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Scientists Develop HANABI Device to Identify Toxic Aggregates in Parkinson’s Patients’ Brains

HANABI

A new test can analyze cerebrospinal fluid samples and help measure how many toxic aggregates of alpha-synuclein can be found in the brains of patients with Parkinson’s disease.

The new assessment strategy was developed by Japanese researchers and was reported in a study, “Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid,” published in Nature Scientific Reports.

Parkinson’s disease is a neurodegenerative disorder mainly resulting from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling body movements.

Overproduction of the protein alpha-synuclein in nerve cells of the brain, another hallmark of the disease, leads to the formation of small toxic deposits called Lewy bodies that will gradually damage and kill nerve cells. Growing evidence has demonstrated that these alpha-synuclein aggregates are associated with Parkinson’s onset and progression.

A therapy that would be able to prevent the accumulation of these protein aggregates in nerve cells could become a potential treatment for people with Parkinson’s disease.

However, to accurately test the efficacy of such therapies, clinicians must be able to tell how many alpha-synuclein aggregates are present in a patient’s brain before and after treatment. Until now, no specific method assessing the degree of protein accumulation in the brain had been successfully established.

But this may be about to change. A group of researchers from Japan’s Osaka University developed the first strategy that is able to measure the exact amount of alpha-synuclein aggregate buildup in the brain.

The HANdai Amyloid Burst Inducer (HANABI) assay is a fully automated tool that can detect the number of alpha-synuclein aggregates in a patient’s cerebrospinal fluid (CSF) — the liquid that circulates in the brain and spinal cord — using a technique called ultrasonication.

Ultrasonication is a technique in which sound waves are transformed into mechanical disruptive energy. Researchers are able to measure the rate at which alpha-synuclein clumps together to form toxic protein aggregates, a process known as alpha-synuclein seeding activity.

Investigators showed that the seeding activity of alpha-synuclein was higher among 44 patients with a diagnosis of confirmed or probable Parkinson’s disease who participated in a prospective observational study, compared with 17 participants who did not have any neurodegenerative or neuroinflammatory disease.

“This system has the potential to distinguish patients with Parkinson’s disease from controls based on seeding activity of alpha-synuclein aggregates in cerebrospinal fluid,” Hideki Mochizuki, MD, PhD, senior author of the study, said in a news release. “This tells us that the HANABI device is sensitive enough to have real clinical potential, and supports the idea that alpha-synuclein aggregation is a marker of the disease.”

The team also found that the seeding activity of alpha-synuclein in CSF was linked to the uptake of 123I-meta-iodobenzylguanidine (MIBG), a radioactive compound whose low uptake has been linked to neurodegeneration and is considered an important clinical feature of Parkinson’s.

“Therefore, our data, showing a correlation between the HANABI assay and MIBG uptake, suggest that the seeding activity of CSF from patients with Parkinson’s disease could reflect the progression of Lewy body [disease],” researchers said.

Scientists said one of the advantages of using the HANABI assay is the speed at which it can measure alpha-synuclein aggregates in the CSF, surpassing other methods by a large margin.

“The HANABI device was developed to overcome limitations of existing methods and process multiple samples simultaneously,” said Keita Kakuda, lead author of the study. “This has allowed us to drastically shorten the time to perform the assay, from around 10 days to only several hours.”

Further studies are still needed to confirm the clinical relevance of these findings. The team is hoping the new assay might be used to aid clinicians diagnosing, assessing disease severity, and selecting the best course of treatment for patients.

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15 CSF Proteins Seen as Possible Biomarkers of Early Parkinson’s Fail at That Task, Study Reports

Parkinson's and biomarkers

Proteins in the cerebrospinal fluid that were seen as possible diagnostic biomarkers of Parkinson’s disease cannot serve in this role, because they lack robustness and reproducibility in earlier stages of the disease, a study has found.

The study, “Evaluation of cerebrospinal fluid proteins as potential biomarkers for early stage Parkinson’s disease diagnosis,” was published in PLOS One.

Parkinson’s is a chronic and progressive neurodegenerative disorder, mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control. It is typically diagnosed based on the presence of motor symptoms, but these can be difficult to determine as disease-causing in Parkinson’s earlier stages.

Previous studies have suggested that specific proteins in the cerebrospinal fluid (CSF) —  which circulates in the brain and spinal cord — could work as early signals, or biomarkers, of disease to assist in a diagnosis. But CSF proteins have never been fully validated as Parkinson’s biomarkers in a clinical setting.

Researchers in Belgium, Germany, and the U.K. tested the suitability of 15 CSF proteins proposed as potential biomarkers for an early stage Parkinson’s diagnosis.

The panel of proteins explored were beta-amyloid (Aβ40 and Aβ42), alpha-synuclein (α-syn), tau (p-Tau and t-Tau),  neurofilament light chain (NFL), interleukin 6 (IL-6), protein deglycase (DJ-1), S100β (a calcium-binding protein), osteopontin (OPN), high-mobility group box 1 (HMGB1), ubiquitin carboxyl-terminal esterase L1 (UCHL1), Fms-related tyrosine kinase 3 ligand (FLT3LG), matrix metalloproteinase 2 (MMP2) and apolipoprotein A-I (ApoA1).

Researchers began by measuring the levels of these CSF proteins in a group of 80 patients with early stage disease and 80 healthy people serving as controls. Out of the 15 CSF proteins tested, six — α-syn, DJ-1, Aβ42, S100β, p-Tau and t-Tau — were significantly dysregulated among patients.

“Aβ42, t-Tau, p-Tau, α-syn and DJ-1 were decreased in early clinical PD [Parkinson’s disease] patients compared to the controls, whereas S100β levels was increased in early clinical PD patients,” the researchers wrote.

To confirm these candidates, researchers next performed this same test in an independent group of 30 Parkinson’s patients with advanced disease and 30 healthy controls. Here, a type of beta-amyloid, Aβ42, was the only CSF protein whose levels were significantly different — significantly lower — in Parkinson’s patients compared to controls.

“Decreased Aβ42 levels in CSF samples from PD patients had been reported recently, suggesting it may be a reliable candidate. However, in this study … analysis showed that this potential marker was not suitable for diagnostic purposes,” the researchers wrote.

Finally, to assess whether a combination of these markers could distinguish early Parkinson’s patients from healthy individuals, they used a machine learning approach based on an algorithm to identify markers that might improve disease diagnosis. Based on this model, a set of markers comprising α-syn, S100β, and UCHL1 were identified as promising candidates.

“[T]his model aligned with findings published in the literature, where α-syn is characterized as the hallmark protein of PD, closely involved in the progression of neuronal degeneration and subsequent motor impairments, while S100β has been considered a possible marker for the accompanying neurodegeneration,” the researchers wrote. However, “the decision tree could not be confirmed” in the second group of patients and controls.

“[C]urrently proposed protein CSF markers for PD diagnosis, as identified in late stage PD cohorts, lack robustness and reproducibility when applied in the early clinical stages of (…) PD,” they added.

The researchers believe that further efforts, including the EU-BIOMARKAPD project that is exploring alternative approaches to biomarker identification, may support the development of potential protein CSF biomarkers for clinical diagnosis or disease monitoring in early stage Parkinson’s disease.

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Biomarkers Identified That Could Help Predict Individuals at Risk for Parkinson’s, Study Says

DOPA, DOPAC levels

Low levels of two dopamine-related molecules in cerebrospinal fluid can help identify patients in the early stages of preclinical Parkinson’s disease, a study suggests.

The study, “Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson’s disease,” was published in Parkinsonism & Related Disorders.

Parkinson’s disease is mainly recognized by its motor symptoms, such as uncontrolled tremors, gait difficulties, and slow movement. However, by the time these symptoms appear, a significant loss of brain cells sensitive to dopamine has already occurred.

Because of this, there is a need for sensitive markers of early brain cell loss that can be used to track disease progression.

DOPAC and DOPA are two dopamine-related molecules whose levels are reduced in patients with untreated Parkinson’s. However, it was not clear if measuring levels of both proteins could help identify asymptomatic, healthy people who are at risk of developing Parkinson’s disease.

A team led by David Goldstein, MD, PhD, principal investigator at the National Institutes of Health, evaluated the levels of DOPAC and DOPA in cerebrospinal fluid samples collected from 26 at-risk people.

This analysis was integrated in the PDRisk prospective study of the National Institute of Neurological Disorders and Stroke (NINDS), which intends to identify early biomarkers of Parkinson’s disease.

Participants had to have at least three previously defined risk factors for Parkinson’s disease, including direct family history of the disease, loss of sense of smell, impaired sleep or abnormal sleep behavior, and low resting blood pressure.

Patients who were already showing signs of Parkinson’s-related motor symptoms during the enrollment phase were excluded from the study.

Of the 26 participants, four developed clinical Parkinson’s disease during the three-year follow-up period. These patients were found to have significantly lower levels of both DOPA and DOPAC in cerebrospinal fluid than the 22 participants who did not develop Parkinson’s for at least a mean follow-up of 4.2 years.

Researchers determined that the optimal cutoff value for defining low diagnostic DOPAC was 1.22 pmol/mL, which accurately predicted Parkinson’s risk in 84.1% of cases. For DOPA, the cutoff value was 2.63 pmol/mL, accurately predicting disease risk in 90.3% of cases.

These data suggest that early dopamine deficiency in at-risk individuals — defined by low DOPAC and DOPA levels — is linked to an increased likelihood of developing clinical Parkinson’s disease within three years.

Researchers believe the identified “predictive strength” reflects the important role of these neurochemical biomarkers in the underlying mechanisms of disease, suggesting that “neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase.”

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Source: Parkinson's News Today

Proteins in Spinal Fluid of Parkinson’s Patients May be Biomarkers for Specific Symptoms, Study Says

CSF proteins BioFIND

Lower levels of two proteins in the spinal fluid of Parkinson’s disease patients were found to be related to specific symptoms, suggesting they could be used as biomarkers for the disease, according to an observational study.

Parkinson’s patients with postural instability and gait difficulty were found to have significantly lower levels of the protein alpha-synuclein in their cerebrospinal fluid. Alpha-synuclein has been linked to protein clumps in the brain that are the hallmarks of Parkinson’s. In addition to the brain, the protein is also found in peripheral tissues and body fluids.

Levels of the protein beta-amyloid — commonly associated with Alzheimer’s disease — were also lower than normal, and related to cognitive impairment in patients with moderate to advanced Parkinson’s disease.

“These associations between protein levels and clinical symptoms can help us select participants for clinical trials. For example, people with lower beta-amyloid may be more likely to develop memory problems and therefore would benefit more from a cognitive therapy,” said Jennifer G. Goldman, MD, MS, associate professor at Rush University Medical Center in Chicago and first author of the study. “Enrolling this population in trials can help us see a treatment effect more clearly than testing the therapy on people who will not have this symptom.”

The study, “Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson’s disease Features, was published in the journal Movement Disorders.

Called BioFIND (NCT01705327), the cross-sectional study is a pioneering effort to differentiate biomarkers of neurodegeneration in Parkinson’s disease based on fluids collected from patients’ spinal fluid, blood, and saliva. Sponsored by the Michael J. Fox Foundation, with support from the National Institute of Neurological Disorders and Stroke and the National Institutes of Health, it aims to ultimately improve diagnosis and treatment of patients with this disease.

Data and body fluid samples were collected from 126 patients with moderately advanced Parkinson’s disease and 106 healthy volunteers from eight clinical sites in the United States.

Led by Un Jung Kang, MD, chief of the division of movement disorders at Columbia University in New York, researchers profiled Parkinson’s-associated protein levels in these biofluids and their relationships to clinical features of the disease.

The study found that while alpha-synuclein levels in cerebrospinal fluid from Parkinson’s patients with certain motor function impairments — specifically balance and walking issues — were lower compared with healthy volunteers, they did not differ when measured in saliva or plasma samples. This correlation was not found for all other proteins analyzed, suggesting that cerebrospinal fluid alpha-synuclein is a specific biomarker for these motor symptoms.

Beta-amyloid protein levels were also lower in cerebrospinal fluid samples of Parkinson’s patients than healthy controls. Only cerebrospinal fluid beta-amyloid was found to correlate with cognitive response in these patients as measured by a cognitive recall test.

“This report is an important contribution in our efforts to understand and quantify Parkinson’s biology to accelerate drug development,” Mark Frasier, PhD, senior vice president of research programs at The Michael J. Fox Foundation for Parkinson’s Research (MJFF), and co-author of the study, said in a press release. “BioFIND is a partnership between our Foundation, academia, government and — most importantly — research volunteers to measure this disease and the impact of new treatments.”

Additional studies in large patient groups are necessary to further validate these findings. The team is planning to evaluate these potential cerebrospinal fluid biomarkers in the Parkinson’s Progression Markers Initiative, an MJFF-sponsored study following more than 1,500 people with Parkinson’s or who are at risk of developing the disease, as well as control volunteers, for more than five years.

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Source: Parkinson's News Today