Project Summary / Abstract: Synucleinopathies are a group of neurodegenerative disorders that result from the deposition of phosphorylated (pathological) α-synuclein within the central and peripheral nervous systems. Synucleinopathies affect over 2 million people in the United States and include Parkinson disease, multiple system atrophy, dementia with Lewy bodies and pure autonomic failure. At present, the clinical diagnosis is made very late in the disease and with moderate sensitivity and specificity. There is an urgent unmet medical need for better diagnostic testing. The long-term goal of this project is to bring recent critical scientific discoveries about cutaneous phosphorylated α-synuclein deposition into clinical practice. The immediate goal of this proposal is to validate an objective pathological test as a diagnostic marker for synucleinopathies by defining the accuracy, precision, sensitivity and specificity of testing and to take a first step in differentiating between synucleinopathies. The central milestone of this project, supported by extensive preliminary data, is to establish that measuring phosphorylated α-synuclein deposition in standard punch skin biopsies will serve as an accurate, precise, sensitive and specific, diagnostic biomarker of synucleinopathy. The rationale for this proposal is that an effective tissue marker (1) will provide an accurate and early diagnosis of alpha- synucleinopathies in clinical practice; (2) will enable assessment of target engagement in the development of disease modifying and neuroprotective therapies; and (3) will accelerate the development of neuroprotective and disease modifying therapies. Guided by strong preliminary data, we plan to objectively test our hypothesis through the following specific aims: (1) To define the test accuracy and precision of skin biopsy detection of phosphorylated α-synuclein. (2) To define the sensitivity and specificity of skin biopsy detection of phosphorylated α -synuclein deposition for the diagnosis of synucleinopathies and (3) To differentiate between the synucleinopathies by quantitative measurement of phosphorylated α -synuclein within skin biopsies in combination with an algorithmic inclusion of clinical data. We will complete these specific aims through a prospective cross-sectional evaluation of 300 individuals with synucleinopathies and 200 control subjects. Synucleinopathy status will be confirmed by a panel of disease experts blinded to biopsy results, while biopsy immunostaining for phosphorylated α-synuclein will be blinded to clinical status. At the conclusion of Aims 1-3, we will have validated skin biopsy detection of phosphorylated α-synuclein by defining the (1) accuracy & precision, (2) sensitivity and specificity and (3) to take the first steps to differentiate between the synucleinopathies. These results will accelerate the translation of skin biopsy detection of phosphorylated α- synuclein into a clinically available, cost effective and ...