Can a Blood-Based Test Serve as a Biomarker for Parkinson’s Disease?
March 15, 2023 3 minutes read
By Rivka Sachdev, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medicine
SYNOPSIS: The authors of this proof-of-concept study proposed that a noninvasive assay detecting pathology-associated α-synuclein extracted from blood may reveal a reliable biomarker for Parkinson’s disease.
SOURCE: Kluge A, Bunk J, Schaeffer E, et al. Detection of neuron-derived pathological α-synuclein in blood. Brain 2022;145:3058-3071.
An objective and reliable biomarker to improve accuracy in diagnosing Parkinson’s disease and measuring its progression is an urgent need that remains unmet. Currently, we diagnose Parkinson’s disease by assessing signs evident on physical exam after eliciting a history of motor and nonmotor symptoms. Progression of the disease also is assessed clinically using rating scales to document exam findings over time. But these methods have shortcomings, since clinician/rater experience and the psychological and motor status of the patient at the time of the exam are variable. Furthermore, abnormalities on exam only become apparent long after the process of neurodegeneration has begun. By the time motor signs are evident, it is estimated that up to 60% of dopaminergic neurons have been lost.
Today, the diagnosis of Parkinson’s disease can be confirmed with certainty only by neuropathological findings from postmortem tissue analysis — specifically, the detection of misfolded α-synuclein that comprises Lewy bodies found in neurons in particular regions of the brain. Occasionally, postmortem analysis of brain tissue reveals clinical diagnoses of Parkinson’s disease in life that were misdiagnosed, showing that our current clinical methods have limitations in diagnostic accuracy.
One focus of research in recent years involves the migration of extracellular vesicles and the pathogenesis of neurodegenerative disorders. Extracellular vesicles released by cells of the central nervous system are called neuron-derived extracellular vesicles. These vesicles can cross the blood-brain barrier and can transport/spread neuropathological proteins, including misfolded α-synuclein. It is widely accepted that the accumulation and aggregation of misfolded α-synuclein plays a primary role in the pathogenesis of Parkinson’s disease, and, therefore, much research on Parkinson’s focuses on this pathological protein form.
Studying α-synuclein in cerebrospinal fluid is invasive, since it requires a lumbar puncture. Kluge et al revealed the potential of a biomarker, obtainable by a blood test, for reliably distinguishing Parkinson’s disease patients from controls. Their novel method for detecting and examining extracellular vesicle-derived α-synuclein from blood samples allowed them to accurately distinguish patients with Parkinson’s disease from control participants. These methods may be the basis for developing a dependable, noninvasive blood-based test for diagnosing Parkinson’s disease.
In the study, 30 patients with Parkinson’s disease (all met requirements for diagnosis based on the UK Brain Bank Criteria) and 50 participants without Parkinson’s disease (controls) provided blood samples obtained by venipuncture. Samples underwent several steps of centrifugation, after which extracellular vesicle precipitation reagents were added and, ultimately, precipitated extracellular vesicles were isolated. Neuron-derived extracellular vesicles were identified and filtered out based on surface protein markers. Then, the researchers tested the α-synuclein contents within these vesicles and detected the pathogenic misfolded form of α-synuclein using structure-specific antibodies.
The authors carried out a quantitative analysis of the total α-synuclein in neuron-derived extracellular vesicles. Although there were no significant differences between Parkinson’s patients vs. controls, the Parkinson’s patients recorded significantly higher levels of the specific disease-associated abnormal form of α-synuclein vs. controls. This finding provides useful information for future research, which the authors argued should focus on detecting pathological α-synuclein conformers rather than quantitative levels of α-synuclein in body fluids or tissues. The last part of their protocol involved successfully reproducing and amplifying the extracted misfolded α-synuclein forms from Parkinson’s patients.
COMMENTARY
Kluge et al concluded detection and amplification of pathological α-synuclein conformers in plasma neuron-derived extracellular vesicles is a promising biomarker for distinguishing Parkinson’s disease patients from healthy controls. However, further studies that include larger cohorts and are blinded are needed to validate this protocol. More investigations will be needed to confirm these findings for patients in various stages of disease, including early prodromal stages, such as in patients with confirmed rapid eye movement sleep behavior disorder.
The authors suggested future work should include how these biomarkers eventually can be used for distinguishing Parkinson’s disease from other synucleinopathies, such as dementia with Lewy bodies and multiple system atrophy. Although the diagnosis of Parkinson’s disease in current neurological practice remains a clinical one, this exciting research brings us a step closer to realizing a noninvasive biomarker that can reflect disease pathophysiology, progression, and severity and, therefore, a step closer to the development of new therapies for Parkinson’s disease patients.
The authors of this proof-of-concept study proposed that a noninvasive assay detecting pathology-associated α-synuclein extracted from blood may reveal a reliable biomarker for Parkinson’s disease.
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