31 patients, with and without mild cognitive impairment, underwent overnight polysomnogram with blood draw for biomarkers.
Neurofilament light chain levels were elevated in those with MCI by morning.
DENVER — Cognitive impairment in Parkinson’s is a mitigating factor for presence of blood-based biomarkers during sleep as indicator of disease progression, according to a poster at the American Academy of Neurology annual meeting.
“The glymphatic system is very active during sleep and we’re looking to see if sleep could be some sort of intervention for people with Parkinson’s disease,” Caileigh Dintino, BS, a research assistant in the Parkinson’s and Movement Disorders Center at Virginia Commonwealth University, told Healio.
New research suggests that presence of biomarker neurofilament light chain impacts both sleep and cognition in those with Parkinson’s disease.Image: Adobe Stock
Prior research suggests sleep disturbances in PD can contribute to disease progression and increase risk of dementia, but it is unknown whether disrupted sleep in PD alters neuroinflammatory and neurodegenerative biomarkers, which typically indicate disease progression and cognitive decline.
Dintino and colleagues aimed to investigate whether sleep in PD is associated with changes in blood-based biomarker levels such as neurofilament light chain, over the course of a single night.
Their study included 31 individuals with PD (mean age 67.4±6.0 years; 58% male), including 23 with normal cognition (52.1% female, mean age 67.4 ±6.0 years) and eight with mild cognitive impairment (87.5% male, mean age 68.4 ±6.6 years). All patients underwent an overnight polysomnogram with blood draws twice during the session, once at 8 p.m. and once at 6:30 a.m.
All participants also submitted to a full cognitive testing battery. Mild cognitive impairment (MCI) was defined by Z score on any two tests among five categories: executive function, memory, language, attention, visuospatial).
Plasma samples were analyzed using Meso Scale Discovery immunoassays for neuroinflammatory biomarkers interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor alpha (TNF-a), as well as the U-PLEX assay for alpha-synuclein.
Neurofilament light chain (NfL), which is released from axons upon injury or neuronal death, was measured using Quanterix Simoa assays, while T-tests were employed to compare overnight changes in biomarker levels. Subsequent correlations were tested with Pearson coefficients and a significance threshold of P < 0.05.
Dintino and colleagues reported that morning NfL levels were 16.5% higher in those with PD and MCI (PM: 13.70 ±4.15, AM: 16.38 ±7.79; P = 0.043), but not significantly different for those without cognitive issues (PM: 17.24 ±7.88, AM: 18.82 ±7.93; P = 0.091).
Morning levels of TNF-a were also elevated in the PD-MCI (PM: 1.83 ±0.88, AM: 1.86 ±0.87; P = 0.02) population but not for those without MCI (PM: 1.65 ±0.54, AM: 1.71 ±0.5; P = 0.38).
“Sleep is a big complaint [among those with Parkinson’s disease],” Dintino said. “Harnessing sleep, as a way to not only to improve quality of life, but to eventually slow disease progression … could be life-changing for these people.”
A small new trial suggests that stool transplants could be a helpful treatment option in early-stage Parkinson’s disease.
Parkinson’s disease is one of the leading causes of disability worldwide, and while treatment options are available, they can become less effective over time.
A recent paper has highlighted the potential effect of fecal transplants on motor symptoms, which are one of the main markers of Parkinson’s disease.
The study could pave the way for further research into the role of the gut microbiome on neurodegenerative conditions, say experts.
Fecal transplants could have an effect on the motor symptoms of people with Parkinson’s disease, a recent study suggests.
A small, single-center clinical trial carried out in Belgium found that people with Parkinson’s disease who received a single dose of a fecal transplant from a healthy donor, had improved symptoms compared to those who received a placebo.
Results, published in eClinicalMedicine, suggested that the motor score for people who received a donor transplant had improved by 5.8 points after 12 months, compared with an improvement of 2.7 points in people who received a placebo transplant.
Significant improvements were also found for an objective measure of constipation (colon transit time), although there was no significant difference in patient-reported scores for constipation.
Mild gastrointestinal symptoms were a common negative side effect at the time of the transplant and were more frequently observed in people who received the donor transplant. Donor transplant recipients were also more likely to have worsened fatigue after 12 months.
For the study, a total of 22 participants with early-stage Parkinson’s disease received the transplants from healthy donors, and 24 received their own fecal matter as a placebo, as part of the GUT-PARFECT trial carried out at Ghent University Hospital, Belgium between December 1, 2020 and December 12, 2022.
The fecal transplant for both the treated cohort and the placebo cohort was delivered via a tube inserted in the jejunum, a part of the small intestine, via the nose.
Researchers followed up with the participants at 3, 6 and 12 months post-transplant. They collected data on gastrointestinal symptoms, non-motor symptoms, depression and anxiety, sleep and fatigue, and cognition.
While people who received fecal transplants from healthy donors registered improvements in their motor symptoms, they appeared to experience increased fatigue.
The reason for this negative effect was unclear, said lead author of the study Patrick Santens, MD, PhD, professor of neurology at Ghent University Hospital.
“We don’t have a good explanation [for this phenomenon], but suspect that inflammatory mechanisms may be involved. Fatigue is prevalent in inflammatory gut disorders,” he told Medical News Today.
One of the limitations of the study is that a strong placebo effect was observed, potentially because the placebo treatment was likely to have been viewed as invasive by the participants.
There is evidence to suggest that the more invasive a placebo treatment is, the greater the placebo effect.
It was also possible that some of the effect seen in the placebo group, was not just placebo effect, Santens suggested:
“The placebo effect was quite large. This may be due to the nature of the treatment with large expectations, on the one hand. On the other hand, there is preliminary evidence that [fecal transplant] with one’s own stool might also have a limited positive effect, at least on gut function. Therefore, we will try placebo treatment with colored inactive solutions in the next steps.”
Small improvements have been seen in other trials of fecal transplants in Parkinson’s disease patients.
Herbert DuPont, MD, clinical professor of medicine – infectious disease at Baylor College of Medicine, Houston, TX was the first author of a paper published in Frontiers In Neurology in 2023, which showed that fecal transplants could have some effect on the symptoms of Parkinson’s disease.
He was not involved in this latest research, but in commenting on its findings for MNT, he explained that disturbances to the microbiome in Parkinson’s disease patients have been known about for years, and there are various ways in which the gut can affect Parkinson’s disease.
“One is through the central nervous system, through the vagus nerve to the enteric nervous system through spinal nerves to the brain, and that’s direct neural connections.“ he said.
“The other way is through the immune system. Eighty percent of immune cells of the body are in the gastrointestinal tract, and our immune response is dependent on a healthy microbiome,“ DuPont added.
“And then the final thing is hormone production,“ he told us. “Chemicals, biochemicals and metabolites produced by the microbes go through the bloodstream or through the vagus nerve to the brain and have an effect. These three routes are all very important.”
Relevant to the context of this research is Braak’s hypothesis of Parkinson’s disease, which proposes that Parkinson’s disease starts to develop when a pathogen enters the body through the nose, reaches the gut, and initiates the accumulation of alpha-synucleinTrusted Source in the nose and the digestive tract.
Some researchers think that this then spreads to the nervous system and brain, potentially causing Parkinson’s disease.
DuPont explained:
“We believe that neural connections are very important in the movement of alpha-synuclein, the small protein that is involved in producing cell death in the brain. And this is the so-called Braak’s hypothesis. And I think this is correct, but I think the biochemicals are very important. And I think the immune system is very important.”
“I thought [it] was very important to show that a single dose [fecal transplant] could have a durable effect,“ DuPont told us, commenting on the study findings.
“I felt if it was a chronic disease where there are genetic disorders and chronic changes in the body then you would have to give [fecal matter] multiple times to have an effect and that’s been the way we’ve done our studies. But this shows that [even] one dose will have an effect,” he added.
Multiple dosing may necessitate providing the transplant via capsules, for example, which would involve processing the fecal matter in a way that might destroy many of the cells, microorganisms, enzymes and biochemicals that could be beneficial.
Previous research conducted by DuPont looked at transplants carried out with fresh, frozen, and freeze-dried fecal matter. “This study has given me an encouragement to think about giving, maybe, frozen or fresh samples in the future,“ DuPont told us.
“I think the Parkinson’s studies are a lead into [similar research for] other neurodegenerative disorders. Multiple sclerosis and Alzheimer’s may well follow, and may well have a similar success story,” he hypothesized.
Santens told us that the team behind the latest study was conducting further research into the microbial compositions of the different participants in relation to the recent study outcomes.
“We hope to get funding for a larger and multicenter trial, taking into account the findings of this pilot trial […] We are also looking at patient profiles to potentially delineate subgroups that might be optimal candidates for this treatment,” he told us.
Neurologists at Beth Israel Deaconess Medical Center (BIDMC) in Boston have developed a skin biopsy test able to assist in the early diagnosis of Parkinson’s disease and related neurodegenerative disorders, collectively known as synucleinopathies.
The study, published in the Journal of the American Medical Association (JAMA), highlights the effectiveness of the test in detecting the abnormal presence of alpha-synuclein, a key biomarker for synucleinopathies with impressive accuracy.
“Nearly 200,000 individuals in the U.S. receive a diagnosis of Parkinson’s disease, dementia with Lewy bodies, and related disorders annually. Unfortunately, the path to reaching an accurate diagnosis is often fraught with delays and misdiagnoses due to the intricate nature of these conditions,” said Christopher Gibbons, MD, a neurologist at BIDMC and professor of neurology at Harvard Medical School (HMS), who led the research.
“Our study showcases the potential of a minimally invasive skin biopsy test to significantly enhance diagnostic precision and patient care.”
Synucleinopathies, which affect an estimated 2.5 million Americans, include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). Although these conditions share some clinical symptoms and are all marked by the abnormal accumulation of phosphorylated alpha-synuclein (P-SYN) in cutaneous nerves, they differ significantly in prognosis and response to treatment.
For their study, Gibbons, along with his colleagues and contributors from 30 neurology practices nationwide, enrolled 428 participants aged 40–99, including individuals clinically diagnosed with one of the synucleinopathies and healthy controls. The study involved taking three skin punch biopsies from each participant at different body sites.
Roy Freeman, MD, director of the Center for Autonomic and Peripheral Nerve Disorders at BIDMC and a professor of neurology at HMS, expressed enthusiasm about the diagnostic accuracy of the test. “Our findings confirm the presence of alpha-synuclein in the skin’s nerve fibers, a discovery that could revolutionize how we diagnose and manage these complex disorders.”
The study’s results were striking: 93 percent of PD cases, 96 percent of DLB cases, 98 percent of MSA cases, and 100 percent of PAF cases showed positive biopsies for P-SYN. Interestingly, a small fraction of the control group also tested positive for P-SYN, suggesting a potential early marker of synucleinopathy risk.
This research builds on prior efforts by Freeman, Gibbons, and Ningshan Wang, PhD, an immunohistochemist at BIDMC and assistant professor of neurology at HMS, who have been investigating reliable biomarkers for synucleinopathies since 2009. Their collaboration with CND Life Sciences, a neurodiagnostics company, aims to refine and commercialize this diagnostic method.
Looking ahead, the BIDMC team is optimistic about the impact of their work on the development of new treatments for synucleinopathies. By accurately identifying patients with specific biomarkers, researchers can more effectively design and implement clinical trials for investigational drugs targeting alpha-synuclein, potentially accelerating the path to finding effective therapies for these debilitating conditions.
Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson’s disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively.
Results
Brain metabolites were measured using 7-Tesla 31P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD+/NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD+/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including β-ATP and phosphorylation potential across both cohorts.
Conclusions
Our results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS.
Summary: A new study explains how dopamine influences movement sequences, offering hope for Parkinson’s disease (PD) therapies. Researchers observed that dopamine not only motivates movement but also controls the length and lateralization of actions, with different neurons activating for movement initiation and reward reception.
Through innovative experiments involving genetically modified mice, the team discovered that dopamine’s effect on movement is side-specific, enhancing actions on the opposite side of the body where neurons are active.
These findings underscore dopamine’s complex role in movement and its potential for developing targeted treatments for PD, focusing on the restoration of specific motor functions.
Key Facts:
Dopamine and Movement Sequences: Dopamine signals directly influence the length and initiation of movement sequences, suggesting a nuanced role beyond general motivation.
Lateralization of Dopamine’s Effects: The study reveals that dopamine’s impact on movement is contralateral, meaning it specifically enhances movements on the opposite side of the body from where the dopamine neurons are active.
Potential for Targeted PD Therapies: Understanding the distinct roles of movement-related and reward-related dopamine neurons opens new avenues for creating PD treatments that address specific movement impairments.
Source: Champalimaud Centre for the Unknown
Imagine the act of walking. It’s something most able-bodied people do without a second thought. Yet it is actually a complex process involving various neurological and physiological systems. PD is a condition where the brain slowly loses specific cells, called dopamine neurons, resulting in reduced strength and speed of movements.
However, there’s another important aspect that gets affected: the length of actions. Someone with PD might not only move more slowly but also take fewer steps in a walking sequence or bout before stopping.
This study shows that dopamine signals directly affect the length of movement sequences, taking us a step closer to unlocking new therapeutic targets for enhancing motor function in PD.
The team noticed that the neurons excited by movement lit up more when the mouse used the paw opposite to the brain side being observed.
“Dopamine is most closely associated with reward and pleasure, and is often referred to as the ‘feel-good’ neurotransmitter”, points out Marcelo Mendonça, the study’s first author. “But, for dopamine-deficient individuals with PD, it’s typically the movement impairments that most impact their quality of life. One aspect that has always interested us is the concept of lateralisation.
“In PD, symptoms manifest asymmetrically, often beginning on one side of the body before the other. With this study, we wanted to explore the theory that dopamine cells do more than just motivate us to move, they specifically enhance movements on the opposite side of our body”.
Shedding Light on the Brain
To this end, the researchers developed a novel behavioural task, which required freely-moving mice to use one paw at a time to press a lever in order to obtain a reward (a drop of sugar water). To understand what was happening in the brain during this task, the researchers used one-photon imaging, similar to giving the mice a tiny, wearable microscope.
This microscope was aimed at the Substantia nigra pars compacta (SNc), a dopamine-rich region deep within the brain that is significantly impacted in PD, allowing the scientists to see the activity of brain cells in real-time.
They genetically engineered these mice so that their dopamine neurons would light up when active, using a special protein that glows under the microscope. This meant that every time a mouse was about to move its paw or succeeded in getting a reward, the scientists could see which neurons were lighting up and getting excited about the action or the reward.
Observing these glowing neurons, the discoveries were, quite literally, illuminating. “There were two types of dopamine neurons mixed together in the same area of the brain”, notes Mendonça. “Some neurons became active when the mouse was about to move, while others lit up when the mouse got its reward. But what really caught our attention was how these neurons reacted depending on which paw the mouse used”.
How Dopamine Chooses Sides
The team noticed that the neurons excited by movement lit up more when the mouse used the paw opposite to the brain side being observed. For example, if they were looking at the right side of the brain, the neurons were more active when the mouse used its left paw, and vice versa. Digging deeper, the scientists found that the activity of these movement-related neurons not only signalled the start of a movement but also seemed to encode, or represent, the length of the movement sequences (the number of lever presses).
Mendonça elaborates, “The more the mouse was about to press the lever with the paw opposite the brain side we were observing, the more active neurons became. For example, neurons on the right side of the brain became more excited when the mouse used its left paw to press the lever more often.
“But when the mouse pressed the lever more with its right paw, these neurons didn’t show the same increase in excitement. In other words, these neurons care not just about whether the mouse moves, but also about how much they move, and on which side of the body”.
To study how losing dopamine affects movement, the researchers used a neurotoxin to selectively reduce dopamine-producing cells on one side of a mouse’s brain. This method mimics conditions like PD, where dopamine levels drop and movement becomes difficult. By doing this, they could see how less dopamine changes the way mice press a lever with either paw.
They discovered that reducing dopamine on one side led to fewer lever presses with the paw on the opposite side, while the paw on the same side remained unaffected. This provided further evidence for the side-specific influence of dopamine on movement.
Implications and Future Directions
Rui Costa, the study’s senior author, picks up the story, “Our findings suggest that movement-related dopamine neurons do more than just provide general motivation to move – they can modulate the length of a sequence of movements in a contralateral limb, for example. In contrast, the activity of reward-related dopamine neurons is more universal, and doesn’t favour one side over the other. This reveals a more complex role of dopamine neurons in movement than previously thought”.
Costa reflects, “The different symptoms observed in PD patients could be perhaps related to which dopamine neurons are lost—for instance, those more linked to movement or to reward. This could potentially enhance management strategies in the disease that are more tailored to the type of dopamine neurons that are lost, especially now that we know there are different types of genetically defined dopamine neurons in the brain”.
Abstract
Dopamine neuron activity encodes the length of upcoming contralateral movement sequences
Highlights
Developed a freely moving task where mice learn individual forelimb sequences
Movement-modulated DANs encode the length of contralateral movement sequences
The activity of reward-modulated DANs is not lateralized
Dopamine depletion impaired contralateral, but not ipsilateral, sequence length
Summary
Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson’s disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter.
However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences.
We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length.
In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length.
These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.
There’s an increasing link between the debilitating neurological illness and the microbes that live in our intestines.
It can start small: a peculiar numbness, a subtle facial tic, an inexplicably stiff muscle. But then time goes by — and eventually, the tremors set in.
Roughly a million people in the United States (and roughly 10 million people worldwide) live with Parkinson’s disease, a potent neurological disorder that progressively kills neurons in the brain. As it does so, it can trigger a host of crippling symptoms, from violent tremors to excruciating muscle cramps, terrifying nightmares, and constant brain fog. While medical treatments can alleviate some of these effects, researchers still don’t know exactly what causes the disease to occur in the first place.
A growing number of studies, however, are suggesting that it may be tied to an unlikely culprit: bacteria living inside our guts.
Every one of us has hundreds or thousands of microbial species in our stomachs, small intestines, and colons. These bacteria, collectively called our gut microbiome, are usually considerate guests: Although they survive largely on food that passes through our insides, they also give back, cranking out essential nutrients like niacin (which helps our body convert food into energy) and breaking down otherwise indigestible plant fiber into substances our bodies can use.
As Parkinson’s advances in the brain, researchers have reported that the species of bacteria present in the gut also shift dramatically, hinting at a possible cause for the disease. A 2022 paper published in the journal Nature Communications recorded those differences in detail. After sequencing the mixed-together genomes of fecal bacteria from 724 people — a group with Parkinson’s and another without — the authors saw a number of distinct changes in the guts of people who suffered from the disease.
The Parkinson’s group had dramatically lower amounts of certain species of Prevotella, a type of bacterium that helps the body break down plant-based fiber (changes like this in gut flora could explain why people with Parkinson’s disease often experience constipation). At the same time, the study found two harmful species of Enterobacteriaceae, a family of microbes that includes Salmonella, E. coli, and other bugs, proliferated. Those bacteria may be involved in a chain of biochemical events that eventually kill brain cells in Parkinson’s patients, says Tim Sampson, a biologist at Emory University School of Medicine and co-author of the study.
At first glance, the relationship between bacteria and brain disease isn’t exactly obvious. How can a change in gut microbes kick off a devastating neurodegenerative disorder? The relationship between the two may seem counterintuitive — but Sampson says it comes down to the subtle ways that the brain and the gut are connected.
In the walls of the intestines, a network of neurons called the enteric nervous system lets the body sense what’s going on in the gut and respond accordingly. This circuitry controls muscle movement, local blood flow, secretion of mucus, and other essential digestive functions.
Since the cells of the enteric nervous system are embedded in the gut wall, many of them come into close contact with the lumen — the cavity of the gut that contains the microbiome — where they can interact directly with biochemicals created by bacteria. Some of these are sticky proteins called curli (pronounced CURL-eye) that may be implicated in Parkinson’s.
Under normal circumstances, curli proteins let Enterobacteria build biofilms, the gooey mats that protect the microbes and help them stay put in the gut. Yet if a curli molecule touches a common protein created by nerve cells — called alpha-synuclein — that protein begins to misfold and form a dangerous mass called an aggregate. Once created, these aggregates can spread widely through the nervous system, leapfrog from cell to cell, and eventually enter the brain through the vagus nerve, the main pathway that carries signals between the brain and the gut. It’s thought that in some cases of Parkinson’s in humans, changes in the gut microbiome may activate that process, says Emeran Mayer, a gastroenterologist, and neuroscientist at UCLA and coauthor of a recent overview of the gut-brain connection in the Annual Review of Medicine.
The suspicion that the vagus plays a key role in neurodegenerative disease has been growing in recent years. A 2017 study in the journal Neurology, Mayer notes, showed that “If you cut the vagus nerve, it decreases the risk for Parkinson’s disease. That’s a pretty strong indication that … this degenerative material is transported, apparently, through the vagus nerve.”
Over the past few decades, a number of animal studies have shown that the vagus provides a physical conduit that molecules can use to move between the gut and brain — but although this neurological superhighway could play an important role in Parkinson’s, it’s still not clear if the nerve is a lynchpin in causing the disease itself.
In addition to aggregates moving through the vagus, different triggers — like the lipids, vitamins, and other organic compounds that gut bacteria produce — could travel through blood vessels to the brain, where they may cause inflammation and damage tissue. Likewise, says David Hafler, a neuroimmunologist at Yale University, immune cells that are activated in the gut may contribute to the neurological damage and dysfunction that occurs in Parkinson’s.
These immune cells, called T cells, can migrate out of the gut, enter the bloodstream, and cross the blood-brain barrier, where they may ultimately kill off neurons. This sort of autoimmune response is the driver for other neurological diseases like multiple sclerosis and Hafler reasons, so it’s feasible that it plays a role in Parkinson’s as well. In both diseases, changes in the gut microbiome could be the potential trigger.
There’s already strong evidence for this idea. In 2016, Sampson found a direct connection between gut microbes and Parkinson’s disease: Using fecal samples from Parkinson’s patients, Sampson inoculated the guts of germ-free mice (animals with no naturally occurring microbiome), and the animals quickly developed Parkinson’s symptoms. Today, using the new genetic survey of gut microbes he and his colleagues published in Nature Communications, he’s narrowing in on a few microbe families and using similar methods to reveal which precise species are the culprits.
Sampson’s approach comes with some caveats: Parkinson’s disease, after all, might be linked to multiple bacteria interacting in complex ways — so there likely won’t be a single smoking gun. It’s also not totally clear if changes in the microbiome are the root cause or if they just accelerate damage already taking place in the brain. The complexity of the microbiome is mind-boggling: There are hundreds of different types of bacteria involved, and each creates myriad molecules that affect digestion, the immune system, and other important bodily functions. Sorting through all those components and identifying how they change in the face of disease will be an important next step.
And so, as tantalizing as the links between the microbiome and Parkinson’s may be, it could be decades before people who suffer from the disorder can reap any tangible benefits. Many of the researchers examining those links, like Mayer, also warn patients to be wary of sweeping claims about drugs, supplements, or even fecal transplants — seeding the gut with microbes from another, healthy person — that “treat” Parkinson’s by altering the microbiome.
“A lot of people make a lot of money selling individual supplements, telling you that they’re going to slow your cognitive decline or prevent Parkinson’s disease,” says Mayer. But, he adds, “we don’t know the causal roles of the microbiome for sure. We know it from animal studies, so we have indirect evidence for it — but it’s been difficult to show in humans without a doubt that the microbes, and some of their signal molecules, play the main causal role.”
Until definitive answers are found, researchers like Mayer will continue to chip away at the problem, microbe by microbe
Scientists found that tiny plastic particles can enter nerve cells, impair breakdown of structures linked to Parkinson’s disease, and harm certain brain regions in mice.
The findings point to molecular links between plastics and Parkinson’s disease mechanisms that can be further explored through additional research.
The study findings give insight into how polystyrene waste may help contribute to Parkinson’s disease.
Parkinson’s disease and related dementias have been on the rise worldwide. These disorders are marked by an abnormal buildup of the protein alpha-synuclein in the brain. The factors leading to this buildup of alpha-synuclein are unknown. Research points to a potential role for environmental factors.
Small bits of plastic are widely found throughout the environment, including food and water supplies. Microplastics are plastic particles smaller than 5 mm in diameter—tinier than a sesame seed; nanoplastics are less than 1 μm, too small to be seen by the human eye. At least one previous study found that particles of polystyrene and other plastics can be detected in the blood of most healthy adults. Single-use polystyrene products—like plastic cups, utensils, and foam packing—are widespread environmental waste. But despite their ubiquity, the potential health consequences of these plastics are only beginning to be studied and understood.
Previous studies found evidence that alpha-synuclein’s activities can be affected by polystyrene and other particles. An international research team led by Dr. Andrew B. West of Duke University decided to take a closer look at the effects that nanoplastics might have on nerve cells and the brain. The scientists explored interactions between alpha-synuclein and polystyrene nanoplastics both in lab dishes and in mice. Results were reported on November 17, 2023, in Science Advances.
The researchers first showed that human alpha-synuclein binds readily to polystyrene nanoplastics in a test tube. This binding led to the formation of abnormal alpha-synuclein structures called fibrils, a hallmark of Parkinson’s disease and related dementias.
The scientists next examined how alpha-synuclein fibrils and nanoplastics behave with cultured brain cells, or neurons. They found that both the fibrils and the plastics can enter neurons via endocytosis, in which the cell’s outer membrane engulfs targeted items. Once inside, both the fibrils and the plastics entered the cell’s lysosomes, membrane-bound organelles that serve as cellular garbage disposals. The researchers found that nanoplastics disrupted lysosome activities, slowing the breakdown of harmful clumps of alpha-synuclein.
The team next looked at how polystyrene nanoplastics and alpha-synuclein interact in the mouse brain. They found that the nanoplastics and alpha-synuclein fibrils also interacted there, which increased the spread of abnormalities across interconnected brain regions. Neurons in the brain’s substantia nigra region were especially affected. This brain region helps to control movement and is damaged in Parkinson’s disease and related dementias.
Taken together, these findings point to previously unrecognized interactions that could contribute to Parkinson’s disease risk and progression. Further research is needed to study how these interactions affect disease development and whether other types of plastics have similar effects.
“Numerous lines of data suggest environmental factors might play a prominent role in Parkinson’s disease, but such factors have for the most part not been identified,” West explains. “Our study suggests that the emergence of micro and nanoplastics in the environment might represent a new toxin challenge with respect to Parkinson’s disease risk and progression.”
A new study programme funded by F. Hoffmann‐La Roche Ltd aims to understand the role of inflammation in the brain of people with Parkinson’s disease, with a view to identifying new treatments.
People with Parkinson’s disease are invited to join the new study that takes place in state‐of‐the‐art research facilities in Exeter and London. The researchers hope to shed light on the mechanisms causing the disease, about which little is currently known.
Professor Marios Politis, who leads the research group at the University of Exeter, said: “Parkinson’s disease has a devastating impact on individuals and families. We urgently need to understand the cause, so we can find new treatments and improve outlooks. Our research programme has the double aim to understand more about what could be the cause of Parkinson’s disease, and to determine whether a medicine blocking a key part of local brain inflammation could be safe and beneficial for people with the disorder. If our results are positive, we would know much more about the mechanisms involved in the disease developing, so potentially helping us design new and better medicines.”
Parkinson’s disease is a brain disorder that causes slowness of movements, shaking, stiffness, and difficulty with balance and coordination. These symptoms usually begin subtly and gradually worsen over time. As the disease progresses, people may have difficulty walking and talking properly.
One theory about the cause involves local brain inflammation ‐ a state of activation of certain cells of the brain, called glia. Generally, this is a healthy process because the activated glia produce some substances, which help clean up the brain from unwanted agents. However, when this process is continuous, it turns against the cells of the brain, attacking them and causing them to die, and possibly causing Parkinson’s disease.
Researchers believe that identifying the reasons for increased local brain inflammation may lead to new treatments that suppress the inflammation and decrease the damage to the brain.
The study will take a two‐pronged approach, involving two different clinical trials.
The first study, led by the University of Exeter’s Neurodegeneration Imaging Group, is a brain imaging study to test whether people with Parkinson’s disease are particularly susceptible to an induced temporary, mild state of local brain inflammation, and to measure the mechanisms involved.
The second study, involving the Royal Devon University Healthcare NHS Foundation Trust, is an early‐ stage multicenter trial of a new medicine by F.Hoffmann‐La Roche designed to block the activity of a specific mechanism, called inflammasome activation. This mechanism is thought to be the key driver of increased local brain inflammation.
Dr Gennaro Pagano, Group Leader and Expert Medical Director at Roche, Honorary Associate Professor at University of Exeter, and lead of clinical development of the new medicine, added: “This trial is extremely innovative and is testing a new approach to reduce brain inflammation and neurodegeneration, thereby aiming to slow down Parkinson’s disease progression. Thanks to its cutting‐ edge state‐of‐the‐art research facilities, the University of Exeter is uniquely positioned to deliver this study.“
Secondary school teacher Tim Walker, from Somerset, is one of those involved in the first study. The long‐distance cyclist, 56, first noticed abnormalities with his movement in early 2020, before a tremor developed in his left hand. His wife Liz is a doctor and suggested he saw a neurologist. Tim was diagnosed with Parkinson’s disease in December 2020. This year, he took ill health retirement from teaching, although still works as an examiner
Tim decided to take part in research after his mother‐in‐law saw a TV report asking for participants. He said: “Very little is known about Parkinson’s and what causes it – and there have been very few recent advancements in drugs for the disease. So, any information researchers can get to find out what causes it ‐ and therefore how they can help treat it ‐ is going to be beneficial.”
Tim knows that keeping physically and mentally active can help manage the symptoms of Parkinson’s. He regularly hits the roads on his bike, In and in summer 2022, he took on La Marmotte, a 100‐mile plus alpine ride from the Tour de France.
But while Tim says his wife, two daughters, and other family and friends are very supportive, he admits that Parkinson’s has impacted his life.
“It’s probably made me slightly more withdrawn. It’s hard being in social situations, especially if I don’t know people and am meeting them for the first time. I find that quite difficult because I will be standing there shaking.”
He is confident that the trial will help others with the disease: “I’m optimistic that steps forward will be made as people understand more about Parkinson’s. Whether it’s in time for me, I don’t know. The drugs being trialed now are probably five or ten years away from being available ‐ and by that stage it may be too late for me to avoid the worst consequences of Parkinson’s. But I can do my bit to help now so hopefully someone else in years to come can benefit.”
Dr Heather Wilson, a member of the study team, added: “Without people coming forward to volunteer to take part in research, these studies would not be possible. We’re extremely grateful to the Parkinson’s community for dedicating time and effort to support research. We hope that both clinical trial programmes will help in finding solutions for all people affected, and their loved ones.”
Researchers at the University of Southern California (USC) reported this week they have newly identified a genetic mutation in a small protein that provides significant protection against the development of Parkinson’s disease. This new finding, reported in the journal Molecular Psychiatry, makes this beneficial variant an important target for developing new treatments against the disease.
The variant, located on the mitochondrial protein called SHLP2, was found to be highly protective against Parkinson’s disease. Those people who harbor the mutation had half the risk of developing the disease compared with those who don’t have it. The investigators further noted that the variant form of the protein is rare and found primarily in people of European descent.
“This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease,” said senior author Pinchas Cohen, professor of gerontology, medicine and biological sciences at the USC Leonard Davis School of Gerontology. “Also, because most research is done on well-established protein-coding genes in the nucleus, it underscores the relevance of exploring mitochondrial-derived microproteins as a new approach to the prevention and treatment of diseases of aging.”
Cohen first discovered SHLP2 in 2016 and other research conducted in his lab has found that the microprotein is associated with protection from aging-related diseases and cancer. His lab also discovered that in patients with Parkinson’s, levels of the SHLP2 change—rising as the body tries to fight against the disease’s pathology, then lessening production as the disease progresses.
For this research, Su-Jeong Kim an adjunct research assistant professor of gerontology at the USC Leonard Davis School and the study’s first author used big data analysis to identify variants associated with Parkinson’s by screening the data from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study to identify those people who possessed the SHLP2 variant. This variant, found in 1% of all patients of European descent, reduced the risk of Parkinson’s by two-fold, or 50%.
The team then demonstrated that the mutation is a single-nucleotide polymorphism, or SNP, and acts as a gain of function variant that is associated with higher SHLP2 expression, which also makes the protein more stable. This added stability is exhibited in SHLP2’s binding to the mitochondrial complex 1, which prevents the decline of the enzyme’s activity, which, in turn, reduces mitochondrial dysfunction. The investigators demonstrated this effect in both human tissue samples and Parkinson’s disease mouse models.
“Our data highlights the biological effects of a particular gene variant and the potential molecular mechanisms by which this mutation may reduce the risk for Parkinson’s disease,” said Kim. “These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”
In a clinical trial, a procedure using ultrasound and requiring no incisions successfully reduced a side effect of Parkinson’s treatments known as dyskinesia, which is an involuntary movement of the body. The ultrasound also improved motor impairment in people with Parkinson’s disease.
The procedure used in the trial is called focused ultrasound ablation, which is different than using ultrasound for imaging purposes. Instead, focused ultrasound ablation is like using a magnifying glass to focus sunlight on a target. The ultrasound wavelengths can target body tissue, heat it, and destroy it. For the Parkinson’s procedure, the target was in the brain.
“Focused ultrasound is an exciting new treatment for patients with certain neurological disorders,” said researcher Vibhor Krishna, MD, associate professor of neurosurgery at UNC School of Medicine, in a statement. “The procedure is incisionless, eliminating the risks associated with surgery. Using focused ultrasound, we can target a specific area of the brain and safely ablate the diseased tissue.”
The study was published this week in The New England Journal of Medicine. A total of 94 patients were randomly assigned to receive the treatment or to participate in a sham procedure, which acted as a control. After 3 months, 69% of patients who got the treatment showed improvement.
Parkinson’s is a brain disease that disables brain cells that make dopamine, which helps coordinate body movement. Dyskinesia tends to arise when Parkinson’s treatments are working to control the common symptoms of the root illness such as tremor, slowness, stiffness, and balance problems.
“Feeling stressed or excited also can bring out dyskinesia,” according to information on the disorder from The Michael J. Fox Foundation for Parkinson’s Research. “Many people say they prefer dyskinesia to stiffness or decreased mobility. Others, though, have painful dyskinesia or movements that interfere with exercise or social or daily activities.”
The foundation estimates that nearly 1 million people in the U.S. have Parkinson’s, which is a progressive disorder for which there is no cure.
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