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

PROJECT SUMMARY—In this Direct-to-Phase II SBIR, CND Life Sciences proposes to 1) advance the development of a test to identify patients with essential tremor (ET) who have deposits of phosphorylated a- synuclein (P-SYN), a pathological hallmark of Parkinson’s disease (PD), and 2) determine whether the test can predict which patients will phenoconvert to PD. ET is the most common movement disorder, affecting more than 5% of people over 60 and ~ 20% of people over 80. Each year, ~ 1% of patients with ET develop PD—a rate almost 10 times higher than in older adults without ET. Because the treatments and clinical course of ET and PD differ substantially, there is a pressing need to identify patients who are at risk for phenoconversion from ET to PD. In PD, progressive deposition of P-SYN in the central and peripheral nervous systems is associated with a progressive degeneration of nerve fibers and loss of motor functions. Recent post-mortem analyses showed that P-SYN is present in the brains of about 25% of patients with ET, and ~ 80% of these P-SYN-positive individuals exhibited “soft” neurological features of PD prior to death. Unfortunately, the current confirmatory test for PD (i.e., DaT scan) is insensitive early in the disease course, and its high price and limited availability prevents routine screening in patients diagnosed with ET. A cerebrospinal fluid a-synuclein seed amplification assay can detect P-SYN early in the disease course, but clinicians and patients consider it too invasive to use as a general screen in ET. Therefore, there is a critical need for a simple, safe, affordable test that can identify patients with ET who have P-SYN pathology. CND Life Sciences has developed a highly accurate, affordable, minimally-invasive test for P-SYN that is well-positioned to address this need. The Syn-One Test™ is designed to detect P-SYN in peripheral nerve fibers contained in small skin punch biopsies. It has > 92% sensitivity and > 96% specificity for detecting P-SYN in patients with PD as verified in parallel blinded and unbiased biopsy analyses. In a pilot study, the Syn-One Test™ detected P-SYN in 38% of patients with clinically-diagnosed ET or ET-Plus (N = 53). CND Life Sciences now proposes a 15-site clinical study with 360 patients (160 ET, 160 ET-Plus) to 1) determine the prevalence of P-SYN pathology in patients with ET and ET-Plus and thereby demonstrate the potential diagnostic utility of the Syn-One Test™ and 2) demonstrate its potential for tracking pathology progression and predicting which P-SYN-positive patients will phenoconvert to PD. Aim 1. Use CND Life Sciences’ Syn-One Test™ to define the prevalence of P-SYN in patients with ET and characterize the relationship between P-SYN and clinical features of the disease. Aim 2. Demonstrate the potential utility of measuring P-SYN deposition and associated nerve fiber degeneration to track the progression of cutaneous pathology and predict phenoconversion from ET to PD in P-SYN-positive patients. Impact—Commercial deployment of the SYN-One Test™ for routine screening in ET is expected to a) improve clinical care, b) inform long-term care planning, and C) increase the efficiency and success of ET and PD drug trials by improving patient stratification and endpoint analysis.