease, who, despite using both surgical and pharmacologic treatments, endured substantial and incapacitating freezing episodes more than 10 times a day, causing him to fall frequently. These episodes prevented him from walking around his community and forced him to rely on a scooter to get around outside.

In previous research, Walsh and his team leveraged human-in-the-loop optimization to demonstrate that a soft, wearable device could be used to augment hip flexion and assist in swinging the leg forward to provide an efficient approach to reduce energy expenditure during walking in healthy individuals.

Here, the researchers used the same approach but to address freezing. The wearable device uses cable-driven actuators and sensors worn around the waist and thighs. Using motion data collected by the sensors, algorithms estimate the phase of the gait and generate assistive forces in tandem with muscle movement.

The effect was instantaneous. Without any special training, the patient was able to walk without any freezing indoors and with only occasional episodes outdoors. He was also able to walk and talk without freezing, a rarity without the device.

“Our team was really excited to see the impact of the technology on the participant’s walking,” said Jinsoo Kim, former PhD student at SEAS and co-lead author on the study.

During the study visits, the participant told researchers: “The suit helps me take longer steps and when it is not active, I notice I drag my feet much more. It has really helped me, and I feel it is a positive step forward. It could help me to walk longer and maintain the quality of my life.”

“Our study participants who volunteer their time are real partners,” said Walsh. “Because mobility is difficult, it was a real challenge for this individual to even come into the lab, but we benefited so much from his perspective and feedback.”

The device could also be used to better understand the mechanisms of gait freezing, which is poorly understood.

“Because we don’t really understand freezing, we don’t really know why this approach works so well,” said Ellis. “But this work suggests the potential benefits of a ‘bottom-up’ rather than ‘top-down’ solution to treating gait freezing. We see that restoring almost-normal biomechanics alters the peripheral dynamics of gait and may influence the central processing of gait control.”

Source: Harvard John A. Paulson School of Engineering and Applied Sciences