March 1, 2021

Volume XI, Number 60

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March 01, 2021

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Getting Closer to a Definitive Biomarker for Parkinson’s Disease

Parkinson’s disease is a devastating, incurable, progressive and degenerative neurological disease that affects movement.  There are no biomarkers available and it is diagnosed by symptomology alone.  Unfortunately, the symptoms can be similar to many other neurological diseases.  This often leads to misdiagnoses resulting in delayed treatment.  Currently, definitive diagnosis can only be made at autopsy.  A new skin test has been developed that may be able to diagnose Parkinson’s in living patients and at an earlier time in the disease.

The development and use of biomarkers comes with numerous ethical and legal concerns.  How do we determine disease and disability? Could biomarkers exacerbate the disparities between diseases that have objective findings and those that do not, making it more difficult for physicians to recognize a condition even in the absence of a marker? Additionally, we should be concerned about who has access to biomarker information and how that information might be misused.

In Parkinson's disease, certain nerve cells (neurons) in the brain gradually break down or die. Many of the symptoms are due to a loss of neurons that produce a chemical messenger called dopamine. When dopamine levels decrease, it causes abnormal brain activity, leading to impaired movement and other symptoms.  The cause of Parkinson's disease is unknown, but researchers have noted many changes that occur in the brains of people with Parkinson's disease. These changes include the presence of Lewy bodies.  Lewy bodies are clumps of specific substances within brain cells. Although many substances are found within Lewy bodies, scientists believe an important one is the natural and widespread protein called alpha-synuclein (a-synuclein). It's found in all Lewy bodies in a clumped form that cells can't break down. 

A study by Manne et al., published online in the journal Movement Disorders on September 22, 2020 reports the use of a method known as the real-time quaking-induced conversion (RT-QuIC) protein misfolding assay to detect pathological a-synuclein protein present in human skin tissues.  This assay was originally developed to detect bovine spongiform encephalopathy, more commonly known as mad cow disease, a neurodegenerative disease of cattle.  The "quaking" in the name of the assay refers to the fact that samples are literally subjected to shaking. This action breaks apart clumps of a specific protein that are then further incubated, amplifying the amount of misfolded protein to detectable levels.  The RT-QuIC protein misfolding assay has found misfolded a-synuclein proteins in many body tissues including the submandibular gland, colon, heart, stomach and skin. Manne et al., optimized this ultra-sensitive and specific assay for both frozen and formalin-fixed paraffin embedded sections of skin tissues obtained at autopsy. They determined the seeding kinetics of the a-synuclein present in the skin from individuals diagnosed with Parkinson’s disease and controls. In the blinded study they correctly identified 24/25 Parkinson and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 Parkinson and 10/12 controls using formalin-fixed paraffin embedded skin sections (75% sensitivity and 83% specificity).  

Further studies will be needed to determine if a-synuclein seeding activity can be detected in skin before clinical signs develop in Parkinson’s disease. This possibility is supported by findings reported by Wang et al. (2019, 2020) that skin prion activity (the pathologic agent that is able to induce abnormal folding of prion proteins found in neural tissues) is detectable not only in all patients with Creutzfeldt-Jakob disease (the human equivalent of mad cow disease) but also far in advance of neuronal damage and clinical signs of prion disease in rodents.

The researchers are now starting a study in living patients in which they will repeat the RT-QuIC protein misfolding assay and compare skin samples from patients with clinically diagnosed Parkinson’s disease and controls. If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson's, a skin test could allow earlier diagnosis.  

While the development of a definitive biomarker would be eagerly received, the current state of research in neurodegenerative diseases is widening the gap between early diagnostic options and very limited preventive and therapeutic options. The ethical/legal framework should therefore focus on minimizing potential negative effects for patients while considering the medical and social consequences as well as the appropriate regulatory and research measures.  Consent, disclosure, or failure to disclose information from genetic and predictive biomarkers raises significant ethical concerns that should be proactively addressed. 

Sources

Manne S, Kondru N, Jin H, Serrano GE, Anantharam V, Kanthasamy A, Adler CH, Beach TG, Kanthasamy AG.  Blinded RT-QuIC Analysis of α-Synuclein Biomarker in Skin Tissue From Parkinson’s Disease Patients.  Movement Disorders.  2020; 35(12): 2230-2239.

Wang Z, Manca M, Foutz A, Camacho MV, Raymond GJ, Race B, Orru CD, Yuan J, Shen P, Li B, Lang Y, Dang J, Adornato A, Williams K, Maurer NR, Gambetti P, Xu B, Surewicz W, Petersen RB, Dong X, Appleby BS, Caughey B, Cui L, Kong Q, Zou WQ. Early preclinical detection of prions in the skin of prion-infected animals. Nat Commun. 2019 Jan 16;10(1):247. doi: 10.1038/s41467-018-08130-9. Erratum in: Nat Commun. 2019 Feb 4;10(1):640. PMID: 30651538; PMCID: PMC6335425.

Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, Incensi A, Kuzkina A, Orrú CD, Tatsuoka C, Liguori R, Gunzler SA, Caughey B, Jimenez-Capdeville ME, Zhu X, Doppler K, Cui L, Chen SG, Ma J, Zou WQ. Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease. JAMA Neurol. 2020 Sep 28:e203311. doi: 10.1001/jamaneurol.2020.3311. Epub ahead of print. PMID: 32986090; PMCID: PMC7522783.

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Copyright © 2020 Womble Bond Dickinson (US) LLP All Rights Reserved.National Law Review, Volume XI, Number 27
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About this Author

Daniel Meckley Research Consultant Womble Bond Dickinson Salem, NC
Research Consultant

Dan Meckley is not licensed to practice law. His activities are directly supervised by members of the firm licensed to practice law in the firm’s Winston-Salem office.

As a Research Consultant, Dan provides medical and scientific research to defense attorneys and expert witnesses to support critical litigation points.

Dan has a particular focus on smoking and health litigation. He brings 30 years of prior experience in toxicology and environmental consulting to his role as a researcher.  He has conducted research in the...

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