Analysis of Cutaneous Phosphorylated Alpha-Synuclein to Identify Patients at Risk of Progressing From Essential Tremor to Parkinson's Disease

Analysis of Cutaneous Phosphorylated Alpha-Synuclein to Identify Patients at Risk of Progressing From Essential Tremor to Parkinson's Disease

Background and Rationale Essential tremor (ET) affects over 6 million Americans and approximately 5% of adults over age 60. Patients with ET have a 10-20 times higher risk of developing Parkinson's disease (PD) compared to age-matched populations, with approximately 1% converting to PD annually. Post-mortem studies reveal Lewy body pathology in some ET patients, suggesting a subset may have prodromal PD. Current diagnostic tools (DaTscan, SYNTap) are either insufficiently sensitive for early disease, too expensive, or too invasive for routine screening. The Syn-One Test offers a minimally invasive approach to detect phosphorylated α-synuclein (P-SYN) pathology in skin biopsies.

Primary Objectives

1. Identify which ET patients have P-SYN pathology indicative of prodromal PD
2. Predict which patients are most likely to phenoconvert to PD

Inclusion Criteria:

• Age 50-85 years old
• Diagnosis of ET as defined by the 2018 MDS Task force paper "1) isolated tremor syndrome of bilateral upper limb action tremor 2) at least 3 years' duration 3) with or without tremor in other locations (e.g., head, voice, or lower limbs) 4) absence of other neurological signs, such as dystonia, ataxia, or parkinsonism." OR
• Diagnosis of ET-Plus as stated by the 2018 MDS Task force paper, "Tremor with the characteristics of ET and additional neurological signs of uncertain significance such as impaired tandem gait, questionable dystonic posturing, memory impairment, or other mild neurologic signs of unknown significance that do not suffice to make an additional syndrome classification or diagnosis. ET with tremor at rest should be classified here."
• Willing to participate in all study procedures
• Able and willing to provide written informed consent

Exclusion Criteria:

• Under age 50, Over age 85
• Clinical evidence of severe peripheral vascular disease
• Clinically active coronary artery or cerebrovascular disease
• Participant is currently on anticoagulant or dual anti-platelet therapy
• Alcoholism
• Allergic reaction to local anesthesia
• History of or increased risk for impaired wound healing, scarring, or keloid formation
• Diagnosis of ET or ET-Plus that is clinically determined to likely be secondary to brain injury or vascular compromise
• History of other neurodegenerative disorder or evidence of neurological co-pathology
• Abnormal DaTscan
• Participant is currently receiving treatment with carbidopa-levodopa for PD
• Isolated focal tremors (head, voice)
• Task-specific tremor (e.g., primary writing tremor)
• Position-specific tremors that does not otherwise meet clinical diagnostic criteria for ET
• Sudden onset and step-wise deterioration