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Saliva Test May Help Diagnose Parkinson’s, Assess Disease Severity, Early Study Finds

saliva

A saliva test may help diagnose Parkinson’s and assess disease severity, according to a recent study.

Biomarkers that reflect problems in the production of energy, with nerve cell messengers, and in gut microflora — each easily detected in saliva — may all contribute to the metabolic changes associated with Parkinson’s disease (PD), the study found.

Titled “Quantitative metabolomics of saliva using proton NMR spectroscopy in patients with Parkinson’s disease and healthy controls,” the study was published in the journal Neurological Sciences.

Because Parkinson’s symptoms are similar to and can be mistaken with those of other neurodegenerative diseases, a precise and early diagnosis can prove challenging. As such, there is a need to identify potential biomarkers that can aid in the diagnosis, understanding, and treatment of this disease.

Changes in metabolism related to energy, neurotransmitters, and oxidative stress — cellular damage as a consequence of high levels of oxidant molecules — have been associated with Parkinson’s. A person’s metabolism involves natural reactions occurring within cells to produce energy and all the necessary compounds for growth, survival, and function.

Prior studies have looked at a few metabolites — any of the intermediate products of metabolic reactions — present in the blood or cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord.

Now, researchers from the All India Institute of Medical Sciences in New Delhi wanted to track down possible disease biomarkers present in saliva to further understand the metabolic pathways involved in Parkinson’s.

Testing saliva is a painless, non-invasive, cost-effective, simple, and safe method of investigation, the researchers noted.

The volume and composition of saliva are regulated by a branch of the nervous system controlled by the brain. In addition to molecules unique to saliva, this biologic fluid also carries molecules present in the blood, which together may reflect the presence and stage of disease.

As such, “the analysis of saliva may provide valuable information even at early stages of PD,” the researchers said.

The team collected saliva samples from 76 patients with Parkinson’s, ages 33 to 68, and 37 healthy people (controls). They then applied a powerful technique — called Nuclear Magnetic Resonance (NMR) spectroscopy — to run metabolic profiling to determine the types of metabolites and their concentration in the saliva samples, and to spot potential biomarkers.

The levels of 15 metabolites were significantly increased in patients’ samples compared with those of controls. Specifically, these were: phenylalanine, tyrosine, histidine, glycine, acetoacetate, trimethylamine-N-oxide (TMAO), gammaaminobutyric acid (GABA), N-acetylglutamate (NAG), acetoin, acetate, alanine, fucose, propionate, isoleucine, and valine.

Alterations in histidine, tyrosine, and phenylalanine reflect alterations in neurotransmitters — chemical messengers that allow nerve cells to communicate. Changes in these molecules specifically flag alterations in the production of the neurotransmitter dopamine, whose loss in certain regions of the brain is a hallmark of Parkinson’s.

To understand whether metabolic changes correlated with Parkinson’s disease stages, an additional analysis was done in which patients were divided into two groups. One group, comprising 52 people, were individuals  in the early stages of disease (Hoehn and Yahr scale stages 1–2). The other group, with 24 patients, was composed of those with advanced Parkinson’s (Hoehn and Yahr scale stages 2.5 – 3). The Hoehn and Yahr scale, known as H&Y, is an instrument used to measure symptoms’ severity in Parkinson’s.

Contrary to patients in advanced stages, those with early disease had greater saliva concentrations of propionate, valine, acetoin, TMAO, tyrosine, histidine, isoleucine, glycine, GABA, and N-acetylglutamate, when compared with healthy subjects.

“These features may highlight the characteristic changes in metabolite levels during the onset of PD,” the researchers said. They added that a less pronounced concentration of such markers in patients at more advanced stages may be related to their use of dopaminergic therapy (dopamine agonists).

The metabolic profile of the participants’ saliva also correlated with disease duration. A higher concentration of propionate and acetoin correlated with longer disease duration, with lesser amounts of these metabolites correlating to shorter disease duration.

“Acetate and propionate are intestinal microbial metabolites that influence the formation of gut microbiota and the host metabolome [all metabolites present within an organism],” the researchers noted.

In recent years, data has emerged that suggests an association between the gut and the development of Parkinson’s disease. It is believed that gut microbiota may control brain development and behavior through these metabolites. Therefore, imbalances in this environment in response to the loss of dopaminergic neurons may impact both the enteric nervous system — the network of nerves that innervate the gastrointestinal tract — and the central nervous system.

“Motor and gastrointestinal dysfunctions may be associated with the involvement of the enteric nervous system (ENS) in the pathological progression of PD towards the CNS or vice versa,” the researchers said.

The new data from this study reveal potential salivary biomarkers of Parkinson’s disease and pinpoint metabolic pathways deranged by the disease, the researchers said. Such pathways include those involved in the metabolism of amino acids (the building blocks of proteins), energy, neurotransmitters, alterations in the gut microflora, or microbial communities that live in the body’s gastrointestinal tract.

“The results also suggest that symptoms of impaired metabolism may help diagnose PD and assess disease severity,” the team said, noting that larger studies are needed to confirm the link between salivary metabolic profiling and clinical features.

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2 Distinct Types of Parkinson’s May Exist Based on Nervous System Origin of Disease, Study Suggests

nervous system

Parkinson’s disease may be classified by into two distinct subtypes based on where in the nervous system the disease starts, a study proposes. Its findings could have major implications for the development of new treatments.

The paper, “Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis,” was published in the Journal of Parkinson’s Disease.

The nervous system can be divided, broadly, into two parts: the central nervous system (CNS), which contains the brain and spinal cord, and the peripheral nervous system (PNS), which covers everything else.

Although Parkinson’s disease (PD) is generally thought of as a disorder of the brain, a paper published in 2003 suggested it actually starts in the PNS — specifically, in the nerves in and around the gut and the nose — and then spreads to the brain.

Researchers here reviewed a plethora of available evidence — including data from humans and from animal models — and proposed that this PNS-first model may indeed be correct, but only some of the time. In other cases, Parkinson’s might actually start in the CNS.

“The discussion about the origins of PD is often framed as an ‘either-or’, i.e., either all PD cases start in the gut or all cases start in the brain. However, much of the evidence seems compatible with both these interpretations. Thus, we need to entertain the possibility that both scenarios are actually true,” Nathalie Van Den Berge, MSc, PhD, a postdoc at Aarhus University in Denmark and a study co-author, said in a press release.

While some post-mortem studies of brain tissue from Parkinson’s patients suggest the disease starts in PNS of the gut and nose before spreading “via the nerves into the brain,” others do not agree.

“In some cases, the brains do not contain pathology at the important ‘entry points’ into the brain, such as the dorsal vagus nucleus at the bottom of the brainstem. The gut-first versus brain-first hypothesis posited in this review provides a scenario that can reconcile these discrepant findings … into one single coherent theory about the origins of PD,” Per Borghammer, MD, PhD, DMSc, also a study author and Aarhus professor, added.

The researchers particularly focused on one Parkinson’s symptom, REM [rapid eye movement] sleep behavior disorder (RBD), characterized by uncontrolled and violent arm and leg movements, and acting out dreams during sleep.

This often occurs in the early stages of PD, but not always. The researchers suggested that this may be because RBD is associated with Parkinson’s that originates in the PNS, but not with the disease that originates in the CNS.

Supporting this idea, they noted that previous imaging studies of Parkinson’s patients showed those with RBD had more evident PNS damage than those without RBD or whose RBD status was unknown. In contrast, in many people with RBD, the dopamine pathways in the brain that become dysregulated in PD appear within normal limits in the earliest stages.

“Put together, it appears that [alpha-synuclein] pathology in the PNS is more frequent in RBD-positive PD compared to RBD-negative cases,” the researchers wrote.

Regarding familial forms of Parkinson’s disease (those caused by specific mutations), the researchers believe that some mutations are mainly associated with a CNS-first hypothesis, such as those in the PARKIN, PARK7 or PINK1 genes, while others, such as those in the GBA and SNCA genes, are associated with a PNS-first hypothesis.

This hypothesis could have major implications for Parkinson’s studies and treatment.

“If the brain-first vs body-first hypothesis is correct, we need to intensify the research into understanding risk factors and triggering factors for these two subtypes,” Van Den Berge said.

Treatment could be tailored to a patient’s subtype, Borghammer added.

“It is probable that these different types of PD need different treatment strategies. It may be possible to prevent the ‘gut-first’ type of PD through interventions targeting the gut, such as probiotics, fecal transplants, and anti-inflammatory treatments,” Borghammer said. “However, these strategies might not work with respect to treating and preventing the brain-first type. Thus, a personalized treatment strategy will be required, and we need to be able to identify these subtypes of PD in the individual patient.”

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MIT Scientists Building Artificial Gut to Study Bacteria’s Influence on Parkinson’s, Other Diseases

gut microbiome study

MIT Lincoln Laboratory researchers are developing an artificial gut to study how the human microbiome — the trillions of microorganisms and their genetic material that live within our body, and are as unique to a person as fingerprints — influences the onset and progression of diseases linked to changes in gut bacterial constitution, such as Parkinson’s disease.

The so-called “gut-brain axis” is a highly complex and interactive network between the gut and the brain, composed of endocrine (hormonal), immunological, and neural mediators. Dysregulation of “cross-talk” within this axis has been associated with metabolic syndrome, depression, anxiety and autism, as well as to neurodegenerative diseases like Parkinson’s, and Alzheimer’s.

By manipulating the gut microbiome in Parkinson’s patients, researchers could study its effects on neurodegenerative processes.

“Until now, no one has been able to culture a microbiome sample and maintain it,” David Walsh, a PhD with the Biological and Chemical Technologies Group at MIT who led the prototype device’s development and fabrication, said in a university news story by Anne McGovern. Further refinements are still being made.

“The question from the mechanical side is, how do you emulate the colon?” said Todd Thorsen, PhD, the project’s principal investigator and an assistant professor with the MIT group.

“Bacteria in the colon occupy lots of ecological niches,” Thorsen added. This means that all bacteria living in the colon have organism-specific demands for survival, including nutritional and environmental requirements. For instance, some are oxygen-dependent and others not.

To mimic the intestinal microenvironment, Lincoln Laboratory investigators are developing an easily accessible and cost-effective platform made of permeable silicon rubber and other plastics, like polystyrene. Importantly, in this “artificial gut,” scientists can regulate oxygen and mucus concentrations within microculture chambers, modeling the human colon. Because it can be easily replicated, it might also be of use to others studying the gut microbiome, and the impact of disease or treatment on it.

“If we can maintain a culture, we can do things like add toxins and therapeutics to see how they change the culture over time,” Walsh said. Such an ability could move research a step closer to tackling real-world problems, including bacterial resistance.

Using gut microbiome samples from Parkinson’s patients and healthy people, the scientists plan to use their device to study intestinal bacteria’s influence on the neurodegenerative processes seen in Parkinson’s.

Experiments are expected to begin soon, in collaboration with researchers at the University of Alabama at Birmingham, Northeastern University, and the University of California at San Francisco.

The team also plans to build a tube-shaped origami-like gut that rolls up during assembly to simulate the colon and the surrounding vascularized tissue, and to develop modeling software to predict how different bacterial communities change over time.

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Parkinson’s May Originate From Alpha-Synuclein Migrating From the Gut, Rat Study Shows

gut Parkinson's alpha-synuclein

New experimental evidence collected from rats shows that alpha-synuclein — the protein that causes Parkinson’s disease — can travel from the intestines to other organs, such as the heart and brain.

These findings, reported in the study “Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats,” provide further support to the hypothesis that the development of Parkinson’s disease is directly linked to the intestinal system.

The study was published in Acta Neuropathologica.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of alpha-synuclein, called Lewy bodies.

Prior work in postmortem human brains has shown that the misfolded protein primarily accumulates in brain areas controlling movement, which explains the characteristic motor symptoms associated with the disease. But that work also revealed the protein’s accumulation in the vagus nerve – which connects the brain to the gut.

This led to the theory that Parkinson’s progression could require communication between the gut and the brain.

To further explore this association, researchers from Aarhus University and its clinical center, in Denmark, conducted a new study in rats. The team used rats that were genetically modified to produce excessive amounts of alpha-synuclein, and which were susceptible to accumulating harmful versions of the protein in nerve cells. Human alpha-synuclein or an inactive placebo was injected into the small intestines of these rats.

With this approach, the investigators found that both groups of rats — those injected with alpha-synuclein or placebo — had high levels of the protein in the brain. However, only those injected with alpha synuclein showed Parkinson’s characteristic clump build-up patterns, which affected the motor nucleus and substantia nigra in the brain.

“After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson’s disease in humans,” Per Borghammer, an Aarhus University professor and the study’s senior author, said in a press release written by Mette Louise Ohana.

“After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened,” Borghammer said.

Alpha-synuclein also was found to accumulate in the heart and stomach, which suggests a secondary propagation pathway. That pathway likely is mediated by the celiac ganglia, which are abdominal nerve bundles that innervate the gastrointestinal tract.

A recent study conducted by researchers at Johns Hopkins University School of Medicine revealed similar data, but in mice. The Hopkins team also found that, when they injected an altered form of alpha-synuclein in the intestine of mice, it would first accumulate in the vagus nerve and subsequently spread throughout the brain.

With the findings from the new study, researchers now have more detailed evidence on how the disease most likely spreads.

This may put the scientific community one step closer toward developing more effective medical strategies to halt the disease, Borghammer said.

“For many years, we have known that Parkinson patients have extensive damage to the nervous system of the heart, and that the damage occurs early on. We’ve just never been able to understand why. The present study shows that the heart is damaged very fast, even though the pathology started in the intestine, and we can continue to build on this knowledge in our coming research,” he said.

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