Screening for Skin-Based Biomarker Helps Diagnose Parkinson’s

BOSTON, MA — In a paper published in the Journal of the American Medical Association (JAMA), neurologists at Beth Israel Deaconess Medical Center (BIDMC) showed that a simple skin biopsy test detects a phosphorylated form of α-synuclein—the pathological hallmark of Parkinson’s disease and the subgroup of neurodegenerative disorders, known as synucleinopathies, at high positivity rates. Results from this landmark study sponsored by the National Institutes of Health (NIH) validate this cutaneous method as a reliable and convenient tool to help clinicians make more accurate diagnoses for patients and support future clinical trials for investigational drugs targeting α-synuclein.

“Each year, there are nearly 200,000 people in the US who face a diagnosis of Parkinson’s disease, dementia with Lewy bodies, and related disorders,” said lead author Christopher Gibbons, MD, a neurologist at BIDMC and professor of neurology at Harvard Medical School (HMS). “Too often patients experience delays in diagnosis or are misdiagnosed due to the complexity of these diseases. With a simple, minimally invasive skin biopsy test, this blinded multicenter study demonstrated how we can more objectively identify the underlying pathology of synucleinopathies and offer better diagnostic answers and care for patients.”

The Synuclein-One study

Affecting an estimated 2.5 million people in the United States, the synucleinopathies include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). While the four progressive neurodegenerative diseases have varying prognoses and do not respond to the same therapies, they do share some overlapping clinical features, such as tremors and cognitive changes. Additionally, all are characterized by the presence of an abnormal protein present in the nerve fibers in the skin called phosphorylated α-synuclein (P-SYN).

In this investigation, titled the Synuclein-One Study, Gibbons and colleagues at 30 academic and community-based neurology practices enrolled 428 people, ages 40–99 years, with a clinical diagnosis of one of the four synucleinopathies based on clinical criteria and confirmed by an expert panel or healthy control subjects with no history of neurodegenerative disease. Participants underwent three 3-millimeter skin punch biopsies taken from the neck, the knee, and the ankle.

“These are systemic disorders that impact the peripheral and central nervous systems in profound ways,” said senior author Roy Freeman, MD, director of the Center for Autonomic and Peripheral Nerve Disorders at BIDMC and professor of neurology at HMS. “While we have been aware of the presence of α-synuclein in cutaneous nerves for many years, we were thrilled with the accuracy of this diagnostic test.”

Skin biopsies and P-SYN levels

Among the participants with clinically confirmed PD, 93 percent demonstrated a positive skin biopsy for P-SYN. Participants with DLB and MSA tested 96 percent and 98 percent positive, respectively. All of the participants with PAF were positive for the abnormal protein. 

Among the controls, just over 3 percent tested positive for P-SYN—an error rate the authors suspect may indicate some healthy controls are at risk for a synucleinopathy. “Parkinson’s disease and its subgroup of progressive neurodegenerative diseases show gradual progression, but α-synuclein is present in the skin even at the earliest stages,” noted Freeman.

The team’s findings are built on earlier work by Freeman and Gibbons. The pair—together with immunohistochemist Ningshan Wang, PhD, a research scientist at BIDMC and an assistant professor of neurology at HMS—have been focused on finding a reliable biomarker for synucleinopathies since 2009. 

The authors anticipate that this research will play a role in accelerating drug development for synucleinopathies. “Enrolling the right patients in clinical trials for these complex diseases is of utmost importance,” said Freeman. “Identifying the relevant biomarker in a patient and tracking it over the course of a clinical trial is an essential component of drug development in the neurodegeneration field.”

- This press release was originally published on the Beth Israel Deaconess Medical Center website