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2 Blood Biomarkers of Parkinson’s Seen in Multi-step Protein Analysis

blood biomarkers of disease

Levels of two mitochondrial-related proteins, clusterin and VPS35, may accurately diagnose Parkinson’s disease using a single blood drop, findings from a new study suggest.

The research also suggests that a translational approach — one that moves from cell lab work to patients — which also incorporates relevant protein biological functions may be a more efficient way of identifying disease biomarkers circulating in the blood, for Parkinson’s and other disorders.

The study, “A different vision of translational research in biomarker discovery: a pilot study on circulatory mitochondrial proteins as Parkinson’s disease potential biomarkers,” was published in the journal Translational Neurodegeneration.

Disease biomarkers are fundamental in medicine, helping to diagnose people with a given condition earlier, determine the severity of disease, predict responses to treatments, and have a sense of a person’s prognosis.

But most studies aiming at discovering circulating, or blood, biomarkers of Parkinson’s disease have failed to have reproducible results. This is likely because biomarker studies require large patient samples due to the high variability of each sample, and very complex analysis.

Researchers at the University of Coimbra, in Portugal, proposed a translational method to identify disease biomarkers, which first uses cells under well-defined circumstances that make sense in the context of disease, then selects proteins based on the function that is most important for the disease, and only then incorporates these findings with those of patient samples.

They demonstrated the potential of this approach in identifying circulating biomarker candidates of neurodegenerative diseases, particularly Parkinson’s.

The researchers started out by comparing proteins that are secreted by cells cultured in normal conditions, and in a setting of oxidative stress — an imbalance between the production and clearance of toxic reactive species that are harmful to cells, and which plays a key role in neurodegenerative diseases like Parkinson’s.

To narrow down biomarker candidates, they then selected only mitochondrial-related proteins, which are central in the modulation of oxidative stress and also participate in Parkinson’s and other neurodegenerative conditions. (Mitochondria are small organelles inside cells that function as a cell’s energy source or “powerhouse.”)

In total, their analysis retrieved 23 mitochondrial-related proteins that were differentially secreted by cells under these two conditions, including 19 proteins whose levels were significantly increased in the presence of oxidative stress, and four proteins with significantly decreased levels in this setting.

Next, a similar analysis was conducted to identify proteins whose levels were higher than normal in the blood of Parkinson’s patients. That is, higher compared to healthy people serving as a control group.

For that purpose, they examined blood plasma samples from 31 Parkinson’s patients, ages 65 to 86 and being followed at the Centro Hospitalar Cova da Beira in Portugal. They then compared these sample with 28 from matched controls, whose ages ranged from 55 to 83.

In addition to a conventional analysis in which data is extracted from a list of sample-specific identified proteins, researchers  considered the list of proteins identified in their previous experiment with cells exposed (or not) to oxidative stress.

This combined approached yielded a total of 98 proteins that were significantly different between patients and controls. But a review of mitochondrial-related proteins retrieved only two candidates — clusterin and the vacuolar protein sorting-associated protein 35 (VPS35).

These two proteins were previously associated with Parkinson’s, but while clusterin was seen as a potential blood biomarker of this disease, VSP35 had never been identified in blood samples. VSP35 was only identified here because researchers also included the 23 proteins from the cellular experiment in this analysis.

Levels of these two mitochondrial-related proteins combined were better than each single protein at discriminating patients from controls, showing an accuracy of 82.1%.  The rate of incorrectly classified patients also dropped significantly when people with more advanced disease were examined, the researchers reported.

In a final analysis, the team examined these two biomarkers in another group of patients and controls. While clusterin, but not VPS35, was significantly increased in plasma samples of patients compared to controls, a combined score of both proteins still provided a good way of distinguishing patients from controls.

The research suggests that studies looking for circulating disease biomarkers may benefit from complementary information of secreted proteins from cells cultured under well-defined, disease-associated conditions, and from selecting candidates based on relevant biological functions.

“From the application of this adapted pipeline, two mitochondrial-related proteins were identified as potential candidates for Parkinson’s disease diagnosis,” the researchers concluded.

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Immune Biomarkers May Better Classify Patients, Direct Therapy, Study Says

biomarkers, brain inflammation

Biomarkers of brain inflammation could provide a useful means for classifying Parkinson’s and Alzheimer’s patients and defining the mechanisms underpinning each person’s disease.

Testing for these biomarkers could support clinicians in providing precision medicine, by helping people with the progressive neurodegenerative disorders to choose treatments with a greater chance of benefiting them, based on their individual characteristics.

The study, “Multicenter Alzheimer’s and Parkinson’s disease immune biomarker verification study,” was published in the journal Alzheimer’s & Dementia.

Typically, diseases such as Parkinson’s are defined largely on the basis of patients’ symptoms. But while individuals share the same diagnosis, the underlying molecular and cellular causes of their illness may differ.

This also could explain why treatments do not work equally for all patients. Using these individual differences to identify patient groups may help clinicians choose more tailored treatment choices.

Many researchers propose that neurodegenerative illnesses could be defined on the basis of their molecular features, before evident symptoms occur in later stages of the disease.

To address this hypothesis, the AETIONOMY project, an European public-private partnership funded by the Innovative Medicines Initiative, is exploring potential molecular classifiers for Alzheimer’s and Parkinson’s.

Candidate markers include tracers of neuroinflammation, meaning trackers of the inflammatory reactions occurring in the brain and spinal cord, which comprise the central nervous system, or CNS.

Neuroinflammation probably begins early in neurodegenerative diseases, when the immune system senses the presence of misshaped or aggregated proteins — including beta-amyloid in Alzheimer’s, or alpha‐synuclein in Parkinson’s.

The formation of abnormal clumps of each of these proteins in the brain is believed to be at the root cause of each disease. In Parkinson’s, alpha-synuclein proteins clump together in aberrant aggregates termed protofibrils, which are toxic and thought to play an important role in the death of nerve cells (neurodegeneration).

In the first stages of the disease, these aggregates are known to activate immune cells called microglia and other supportive cells in the brain, known as astroglia. Later, immune reactivity — in which the body mistakenly attacks its own healthy cells — propagates in response to nerve cell death, with immune signals released as a consequence of the damage.

A team of researchers involved in the AETIONOMY project now sought to identify neuroinflammation-specific biomarkers. They screened 227 samples of cerebrospinal fluid or CSF, the fluid that surrounds the brain and spinal cord, collected from Alzheimer’s and Parkinson’s patients.

The goal was to look for relationships between the levels of these markers and patients’ characteristics — for example, age and sex — as well as their link with markers of neurodegeneration, such as tau, and measures of disease progression, like the Hoehn and Yahr scale for Parkinson’s.

People without dementia and patients diagnosed with mild cognitive impairment also were included for comparison.

The researchers specifically focused on 21 selected immunity markers. These included chemical messengers known as cytokines or chemokines, namely YKL‐40, TGF‐beta1, IP‐10, MCP‐1, MIF, and MIP‐1beta. The immune receptors sIl‐1RAcP, sAXL, sTyro3, sTREM2, sTNF‐RI/II, and sICAM‐1 also were targeted, as well as other complement and innate immune factors, including C-reactive protein and C1q, C3, C3b, C4, B, H, and properdin.

The findings were highly reproducible and consistent with previous findings. However, they revealed that immune markers were more tightly related to neurodegeneration — reflected by the levels of the protein tau — than having a diagnosis of Alzheimer’s, Parkinson’s, or mild cognitive impairment.

This suggests that such biomarkers may work better to discriminate the mechanisms underlying each patient’s illness.

Age was the “most striking covariate” with a “strong influence” on immunity markers. Older patients had increased levels of most immune proteins, and also tended to have more advanced disease.

The individual’s sex also influenced marker levels, as did APOE genetic variants — one of the strongest genetic risk factors for Alzheimer’s and a proposed risk factor for Parkinson’s — and center‐specific factors, or variations from the different centers from which patient data was obtained.

“These results are supportive of the use of mechanism‐based disease taxonomies [classifications] in addition to clinical features,” the researchers said.

Ageing seems to have a strong link with increased neuroinflammation; thus it should be taken into account when translating marker results to clinical practice or studies, the team said.

“Immunity biomarker levels in CSF reflect molecular and cellular pathology [disease characteristics] rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration,” the researchers concluded.

Looking ahead, the researchers reaffirm the need to characterize patients not only by symptoms but also by molecular markers that reflect their complex neurodegenerative disorders.

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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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Review Addresses Problems in Studies of the Gut Microbiome in Parkinson’s

gut microbiome study, Parkinson's

Studies on gut bacteria in Parkinson’s disease differ in their findings and important methodological details, according to a new review that highlights these differences and proposes strategies to mitigate them in the future.

The study, titled “Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson’s Disease: A Systematic Review,” was published in the Journal of Parkinson’s Disease.

Although Parkinson’s is often thought of as a disorder of the brain, the gut likely plays an important role in the disease, but it has only been seriously studied in recent years. A number of studies have recently focused on how the gut microbiome — the bacteria that live inside the intestines — might impact Parkinson’s.

“As more studies investigate the gut microbiome composition in [Parkinson’s], it is important to compare the findings of these studies to get an overview of the changes present in the disease,” Jeffrey M. Boertien, MSc, a PhD candidate at the University of Groningen and co-author of the new review, said in a press release. “It is even more important to compare the methods used in the various studies. Especially as the studies report different and sometimes even contradictory results.”

The review focused on 16 studies published in the past five years. These studies included populations ranging from 10 to 197 people with Parkinson’s and 10 to 130 people without the disease. Notably, even at the level of selecting individuals to include, several studies run into methodological problems; many had large differences in age and sex distribution between the two groups, and “age and sex are well-known determinants of gut microbiome composition,” the review authors wrote.

The authors speculated that one reason for the differences may be the inclusion of spouses or other people living with Parkinson’s patients for use as controls. On one level, this may help account for environmental factors, which can influence the gut microbiome, but the authors stressed that “differences in age and sex distribution should be accounted for as potential confounders in all case-control gut microbiome studies.”

Major differences were also found between studies in how the gut bacteria were assessed — from what taxonomic levels were investigated (phylum, genus, etc.), to how samples were collected, to what bioinformatics techniques were used to analyze the data. All of these could account, at least in part, for different results found from study to study.

A number of differences between studies were found. While the researchers noted that, “several findings, such as an increase of Verrucomicrobiaceae and Akkermansia, and a decrease of Prevotellaceae were robustly replicated,” other findings were inconsistent or even directly contradictory. For example, some studies reported increased numbers of the bacterial groups Lactobacillaceae and Bacteroidetes in people with Parkinson’s, while others found the opposite.

In addition, the effect of dopaminergic medication on gut microbiome composition has not been studied directly, the authors said.

“Nonetheless, the effect of dopaminergic medication can be hypothesized to be substantial, as effects of various medications on gut microbiota composition have been described,” they wrote.

“There is currently no consensus on [Parkinson’s]-specific changes in microbiome composition and their pathophysiological implications due to inconsistent results, differences in methodologies and unaddressed confounders,” said review co-author Filip Scheperjans, MD, PhD, of Helsinki University Hospital.

As to strategies to help address this problem, some — such as more careful selection of study participants — are self-evident. More broadly, the authors suggested that greater transparency and sharing data, particularly raw data, could make it easier to draw broad conclusions: “public availability of raw sequencing data and sample metadata would allow for an integrative dataset of [Parkinson’s] microbiome studies that could address various possible confounders.”

“If we combine all data, it will be easier to distinguish changes that are associated with [Parkinson’s] from noise,” said Scheperjans. “However, further research is still required to increase our understanding of the possible role of gut microbiota in [Parkinson’s]. It is important to emphasize that no microbiota-based treatment for [Parkinson’s] exists to date. We advise [Parkinson’s] patients not to start self-treatment with probiotics or undergo fecal microbiota transplantation without consulting with their doctors in order to avoid potential harm.”

Still, exploiting the gut microbiome may be a potential strategy for the clinical management of the disease in the future, the researchers said.

“Specific changes might serve as a biomarker with which we can recognize [Parkinson’s] or specific subtypes of [Parkinsons’]. Since gut complaints can occur very early in the disease process, this might help to identify patients in the early stages of the disease, possibly even before the appearance of motor symptoms such as tremor and rigidity,” said Boertien. “If gut microbiota play an important role in the disease process, this might lead to new treatment options for [Parkinson’s].”

Several of the review authors disclosed potential conflicts of interest, such as owning patents related to the gut microbiome and Parkinson’s disease.

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Luxembourg Parkinson’s Study Awarded €6M From FNR for Second Phase

Luxembourg Parkinson's Study

Continuing its support of a collaborative Parkinson’s disease (PD) study, the Luxembourg National Research Fund (FNR) has awarded the National Centre for Excellence in Research on Parkinson’s Disease (NCER-PD) €6 million ($6.68 million) for its second phase.

Comprised primarily of five research partners, the four-year-old Luxembourg-based NCER-PD is conducting an eight-year longitudinal study to better understand how PD works. The goal is to diagnose people with Parkinson’s earlier, so that better treatments can be developed. It’s said to be the first inter-institutional research program of its kind in Luxembourg.

Called the Luxembourg Parkinson’s Study, the ongoing research effort aims to find and validate diagnostic biomarkers by studying clinical data, and blood, urine, and other samples from 800 Parkinson’s patients, and 800 healthy individuals in a similarly structured control group.  About 1,000 people live with PD in Luxembourg. The study is about 100 participants short per group. Patients and healthy men over age 65 are invited to join. Go here for more information.

After four years, the study’s participant numbers already put it among the top 7% of the largest Parkinson’s groups globally, a press release said. One thing that sets it apart, the investigators said, is that participants will be assessed annually over the years. The data collected should give scientists greater insight into disease progression.

“The National Centre of Excellence in Research on Parkinson’s disease is a wonderful example of how research in Luxembourg can achieve outstanding international visibility and at the same time produce a direct impact on healthcare by bringing together patients, researchers, doctors and healthcare professionals,” said Marc Schiltz, FNR secretary general.

Collaborators in the NCER-PD include the Luxembourg Centre for Systems Biomedicine of the University of Luxembourg, the Luxembourg Institute of Health and its Integrated Biobank of Luxembourg, the Laboratoire National de Sante, and the Centre Hospitalier de Luxembourg. NCER-PD also works with hospitals, patient groups, physicians, and other healthcare providers in Luxembourg and surrounding areas.

The NCER-PD was created in 2015 with €8.3 million($9.25M) from the FNR. The new grant will take the project through 2023.

During the next four-year funding period, as participants’ health is monitored, researchers will focus on further categorizing the study groups — a process known as cohort stratification. In addition, the NCER-PD will, for the first time, create a subcohort, or subgroup, based on genetic analysis. In the search for new treatments, researchers will conduct specific tests and personalized clinical trials with participants with mutations in the GBA gene. Such patients tend to have a higher risk of cognitive changes, and earlier age of onset.

The researchers noted that a significant number of people with REM sleep behavior disorder eventually develop Parkinson’s. The team will develop a study group with these participants, which it will closely monitor for additional insight into disease onset and development.

“Parkinson’s disease is a very complex disease with many symptoms and manifestations,” said Rejko Kruger, NCER-PD coordinator. “By studying subgroups of patients, as we have planned for NCER-PD’s second phase, one can better understand the underlying mechanisms and contribute to the development of tailored therapies.”

Despite the study’s relatively short duration thus far, Kruger said it’s already increasing awareness and knowledge of Parkinson’s disease.

“Through communication campaigns and close collaboration with patient associations in Luxembourg and the Greater Region, we informed patients, but also the general public, about the disease, its treatment options and current state of research,” he said. “This plays an important role in reducing stigmatism of people with this chronic disease.”

 

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Globin Protein Levels May Help Assess Efficacy of Dopamine Agonists in Parkinson’s Patients, Study Shows

globin dopamine therapy

Evaluation of two specific proteins circulating in the blood, called alpha- and beta-globin, may help monitor treatment efficacy and risk of side effects among patients with Parkinson’s disease, a study suggests.

The study, “2D-DIGE as a strategy to identify serum protein biomarkers to monitor pharmacological efficacy in dopamine-dictated states of Parkinson’s disease and schizophrenia,” was published in Neuropsychiatric Disease and Treatment.

Parkinson’s disease is triggered by the death of dopamine-producing neurons in the midbrain, which control movement. Lack of dopamine — a crucial chemical messenger that allows nerve cells to communicate — causes impaired body control and induces the motor symptoms that are commonly associated with this disease, such as tremors, gait, and balance problems.

Given the underlying mechanisms of Parkinson’s disease, patients are commonly prescribed dopamine agonists to overcome dopamine loss and manage symptoms. However, the use of these therapeutic compounds is linked to several adverse effects including hallucinations, which are due to increased activity of dopamine in the brain.

Despite research efforts, no tests are currently available to help recognize if a treatment is effective or if a treated patient is reaching a point of dopamine over-activity and increased risk of side effects. As such, clinicians still rely almost completely on patients’ compliance and symptoms to assess therapeutic efficacy.

Therefore, researchers in the study explored whether a simple blood test could identify patients’ at risk of experiencing treatment-related adverse reactions. The team recruited five patients with Parkinson’s disease and five patients with schizophrenia who had never been treated with dopamine-related therapies.

The psychotic symptoms of schizophrenia are known to be caused by overactivity of dopamine in the brain — similar to what occurs as a side effect of dopamine-agonist use in Parkinson’s patients.

Comparing the different proteins in the participants’ blood samples revealed that alpha- and beta-globin proteins were consistently present in Parkinson’s patients but absent in schizophrenia patients.

To better understand if these two proteins could be used as biomarkers of dopamine status, the team further analyzed them in a group of 100 individuals

The cohort included six Parkinson’s patients who had not received any therapy, 44 patients who had received treatment, and five patients who had undergone treatment with different dopamine agonists and had experienced treatment-related adverse effects such as visual or auditory hallucinations.

The remaining participants had been diagnosed with schizophrenia, among whom five had not received prior treatment (treatment-naïve), 36 were treated with dopamine inhibitors, and four were treated and experienced Parkinson’s-like symptoms.

The levels of alpha- and beta-globin were three-fold higher in treatment-naïve Parkinson’s patients compared with treatment-naïve schizophrenic patients. In addition, the expressions of both proteins were significantly higher in patients treated for Parkinson’s disease than in those treated for schizophrenia.

Overall, the amount of these two proteins circulating in the blood was found to be inversely correlated with mid-brain dopamine concentrations. This means that schizophrenic untreated patients (who have the highest dopamine activity) had the lowest levels of alpha- and beta-globin proteins, while Parkinson’s untreated patients (who have the lowest dopamine activity) had the highest levels of both proteins.

Disease scoring, gender, and age had no impact on the levels of the two proteins.

“The inverse relationship between globin expression and dopamine concentration in the brain holds value as a translational tool in the therapeutics of Parkinson’s disease,” the researchers wrote.

Moni­toring the levels of alpha- and beta-globin proteins could be a useful “tool for clinicians to efficiently and effectively treat Parkinson’s disease and schizophrenia,” they said.

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Studying Epigenetic Changes May Help Diagnose Parkinson’s Disease Earlier, Researchers Say

epigenetics, Parkinson's

Understanding and identifying epigenetic changes may become a potential strategy for early Parkinson’s diagnosis, when patients still lack the characteristic symptoms of the disease, according to a recent study.

The study, “DNA methylation changes associated with Parkinson’s disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood,” was published in Epigenetics.

Parkinson’s disease patients carry a unique profile of certain epigenetic marks — modifications that sit on top of DNA and control which genes can become activated or not — that change as disease progresses.

“Using this [epigenetics] approach, you could put patients at risk for PD [Parkinson’s disease] on certain therapies before symptoms arise,” Travis Dunckley, assistant research professor at the Arizona State University’s (ASU)-Banner Neurodegenerative Disease Research Center, said in an ASU news release written by Gabrielle Hirneise.

Parkinson’s disease is characterized by the progressive loss of coordination and movement. These symptoms are currently the basis for Parkinson’s clinical diagnosis. However, they appear when the disease is in an advanced phase, a time during which current therapies are much less effective.

“One of the biggest issues with neurodegenerative diseases like Parkinson’s disease or Alzheimer’s disease is that diagnosis is mostly clinically based, and it comes late in the disease — the brain is already degenerated, and it is extremely difficult to restore brain function at that stage,” Dunckley said.

To increase the likelihood of response to available therapies, identifying the disease during its early stages — before the onset of symptoms — is key.

“When physicians treat PD [Parkinson’s disease] patients, it is usually too late to change the trajectory of the disease. I am interested in early diagnostics to try to identify people prone to the disease before they get it,” Dunckley added.

While there is a genetic component to Parkinson’s disease — estimated to contribute to 40% of disease risk — environmental factors play a key role in the disease, namely by interacting with the genome (our complete set of genes).

Parkinson’s is “about 60% environmental — it’s much less genetic than many other neurodegenerative diseases,” Dunckley said.

One way that the environment interacts with the genome is through epigenetic changes — external chemical modifications to DNA that can turn genes on or off but that do not change the actual DNA sequence.

One type of epigenetic mark is the addition of chemical methyl groups that sit on top of genes and work as “switch off” or “switch on” signals. However, unravelling the role of these epigenetic marks in Parkinson’s disease is challenging.

“It is hard to link them without confounding variables in that there are a lot of environmental factors,” Dunckley said. “It’s difficult to say whether epigenetic changes are based on disease, environmental factors or a combination of disease and environmental factors.”

Dunckley and collaborators at the University California, San Diego(UCSD), Texas A&M University, Harvard University and The Translational Genomics Research Institute (TGen), aimed to characterize the epigenetic landscape, specifically the changes in DNA methylation patterns (called methylome), over time in a group of Parkinson’s patients.

In the largest epigenetics study to date in Parkinson’s research, the scientists profiled the methylome of 189 patients and compared it to that of 191 healthy controls. After two years, the same analysis was performed to assess how the DNA methylation patterns changed in Parkinson’s patients versus controls.

The researchers found that the sites in the DNA that are methylated vary between Parkinson’s and healthy individuals, and that these methylation patterns change over time.

Patients receiving dopamine replacement therapy also had a different methylation pattern compared with untreated patients, with the patterns changing more in the untreated group — further supporting the link between epigenetic changes and Parkinson’s progression.

“The main findings are that one, the epigenome does change as the disease progresses. The second finding is that the PD medications themselves alter the epigenome,” Dunckley said. 

If researchers are able to identify a methylation pattern that is specific to Parkinson’s patients, clinical diagnosis can be made earlier and allow patients to receive treatment before irreversible changes occur in the brain.

The researchers are expanding these early findings by performing the same type of analysis in a new subset of patients but for longer period of time.

“The next study we are doing is a replication and extension of this one to validate the findings and extend the observation period to five years,” Dunckley said.

“We are also including patients that are very early in PD [Parkinson’s disease] progression, patients who have symptoms that are highly predictive of future PD. The ultimate goal is to identify changes in these earliest stages of disease that can be predictive of future PD onset,” he added.

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Trace Amines Potential Biomarkers for Early Parkinson’s and Disease Progression, Study Suggests

trace amines, biomarkers

Trace amines, the product of the metabolism of specific amino acids, could indicate changes that occur early during Parkinson’s disease and may serve as early-stage and disease progression biomarkers, a study suggests.

The study, “Different Circulating Trace Amine Profiles in De Novo and Treated Parkinson’s Disease Patients,” was published in Scientific Reports.

Parkinson’s disease is caused by the loss of dopaminergic neurons — those that produce dopamine — and is mostly recognized by motor symptoms that appear during the middle and later stages of the disease.

Although Parkinson’s actually begins years before the appearance of the first motor manifestations, diagnosing the disease in its early stages is a challenge, mainly because there are no reliable biomarkers.

Previous studies have suggested that disturbances in the metabolism of amino acids — the building blocks of proteins — fatty acids, and in the function of mitochondria (which provide energy to cells) occur during the early stages of Parkinson’s.

Therefore, the levels of trace amines — a group of different molecules that originate during the metabolism of specific amino acids — could indicate different stages of Parkinson’s progression, and could be used as potential biomarkers.

However, trace amines are present in very low concentrations both in the central nervous system and in the blood, which makes it difficult to accurately measure and compare their levels.

Researchers have now  used a new method — called ultra performance chromatography-mass spectrometry (UPLC-MS/MS) — that allows them to quantify even very low amounts of a specific molecule with high sensitivity and evaluate the differences in trace amine levels caused as a consequence of Parkinson’s progression.

They recruited three patient groups: 21 patients (mean age, 64 years) who had been diagnosed for less than two years and had not received any Parkinson’s-related medication; 27 patients (mean age, 69 years) who had been diagnosed for less than five years and were receiving treatment; 10 healthy individuals (mean age, 61 years) who served as controls.

The researchers found that each group had a specific trace amine profile. For example, the healthy group had lower levels of tyramine and higher levels of beta-phenylethylamine, the non-treated group had higher levels of tryptamine and low levels of tryptophan, and the treated group had overall lower levels of trace amines.

They then compared the profile of the healthy participants to that of non-treated patients to identify possible markers of early-stage Parkinson’s and found that tyramine was the best candidate.

They also compared the profile of treated and non-treated groups to identify possible biomarkers of disease progression and found that a combination of tyramine, norepinephrine, and tyrosine showed satisfactory results.

The changes in trace amines indicate that specific metabolic pathways are altered during the early stages of Parkinson’s and that these metabolic changes continue as the disease progresses.

“Regardless of the metabolic pathways involved, our results show, to our knowledge for the first time, that circulating levels of [trace amines] may constitute disease-related metabolic biomarkers in [Parkinson’s disease],” the researchers wrote.

A limitation of the study is that the patients with middle to late stage Parkinson’s were taking medication during the study, and therefore it was not possible to distinguish which changes were caused by disease progression and which could have been influenced as a result of treatment.

“[Trace amine] when assessed in the circulation, have the potential to provide for disease biomarkers, either alone or in combination with other markers. Also, should these changes mirror ongoing changes in the hypothalamus and other dopaminergic centers within the [central nervous system], it is possible that pharmacological agents modulating [trace amine] receptors may represent new avenues in the prevention and/or treatment of [Parkinson’s disease],” the researchers concluded.

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Particular Skin Smell May Help in Early Parkinson’s Diagnosis, Study Suggests

sebum smell Parkinson's

Parkinson’s disease (PD) could be identified through a noninvasive analysis of chemical components of sebum, the oily substance that helps keep skin and hair moisturized, a pilot study suggests.

The study, “Discovery of Volatile Biomarkers of Parkinson’s Disease from Sebum,” was published in the journal ACS Central Science.

In the early ages of medicine, a person’s odor was commonly used to help identify diseases. Although this method is no longer used, modern medical studies have associated some illnesses, in particular metabolic and infectious diseases, with specific smells.

One of the study’s co-authors, Joy Milne, the wife of a Parkinson’s patient who was diagnosed in 1986, has an extremely sensitive sense of smell, called a super smeller, and is able to recognize a particular odor associated with Parkinson’s disease. In preliminary tests, she identified this odor mainly in areas of high sebum production, such as the upper back and forehead.

Overproduction of sebum by skin sebaceous glands (a condition known as seborrhea) is a well-known non-motor symptom of the disease, and toxic forms of the protein alpha-synuclein — a Parkinson’s molecular hallmark — have been found in the skin of Parkinson’s patients.

“Identification and quantification of the compounds that are associated with this distinctive PD odor could enable rapid, early screening of PD as well as provide insights into molecular changes that occur as the disease progresses and enable stratification of the disease in the future,” the researchers wrote.

The team, led by researchers at the University of Manchester, further explored the potential of using smell and sebum analysis as a diagnostic tool for Parkinson’s disease.

They analyzed the volatile chemical components of sebum samples collected from 43 Parkinson’s patients and 21 healthy volunteers who were recruited at 25 clinical sites across the U.K.

These volatile components, which are often associated with odors, were detected by high-throughput chemical analysis as well as by olfactory pattern analysis, with the help of Milne.

Among the 17 particular compounds detected in Parkinson’s patients the team found 3,4-dihydroxy mandelic acid, which is a metabolite of L-dopa — one of the most commonly prescribed medications for Parkinson’s disease.

However, this compound was also identified in untreated patients. These findings suggest that changes in this compound could be indicative of other mechanisms rather than just therapy metabolism.

Further analysis revealed that the compounds perillic aldehyde and eicosane were significantly different between Parkinson’s patients and healthy controls. Perillic aldehyde levels were lower in Parkinson’s samples, while eicosane was present at significantly higher levels than in controls.

The presence of these compounds was consistent with the olfactory patterns of the specific “musky” smell of Parkinson’s.

Next, the team asked Milne to try to validate different mixtures of the identified compounds and compared them between patients and controls.

A mixture of all 17 identified compounds, or specific combinations of just nine or four of these compounds, were identified as being closer to the smell of Parkinson’s patients than healthy individuals.

These results were maintained regardless of whether patients had taken Parkinson’s medications or not.

“Now we have proved the molecular basis for the unique odor associated with Parkinson’s we want to develop this into a test,” Perdita Barran, PhD, a professor at the Manchester Institute of Biotechnology and senior author of the study, said in a press release.

“This could have a huge impact not only for earlier and conclusive diagnosis but also help patients monitor the effect of therapy. We hope to apply this to at risk patient groups to see if we can diagnose pre-motor symptoms, and assist with potential early treatment,” she added.

Main differences in perillic aldehyde and octadecanal levels could be associated with changes in fatty molecule metabolism in Parkinson’s disease. But they may also indicate altered activity of the natural bacteria that populate the skin of Parkinson’s patients.

“These potential explanations for the change in odor in PD patients suggest a change in skin microflora and skin physiology that is highly specific to Parkinson’s disease,” the researchers wrote.

More studies are still needed to further explore the potential of these volatile Parkinson’s biomarkers. In addition, studies with extended olfactory data from human smellers, as well as canine smellers, may help characterize in more detail the sebum odor pattern linked to Parkinson’s.

“Finding changes in the oils of the skin in Parkinson’s is an exciting discovery,” said David Dexter, PhD, deputy director of research at Parkinson’s UK. “More research is needed to find out at what stage a skin test could detect Parkinson’s, or whether it also occurs in other Parkinson’s related disorders, but the results so far hold real potential.”

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Behavioral, Metabolic Changes Linked to Sleep Restriction Could Foretell Parkinson’s, Animal Study Suggests

sleep restriction

Chronic sleep restriction alters movement, worsens cognitive dysfunction and induces changes in the levels of several amino acids — the building blocks of proteins — and other markers in rats with Parkinson’s, according to a new study.

According to researchers, these findings could enable the use of biomarkers to identify those at risk of developing the disease.

The study, “Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers,” was published in the journal Scientific Reports.

Non-motor symptoms of Parkinson’s typically appear years before significant loss of dopamine-producing neurons in the substantia nigra, an area of the brain key to motor control. One such symptom is impaired sleep. Both sleep disturbances and lifestyle-imposed sleep restrictions may contribute to cognitive decline and produce detectable alterations in the body.

However, it remains unclear whether sleep disturbances constitute a risk factor for developing Parkinson’s disease.

An international team of researchers from Brazil, the U.K. and the Netherlands used the rotenone-induced rat model of Parkinson’s disease to evaluate if chronic sleep restriction triggers metabolic changes, cognitive impairment, and changes in the circadian rhythm (the body’s internal clock).

When injected into the substantia nigra, rotenone, an agrochemical, induces similar changes to those seen in early Parkinson’s, including excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder, insomnia, and disruption of spontaneous sleep.

The results revealed that, unlike rotenone, sleep restriction for 21 days (six hours per day) — by soft tapping or gently shaking the cage, or gently disturbing rats’ sleeping nest — did not induce loss of dopamine-producing nerve cells.

Animals subjected to sleep restriction did not show the decreased levels of locomotor activity (movement) observed in  rats injected with rotenone, as assessed using the open field test, which is an experimental test used to evaluate animals’ general locomotor activity levels, anxiety, and willingness to explore.

The object recognition task, which evaluates memory by measuring the time animals spend on a new object, revealed that sleep restriction aggravated rotenone-induced cognitive dysfunction. Sleep recovery for 15 days reversed rats’ memory deficits.

Sleep restriction also impaired the animals’ circadian rhythm, as they showed reduced activity during the first 75 minutes after lights-off (the night period  when rodents become more active) at weeks 2 and 3.

The investigators subsequently looked at biochemical alterations in blood plasma using two metabolic profiling approaches called global 1H nuclear magnetic resonance (NMR) spectroscopy and targeted liquid chromatography/mass spectrometry (LC/MS).

Sleep restriction increased plasma levels of amino acids leucine, isoleucine, valine, ornithine (reportedly increased in Parkinson’s), arginine, lysine, alanine, proline, phenylalanine (a precursor of dopamine) and carnitine, as well as 15 different phospholipids, which is a type of fat that is a key component of cellular membranes.

In contrast, sleep restriction lowered the levels of creatinine (a product of muscle metabolism), acetylcarnitine (a form of the amino acid L-carnitine), and kynurenine (a byproduct of the amino acid L-tryptophan and previously implicated in Parkinson’s), among other molecules.

When combined with rotenone, sleep restriction increased plasma concentrations of most of the same amino acids and also of 54 phospholipids, while decreasing creatinine and forms of amino acids such as acetylcarnitine. Sleep recovery completely eliminated the changes induced by sleep restriction and rotenone regarding these molecules.

A statistical analysis then revealed that the concentrations of isoleucine, leucine and kynerunine were different when comparing animals on sleep restriction to controls. Concentration of the amino acid methionine correlated with rats’ activities.

NMR data additionally showed rotenone alone induced higher levels of circulating triglycerides and lipoproteins as well as LDL cholesterol (the “bad” cholesterol). In contrast, sleep restriction alone did not alter biochemical parameters.

Combined with rotenone, sleep restriction led to a more pronounced increase in amino acids levels, including phenylalanine and tryptophan, whose metabolism has been found altered in early-stage Parkinson’s patients. Sleep recovery again eliminated these changes.

“If combined, our results bring a plethora of parameters that represents reliable early-phase [Parkinson’s] biomarkers which can easily be measured and could be translated to human studies,” researchers wrote. Identifying who is at risk of developing the disease “has the potential to improve therapeutic strategies and possibly delay or attenuate the onset of symptoms,” they added.

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