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Levels of Progranulin Protein May Affect Parkinson’s Severity, Progression

possible disease biomarker

Blood levels of progranulin — a protein whose deficiency has been linked to neurodegeneration — may reflect Parkinson’s severity and progression, and serve as a disease biomarker, a recent study suggested.

The research, “Reduced plasma progranulin levels are associated with the severity of Parkinson’s disease,” was published in Neuroscience Letters.

Progranulin is widely distributed throughout the brain. Studies indicate this protein is a potent regulator of neuroinflammation and a promotor of long-term neuronal survival.

Low progranulin levels have been associated with neurodegenerative and lysosomal storage disorders. Blood levels of progranulin are also suggested to be lower than usual in Parkinson’s patients.

But little is known about how blood levels of progranulin and disease severity in Parkinson’s might correlate.

Researchers explored this possibility by measuring progranulin blood concentrations and correlating them with symptom severity.

Their study involved 55 patients (24 men and 31 women, mean age 71.1) and 55 people without the disease serving as controls, (22 men and 33 women, mean age 67.8).

Disease severity was quantified using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale. Patients’ motor symptoms were assessed using the UPDRS motor section (UPDRS-III).

Blood plasma tests revealed that progranulin levels were significantly lower in Parkinson’s patients compared to controls (333.8 vs. 364.2 ng/ml). Blood levels of progranulin were also found to negatively correlate with Parkinson’s severity, motor symptoms, and disease duration.

This means that lower progranulin levels associated with greater disease severity and motor symptoms, and longer disease duration. It also indicates a possible protective role of progranulin against the neurodegeneration process associated with Parkinson’s.

Previous studies have shown that boosting progranulin production protected dopamine-producing neurons from degeneration in mouse models of Parkinson’s, supporting progranulin’s role in better neuronal survival and neuroinflammation control.

“These results indicate that circulating [progranulin] levels might reflect the severity of neuronal loss and might be developed as a potential biomarker of [Parkinson’s disease],” the researchers wrote.

Progranulin deficiency has also been implicated in other neurodegenerative diseases besides Parkinson’s, including frontotemporal dementia, a group of dementias mainly affecting decision-making and behavior or language and speech, depending on the brain area that’s affected.

More research is necessary to investigate the protein’s diagnostic potential in Parkinson’s disease, the researchers advised.

A Phase 1 clinical trial in healthy volunteers (NCT04111666) is expected to test AL101, a therapeutic compound with a potential ability to raise progranulin levels in the brains of people with neurodegenerative diseases. But this study, listed as starting in December 2019, does not yet appear to be enrolling.

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High Blood Levels of Urate May Help Protect Dopamine-Producing Neurons in Men With Parkinson’s, Study Suggests

urate, Parkinson's

High levels of urate in the blood may help preserve dopamine-producing neurons and be used as a biomarker of positive outcomes in men newly-diagnosed with Parkinson’s disease, a study says.

The study, “Sex dependent association of urate on the patterns of striatal dopamine depletion in Parkinson’s disease,” was published in the European Journal of Neurology.

Purines make up key molecules in cells, including DNA and the energy-carrying molecule adenosine triphosphate (ATP), among others. Urate, also known as uric acid, is a powerful antioxidant end product of purine metabolism.

Previous research suggested has that low levels of urate in the blood are linked to a higher risk of Parkinson’s, while high levels of urate have been associated with a slower progression of motor disability and loss of dopaminergic neurons (a hallmark of Parkinson’s).

Of note, dopaminergic neurons are specialized nerve cells that are responsible for producing dopamine, a neurotransmitter that regulates brain cell activity and function; a neurotransmitter is a chemical substance nerve cells use to communicate.

However, research suggests that the benefits of high levels of urate in the blood seem to be more pronounced in men with Parkinson’s than in women.

Scientists at Yonsei University College of Medicine in South Korea investigated the relationship between the levels of urate in the blood and loss of dopaminergic neurons in the striatum — a brain region involved in voluntary movement control — in patients newly-diagnosed with Parkinson’s.

The study included 167 patients (83 men and 84 women), with a mean age of 69, and a mean disease duration of nearly two years. All patients included in the study had positron-emission tomography brain scans.

No significant differences were found in age, disease duration, or motor symptoms, as assessed using the Unified Parkinson’s Disease Rating Scale Part III scores between the men and women.

When the researchers measured the levels of urate in the blood, they found that men had significantly higher levels (5.26 mg/dL) compared to women (4.77 mg/dL).

They then measured the levels of dopamine transporters (DaT) within subregions of the striatum using brain scans of the patients. For this, they divided the striatum in front-to-back (anterior-posterior) and right-to-left.

Of note, DaT are proteins that regulate the flow of dopamine between nerve cells, and whose levels are usually lower among those with Parkinson’s.

Results indicated that within certain subregions of the striatum, the levels of DaT were significantly higher in women than men.

The researchers then investigated how the levels of urate in the blood and gender might be correlated with DaT.

Analyses showed that the levels of urate in the blood correlated with the abundance of DaT in front-to-back regions of the striatum. In men, an increase in blood levels of urate by 1.0 mg/dL was associated with a significant decrease in the abundance of DaT in these regions of the striatum. The same was not true for women.

No correlations were found between urate levels or gender in left-to-right regions of the striatum.

When they analyzed all patients together, the researchers found a correlation between the blood levels of urate and the abundance of DaT only in the front-to-back regions of the striatum.

Moreover, when analyzing different subregions of the striatum, the posterior putamen — a brain region involved in learning and movement control — was the only region where investigators found a correlation between blood levels of urate and the abundance of DaT. Once again, this was only observed in men.

Overall, this study suggests that the levels of urate in the blood may confer a sex-specific protective effect to dopaminergic neurons within the striatum.

“These results may constitute further evidence that the serum [urate] is a predictor of favorable outcomes in [Parkinson’s disease],” the researchers said.

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VCP, Enzyme in Protein Degradation, May Be Blood Biomarker of Early Stages of Parkinson’s, Study Suggests

VCP enzyme

Blood levels of valosin-containing protein (VCP) — an enzyme involved in protein degradation — may be used as a biomarker of preclinical and early clinical stages of Parkinson’s disease (PD), a study suggests.

Reduced levels of VCP in the blood were found in both animal models of the disease and untreated patients at preclinical and early clinical stages of Parkinson’s.

The study, “VCP expression decrease as a biomarker of preclinical and early clinical stages of Parkinson’s disease,” was published in the journal Scientific Reports.

Parkinson’s neurodegeneration begins many years before the emergence of its hallmark motor symptoms. It is thus crucial to identify biomarkers of presymptomatic, or preclinical, stages of the disease so that patients can benefit more from neuroprotective treatments, potentially preventing further damage.

The VCP enzyme, also known as p97 in mammals, has several cellular functions, including the maintenance of protein balance and quality. It is involved in the degradation of faulty proteins in several cellular compartments, including the mitochondria, known as the cells’ powerhouses.

Increasing evidence suggests that changes in VCP activity may contribute to the development of several neurodegenerative diseases.

Mutations in the VCP gene are responsible for the development of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia, a condition that can affect the muscles, bones, and brain. VCP mutations also have been identified in people with other neurodegenerative disorders, such as Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis (ALS).

Moreover, patients with neurodegenerative diseases and VCP mutations have been reported to show signs of Parkinson’s-like symptoms, including rigidity, tremor, and slowness of movements.

Together, the potential association of impaired VCP function with abnormalities in faulty proteins break-down, neurodegenerative conditions, and Parkinson’s-like symptoms suggest that changes in the enzyme may play a role in Parkinson’s development.

However, no studies have analyzed VCP levels during the early stages of idiopathic (sporadic) Parkinson’s — which is not caused by any mutations and is the most common form of the disease.

To learn more, a team of Russian researchers now evaluated the levels of VCP in a mouse model and in patients at the earliest stages of Parkinson’s.

The team analyzed VCP levels at different time points in both the blood and brain of mice injected with MPTP — a neurotoxin commonly used to induce the death of dopamine-producing neurons and create Parkinson’s models — that mimic early symptomatic stages of PD.

VCP levels also were measured in blood samples of 38 untreated and 14 treated patients with newly diagnosed Parkinson’s — considered to be early clinical stages — and in nine individuals with “predicted” Parkinson’s, considered late preclinical stages.

People with “predicted” Parkinson’s were those with an estimated PD diagnosis based on the presence of known predictors of the disease and who had a confirmed diagnosis two years later.

The researchers also analyzed blood samples of 23 people with neurological disorders other than Parkinson’s and 44 age-matched healthy individuals.

Data showed that VCP levels were similarly reduced in both mice and untreated patients at preclinical and early clinical stages of Parkinson’s disease.

The most significant changes in VCP levels observed in these mice were in the striatum and substantia nigra, two brain regions involved in Parkinson’s. Notably, after a significant reduction in VCP levels in these regions, there was an increase of VCP levels during the late presymptomatic stages, which the researchers hypothesized may be associated with compensatory mechanisms.

Changes in the enzyme levels in the substantia nigra were accompanied by similar alterations in the blood, suggesting that VCP blood levels “can be considered as biomarkers of the neurodegeneration of PD,” the researchers said.

In addition, untreated patients and people with “predicted” Parkinson’s had significantly lower VCP levels — by nearly two-fold — than healthy people. No significant differences were found between treated patients, people with other neurological diseases, and healthy volunteers.

These findings highlighted that a reduction in VCP levels is associated specifically with the development of Parkinson’s, and occurs in late preclinical and early clinical stages of the disease. It also showed that treatment influences the enzyme levels in Parkinson’s patients.

“These data suggest that a decrease in the relative levels of [VCP] might serve as a biomarker for the development of [disease] at the early clinical and preclinical stages of human PD [Parkinson’s disease],” the researchers said.

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Alpha-synuclein Blood Levels May Be Biomarker for Parkinson’s with Motor Symptoms

blood biomarkers of disease

Measuring the levels of alpha-synuclein in red blood cells can reliably distinguish people with Parkinson’s disease and evident motor symptoms from healthy individuals, and could serve as a diagnostic biomarker, a study reports.

These levels in Parkinson’s patients with symptoms of dementia, however, did not measurably differ from healthy people serving as a control group.

The study, “α‐Synuclein in blood cells differentiates Parkinson’s disease from healthy controls,” was published in the journal Annals of Clinical and Translational Neurology.

The hallmark of Parkinson’s disease is the build-up of the protein alpha-synuclein in the brain, which goes on to form clumps of misfolded proteins known as Lewy bodies that damage nerve cells. 

Alpha-synuclein levels in the blood have been evaluated as a biomarker for Parkinson’s, as the ease and accessibility of a blood test would help with treatment during the course of the disease.

Low levels of misfolded alpha-synuclein — originating in neurons — have been found in the blood of Parkinson’s patients and are associated with disease progression.  

However, the primary source of alpha-synuclein in the blood comes from red blood cells, and little is known about the relevance of this source of alpha-synuclein and disease pathology.

To determine if alpha-synuclein levels in blood cells could be a biomarker for Parkinson’s, researchers at The Hebrew University‐Hadassah Medical School in Jerusalem tested the levels of alpha-synuclein in red blood cells isolated from 46 people with Parkinson’s. They compared them to those from 45 healthy controls. 

These blood samples were obtained from The BioFIND Study, an observational clinical study designed to discover and confirm Parkinson’s biomarkers. 

The overall levels of blood cells’ alpha-synuclein and misfolded alpha-synuclein were determined, as were known markers of Parkinson’s: phosphorylated and oxidized forms of alpha-synuclein. 

Alpha-synuclein phosphorylation — a chemical modification in which a phosphate group is added to the protein — and oxidation — which modifies the protein’s side chains —  are known to occur in Parkinson’s disease, and are thought to be critical steps in disease progression. They enhance alpha-synuclein’s toxicity, possibly by increasing the formation of alpha-synuclein aggregates (clumps).

Parkinson’s patients were divided into two groups: 32 people with motor symptoms and 14 with symptoms of dementia as determined by the Montreal Cognitive Assessment. Blood cell alpha-synuclein levels of these two groups were then compared to healthy controls. 

While the average levels of blood cell alpha-synuclein from both Parkinson’s groups combined were slightly lower than those of controls, alpha-synuclein levels in patients with motor symptoms were significantly higher than both controls and patients with dementia symptoms.

The levels of misfolded alpha-synuclein, in addition to its phosphorylated form, followed the same pattern — both were significantly higher in motor symptom patients and were found to correlate with disease severity. 

The test for oxidized alpha-synuclein found no differences between groups.

To validate these three tests as potential Parkinson’s biomarkers, the team collected a second set of blood samples from the Hadassah hospital, comprising 35 Parkinson’s patients with motor symptoms and 28 healthy controls. The levels of total, misfolded, and phosphorylated alpha-synuclein were measured.

This analysis confirmed that these three markers were able to reliably distinguish between Parkinson’s patients with motor symptoms and those without the disease. 

“We conclude that blood cells expressed [alpha-synuclein] can differentiate [Parkinson’s with motor symptoms] and [healthy controls] with a high degree of accuracy. It provides a reliable classification rate, correlates with the severity of disease and is reproducible,” the researchers wrote.

“A longitudinal study that will determine whether alterations in blood cell-expressed [alpha-synuclein] forms are associated with disease progression is required,” they added.

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Neurofilament Light Chain Levels May Be Useful Biomarker for Disease Progression in Parkinson’s, Study Finds

Neurofilament light chain

Levels of neurofilament light chain (NfL) — a protein found in blood plasma — may be a useful biomarker of disease progression for Parkinson’s, a study says.

The study, “Blood NfL: A biomarker for disease severity and progression in Parkinson disease,” was published in the journal Neurology.

A hallmark feature of Parkinson’s disease is the progressive degeneration of brain cells, which can happen at varying rates in different people. As such, researchers have focused on discovering a biomarker of neurodegeneration that could be used to predict the course of the disease for each individual patient.

The protein neurofilament light chain (NfL) is a key component of axons — myelinated nerve segments responsible for the transmission of nerve signals — and the main byproduct of nerve cell degeneration.

In other chronic neurodegenerative disorders — including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inherited peripheral neuropathy, Alzheimer’s dementia, and frontotemporal dementia — studies have reported that the levels of NfL in blood plasma were abnormally high, suggesting its usefulness as a marker of neurodegeneration.

In the case of spinal muscular atrophy (SMA), a genetic neurodegenerative disorder that affects motor neurons, the phosphorylated neurofilament heavy subunit (pNF-H) — a key component of motor nerve cells — is also being investigated as a potential biomarker of neurodegeneration.

In this study, researchers from the National Taiwan University and their collaborators set out to investigate if plasma levels of NfL could also be associated with disease progression in people with Parkinson’s disease.

To that end, they carried out a prospective longitudinal study in which they followed 116 patients with Parkinson’s, 22 people with multiple system atrophy (MSA) — a rare neurodegenerative disorder — and 40 healthy individuals (controls).

Plasma levels of NfL were measured in all study participants using an electrochemiluminescence immunoassay — a technique that allows researchers to measure the levels of a protein of interest based on an electrochemical reaction. Researchers noted that the testing required just a blood sample from each participant.

Those who had Parkinson’s performed motor and cognitive tests at the beginning of the study, and at a mean follow-up interval of three years. The Unified Parkinson’s Disease Rating Scale (UPDRS) Part III and the Hoehn-Yahr scale were used to evaluate the progression of motor symptoms, while the Mini-Mental State Examination (MMSE) was used to assess the progression of cognitive symptoms.

Results showed that plasma levels of NfL were much higher among those with MSA (35.8 pg/mL), compared with those with Parkinson’s (17.6 pg/mL), and controls (10.6 pg/mL).

However, in patients with Parkinson’s, NfL levels were higher among those who had dementia and among those with severe motor impairments (advanced Hoehn-Yahr stage).

Correlation analyses revealed there was a modest association between NfL levels and UPDRS Part III (motor) scores.

Another statistical analysis performed after a mean follow-up of 3.4 years — and normalized for participants’ age, sex, disease duration and baseline symptoms, or symptoms at the start of the study — revealed that higher levels of NfL at baseline were linked to a higher risk of disease progression in patients with Parkinson’s. This was true for either motor or cognitive symptoms.

“Our results suggested that the plasma NfL level could serve as a noninvasive, easily accessible biomarker to assess disease severity and to monitor disease progression in PD,” the researchers said.

“Future large longitudinal follow-up studies that incorporate other biomarkers such as neuroimages are needed to strengthen the possible prognostic role of blood NfL levels in PD progression,” they added.

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Stool Calprotectin May Be Used as Marker of Bowel Inflammation in Parkinson’s Patients, Study Finds

calprotectin

The levels of calprotectin — a protein whose levels increase in response to tissue inflammation — in the stool may be used as a marker of bowel inflammation in patients with Parkinson’s disease, according to a recent study.

The results, “Fecal Calprotectin as a Marker of the Gut Immune System Activation Is Elevated in Parkinson’s Disease,” were published in Frontiers in Neuroscience.

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.

Some scientists believe Lewy bodies form in the enteric nervous system (ENS) — the network of nerves that innervate the gastrointestinal (GI) tract — then spread to the brain, where they gradually damage and destroy brain cells.

It also is thought that lesions in the ENS may be linked to bowel inflammation, dysmotility (impairment of GI tract muscles) and high intestinal permeability, all of which contribute to gastrointestinal symptoms of Parkinson’s disease, such as constipation.

In this study, researchers from Wrocław Medical University in Poland set out to explore the usefulness of calprotectin and zonulin — two proteins whose levels tend to increase in the presence of inflammation and immune system dysfunction — as markers of bowel inflammation and impaired intestinal permeability in patients with Parkinson’s disease.

To that end, they gathered stool samples from 35 patients with Parkinson’s disease who were either hospitalized or routinely followed at the Department of Neurology at Wrocław Medical University, and 20 healthy individuals (controls).

The levels of calprotectin and zonulin in the stool were measured by Enzyme-Linked Immunosorbent Assay (ELISA), a technique that allows researchers to measure the amount of a specific protein of interest using an enzymatic reaction. All study participants were asked to complete a short questionnaire regarding their GI symptoms.

Results showed the median levels of calprotectin found in the stools of patients with Parkinson’s disease were much higher compared to those found in the stools of healthy individuals (54.5 μg/g versus 9.7 μg/g), indicating the presence of bowel inflammation.

“Additionally, we evaluated the percentage of subjects with abnormal results considering the following age-dependent upper cut-off values of normal fecal calprotectin: 51 μg/g for subjects below 60 years of age, and 112 μg/g for subjects above 60 years. Abnormal fecal calprotectin level was found in 43% of all PD patients and in none of the control subjects,” the researchers stated.

Additionally, abnormal calprotectin levels were found more often among patients younger than 60 (50%) than among those who were older than 60 (39%).

No correlations were found between the levels of calprotectin found in the stool of patients and disease duration. Unlike calprotectin, no significant differences were found in the levels of zonulin between the two groups.

The most frequent GI symptoms patients reported in questionnaires included constipation (69%), feeling of incomplete evacuation (51%), bloating (51%), abdominal pain (20%), and changes in bowel movements (17%).

“The results of the present study confirm that [Parkinson’s disease] is characterized by the gut immune system activation,” the researchers said.

“The evaluation of fecal calprotectin level may be a useful tool to detect the signs of gut immune system activation present in a remarkable number of [Parkinson’s disease] patients, also in the early stage of the disease. Calprotectin may constitute a critical link between amyloid formation and neuroinflammatory cascades serving as a prospective diagnostic and therapeutic target,” they added.

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Scientists Identify Potential Biomarker That Could Open New Avenues for Parkinson’s Treatment

Miro1, Parkinson's

Researchers have found a compound that can rescue dopaminergic neurons from cell death and improve locomotor activity in fly models of Parkinson’s disease.

Their findings were published in a study, “Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models,” in the journal Cell Metabolism.

The identification of reliable molecular biomarkers that can distinguish Parkinson’s from other conditions, monitor disease progression, or provide insight about a patient’s response to a given therapeutic intervention would be groundbreaking in the field of Parkinson’s research.

Evidence indicates that dysfunctional mitochondria — i.e. the powerhouses of cells — may be a causative mechanism behind this neurodegenerative disorder. When mitochondria are dysfunctional, the body eliminates them through a process called mitophagy, whereby mitochondria are sent to cellular compartments called lysosomes, the cell’s so-called “recycling center.”

A series of proteins direct damaged mitochondria to lysosomes. For mitochondria to be recycled, these same proteins must remove Miro1, a protein found on the outer membrane of mitochondria that attaches them to the cells’ cytoskeleton. Miro1 has been linked to multiple Parkinson’s-causing genes.

Like the skeletal system, the cytoskeleton offers structural support, helps cells move around, and enables the transport of molecules and organelles, including mitochondria, inside cells.

In Parkinson’s, cells are not able to remove Miro1 from mitochondria, which then don’t get to be recycled and end up becoming toxic and eventually killing the cell — contributing to neurodegeneration.

Stanford University researchers investigated the clinical utility of Miro1 for detecting Parkinson’s and its potential in developing treatment strategies.

The scientists reproduced in the laboratory the biochemical process that leads to mitochondria degradation. They did so in skin fibroblasts from 71 Parkinson’s patients, three at-risk subjects, 10 individuals with other neurological disorders including Huntington’s disease and Alzheimer’s, and 12 healthy controls; all patients were included in the National Institute of Neurological Disorders and Stroke and the Parkinson’s Progression Markers Initiative cell repositories.

Results revealed 94% of Parkinson’s fibroblasts could not remove Miro1 from mitochondria, but cells from the controls and patients with other movement disorders had no trouble doing so. This Miro1 defect was also observed in all of the at-risk subjects.

“We’ve identified a molecular marker that could allow doctors to diagnose Parkinson’s accurately, early and in a clinically practical way,” Xinnan Wang, MD, PhD, associate professor of neurosurgery and lead author of the study, said in a news release.

“This marker could be used to assess drug candidates’ capacity to counter the defect and stall the disease’s progression,” Wang added.

Using artificial intelligence, the scientists screened 6,835,320 commercialized small molecules, all of which were able to bind in some way to the Miro1 protein. Their analysis showed four of these molecules were non-toxic, orally available, able to cross the blood-brain barrier, and would significantly reduce Miro1 levels in fruit flies by facilitating its separation from mitochondria.

One of these four tested compounds, which scientists called a “Miro1 reducer,” was then used to treat fibroblasts from a patient with Parkinson’s of unknown cause (also known as idiopathic). The compound improved Miro1 “detachment” in damaged mitochondria within these cells.

Three distinct fruit-fly strains modelling Parkinson’s-like symptoms were fed the Miro1 reducer for their entire life span (around 90 days). The compound showed no toxicity towards the animals’ physiology, prevented dopaminergic neuronal death in all fly models, and rescued locomotor deficits in two of these models.

“Our hope,” Wang said, “is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who’ve tested positive for the Miro-removal defect but don’t yet have Parkinson’s symptoms, they’ll never get it.”

Stanford’s Office of Technology Licensing has filed a provisional patent for the use of the Miro1 reducer in Parkinson’s and other neurodegenerative diseases. Wang has formed a company called CuraX to speed up the molecule’s development.

“Our results indicate that tracking this Miro1 marker and engaging in Miro1-based therapies could open new avenues to personalized medicine,” the researchers said.

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Researchers Contemplate Salivary Alpha-Synuclein as Parkinson’s Biomarker

biomarker

Alpha-synuclein in saliva may be a potential biomarker for Parkinson’s disease, according to a recent review article, but more research is necessary to determine its reliability as a possible screening approach.

The study with that finding, “Salivary alpha‑synuclein as a biomarker for Parkinson’s disease: a systematic review,” was published in the Journal of Neural Transmission.

In Parkinson’s, a protein called alpha-synuclein clumps together, creating insoluble fibrils (small fibers) that accumulate inside nerve cells. These aggregates, known as Lewy bodies, are harmful to cells, eventually leading to cellular death, which then contributes to the onset of disease-related symptoms.

Unfortunately, alpha-synuclein aggregates can be confirmed only during an autopsy examination, so current diagnosis relies on Parkinson’s-related clinical symptoms instead of objective tissue changes.

That is why researchers are seeking reliable molecular biomarkers that can distinguish Parkinson’s from other conditions, monitor disease progression, or provide insight about a patient’s response to a given therapeutic intervention.

Lewy bodies have been found in the salivary glands of early-stage Parkinson’s patients. “Salivary alpha-synuclein is an easily accessible biomarker for PD [Parkinson’s disease] with promising results,” the researchers wrote.

The team decided to summarize the current knowledge of salivary alpha-synuclein as a potential biomarker for Parkinson’s. They searched the U.S. National Library of Medicine’s MEDLINE database from 1970 to April 2019 for several keywords related to Parkinson’s diseasem including “alpha synuclein,” “Lewy body pathology,” “saliva,” and “biomarker.”

Based on all their established criteria, researchers identified 476 studies, of which only eight had data on salivary alpha-synuclein, totaling 1,240 participants.

Of the eight studies, three reported total salivary alpha-synuclein levels (i.e., including all forms of the protein) were significantly lower in Parkinson’s patients, compared to healthy individuals, but the remaining five indicated no association between total alpha-synuclein concentration in saliva and the neurodegenerative disorder.

“In some studies, total salivary [alpha-synuclein] was associated with demographic and clinical features; however, no consistent pattern emerged. In one study, total [alpha-synuclein] levels were associated with poor cognitive performance in [Parkinson’s disease] patients,” the investigators noted.

Alpha-synuclein can be found in various molecular and structural forms. Half of the studies analyzed showed that people with Parkinson’s had higher levels of salivary oligomeric (aggregated) alpha-synuclein and a higher oligomeric alpha-synuclein/total alpha-synuclein ratio, than controls.

Additionally, one study indicated multiple genetic variants could alter total salivary alpha-synuclein concentrations in Parkinson’s. Nonetheless, in all studies there were important limitations to the scientific protocol and the corresponding results that may have influenced its conclusions. Some of those confounding factors included problems with sample collection, sample contamination, inadequate sample storage, or difficulties performing the tests.

“Utilization of saliva in biomarker discovery has several advantages over other biofluids. For instance, in comparison to CSF [cerebrospinal fluid, the liquid surrounding the brain and spinal cord] or serum/plasma, human saliva is readily accessible and is easier and less invasive to collect in adequate quantities,” the researchers explained.

Because of the minimal risk the approach imposes on the patient, salivary biomarkers may enable monitoring how the disease progresses and the effects of treatments.

Although studies suggest a decrease in total, and an increase in oligomeric,  salivary alpha-synuclein levels, results lack consistency. For now, salivary alpha-synuclein tests have yet to be adopted in clinical practice.

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Lack of Standardized Vitamin D Data Hampers Efforts to Determine Its Role in Parkinson’s, Review Study Says

Vitamin D, Parkinson's risk

Low vitamin D serum levels have been associated with Parkinson’s disease, but the lack of standardized data makes it difficult to determine vitamin D’s exact role in Parkinson’s pathology, according to a recent review article.

The study, “Standardized measurement of circulating vitamin D [25(OH)D] and its putative role as a serum biomarker in Alzheimer’s disease and Parkinson’s disease,” was published in Clinica Chimica Acta.

Vitamin D is essential to maintain homeostasis of the musculoskeletal system, and exists in two forms: 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. The major form found in the blood is 25-hydroxyvitamin D, and as such, testing usually quantifies these levels to monitor vitamin D status in individuals.

Low serum vitamin D levels have been associated with Parkinson’s disease, suggesting that elevated vitamin D levels could protect against this neurodegenerative disorder.

In 2010, researchers analyzed the blood concentrations of vitamin D in 3,173 men and women, 50–79 years old, and found that those with higher levels were less likely to develop Parkinson’s. Standardized techniques were used to measure these levels, which revealed that 50 out of the 3,173 people developed Parkinson’s, which is a relatively small number for scientists to draw conclusions on the “protective power” of vitamin D.

In another study, 25-hydroxyvitamin D blood concentration was found to be significantly associated with motor severity in 145 Parkinson’s patients who were followed for three years. These findings were further supported by two recent meta-analyses evaluating a total of 4,199 patients. Results revealed that serum vitamin D levels were inversely associated with Parkinson’s risk and severity, and that vitamin D supplementation did not improve subjects’ motor function. However, the methods used to quantify vitamin D levels varied between the studies included in the combined statistical analyses.

In an attempt to standardize vitamin D measurements, researchers in the current study reviewed the performance of 25-hydroxyvitamin D assays over the last three decades. So far, “only a few studies evaluating relatively small samples reported standardized data,” the researchers wrote.

“Literature studies in the field of vitamin D mainly report unstandardized results, which hampers the development of consensus guidelines defining optimal vitamin D status,” they said, adding that current data do not support the usefulness of vitamin D as a biomarker for Parkinson’s disease and that further studies “using internationally recognized measurement procedures and materials are required.”

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Brain Changes Might Predict Parkinson’s Mild Cognitive Impairment

Mild cognitive impairment

Early atrophy of a speech-related brain area called temporal lobe and progressive degeneration of a cognitive one (frontal lobe) might be warning signs for Parkinson’s mild cognitive impairment later on, researchers report.

Their study, “Progressive brain atrophy in Parkinson’s disease patients who convert to mild cognitive impairment,” was published in CNS Neuroscience & Therapeutics.

Cognitive impairment is one of the most common non-motor complications of Parkinson’s and is associated with significant disability for patients, worsening their quality of life.

A substantial percentage of Parkinson’s patients will in time develop dementia; this appears to be preceded by mild cognitive impairment. Studies indicate mild cognitive impairment is associated with temporal and frontal cortex atrophy. “However, the consistency between these studies is poor,” the researchers noted.

It is known that the accumulation of harmful proteins and the short supply of the chemical messenger dopamine affect brain structure in Parkinson’s disease, but this exact relationship  remains to be understood, particularly the molecular and structural associations in patients who develop Parkinson’s-related mild cognitive impairment and those that don’t.

A Chinese team of researchers decided to investigate the changes in gray matter volume during cognitive degeneration by comparing Parkinson’s patients who developed mild cognitive impairment, those who did not and healthy subjects. Cognitive impairment has been linked to reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

Ninety-four Parkinson’s patients without cognitive problems at the time of recruitment and 32 healthy subjects were included in this study. Participants underwent magnetic resonance imaging (MRI) and neuropsychological assessment at the study’s beginning and 28 months later.

Of the Parkinson’s sample, 24 subjects (16 men and eight women; mean age 63.1 years) developed disease-related mild cognitive impairment (converters) after 28 months of follow-up, while 70 individuals (43 men and 27 women; mean age 62.3 years) did not develop cognitive problems (non-converters).

Converters had significant right temporal atrophy at the beginning of the study and extensive temporal lobe degeneration 28 months later. Nonetheless, biochemical analysis showed no association between right temporal atrophy and Parkinson’s-related protein levels in cerebrospinal fluid. Sitting behind the ears, the temporal lobe is the region where sound is processed and where auditory language and speech comprehension systems are located.

Those who developed mild cognitive impairment also had progressive bilateral frontal lobe atrophy. Located directly behind the forehead, the frontal lobe carries out higher mental processes such as thinking, decision making, and planning.

Using DaT scan — an imaging technique that allows scientists to visualize the functioning of dopaminergic nerve cells — the team reported that loss of dopamine-producing neurons in the striatum (a brain region involved in motor control) of patients who progressed to mild cognitive impairment was correlated with right temporal atrophy.

The findings suggest that structural changes in the temporal and frontal lobes of Parkinson’s patients might be a biomarker for cognitive decline in the long term.

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